WO2023172640A1 - Treatments for single-mutant waldenström's macroglobulinemia - Google Patents
Treatments for single-mutant waldenström's macroglobulinemia Download PDFInfo
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- WO2023172640A1 WO2023172640A1 PCT/US2023/014834 US2023014834W WO2023172640A1 WO 2023172640 A1 WO2023172640 A1 WO 2023172640A1 US 2023014834 W US2023014834 W US 2023014834W WO 2023172640 A1 WO2023172640 A1 WO 2023172640A1
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- A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
Definitions
- the present invention relates to methods for treating cancer, such as combination therapies comprising a CXCR4 inhibitor and a BTK inhibitor.
- the cancer includes lymphomas such as Waldenstrom’s macroglobulinemia.
- Waldenstrom’s macroglobulinemia is a distinct B-cell lymphoproliferative disorder characterized by the proliferation of lymphoplasmacytic cells in the bone marrow in other organs, along with elevated serum levels of monoclonal immunoglobulin M (IgM) gammopathy (Owen 2003; Treon 2013).
- Waldenstrom’s macroglobulinemia represents a spectrum from early asymptomatic monoclonal gammopathy of undetermined significance (MGUS) (IgM-MGUS), where there are small numbers of lymphoplasmacytic cells in the bone marrow ( ⁇ 10%), to active WM with anemia, hyperviscosity, and widespread disease (Kyle 2004; Kyle 2005).
- WM is an indolent B-cell lymphoma characterized by accumulation of malignant lymphoplasmacytic cells in the bone marrow (BM).
- BM bone marrow
- IgM monoclonal immunoglobulin M
- WM is an indolent B-cell lymphoma characterized by accumulation of malignant lymphoplasmacytic cells in the bone marrow (BM).
- High levels of monoclonal immunoglobulin M (IgM) are secreted by WM cells, resulting in anemia, blood hyperviscosity syndrome, visual impairments, and neurological symptoms. Consequently, lowering serum IgM is a key end point in WM therapy and a common parameter to assess the success of any WM treatment.
- Somatic mutations in clonal populations of cells lead to WM.
- MYD88 innate immune signal transduction adaptor
- TLRs toll-like receptors
- BTK Bruton tyrosine kinase
- CXCR4 C-X-C chemokine receptor 4
- the G protein-coupled receptor CXCR4 binds its natural ligand' C-X-C chemokine ligand 12 (CXCL12), which is produced by the perivascular cells of the bone marrow stroma.
- CXCL12 phosphoinositide 3- kmase
- P13K phosphoinositide 3- kmase
- CXCR4 mutation In WM, CXCR4 mutation generally occurs in the C terminal, intracellular domain of the protein — a region involved in signal transduction. Most CXCR4 C-terminal mutations found in WM cause hyperactivation of the receptor and its downstream signaling pathways, resulting in decreased internalization of the receptor and increased chemotaxis. Patients with MYD88 L26SP CXCR4 Mat WM typically present with higher serum IgM levels and greater BM involvement compared with those wi th MYD88 L265P mutation alone.
- the World Health Organization classification defines WM as lymphoplasmacytic lymphoma with overexpression of a clone of IgM proteins, belonging to the category of non- Hodgkin B cell lymphomas with atypically indolent course.
- Waldenstrom s macroglobulinemia accounts for approximately 2% of all cases of non-Hodgkin lymphoma. It presents with distinctive clinical and laboratory features related to the presence of the monoclonal IgM (Mazzucchelli 2018).
- Clinical manifestation of WM includes symptoms associated with anemia (e.g., pallor, weakness, fatigue), systemic complaints (e g., weight loss, fever, night sweats), organomegaly (e.g., enlarged lymph nodes, spleen, and/or liver), and/or symptoms related to the IgM monoclonal protein in the blood (e.g., hyperviscosity, peripheral neuropathy, and cryoglobulinemia) requiring various degrees of urgency in diagnosis and treatment to avoid secondary complications (Dimopoulos 2000).
- anemia e.g., pallor, weakness, fatigue
- systemic complaints e., weight loss, fever, night sweats
- organomegaly e.g., enlarged lymph nodes, spleen, and/or liver
- symptoms related to the IgM monoclonal protein in the blood e.g., hyperviscosity, peripheral neuropathy, and cryoglobulinemia
- CXCR4 inhibitors such as mavorixafor (X4P-001)
- a second therapeutic agent such as a BTK inhibitor, BTK degrader, BCL-2 inhibitor, BH3 mimetic, or proteasome inhibitor
- BTK inhibitor a BTK inhibitor
- BTK degrader a BTK degrader
- BCL-2 inhibitor a second therapeutic agent
- BH3 mimetic a second therapeutic agent
- proteasome inhibitor are useful in treating a variety of cellular proliferative disorders, such as those described herein.
- the present invention provides a method of treating a cancer in a patient in need thereof, comprising administering to the patient an effective amount of mavorixafor, or a pharmaceutically acceptable salt thereof; in combination with an effective amount of BTK inhibitor, BTK degrader, BCL-2 inhibitor, BH3 mimetic, or proteasome inhibitor or a pharmaceutically acceptable salt thereof; and wherein the cancer includes a somatic mutation and is CXCR4 WT (with WT indicating wild type).
- the somatic mutation is a MYD88 mutation such as MYD88 L265 .
- the cancer is MYD88 W1 CXCR4 W1 .
- the cancer overexpresses CXCR4.
- the present invention provides a method of treating Waldenstrom’s macroglobulinemia (WM) in a patient in need thereof, comprising administering to the patient an effective amount of mavorixafor, or a pharmaceutically acceptable salt thereof; in combination with an effective amount of a BTK inhibitor selected from ibruitinib, acalabrutinib, zanubrutinib, tirabrutinib, evobrutinib, fenebrutinib, poseltinib, vecabrutinib, spebrutinib, LCB 03-0110, LFM-A13, PCI 29732, PF 06465469, (-)-Terreic acid, BMX-IN-1, BI-BTK-1, BMS-986142, CGI-1746, GDC- 0834, olmutimb, PLS-123, PRN1008, RN-486, LOXO-305 (pirtobrutinib
- a BTK inhibitor
- the present invention provides a method of treating Waldenstrom’s macroglobulinemia (WM) in a patient in need thereof, comprising administering to the patient an effective amount of mavorixafor, or a pharmaceutically acceptable salt thereof; in combination with an effective amount of a BCL-2 inhibitor or BH3-mimetic; or a pharmaceutically acceptable salt thereof; and wherein the WM has a CXCR4 WT genomic status (with WT indicating wild type).
- WM macroglobulinemia
- the present invention provides a method of treating Waldenstrom’s macroglobulinemia (WM) in a patient in need thereof, comprising administering to the patient an effective amount of mavorixafor, or a pharmaceutically acceptable salt thereof; in combination with an effective amount of a proteasome inhibitor; or a pharmaceutically acceptable salt thereof; and wherein the WM has a CXCR4 WT genomic status (with WT indicating wild type).
- WM macroglobulinemia
- FIG. 1A shows median IgM levels of relapsed/refractory Waldenstrom’s patients by single mutant vs. double mutant status when treated with ibrutinib (420 mg QD).
- WM tumor cells have either elevated expression of CXCR4'' V I (single-mutant WM) or mutated CXCR4 MU I (double-mutant WM).
- single mutant refers to patients bearing a MYD88 mutation but not a CXCR4 mutation
- double mutant refers to patients bearing a mutation in both MYD88 and CXCR4.
- FIG. 1 This figure is a modification of Figure 2 from Supplement to: Dimopoulos MA, Trotman J, Tedeschi A, et al., on behalf of the INNOVATE Study Group and the European Consortium for Waldenstrom’s Macroglobulinemia.
- IB shows reduced % of apoptotic cells when they are grown in the presence of bone marrow stroma cells (BMSC), indicating that BMSC cause a protective effect in WM cells.
- BMSC bone marrow stroma cells
- FIG. 2 B-Cell Agents in Development/Commercial Lose Anti-Tumor (Apoptosis) Efficacy in WM Cells Protected by Bone Marrow' Stroma. Without wishing to be bound by theory, it is believed that these data indicate that upregulated CXCR4 - CXCL12 - IL-6 axis is responsible for this BM-induced resistance.
- FIG. 3 B-Cell Agents in Development/Commercial Lose IgM Reduction Efficacy in WM Cells Protected by Bone Marrow Stroma. Without washing to be bound by theory, it is believed that upregulated CXCR4 - CXCL12 - IL-6 axis is responsible for this BM-induced resistance.
- FIG. 4 Co-culture of BMSC with MC cells Stroma Induces IL-6 Hypersecretion in BMSC and CXCR4 Overexpression in WM Cells.
- FIG. 5 Mavorixafor Blocks CXCL12-Induced Migration and Adhesion of WM Cells to BM Stroma.
- FIG. 6 Mavorixafor Reduces Cell Viability & Triggers Apoptosis in WM Cells.
- FIG. 7 Mavorixafor Blocks BM Stroma-Induced IgM Hypersecretion in WM
- FIG. 8 Even in Absence of BMSC, Soluble IL-6 Upregulates CXCR4 Expression & IgM Secretion in WM Cells; which is Prevented by Blockade of IL-6/IL6R/STAT3 Axis.
- FIG. 9 Mavorixafor-B Cell Agent Combinations Synergistically Enhance Antitumor Activity in Single-Mutant WM Cells.
- FIG. 10 Mavorixafor-B Cell Agent Combinations Synergistically Enhance Antitumor Activity in WM Cells.
- Combination indices (CI) were generated with CalcuSyn software for each set of combination.
- CI ⁇ 1, 1, and >1 denote synergism, additive effect, and antagonism, respectively.
- FIG. 11 Mavorixafor Overcomes BM Stroma-Induced Resistance to B Cell Agents.
- FIG. 12 Mavorixafor Synergizes w/B Cell Agents to Inhibit BM Stroma-Induced IgM Hypersecretion in WM Cells.
- FIG. 13 BMSC-derived IL-6 causes IgM hypersecretion in WM cells via IL-6R- JAK-STAT3.
- IgM (A) and IL-6 (B) were measured in the supernatants of HS-27A BMSCs cocultured for 72 hours with MWCL-1 cells.
- Viability (C), pathway activation (D), and IgM secretion (E) in starved MWCL-1 cells treated with IL-6 were measured by CellTiter-Glo, phosphoflow, and ELISA, respectively.
- BMSC bone marrow stromal cells
- Ig immunoglobulin
- IL interleukin
- p-AKT phosphor-PI3K-Akt
- p-IKb phosphor-nuclear factor of kappa light polypeptide gene enhancer in C-cells, inhibitor, alpha
- p-JNK phosphor-janus kinase
- p-MAPK phosphor-mitogen-activated protein kinase
- p-STAT signal transducer and activator of transcription
- WM Waldenstrom’s Macroglobulinemia.
- P values ⁇ .05 were considered statistically significant and set as follows: ** — P ⁇ 01; *** — P ⁇ 001
- FIG. 14 BMSC-derived IL-6 increases CXCR4 cell surface expression in WM cells via IL-6R-JAK-STAT3 signaling and enhances WM cell adhesion to BMSCs.
- Expression of CXCR4 was analyzed in publicly available gene expression data sets GSE171739 and GSE9656 (A). MWCL-1 cells were cocultured with HS-27A BMSCs +/- tocilizumab (B) or pretreated with tocilizumab, BP-1-102, or PF-06263276 (C) and CXCR4 cell surface expression measured via flow cytometry.
- BMSC bone marrow stromal cells
- CXCR4 C-X-C chemokine receptor 4
- IL interleukin
- FDR false discovery rate
- WM Waldenstrom’s Macroglobulinemia.
- FIG. 15 Mavorixafor causes disruption of WM cell migration and adhesion to BMSCs.
- the effects of mavorixafor pretreatment on BMSC adhesion to MWCL-1 cells cocultured with HS-27A BMSCs were visualized using Calcein AM (A).
- Migration of MWCL-1 cells toward CXCL12 with and without pretreatment with mavorixafor (B) and/or with and without HS-27A BMSCs coculture (C) was also measured by transwell migration assay.
- the effects of mavorixafor pretreatment on CXCL12-induced Ca 2+ mobilization in MWCL-1 cells cocultured with HS-27A BMSCs were measured via Fluo-4 AM fluorescence (D).
- BMSC bone marrow stromal cells
- CXCR4 C-X-C chemokine receptor 4
- CXCL12 C-X-C chemokine ligand 12
- IL interleukin
- WM Waldenstrom’s Macroglobulinemia.
- FIG. 16 Mavorixafor enhances antitumor activity of B-cell-targeted therapies in WM cells.
- Apoptosis of MWCL-1 cells treated with mavonxafor in combination with B-cell- targeted inhibitors was measured via flow cytometry (A-F).
- Synergistic activity between mavorixafor and B-cell-targeted inhibitors was analyzed via Chou and Talalay analysis (A-F).
- Cleavage of apoptotic markers in the presence of mavorixafor and ibrutinib was measured via immunoblot (G).
- CF cytoplasmic fraction
- MAV mavorixafor
- PARP poly [ADP-ribose] polymerase.
- FIG. 17 Mavorixafor overcomes BMSC-induced drug resistance. Apoptosis of MWCL-1 cells treated with mavorixafor in combination with B-cell-targeted inhibitors in MWC-1 cells/HS-27A BMSCs coculture was measured via flow cytometry (A-F). Cleavage of apoptotic markers in the presence of mavonxafor and ibrutinib was measured via immunoblot (G).
- BMSC bone marrow stromal cells
- CF cytoplasmic fraction
- CXCR4, C- X-C chemokine receptor 4 Evo, evobrutinib; Ibr, ibrutinib; II, interleukin
- PARP-1 poly [ADP-ribose] polymerase 1
- Pir pirtobrutinib
- Mav mavorixafor
- Nem nemtabrutinib
- NS not significant
- Ven venetoclax
- WM Waldenstrom’s Macroglobulinemia.
- FIG. 18 Mavorixafor as a single agent or in combination with B-cell-targeted therapies inhibited BMSC-induced IgM hypersecretion.
- MWCL-1 cells were preincubated with mavorixafor, B-cell-targeted inhibitors, or both, and cocultured with or without HS-27A BMSCs, followed by supernatant IgM measurements after 48 or 72 hours (A-G).
- BMSC bone marrow stromal cells
- CXCR4, C-X-C chemokine receptor 4 Evo, evobrutinib; Ibr, ibrutinib; Ig, immunoglobulin: II, interleukin; PARP-1, poly [ADP-ribose] polymerase 1; Pir, pirtobrutinib; Mav, mavorixafor; Nem, nemtabrutinib; NS, not significant; Ven, venetoclax; WM, Waldenstrom’s Macroglobulinerma.
- FIG. 19 Viability of WM cells in the presence of IL-6R-JAK-STAT3 signaling inhibitors. Relative viability of MWCL-1 cells in the presence of tocilizumab (IL-6R antibody), BP-1-102 (STAT3 inhibitor), or PF-06263276 (pan-janus kinase inhibitor).
- tocilizumab IL-6R antibody
- BP-1-102 STAT3 inhibitor
- PF-06263276 pan-janus kinase inhibitor
- FIG. 20 BMSC-induced resistance of WM cells to B-cell-targeted therapies. Apoptosis and viability of MWCL-1 cells with and without coculture with HS-27A BMSCs in the presence of B-cell-targeted inhibitors (A-F).
- A-F B-cell-targeted inhibitors
- FIG. 21 BMSC-induced IgM secretion by WM cells treated with B-cell-targeted therapies. IgM secretion by MWCL-1 cells with and without coculture with HS-27A BMSCs in the presence of B-cell-targeted inhibitors (A-F).
- A-F B-cell-targeted inhibitors
- FIG. 22 HS-5 BMSCs reduced sensitivity of WM cells to B-cell-targeted therapies. Apoptosis of MWCL-1 cells (A,B) and IgM secretion by MWCL-1 cells (C,D) with and without coculture with HS-5 BMSCs in the presence of B-cell-targeted inhibitors, ibrutinib and zanubrutimb.
- FIG. 23 Effect of mavorixafor on apoptosis of BMSCs in coculture with WM cells.
- FIG. 24 IL-6 release in WM/BMSC coculture model. Effects of mavorixafor on IL-6 release in WM/BMSC coculture model.
- FIG. 25 In vitro dose-response showing apoptosis of WM cells (not co-cultured with BMSC) that were treated with ixazomib with 0-10 micromolar mavorixafor. As can be seen, mavorixafor enhances the apoptosis efficacy of ixazomib.
- Timeframe of assay 72 h.
- FIG. 26 % apoptotic cells (WM cells cultured in absence or presence of BMSC) treated with ixazomib and 0-10 micromolar mavorixafor.
- FIG. 27 Mavorixafor synergizes with ixazomib to inhibit BM stroma-induced IgM hypersecretion in WM cells.
- Ixa Ixazomib;
- Mav Mavorixafor.
- FIG. 28 Mavorixafor enhances apoptosis of lymphoma and leukemia cells when combined with venetoclax or ibrutinib.
- Panel (A) shows apoptosis of OCI-LY19 (DLBCL) cells.
- Panel (B) shows DOHH2 (FL) cells treated with mavorixafor in combination with venetoclax.
- Panel (C) shows apoptosis of OCI-LY19 (DLBCL) cells, DOHH2 (FL) cells (Panel (D)), and MEC-1 (CLL) cells (Panel (E)) treated with mavorixafor in combination with ibrutinib.
- Combination of mavorixafor with venetoclax or ibrutinib significantly increased apoptosis in lymphoma and leukemia cells compared to ibrutinib or venetoclax alone in the majority of dose combinations.
- FIG. 29 Apoptosis of lymphoma cells treated with venetoclax or ibrutinib with or without BMSC coculture.
- Apoptosis of OCI-LY19 (DLBCL) cells (A), D0HH2 (FL) cells (B) and MINO (MCL) cells (C) are shown with or without coculture with HS-27A BMSCs in response to venetoclax.
- P values ⁇ 05 are considered statistically significant and set as follows: ns, not significant; * — P ⁇ 05; ** — P ⁇ .01; *** — P ⁇ 001.
- FIG. 30 Apoptosis of lymphoma cells after treatment with venetoclax or ibrutinib ⁇ mavorixafor with or without BMSC coculture.
- FIG. 31 Cell migration of lymphoma cells to CXCL12 with or without mavorixafor pretreatment. Effects of increasing concentrations of mavorixafor on migration of OCI-LY19 (DLBCL) cells (A), D0HH2 (FL) cells (B) toward CXCL12.
- P values ⁇ .05 are considered statistically significant and set as follows: ns, not significant; * — P ⁇ 05; ** — p ⁇ 0i; **** — P ⁇ 0001.
- FIG. 32 the top panel shows apoptosis of Waldenstrom’s Macroglobulinemia (WM) cells (MWCL-1; MYD88 L265P -CXCR4 WT ) exposed to venetoclax with or without Compound 3.
- the botom panel shows apoptosis of WM cells exposed to venetoclax at 3.2 nM grown in the presence or absence of bone marrow stromal cells (BMSC) with or without Compound 3.
- BMSC bone marrow stromal cells
- Compound 3 successfully overcame BMSC-induced resistance of the WM cells to venetoclax to restore apoptotic efficacy.
- Venetoclax is not cytotoxic to BMSCs at concentrations tested. Compound 3 alone does not induce apoptosis at 5 pM.
- Vene venetoclax.
- BMSC Bone Marrow Stroma Cell line HS27A. Time frame of assay: 48 h.
- FIG. 33 the top panel shows apoptosis of Waldenstrom’s Macroglobulinemia (WM) cells (MWCL-1; MYD88 L265P -CXCR4 WT ) exposed to zanubrutinib wdth or without
- the botom panel shows apoptosis of WM cells exposed to zanubrutinib grown in the presence or absence of bone marrow stromal cells (BMSC) with or without Compound 3.
- BMSC bone marrow stromal cells
- Compound 3 successfully overcame BMSC-induced resistance of the WM cells to zanubrutinib to restore apoptotic efficacy.
- Zanubrutinib is not cytotoxic to BMSCs at concentrations tested. Compound 3 alone does not induce apoptosis at 5 pM.
- Zanub zanubrutinib.
- BMSC Bone Marrow Stroma Cell line HS27A. Time frame of assay: 72 h.
- FIG. 34 the top panel shows inhibition of BMSC-induced IgM hypersecretion in WM cells (MWCL-1; MYD88 L265P -CXCR4 WT ) by Compound 3.
- the bottom panel shows inhibition of BMSC-induced TgM hypersecretion in WM cells with or without zanubrutinib.
- FIG. 35 inhibition of CXCL12-CXCR4 mediated migration in WM cells by Compound 3.
- WM Waldenstrom’s Macroglobulinemia (MWCL-1; MYD88 L265P - CXCR4 WT ).
- Time frame of assay 4 h.
- FIG. 36 the top panel shows that Compound 3 synergizes with ibrutinib to induce apoptosis in DLBCL cells (OCI-LY19). Higher concentrations of ibrutinib (8 pM) further synergizes with Compound 3 (2-5 pM) to induce 60% apoptosis in DLBCL cells (data not shown). The bottom panel shows that Compound 3 synergizes with venetoclax to induce apoptosis in DLBCL cells (OC1-LY19). Time frame of assays: 72 h.
- FIG. 37 the top panel shows that Compound 3 overcomes BM stroma-induced resistance of DLBCL cells (OCI-LY19) to venetoclax.
- Compound 3 successfully overcame BMSC-induced resistance of the DLBCL cells to venetoclax to restore apoptotic efficacy.
- Compound 3 and Venetoclax are not cytotoxic to BMSCs at concentrations tested.
- Time frame of assay 72 h.
- the bottom panel shows inhibition of CXCL12-CXCR4 mediated migration in DLBCL cells (OCI-LY19) by Compound 3.
- Time frame of assay 4 h.
- FIG. 38 the top panel shows that Compound 3 synergizes with ibrutinib to induce apoptosis in CLL cells (MEC-1).
- the bottom panel shows that Compound 3 synergizes with zanubrutinib to induce apoptosis in CLL cells (MEC-1).
- Time frame of assays 72 h.
- FIG. 39 Compound 3 synergizes with venetoclax to induce apoptosis in CLL cells (MEC-1).
- Time frame of assay 72 h.
- WM macroglobulinemia
- IgM immunoglobulin M
- WM is sometimes referred to as a lymphoplasmacytic lymphoma (LPL) with an associated monoclonal IgM paraprotein.
- WM cells have characteristics of both B-lymphocytes and plasma cells, and they are called lymphoplasmacytic cells. For that reason, WM is classified as a type of non-Hodgkin’s lymphoma called lymphoplasmacytic lymphoma (LPL). About 95% of LPL cases are WM; the remaining 5% do not secrete IgM and consequently are not classified as WM. WM is a very rare disease - only about 1,500 patients are diagnosed with it each year in the US. For reference, approximate normal levels of IgM are described, e.g., in Gonzalez-Quintela et al. (2007) Clinical and Experimental Immunology 151: 42-50.
- Normal levels are approximately: 70 mg/190 ml for males; and 80-250 mg/100 ml for females. See also “Range of normal serum immunoglobulin (IgG, IgA and IgM) values in Nigerians,” Oyeyinko et al., Afr J Med Med Sci 1984, Sep-Dec; 13(3-4): 169-76. Mean values of IgM varied from 65 to 132 mg/100 ml in the males and from 96 to 114 mg/100 ml in the females.
- the lymphoplasmacytic cells of WM may interfere with normal functioning.
- the WM cells “crowd out” the normal blood cells and may lead to a reduction in normal blood counts; in the lymph nodes and other organs, the WM cells may lead to enlargement of these structures and other complications.
- Somatic mutation in myeloid differentiation primary response 88 is found in over 90% of patients with WM. Mutations in chemokine (C-X-C motif) receptor 4 (CXCR4) are the next most common mutations and found to be present in 43% of patients with WM (Xu 2016). Published pivotal clinical studies conducted with ibrutinib have reported MYD88 and CXCR4 mutation status affected responses to ibrutinib.
- MYD88 L265 CXCR4 WT [with WT indicating wild type]
- MYD88 L265 PCXCR4 WHIM [with WHIM indicating warts, hypogammaglobulinemia, infections, and myelokathexis]
- MYD88 WT CXCR4 WT 3.
- WHIM-like mutations result in a gain of function in CXCR4, which in turn decreases chemokine (C-X-C motif) 12 (CXCL12) mediated receptor down regulation and ultimately inhibits egress of cells bearing the mutant CXCR4 from sequestered areas in bone marrow and lymph nodes (Lei 2016; Majumdar 2018).
- VGPR very good partial response
- major response defined as complete response +VGPR + partial response
- CXCR4 WHIM mutations have been associated with more aggressive disease features, such as higher IgM levels and bone marrow involvement.
- the present invention provides a method of treating Waldenstrom’s macroglobulinemia (WM) that bears a somatic mutation and which is wild type in the CXCR4 receptor (CXCR4WT).
- WM macroglobulinemia
- CXCR4WT CXCR4 receptor
- Chemokines are major regulators of cell trafficking and adhesion.
- the chemokine CXCL12 stromal cell-derived factor-la
- CXCL12 stromal cell-derived factor-la
- HSCs hematopoietic stem cells
- T cells T cells
- B cells monocytes and macrophages
- neutrophils neutrophils
- eosinophils eosinophils
- CXCL12 When CXCL12 activates CXCR4, it enhances and sustains AKT, extracellular signal-regulated kinase, and Bruton’s tyrosine kinase (BTK) signaling pathways, as well as increases cell migration, adhesion, growth, and survival of WM cells (Cao 2014).
- the chemokine CXCL12 binds primarily to CXC receptor 4 (CXCR4; CD 184).
- CXCR4 CXC receptor 4
- CD 184 CXC receptor 4
- the binding of CXCL12 to CXCR4 induces intracellular signaling through several divergent pathways initiating signals related to chemotaxis, cell survival and/or proliferation, increase in intracellular calcium, and gene transcription.
- CXCR4 is expressed on multiple cell types including lymphocytes, HSCs, endothelial and epithelial cells, and cancer cells.
- the CXCL12/CXCR4 axis is involved in tumor progression, angiogenesis, metastasis, and survival. This pathway is a target for the development of therapeutic agents that can block the CXCL12/CXCR4 interaction or inhibit downstream intracellular signaling.
- WM Puloulain 2016; Xu 2016; Stone 2004
- the nonsense mutations truncate the distal 15- to 20 amino acid region and the frameshift mutations comprise a region of up to 40 amino acids in the C-terminal domain (Hunter 2014).
- Nonsense and frameshift mutations are almost equally divided among WM patients.
- the most common CXCR4 mutation in WM is a nonsense mutation of S338X.
- the presence of CXCR4 somatic mutations can affect disease presentation in WM.
- CXCR4 mutations present with a significantly lower rate of adenopathy, and those with CXCR4 nonsense mutations have an increased bone marrow disease burden, serum IgM levels, and/or risk of symptomatic hyperviscosity (Stone 2004; Treon 2014).
- WM develops resistance to BTK inhibitors and other therapeutics via association with bone marrow stroma cells (BMSCs).
- CXCL12 produced in BMSCs induce a chemotactic response through CXCR4 promoting homing of malignant WM cells to bone marrow (BM).
- BM bone marrow stroma cells
- Hypersecretion of CXCL12 and IL-6 in BM promotes survival and growth and confers resistance of WM cells to chemotherapeutic agents.
- Mavorixafor studies support the potential of CXCR4 antagonism to work synergistically with BTK inhibitors to overcome BMSC-induced resistance of WM cells to chemotherapeutics.
- Waldenstrom s macroglobulinemia patients are often treated with rituximab, an anti-CD20 antibody, as monotherapy or in combination with alkylating agents (bendamustine and cyclophosphamide) or nucleoside analogues (fludarabine and cladribine).
- BTK inhibitors such as ibrutinib, acalabrutinib and zanubrutinib
- proteasome inhibitors ixazomib, bortezomib and carfilzomib
- thalidomide and everolimus
- BTK inhibitors such as ibrutinib, acalabrutinib and zanubrutinib
- proteasome inhibitors ixazomib, bortezomib and carfilzomib
- thalidomide thalidomide
- everolimus Buske 2013; Dimopoulos 2014; Treon 2015 [2]; Owen 2014; Dimopoulos 2007; Olszewski 2016.
- Ibrutinib has been approved as a single agent to treat WM in both US and European Union (EU) (ibrutinib (IMBRUVICA®)).
- EU European Union
- ibrutinib can be used in any line of treatment while in the EU, ibrutinib is approved for patients who have received at least one prior therapy, or in first-line treatment for patients unsuitable for chemo-immunotherapy.
- the ibrutinib monotherapy and rituximab combination pivotal trials have identified genetic mutation patients who have not benefited to the same extent of those patients without genetic mutations.
- MYD88 L265P CXCR4 WIIIM population estimated at approximately 27% of the WM population (Treon 2015 [1], Treon 2018 [1]; Hunter 2014). Patients with the double mutations had a significantly reduced VGPR (9.5%) as compared with patients with the MYD88 L265P CXC 4 W I mutations (44.4%) (Treon 2015 [2]; Treon 2018 [2]).
- X4P-001 (mavorixafor) is an orally bioavailable, small molecule inhibitor of
- the present invention provides a method of treating a cancer, such as those described herein, by administering to a patient in need thereof an effective amount of mavorixafor, or a pharmaceutically acceptable salt thereof or pharmaceutical composition thereof, and comprising co-administering simultaneously or sequentially an effective amount of one or more additional therapeutic agents, such as those described herein.
- the method includes co-administering one additional therapeutic agent.
- the method includes co-administering two additional therapeutic agents.
- the combination of mavorixafor and the additional therapeutic agent or agents acts synergistically to prevent or reduce immune escape and/or angiogenic escape of the cancer.
- the patient has previously been administered another anticancer agent, such as an adjuvant therapy or immunotherapy.
- the cancer is refractory.
- mavorixafor or a pharmaceutically acceptable salt thereof or pharmaceutical composition thereof is used in combination with an approved cancer therapy such as radiation, a chemotherapeutic, or an immunotherapy or targeted therapeutic.
- the approved cancer therapy is chemotherapy, a targeted drug, a biological therapy, plasmapheresis (plasma exchange), stem cell transplant, or radiation therapy.
- the present invention provides a method of treating a cancer such as a B-cell disorder, wherein mavorixafor replaces the use of tocilizumab (anti- IL6 monoclocal antibody); and wherein mavorixafor is used for treatment of the B-cell disorder, comprising administering to a patient in need thereof an effective amount of mavorixafor, or a pharmaceutically acceptable salt thereof.
- the present invention provides a method of treating a cancer in a patient in need thereof, comprising administering to the patient an effective amount of mavorixafor, or a pharmaceutically acceptable salt thereof; in combination with an effective amount of BTK inhibitor, BTK degrader, BCL-2 inhibitor, BH3 mimetic, or proteasome inhibitor or a pharmaceutically acceptable salt thereof; and wherein the cancer includes a somatic mutation and is CXCR4 WT (with WT indicating wild type).
- the somatic mutation is a MYD88 mutation such as MYD88 L265 .
- the cancer is MYD88 w r CXCR4 w l .
- the cancer overexpresses CXCR4.
- the BTK inhibitor is selected from ibruitinib, acalabrutinib, zanubrutinib, tirabrutinib, evobrutinib, fenebrutinib, poseltinib, vecabrutinib, spebrutinib, LCB 03-0110, LFM-A13, PCI 29732, PF 06465469, (-)- Terreic acid, BMX-IN-1, BI-BTK-1, BMS-986142, CGI-1746, GDC-0834, olmutinib, PLS-123, PRN1008, RN-486, LOXO-305 (pirtobrutinib), and ARQ-531 (nemtabrutinib; MK-1026).
- the BTK inhibitor is selected from tirabrutinib, evobrutinib, fenebrutinib, poseltinib, vecabrutinib, spebrutinib, LCB 03-0110, LFM-A13, PCI 29732, PF 06465469, (-)-Terreic acid, BMX-IN-1, BI-BTK-1, BMS-986142, CGI-1746, GDC-0834, olmutinib, PLS-123, PRN1008, RN-486, LOXO-305 (pirtobrutinib), and ARQ- 531 (nemtabrutinib; MK-1026).
- the cancer is a B-cell disorder such as WM.
- the patient has previously undergone treatment with a BTK inhibitor, BTK degrader, BCT-2 inhibitor, BH3 mimetic, or proteasome inhibitor.
- the cancer is refractory or resistant to the BTK inhibitor, BTK degrader, BCL- 2 inhibitor, BH3 mimetic, or proteasome inhibitor.
- the patient has undergone one previous treatment with a BTK inhibitor, BTK degrader, BCL-2 inhibitor, BH3 mimetic, or proteasome inhibitor, but has not been treated with a CXCR4 inhibitor, e.g., mavorixafor or a pharmaceutically acceptable salt thereof.
- the mavorixafor or pharmaceutically acceptable salt thereof is administered in an amount effective to reduce IL-6 overexpression in WM cells.
- the mavonxafor or pharmaceutically acceptable salt thereof is administered in an amount effective to reduce CXCL12-induced migration and adhesion of WM cells.
- the mavorixafor or pharmaceutically acceptable salt thereof is administered in an amount effective to increase apoptosis and decrease viability of WM cells.
- the mavorixafor or pharmaceutically acceptable salt thereof synergizes with a co-administered B cell agent to increase apoptosis and decrease viability of WM cells.
- the mavonxafor or pharmaceutically acceptable salt thereof is administered in an amount effective to decrease relative IgM release.
- the mavorixafor or pharmaceutically acceptable salt thereof is administered in an amount effective to overcome bone marrow stroma-induced resistance of WM cells to BTK inhibitor treatment.
- the mavorixafor or pharmaceutically acceptable salt thereof is administered in an amount effective to overcome bone marrow stroma-induced resistance due to IL6 overexpression and IgM hypersecretion.
- the cancer is refractory or relapsed.
- the cancer is refractory, relapsed, or resistant with respect to the BTK inhibitor, BTK degrader, BCL-2 inhibitor, BH3 mimetic, or proteasome inhibitor.
- the cancer is a lymphoma.
- the cancer is a Central Nervous System (CNS) lymphoma.
- the cancer is a leukemia.
- the leukemia is multiple myeloma (MM), acute lymphocytic leukemia (ALL), myeloid cell leukemia 1 (MCL-1), small lymphocytic lymphoma (SLL), or chronic lymphocytic leukemia (CLL).
- MM multiple myeloma
- ALL acute lymphocytic leukemia
- MCL-1 myeloid cell leukemia 1
- SLL small lymphocytic lymphoma
- CLL chronic lymphocytic leukemia
- the cancer is non-Hodgkin’s lymphoma. In some embodiments, the cancer is Hodgkin’s lymphoma.
- the cancer is diffuse large B cell lymphoma (DLBCL), follicular lymphoma (FL), mantle cell lymphoma (MCL), marginal zone lymphoma (MZL), or chronic lymphocytic leukemia (CLL).
- DLBCL diffuse large B cell lymphoma
- FL follicular lymphoma
- MCL mantle cell lymphoma
- MZL marginal zone lymphoma
- CLL chronic lymphocytic leukemia
- the present invention provides a method of treating Waldenstrom’s macroglobulinemia (WM) in a patient in need thereof, comprising administering to the patient an effective amount of mavorixafor, or a pharmaceutically acceptable salt thereof; in combination with an effective amount of BTK inhibitor, BTK degrader, BCL-2 inhibitor, BH3 mimetic, or proteasome inhibitor or a pharmaceutically acceptable salt thereof; and wherein the WM includes a somatic mutation and is CXCR4 WT (with WT indicating wild type).
- the somatic mutation is MYD88 L2fi5 .
- the WM is MYD88 WT CXCR4 WT .
- the WM overexpresses CXCR4.
- the BTK inhibitor, BTK degrader, BCL-2 inhibitor, BH3 mimetic, or proteasome inhibitor may be simultaneously or sequentially administered with the mavorixafor or a pharmaceutically acceptable salt thereof.
- the mavonxafor and the BTK inhibitor, BTK degrader, BCL-2 inhibitor, BH3 mimetic, or proteasome inhibitor are co-administered, for example, as part of the same pharmaceutical composition.
- the mavorixafor and the BTK inhibitor, BTK degrader, BCL-2 inhibitor, BH3 mimetic, or proteasome inhibitor are co-administered as part of separate pharmaceutical compositions.
- a BTK inhibitor is co-administered with mavorixafor or a pharmaceutically acceptable salt thereof.
- the BTK inhibitor is ibrutinib, acalabrutinib, or zanubrutinib; or a pharmaceutically acceptable salt thereof.
- the chemical name for ibrutinib is l-[(3R)-3-[4-amino-3-(4-phenoxyphenyl)- lHpyrazolo[3,4-d]pyrimidin-l-yl]-l-piperidinyl]-2-propen-l-one and has the following structure:
- IMBRUVICA® (ibrutinib) capsules for oral administration are available in the following dosage strengths: 70 mg and 140 mg.
- Each capsule contains ibrutinib (active ingredient) and the following inactive ingredients: croscarmellose sodium, magnesium stearate, microcrystalline cellulose, sodium lauryl sulfate.
- the capsule shell contains gelatin, titanium dioxide, yellow iron oxide (70 mg capsule only), and black ink.
- Ibrutinib tablets for oral administration are available in the following dosage strengths: 140 mg, 280 mg, 420 mg, and 560 mg.
- Each tablet contains ibrutinib (active ingredient) and the following inactive ingredients: colloidal silicon dioxide, croscarmellose sodium, lactose monohydrate, magnesium stearate, microcrystalline cellulose, povidone, and sodium lauryl sulfate.
- the film coating for each tablet contains ferrosoferric oxide (140 mg, 280 mg, and 420 mg tablets), polyvinyl alcohol, polyethylene glycol, red iron oxide (280 mg and 560 mg tablets), talc, titanium dioxide, and yellow iron oxide (140 mg, 420 mg, and 560 mg tablets).
- Ibrutinib (Ibruvica® Pharmacyclics; AbbVie) is approved for:
- CLL chronic lymphocytic leukemia
- SLL small lymphocytic lymphoma
- MZL Marginal zone lymphoma
- CLL/SLL, WM, and cGVHD 420 mg taken orally once daily.
- acalabrutinib (Calquence® AstraZeneca Pharmaceuticals) is approved for:
- CLL chronic lymphocytic leukemia
- SLL small lymphocytic lymphoma
- zanubrutinib (Brukinsa® Beigene, USA) is approved for:
- the present invention provides a method of treating Waldenstrom’s macroglobulinemia (WM) in a patient in need thereof, comprising administering to the patient an effective amount of mavorixafor, or a pharmaceutically acceptable salt thereof; in combination with an effective amount of a BTK inhibitor, or a pharmaceutically acceptable salt thereof; and wherein the WM bears one or more somatic mutations and is CXCR4 WT .
- WM macroglobulinemia
- the present invention provides a method of determining whether a patient’s WM will respond to treatment, comprising:
- the method further comprises the step of treating the patient with a combination of an effective amount of mavorixafor, or a pharmaceutically acceptable salt thereof; and an effective amount of a BTK inhibitor, BTK degrader, BCL-2 inhibitor, BH3 mimetic, or proteasome inhibitor.
- the BTK inhibitor is selected from ibruitinib, acalabrutinib, zanubrutinib, tirabrutinib, evobrutinib, fenebrutinib, poseltinib, vecabrutinib, spebrutinib, LCB 03-0110, LFM-A13, PCI 29732, PF 06465469, (-)-Terreic acid, BMX-IN- 1, BI-BTK-1, BMS-986142, CGI-1746, GDC-0834, olmutinib, PLS-123, PRN1008, RN-486, LOXO-305 (pirtobrutinib), and ARQ-531 (nemtabrutinib; MK-1026).
- the BTK inhibitor is selected from tirabrutinib, evobrutinib, fenebrutinib, poseltinib, vecabrutinib, spebrutinib, LCB 03-0110, LFM-A13, PCI 29732, PF 06465469, (-)-Terreic acid, BMX-IN-1, BI-BTK-1, BMS-986142, CGI-1746, GDC-0834, olmutinib, PLS-123, PRN1008, RN-486, LOXO-305 (pirtobrutinib), and ARQ- 531 (nemtabrutinib; MK-1026).
- the one or more somatic mutations do not comprise a CXCR4(S338X) somatic mutation.
- the WM further comprises a somatic MYD88 mutation and optionally a somatic deletion associated with B-cell lymphomagenesis.
- the MYD88 mutation is MYD88 L265P .
- the BTK inhibitor is other than ibrutinib, acalabrutinib, or zanubrutinib, or a pharmaceutically acceptable salt thereof.
- the BTK inhibitor is other than ibrutinib or a pharmaceutically acceptable salt thereof.
- the patient has previously received at least one course of treatment with a BTK inhibitor, or a pharmaceutically acceptable salt thereof, before treatment with mavorixafor, or a pharmaceutically acceptable salt thereof.
- the patient is treatment naive, i.e., the patient has not received a previous treatment for WM.
- the patient has not received previous treatment with a BTK inhibitor (such as ibrutinib), or a pharmaceutically acceptable salt thereof.
- the patient has not received previous treatment with a BTK inhibitor (such as ibrutinib), or a pharmaceutically acceptable salt thereof, and has not received previous treatment with mavorixafor, or a pharmaceutically acceptable salt thereof.
- the patient’s WM is resistant to treatment with a BTK inhibitor.
- the patient has previously received at least one course of treatment with a BTK inhibitor, such as ibrutinib, acalabrutinib, or zanubrutinib, before treatment with mavorixafor or a pharmaceutically acceptable salt thereof.
- the patient’s WM has show n disease progression.
- the present invention provides a method of treating Waldenstrom’s macroglobulinemia (WM) in a patient in need thereof, comprising administering to the patient an effective amount of mavorixafor, or a pharmaceutically acceptable salt thereof; in combination with an effective amount of a BTK inhibitor selected from ibrutinib, acalabrutinib, zanubrutinib, tirabrutinib, evobrutinib, fenebrutinib, poseltinib, vecabrutinib, spebrutinib, LCB 03-0110, LFM-A13, PCI 29732, PF 06465469, (-)-Terreic acid, BMX-IN-1, BI-BTK-1, BMS-986142, CGI-1746, GDC-0834, olmutinib, PLS-123, PRN1008, RN-486, LOXO-305 (pirtobrutini
- a BTK inhibitor
- the present invention provides a method of treating Waldenstrom’s macroglobulinemia (WM) in a patient in need thereof, comprising administering to the patient an effective amount of mavorixafor, or a pharmaceutically acceptable salt thereof; in combination with an effective amount of a BTK inhibitor selected from tirabrutinib, evobrutinib, fenebrutinib, poseltinib, vecabrutinib, spebrutinib, LCB 03- 0110, LFM-A13, PCI 29732, PF 06465469, (-)-Terreic acid, BMX-IN-1, BI-BTK-1, BMS-986142, CGI-1746, GDC-0834, olmutinib, PLS-123, PRN1008, RN-486, LOXO-30 (pirtobrutinib), and ARQ-531 (nemtabrutinib; MK-1026); or a pharmaceutically acceptable salt
- the WM is selected from one of the following genomic groups: 1) MYD88 L265 CXCR4 WI (with WT indicating wild type), and 2)
- the MYD88 L265 mutation is MYD88 L265P .
- the mavorixafor or a pharmaceutically acceptable salt thereof is co-administered with a BTK inhibitor selected from evobrutinib, LOXO-305, and ARQ-531, or a pharmaceutically acceptable salt thereof.
- the patient has previously received at least one course of treatment with a BTK inhibitor, or a pharmaceutically acceptable salt thereof, before treatment with mavorixafor, or a pharmaceutically acceptable salt thereof.
- the patient’s WM is resistant to treatment with a BTK inhibitor.
- the patient has previously received at least one course of treatment with ibrutinib before treatment with mavorixafor or a pharmaceutically acceptable salt thereof.
- the patient’s WM has shown disease progression.
- the present invention provides a method of treating Waldenstrom’s macroglobulinemia (WM) in a patient in need thereof, comprising administering to the patient an effective amount of mavorixafor, or a pharmaceutically acceptable salt thereof; in combination with an effective amount of a BCL-2 inhibitor or BH3-mimetic; or a pharmaceutically acceptable salt thereof; and wherein the WM has a CXCR4 WT genomic status (with WT indicating wild type).
- WM macroglobulinemia
- the BCL-2 inhibitor or BH3 mimetic is selected from venetoclax, BGB-11417, LOXO-338, LP-108, S55746, APG-2575, APG-1252 (pelcitoclax), AT-101, TQB3909, obatoclax, GDC-0199, ABT-737, and navitoclax (ABT-263); or a pharmaceutically acceptable salt thereof.
- the mavorixafor or pharmaceutically acceptable salt thereof is co-administered with venetoclax or a pharmaceutically acceptable salt thereof.
- the mavorixafor or pharmaceutically acceptable salt thereof is co-administered with ABT-737 or navitoclax (ABT-263); or a pharmaceutically acceptable salt thereof or a pharmaceutically acceptable salt thereof.
- the WM is selected from one of the following genomic groups: 1) MYD88 L265 CXC 4 W I (with WT indicating wild type), and 2) MYD88 WT CXCR4 WT .
- the MYD88 L265 mutation is MYD88 L265P .
- mavorixafor or a pharmaceutically acceptable salt thereof is administered to the patient in a dose of about 100 mg to about 1000 mg per day.
- mavorixafor or a pharmaceutically acceptable salt thereof is administered to the patient in a dose of about 200 mg to about 600 mg per day.
- mavorixafor or a pharmaceutically acceptable salt thereof is administered to the patient in a dose of about 200 mg, about 400 mg, or about 600 mg per day.
- mavorixafor or a pharmaceutically acceptable salt thereof is administered to the patient in a single daily dose (QD).
- QD single daily dose
- the method provides about a 75-95% percent reduction in IgM from baseline.
- the method reduces IgM to within 2 times the normal range for a non-diseased adult human (non-WM patient).
- the mavorixafor, or a pharmaceutically acceptable salt thereof, and the BCL-2 inhibitor, BH3 mimetic, or a pharmaceutically acceptable salt thereof act synergistically.
- the method further comprises the step of obtaining a biological sample from the patient and measuring the amount of a disease-related biomarker.
- the biological sample is a blood sample.
- the disease-related biomarker is selected from circulating CD8+ T cells or the ratio of CD8+ T cells:Treg cells.
- the disease-related biomarker is IgM and/or Hgb.
- mavorixafor or a pharmaceutically acceptable salt thereof is administered to the patient in a dose of about 100 mg to about 1000 mg per day. In some embodiments, mavorixafor or a pharmaceutically acceptable salt thereof is administered to the patient in a dose of about 200 mg to about 800 mg per day.
- mavorixafor or a pharmaceutically acceptable salt thereof is administered to the patient in a dose of about 200 mg to about 600 mg per day.
- mavorixafor or a pharmaceutically acceptable salt thereof is administered to the patient in a dose of about 200 mg, about 400 mg, or about 600 mg per day.
- mavorixafor or a pharmaceutically acceptable salt thereof is administered to the patient in a single daily dose (QD).
- mavorixafor or a pharmaceutically acceptable salt thereof and the BTK inhibitor or a pharmaceutically acceptable salt thereof are administered to the patient in a fasted state.
- ibrutinib or a pharmaceutically acceptable salt thereof is administered to the patient in a dose of about 70 mg to about 840 per day.
- ibrutinib or a pharmaceutically acceptable salt thereof is administered to the patient in a dose of about 140 mg to about 420 mg per day.
- ibrutinib or a pharmaceutically acceptable salt thereof is administered to the patient in a dose of about 140 mg, about 280 mg, or about 420 mg per day.
- mavorixafor is administered to the patient in a dose of about 200 mg to about 600 mg per day in combination with ibrutinib in a dose of about 140 mg to about 420 mg per day.
- mavorixafor is administered to the patient in a dose of about 200 mg, about 400 mg, or about 600 mg per day in combination with ibrutinib in a dose of about 140 mg, about 280 mg, or about 420 mg per day.
- mavorixafor is administered to the patient in a dose of about 200 mg per day in combination with ibrutinib in a dose of about 140 mg, about 280 mg, or about 420 mg per day.
- mavorixafor is administered to the patient in a dose of about 400 mg per day in combination with ibrutinib in a dose of about 140 mg, about 280 mg, or about 420 mg per day.
- mavorixafor is administered to the patient in a dose of about 600 mg per day in combination with ibrutinib in a dose of about 140 mg, about 280 mg, or about 420 mg per day.
- mavorixafor is administered to the patient in a dose of about 200 mg per day in combination with ibrutinib in a dose of about 140 mg per day.
- mavorixafor is administered to the patient in a dose of about 400 mg per day in combination with ibrutinib in a dose of about 280 mg per day.
- mavorixafor is administered to the patient in a dose of about 600 mg per day in combination with ibrutinib in a dose of about 420 mg per day.
- the method provides at least a 50% percent decrease in IgM levels from baseline. In some embodiments, the method provides at least a 10%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 60%, 70%, 75%, 80%, 85%, 90%, 95%, or 98% decrease in IgM levels from baseline. In some embodiments, the method provides about a 50% decrease in IgM levels from baseline. In some embodiments, the method provides about a 10%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 60%, 70%, or 75% decrease in IgM levels from baseline.
- the method provides about a 10-20%, 10-25%, 15- 30%, 15-35%, 20-40%, 20-45%, 25-50%, 30-60%, 35-70%, 50-60%, 50-75%, 60-90%, 70- 90%, 80-90%, 80-95%, 80-98%, 85-98%, 90-98%, or 95-98% decrease in IgM levels from baseline.
- the method reduces IgM and/or Hgb to within 2 times the normal range for a non-diseased adult human (non-WM patient), 1.5 times, 1.25 times, or to within the normal range for a non-diseased adult human.
- the method decreases Hgb to between 2 times the upper limit of normal (ULN) and the lower limit of normal.
- mavorixafor, or a pharmaceutically acceptable salt thereof, and the BTK inhibitor, or a pharmaceutically acceptable salt thereof act synergistically.
- the dose of the BTK inhibitor, or a pharmaceutically acceptable salt thereof, required for effective treatment is decreased by at least 20% relative to the effective dose of the BTK inhibitor, or a pharmaceutically acceptable salt thereof, as a monotherapy.
- the method further comprises administering an additional therapeutic agent, such as rituximab or another described herein.
- the method further comprises the step of obtaining a biological sample from the patient and measuring the amount of a disease-related biomarker.
- the biological sample is a blood sample.
- the disease-related biomarker is selected from circulating CD8+ T cells or the ratio of CD8+ T cells:Treg cells.
- the disease-related biomarker is IgM and/or Hgb.
- the biomarker is absolute neutrophil count (ANC).
- the additional therapeutic agent is an immunostimulatory therapeutic compound.
- the immunostimulatory therapeutic compound is selected from elotuzumab, rmfamurtide, an agonist or activator of a toll-like receptor, or an activator of RORyt.
- the method further comprises administering to said patient an additional therapeutic agent, such as an immune checkpoint inhibitor.
- an additional therapeutic agent such as an immune checkpoint inhibitor.
- the method comprises administering to the patient in need thereof three therapeutic agents selected from mavorixafor or a pharmaceutically acceptable salt thereof, a BTK inhibitor, and an immunostimulatory therapeutic compound or immune checkpoint inhibitor.
- the immune checkpoint inhibitor is selected from nivolumab, pembrolizumab, ipilimumab, avelumab, durvalumab, atezolizumab, or pidilizumab.
- the additional therapeutic agents are selected from an indoleamine (2,3)-dioxygenase (IDO) inhibitor, a Poly ADP ribose polymerase (PARP) inhibitor, a histone deacetylase (HDAC) inhibitor, a CDK4/CDK6 inhibitor, or a phosphatidylinositol 3 kinase (PI3K) inhibitor.
- IDO indoleamine (2,3)-dioxygenase
- PARP Poly ADP ribose polymerase
- HDAC histone deacetylase
- CDK4/CDK6 phosphatidylinositol 3 kinase
- PI3K phosphatidylinositol 3 kinase
- the IDO inhibitor is selected from epacadostat, mdoximod, capmanitib, GDC-0919, PF-06840003, BMS:F001287, Phy906/KD108, or an enzyme that breaks down kynurenine.
- the PARP inhibitor is selected from olaparib, rucaparib, or niraparib.
- the HDAC inhibitor is selected from vorinostat, romidepsin, panobinostat, belinostat, entinostat, or chidamide.
- the CDK 4/6 inhibitor is selected from palbociclib, ribociclib, abemaciclib or trilaciclib.
- the method further comprises administering to said patient a third therapeutic agent, such as an immune checkpoint inhibitor.
- a third therapeutic agent such as an immune checkpoint inhibitor.
- the method comprises administering to the patient in need thereof three therapeutic agents selected from mavorixafor or a pharmaceutically acceptable salt thereof, a BTK inhibitor, and a third therapeutic agent selected from an indoleamme (2,3)-dioxygenase (IDO) inhibitor, a Poly ADP ribose polymerase (PARP) inhibitor, a histone deacetylase (HDAC) inhibitor, a CDK4/CDK6 inhibitor, or a phosphatidylinositol 3 kinase (PI3K) inhibitor, and an immune checkpoint inhibitor.
- IDO indoleamme (2,3)-dioxygenase
- PARP Poly ADP ribose polymerase
- HDAC histone deacetylase
- CDK4/CDK6 CDK4/CDK6 inhibitor
- the immune checkpoint inhibitor is selected from nivolumab, pembrolizumab, ipilimumab, avelumab, durvalumab, atezolizumab, or pidilizumab.
- the PI3K inhibitor is selected from idelalisib, alpelisib, taselisib, pictilisib, copanlisib, duvelisib, PQR309, or TGR1202.
- the method further comprises administering to said patient a platinum-based therapeutic, a taxane, a nucleoside inhibitor, or a therapeutic agent that interferes with normal DNA synthesis, protein synthesis, cell replication, or will otherwise inhibit rapidly proliferating cells.
- the platinum-based therapeutic is selected from cisplatin, carboplatin, oxaliplatin, nedaplatin, picoplatin, or satraplatin.
- the taxane is selected from paclitaxel, docetaxel, albuminbound paclitaxel, cabazitaxel, or SID530.
- the therapeutic agent that interferes with normal DNA synthesis, protein synthesis, cell replication, or will otherwise interfere with the replication of rapidly proliferating cells is selected from trabectedin, mechlorethamine, vincristine, temozolomide, cytarabine, lomustine, azacitidine, omacetaxine mepesuccinate, asparaginase Erwinia chrysanthemi, eribulin mesylate, capacetrine, bendamustine, ixabepilone, nelarabine, clorafabine, trifluridine, or tipiracil.
- the patient has a solid tumor.
- Solid tumors generally comprise an abnormal mass of tissue that typically does not include cysts or liquid areas.
- the cancer is Waldenstrom’s macroglobulinemia.
- the patient has a resectable solid tumor, meaning that the patient’s tumor is deemed susceptible to being removed by surgery.
- the patient has an unresectable solid tumor, meaning that the patient’s tumor has been deemed not susceptible to being removed by surgery, in whole or in part.
- the present invention provides a method for treating refractory cancer in a patient in need thereof comprising administering to a patient in need thereof an effective amount of mavorixafor or a pharmaceutically acceptable salt thereof or pharmaceutical composition thereof, in combination with a BTK inhibitor and optionally further in combination with an additional therapeutic agent such as those described herein.
- the patient completed a previous treatment.
- the previous treatment is a protein kinase inhibitor.
- the previous treatment is a VEGF-R antagonist.
- the previous treatment is an immune checkpoint inhibitor.
- the previous treatment is an immune checkpoint inhibitor selected from nivolumab (Opdivo®, Bristol-Myers Squibb), pembrolizumab (Keytruda®, Merck), or ipilumumab (Yervoy®, Bristol-Myers Squibb).
- the patient experienced disease progression after the previous treatment.
- the patient s cancer, e.g., WM, is resistant or refractory to the previous treatment.
- mavorixafor, or a pharmaceutically acceptable salt thereof or pharmaceutical composition thereof is administered to a patient in a fasted state.
- mavorixafor or a pharmaceutically acceptable salt thereof, or another CXCR4 antagonist is administered in combination with an additional therapeutic agent.
- mavorixafor or a pharmaceutically acceptable salt thereof, or another CXCR4 antagonist is administered in combination with one additional therapeutic agent.
- mavorixafor or a pharmaceutically acceptable salt thereof, or another CXCR4 antagonist is administered in combination with two additional therapeutic agents.
- mavorixafor or a pharmaceutically acceptable salt thereof, or another CXCR4 antagonist is administered in combination with three or more additional therapeutic agents.
- a CXCR4 inhibitor is co-administered in the combination therapies disclosed above.
- the CXCR4 may be administered prior to, concurrently with, or subsequent to administration of the targeted B-cell therapy and the IL-6 modulator.
- the CXCR4 inhibitor is selected from CXCR4 inhibitors disclosed in WO2017/223229 (including compounds 1-1 through 1-184 disclosed therein),
- WO2017/223243 (including compounds 1-1 through 1-149 disclosed therein).
- WO2020/264292 (including compounds 1-1 through 1-31 disclosed therein), and
- WO2021/263203 (including compounds 1-1 through 1-118 disclosed therein).
- the CXCR4 inhibitor is selected from the small molecule
- the CXCR4 inhibitor is selected from mavorixafor; plerixafor (AMD-3100; Sanofi); locuplumab (BMS-936564/MDX1338, Bristol Myers), a fully human anti-CXCR4 antibody, Kashyap et al. (2015) Oncotarget 7:2809-2822; Motixafortide (BL-8040; BKT-140; BiolineRx) Crees et al. (2021) Blood, 138 (Suppl):475 Abstract 711; POL6326 (balixafortide, Polyphor) Karpova et al.
- the CXCR4 inhibitor is mavorixafor, plerixafor, ulocuplumab, motixafortide, POL6326, PRX177561, USL311, burixafor (e.g., burixafor HBr), LY2510924, PF06747143, CX549, BPRCX807, TC14012, USL-311, FC131, CTCE- 9908, or GMI 1359; or a pharmaceutically acceptable salt thereof.
- the CXCR4 inhibitor is selected from one of the following:
- mavorixafor or a pharmaceutically acceptable salt thereof, or another CXCR4 antagonist is administered in combination with an additional therapeutic agent.
- mavorixafor or a pharmaceutically acceptable salt thereof, or another CXCR4 antagonist is administered in combination with one additional therapeutic agent.
- mavorixafor or a pharmaceutically acceptable salt thereof, or another CXCR4 antagonist is administered in combination with two additional therapeutic agents.
- mavorixafor or a pharmaceutically acceptable salt thereof, or another CXCR4 antagonist is administered in combination with three or more additional therapeutic agents.
- the additional therapeutic agent is a kinase inhibitor or VEGF-R antagonist.
- Approved VEGF inhibitors and kinase inhibitors useful in the present invention include: bevacizumab (Avastin®, Genentech/Roche) an anti-VEGF monoclonal antibody: ramucirumab (Cyramza®, Eli Lilly), an anti-VEGFR-2 antibody and ziv- aflibercept, also known as VEGF Trap (Zaltrap®; Regeneron/Sanofi).
- VEGFR inhibitors such as regorafenib (Stivarga®, Bayer); vandetanib (Caprelsa®, AstraZeneca); axitinib (Inlyta®, Pfizer); and lenvatimb (Lenvima®, Eisai); Raf inhibitors, such as sorafenib (Nexavar®, Bayer AG and Onyx); dabrafenib (Tafinlar®, Novartis); and vemurafenib (Zelboraf®, Genentech/Roche); MEK inhibitors, such as cobimetanib (Cotellic®, Exelexis/Genentech/Roche); trametinib (Mekinist®, Novartis); Bcr-Abl tyrosine kinase inhibitors, such as imatinib (Gleevec®, Novartis); nilotinib (Tasigna®, Novart
- kinase inhibitors and VEGF-R antagonists that are in development and may be used in the present invention include tivozanib (Aveo Pharmaecuticals); vatalanib (Bayer/Novartis); lucitanib (Clovis Oncology); dovitinib (TKI258, Novartis); Chiauanib (Chipscreen Biosciences); CEP-11981 (Cephalon); linifanib (Abbott Laboratories); neratinib (HKI-272, Puma Biotechnology); radotinib (Supect®, IY5511, Il-Yang Pharmaceuticals, S.
- BTK inhibitors for use in the present invention include those described herein, such as ibruitinib, acalabrutinib, zanubrutinib, tirabrutinib, evobrutinib, fenebrutinib, poseltinib, vecabrutinib, spebrutinib, LCB 03-0110, LFM-A13, PCI 29732, PF 06465469, (-)- Terreic acid, BMX-IN-1, BI-BTK-1, BMS-986142, CGI-1746, GDC-0834, olmutinib, PLS- 123, PRN1008, RN-486, LOXO-305 (pirtobrutinib), and ARQ-531 (nemtabrutinib; MK- 1026); or a pharmaceutically acceptable salt thereof.
- PROTAC proteolysis-targeting chimera
- Ubiquitin which is highly conserved in eukaryotic cells, is a modifier molecule, composed of 76 amino acids, that covalently binds to and labels target substrates via a cascade of enzymatic reactions involving El, E2, and E3 enzymes. Subsequently, the modified substrate is recognized by the 26S proteasome complex for ubiquitination-mediated degradation.
- El, E2, and E3 enzymes Two El enzymes have been discovered, whereas ⁇ 40 E2 enzymes and more than 600 E3 enzymes offer the functional diversity to govern the activity of many downstream protein substrates.
- VHL Von Hippel-Lindau disease tumor suppressor protein
- MDM2 Mouse Double Minute 2 homologue
- cIAP Cellular Inhibitor of Apoptosis
- NX-2127 a novel orally bioavailable degrader of the Bruton tyrosine kinase (BTK), demonstrated clinically meaning degradation of the BTK in patients with relapsed/refractory chronic lymphocytic leukemia (CLL) and other B-cell malignancies.
- BTK Bruton tyrosine kinase
- CLL chronic lymphocytic leukemia
- NX-2127 carries the normal cellular protein degradation mechanism which allows it to catalyze degradation of BTK. This mechanism is important in B-cell malignancies because the BTK enzyme is present in the B-cell development, differentiation, and signaling that helps lymphoma and leukemia cells survive.
- the phase 1 clinical trial was designed to investigate the safety and tolerability of NX-2127 in patients with B-cell malignancies, including CLL, small lymphocytic lymphoma (SLL), mantle cell lymphoma, marginal zone lymphoma, Waldenstrom macroglobulinemia (WM), follicular lymphoma, and diffuse large B-cell lymphoma.
- CLL small lymphocytic lymphoma
- SLL small lymphocytic lymphoma
- WM Waldenstrom macroglobulinemia
- follicular lymphoma diffuse large B-cell lymphoma.
- BTK degraders such as NX-2127, MT802, L18I, SPB5208, or RC-1 may be used in the present invention. See, e g., Yu, F., et al., Front. Chem, 30 June 2021, which is hereby incorporated by reference.
- the BCL-2 protein is the founding member of the BCL-2 family of apoptosis regulators and was the first apoptosis modulator to be associated with cancer.
- the recognition of the important role played by BCL-2 for cancer development and resistance to treatment made it a relevant target for therapy for many diseases, including solid tumors and hematological neoplasias.
- BH3-mimetics have emerged as a novel class of compounds with favorable results in different clinical settings, including chronic lymphocytic leukemia (CLL).
- BCL-2 family members of this family can be grouped in three main categories.
- the anti-apoptotic subfamily is characterized by the presence of four BCL-2 homology (BH) domains (BH1, BH2, BH3, and BH4) and, in humans, includes the proteins BCL-2 (the founding member), BCL-XL, BCL-W, BCL-2-related protein Al (Bfl-l/Al), myeloid cell leukemia 1 (MCL-1), and BCLB/Boo.
- BH BCL-2 homology domains
- the pro-apoptotic members can be divided in two subfamilies: the multi-domain pro-apoptotic ‘effectors’ (such as BAK and BAX) and those members known as ‘BH3-only proteins’ as they only have the short BH3 domain.
- the latter subfamily includes BAD, BID, BIK, BIM, BMF, HRK, PUMA, and NOXA
- BCL-2 high levels are observed in patients with FL, CLL, mantle-cell lymphoma (MCL), and Waldenstrom’s macroglobulinemia.
- a heterogeneous pattern of expression of BCL-2 is reported among other hematological neoplasms, such as diffuse large B-cell lymphoma (DLBCL), for which certain subtypes present low levels of this molecule; and multiple myeloma (MM), in which BCL-2 expression is especially elevated in patients harboring t(l 1 ;14).
- DLBCL diffuse large B-cell lymphoma
- MM multiple myeloma
- venetoclax has a distinct mode of action as it binds and neutralizes BCL-2 with subnanomolar affinity (Ki ⁇ 0.010 nM), while interacting only weakly with BCL-XL and BCL-W. By sparing BCL-XL, it exerts little effect on platelet numbers. In preclinical studies, this orally bioavailable inhibitor showed cell-killing activity' against a variety of cell lines, including cell lines derived from ALL, NHL, and AML. When investigated in xenografts models using hematological tumors, venetoclax promoted tumor growth inhibition in a dosedependent fashion.
- Venetoclax has been investigated for treatment of CLL and been tested in combination with numerous anticancer agents for cancers such as AML, MM, MCL, CLL/SLL, B-cell lymphoma, and DLBCL.
- Exemplary BCL-2 inhibitors useful in the present invention include venetoclax (Velcade®), and navitoclax.
- Another useful BCL-2 inhibitor is AT-101.
- AT-101 is an orally active pan-Bcl-2 inhibitor that consists of gossypol, a natural compound derived from the cotton plant.
- AT-101 has shown potential efficacy in combinations with other drugs for treatment of solid tumors, such as in combination with docetaxel, topotecan, paclitaxel and carboplatin, cisplatin and etoposide.
- Other BCL-2 inhibitors include sabutoclax, S55746, HA-14-1 and gambogic acid (Han et al. (2019) BioMed Research International 2019:Article ID 1212369: Drugs and Clinical Approaches Targeting the Antiapoptotic Protein: A Review).
- BH3 mimetics comprise a novel class of BCL-2 inhibitors that have shown promising results in several hematological malignancies, both as single agents and in combination with other anti-cancer drugs.
- venetoclax also known as ABT-199
- ABT-199 a potent and selective inhibitor of BCL-2
- CLL chronic lymphocytic leukemia
- This novel class of compounds is designed to selectively kill cancer cells by targeting the mechanism involved in their survival. These agents induce apoptosis by mimicking the activity of natural antagonists of BCL-2 and other related proteins.
- ABT-737 developed by Abbott Laboratories (North Chicago, IL, USA), is considered the prototype of BH3 mimetics as it was the ’first- in-class' compound developed to mimic the function of BH3 -only -proteins.
- ABT-737 binds with a much higher affinity ( ⁇ 1 nmol/L) than previous compounds to anti-apoptotic proteins BCL-2, BCL-XL and BCL-w, blocking their function.
- Navitoclax a potent and selective inhibitor of BCL-2, is the second generation, orally bioavailable form of ABT-737. Like its predecessor, navitoclax interacts with high affinity and abrogates BCL-2, BCL-XL, and BCL-w, but has no activity against Al and MCL-1. Navitoclax showed in vitro activity against a broad panel of tumor cell lines both as single agent and in combination with chemotherapy. In in vivo experiments, treatment with this inhibitor induced rapid and complete tumor responses in multiple xenograft models developed using small-cell lung cancer and hematologic cell lines, with responses lasting several weeks in some models.
- BH3 Mimetics useful in the present invention include ABT-737, navitoclax and obatoclax mesylate (GX15-070).
- Proteasome inhibitors useful in the present invention include ixazomib (Ninlaro®), bortezomib (Velcade®), carfilzomib (Kyprolis®), marizomib (NPI-0052), oprozomib (ONX0912), ONX 0914 (an immunoproteasome selective inhibitor), and KZR-616 (an immunoproteas ome inhibitor).
- the present invention provides a method of treating Waldenstrom’s macroglobulinemia in a patient in need thereof, comprising administering to the patient an effective amount of mavorixafor in combination with an effective amount of a BTK inhibitor, and optionally further in combination with one or more standard of care treatments, or a combination thereof, for Waldenstrom’s macroglobulinemia.
- Standard of care treatments for Waldenstrom’s macroglobulinemia are well known to one of ordinary skill in the art and include chemotherapy, or immunotherapy, or a combination thereof.
- the standard of care chemotherapy is selected from chlorambucil, cladribine, cyclophosphamide, fludarabine, bendamustine, or a BTK inhibitor, such as ibrutinib, acalabrutinib, or zanubrutinib.
- the additional therapeutic agent is ibrutinib (Imbruvica 5 ) Pharmacychcs/Janssen/AbbVie).
- mavorixafor is administered to the patient as a monotherapy and as the first-line treatment for the Waldenstrom’s macroglobulinemia. In other embodiments, mavorixafor is administered to the patient as a first-line treatment in combination with a standard of care treatment for Waldenstrom’s macroglobulinemia (e.g., immunotherapy, or chemotherapy, or a combination thereof).
- a standard of care treatment for Waldenstrom’s macroglobulinemia e.g., immunotherapy, or chemotherapy, or a combination thereof.
- a second-line treatment is used that can include a well-known second-line treatment to treat Waldenstrom’s macroglobulinemia.
- the present invention provides a method of treating Waldenstrom’s macroglobulinemia in a patient wherein the cancer is resistant to a first-line therapy, said method comprising administering mavorixafor optionally in combination with a second-line treatment.
- the present invention provides a method of treating a resistant Waldenstrom’s macroglobulinemia comprising administering mavorixafor as the second-line treatment.
- the present invention provides a method of treating a resistant Waldenstrom’s macroglobulinemia comprising administering mavorixafor in combination with another second-line treatment or standard of care second-line treatment for Waldenstrom’s macroglobulinemia (e.g., immunotherapy, chemotherapy, etc.).
- the second-line treatment is selected from a chemotherapy.
- mavorixafor is administered as a second-line therapy in combination with a chemotherapy for the treatment of relapsed and refractory Waldenstrom’s macroglobulinemia.
- a third-line treatment is administered to the patient that can include a well-known third-line treatment to treat Waldenstrom’s macroglobulinemia.
- the present invention provides a method of treating a Waldenstrom’s macroglobulinemia resistant to both first-line therapy and second-line therapy comprising administering mavorixafor as the third-line treatment.
- the present invention provides a method of treating a Waldenstrom’s macroglobulinemia resistant to both first-line therapy and second-line therapy comprising administering mavorixafor in combination with another third-line treatment or standard of care third-line treatment for Waldenstrom’s macroglobulinemia (e.g., immunotherapy, chemotherapy, etc.).
- a Waldenstrom’s macroglobulinemia resistant to both first-line therapy and second-line therapy comprising administering mavorixafor in combination with another third-line treatment or standard of care third-line treatment for Waldenstrom’s macroglobulinemia (e.g., immunotherapy, chemotherapy, etc.).
- mavorixafor is administered as a sensitizer for the treatment of Waldenstrom’s macroglobulinemia. Without wishing to be bound by any particular theory, it is believed that mavorixafor increases the efficacy of the standard of care, first-line, second-line, or third-line treatments for Waldenstrom’s macroglobulinemia, wherein the Waldenstrom’s macroglobulinemia comprises a CXCR4 mutation such as one of those described herein.
- the present invention provides a method of treating a Waldenstrom’s macroglobulinemia in a patient in need thereof, comprising administering mavorixafor to the patient prior to administration of one or more of a standard of care, first-line, second-line, or third-line treatment.
- administration of mavorixafor results in a more effective treatment of the Waldenstrom’s macroglobulinemia compared to treatment of Waldenstrom’s macroglobulinemia in the absence of administration of mavorixafor.
- the present invention provides a method of treating a Waldenstrom’s macroglobulinemia in a patient in need thereof, comprising administering mavorixafor to the patient after administration of one or more of a standard of care, first-line, second-line, or third-line treatment.
- the present invention provides a method of treating a Waldenstrom’s macroglobulinemia in a patient in need thereof, comprising administering mavorixafor to the patient in combination with an additional therapeutic agent suitable for treating the Waldenstrom’s macroglobulinemia.
- the additional therapeutic agent is a BTK inhibitor.
- the additional therapeutic agent is selected from chlorambucil, cladribine, cyclophosphamide, fludarabine, bendamustine, and ibrutinib.
- the additional therapeutic agent is ibrutinib (Imbruvica®; Pharmacy clips/Janssen/AbbVie).
- the present invention provides a method of treating a cancer in a patient in need thereof, as described herein, comprising administering to the patient mavorixafor in combination with one or more additional therapies wherein the combination of mavorixafor and the one or more additional therapies acts synergistically.
- the administration of mavorixafor in combination with an additional therapeutic agent results in a reduction of the effective amount of that additional therapeutic agent as compared to the effective amount of the additional therapeutic agent in the absence of administration in combination with mavorixafor.
- the effective amount of the additional therapeutic agent administered in combination with mavorixafor is about 90%, about 80%, about 70%, about 60%, about 50%, about 40%, about 30%, about 20%, or about 10% of the effective amount of the additional therapeutic agent in the absence of administration in combination with mavorixafor.
- the mavonxafor or pharmaceutically acceptable salt thereof and additional therapy have a combination index (CI) of about 0.9 or less. In some embodiments, the mavorixafor or pharmaceutically acceptable salt thereof and additional therapy have a combination index (CI) of about 0.8 or less. In some embodiments, the mavorixafor or pharmaceutically acceptable salt thereof and additional therapy have a combination index (CI) of about 0.7 or less. In some embodiments, the mavorixafor or pharmaceutically acceptable salt thereof and additional therapy have a combination index (CI) of about 0.6 or less. In some embodiments, the mavorixafor or pharmaceutically acceptable salt thereof and additional therapy have a combination index (CI) of about 0.5 or less.
- the mavonxafor or pharmaceutically acceptable salt thereof and additional therapy have a combination index (CI) of about 0.4 or less. In some embodiments, the mavorixafor or pharmaceutically acceptable salt thereof and additional therapy have a combination index (CI) of about 0.3 or less. In some embodiments, the mavorixafor or pharmaceutically acceptable salt thereof and additional therapy have a combination index (CI) of about 0.2 or less. In some embodiments, the mavorixafor or pharmaceutically acceptable salt thereof and additional therapy have a combination index (CI) of about 0.1 or less.
- the mavorixafor or pharmaceutically acceptable salt thereof and additional therapy have a combination index (CI) of about 0.1 to about 0.9. In some embodiments, the mavorixafor or pharmaceutically acceptable salt thereof and additional therapy have a combination index (CI) of about 0.1 to about 0.8. In some embodiments, the mavorixafor or pharmaceutically acceptable salt thereof and additional therapy have a combination index (CI) of about 0. 1 to about 0.7. In some embodiments, the mavorixafor or pharmaceutically acceptable salt thereof and additional therapy have a combination index (CI) of about 0.1 to about 0.6. In some embodiments, the mavorixafor or pharmaceutically acceptable salt thereof and additional therapy have a combination index (CI) of about 0.1 to about 0.5.
- the mavorixafor or pharmaceutically acceptable salt thereof and additional therapy have a combination index (CI) of about 0. 1 to about 0.4. In some embodiments, the mavorixafor or pharmaceutically acceptable salt thereof and additional therapy have a combination index (CI) of about 0.1 to about 0.3. In some embodiments, the mavorixafor or pharmaceutically acceptable salt thereof and additional therapy have a combination index (CI) of about 0.1 to about 0.2. In some embodiments, the mavorixafor or pharmaceutically acceptable salt thereof and additional therapy have a combination index (CI) of about 0.2 to about 0.9. In some embodiments, the mavorixafor or pharmaceutically acceptable salt thereof and additional therapy have a combination index (CI) of about 0.3 to about 0.9.
- the mavorixafor or pharmaceutically acceptable salt thereof and additional therapy have a combination index (CI) of about 0.4 to about 0.9. In some embodiments, the mavorixafor or pharmaceutically acceptable salt thereof and additional therapy have a combination index (CI) of about 0.5 to about 0.9.
- the mavorixafor or pharmaceutically acceptable salt thereof and additional therapy have a combination index (CI) of about 0.01 to about 0.3. In some embodiments, the mavorixafor or pharmaceutically acceptable salt thereof and additional therapy have a combination index (CI) of about 0.05 to about 0.3. In some embodiments, the mavorixafor or pharmaceutically acceptable salt thereof and additional therapy have a combination index (CI) of about 0.8 to about 0.3.
- Mavorixafor (X4P-001) is a CXCR4 antagonist, with molecular formula C21H27N5; molecular weight 349.48 amu; and appearance as a white to pale yellow solid. Solubility: freely soluble in the pH range 3.0 to 8.0 (>100 mg/mL), sparingly soluble at pH 9.0 (10.7 mg/mL) and slightly soluble at pH 10.0 (2.0 mg/mL). Mavorixafor is only slightly soluble in water. Melting point: 108.9 °C.
- a pharmaceutical composition containing mavorixafor or a pharmaceutically acceptable salt thereof is administered orally in an amount from about 200 mg to about 1200 mg daily.
- the dosage composition may be provided twice a day in divided dosage, approximately 12 hours apart. In other embodiments, the dosage composition may be provided once daily.
- the terminal half-life of mavorixafor has been generally determined to be between about 12 to about 24 hours, or approximately 14.5 hrs.
- Dosage for oral administration may be from about 100 mg to about 1200 mg once or twice per day.
- the dosage of mavorixafor or a pharmaceutically acceptable salt thereof useful in the invention is from about 200 mg to about 600 mg daily.
- the dosage of mavorixafor or a pharmaceutically acceptable salt thereof useful in the invention may range from about 400 mg to about 800 mg, from about 600 mg to about 1000 mg or from about 800 mg to about 1200 mg daily.
- the invention comprises administration of an amount of mavorixafor or a pharmaceutically acceptable salt thereof of about 10 mg, about 20 mg, about 25 mg, about 50 mg, about 75 mg, about 100 mg, about 125 mg, about 150 mg, about 200 mg, about 250 mg, about 300 mg, about 400 mg, about 450 mg, about 500 mg, about 600 mg, about 650 mg, about 700 mg, about 750 mg, about 800 mg, about 850 mg, about 900 mg, about 950 mg, about 1000 mg, about 1100 mg, about 1200 mg, about 1300 mg, about 1400 mg, about 1500 mg, or about 1600 mg.
- a provided method comprises administering to the patient a pharmaceutically acceptable composition comprising mavorixafor or a pharmaceutically acceptable salt thereof wherein the composition is formulated for oral administration.
- the composition is formulated for oral administration in the form of a tablet or a capsule.
- the composition comprising mavorixafor or a pharmaceutically acceptable salt thereof is formulated for oral administration in the form of a capsule.
- a provided method comprises administering to the patient one or more unit doses, such as capsules, comprising 100-1200 mg mavorixafor or a pharmaceutically acceptable salt thereof as an active ingredient; and one or more pharmaceutically acceptable excipients.
- a composition according to the present invention comprises a compound for use in the invention or a pharmaceutically acceptable salt or derivative thereof and a pharmaceutically acceptable carrier, adjuvant, or vehicle.
- the amount of compound in compositions of this invention is an amount effective to measurably inhibit CXCR4, or a mutant thereof, in a biological sample or in a patient.
- a composition of this invention is formulated for administration to a patient in need of such a composition.
- a composition of this invention is formulated for oral administration to a patient.
- patient means an animal, preferably a mammal, and most preferably a human.
- the term “pharmaceutically acceptable salt” refers to those salts which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of humans and lower animals without undue toxicity, irritation, allergic response and the like, and are commensurate with a reasonable benefit/risk ratio.
- Pharmaceutically acceptable salts are well known in the art. For example, S. M. Berge et al., describe pharmaceutically acceptable salts in detail in J. Pharmaceutical Sciences, 1977, 66, 1-19, incorporated herein by reference.
- Pharmaceutically acceptable salts of the compounds of this invention include those derived from suitable inorganic and organic acids and bases.
- Examples of pharmaceutically acceptable, nontoxic acid addition salts are salts of an amino group formed with inorganic acids such as hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid and perchloric acid or with organic acids such as acetic acid, oxalic acid, maleic acid, tartaric acid, citric acid, succinic acid or malonic acid or by using other methods used in the art such as ion exchange.
- inorganic acids such as hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid and perchloric acid
- organic acids such as acetic acid, oxalic acid, maleic acid, tartaric acid, citric acid, succinic acid or malonic acid or by using other methods used in the art such as ion exchange.
- salts include adipate, alginate, ascorbate, aspartate, benzenesulfonate, benzoate, bisulfate, borate, butyrate, camphorate, camphorsulfonate, citrate, cyclopentanepropionate, digluconate, dodecylsulfate, ethanesulfonate, formate, fumarate, glucoheptonate, glycerophosphate, gluconate, hemisulfate, heptanoate, hexanoate, hydroiodide, 2-hydroxy-ethanesulfonate, lactobionate, lactate, laurate, lauryl sulfate, malate, maleate, malonate, methanesulfonate, 2- naphthalenesulfonate, nicotinate, nitrate, oleate, oxalate, palmitate, pamoate, pectinate
- Salts derived from appropriate bases include alkali metal, alkaline earth metal, ammonium and N + (Ci-4alkyl)4 salts.
- Representative alkali or alkaline earth metal salts include sodium, lithium, potassium, calcium, magnesium, and the like.
- Further pharmaceutically acceptable salts include, when appropriate, nontoxic ammonium, quaternary ammonium, and amine cations formed using counterions such as halide, hydroxide, carboxylate, sulfate, phosphate, nitrate, loweralkyl sulfonate and aryl sulfonate.
- compositions of this invention refers to a non-toxic carrier, adjuvant, or vehicle that does not destroy the pharmacological activity of the compound with which it is formulated.
- Pharmaceutically acceptable carriers, adjuvants or vehicles that may be used in the compositions of this invention include, but are not limited to, ion exchangers, alumina, aluminum stearate, lecithin, serum proteins, such as human serum albumin, buffer substances such as phosphates, glycine, sorbic acid, potassium sorbate, partial glyceride mixtures of saturated vegetable fatty acids, water, salts or electrolytes, such as protamine sulfate, disodium hydrogen phosphate, potassium hydrogen phosphate, sodium chloride, zinc salts, colloidal silica, magnesium trisilicate, polyvinyl pyrrolidone, cellulose- based substances, polyethylene glycol, sodium carboxymethylcellulose, polyacrylates, waxes, polyethylene-poly
- a “pharmaceutically acceptable derivative” means any non-toxic salt, ester, salt of an ester or other derivative of a compound of this invention that, upon administration to a patient, is capable of providing, either directly or indirectly, a compound of this invention.
- compositions of the present invention may be administered orally, parenterally, by inhalation spray, topically (as by powders, ointments, or drops), rectally, nasally, buccally, intravaginally, intracisternally, or via an implanted reservoir.
- parenteral as used herein includes subcutaneous, intravenous, intramuscular, intra-articular, intra-synovial, intrastemal, intrathecal, intrahepatic, intralesional, and intracranial injection or infusion techniques.
- the compositions are administered orally, intraperitoneally or intravenously.
- Sterile injectable forms of the compositions of this invention may be aqueous or oleaginous suspension.
- suspensions may be formulated according to techniques known in the art using suitable dispersing or wetting agents and suspending agents.
- the sterile injectable preparation may also be a sterile injectable solution or suspension in a non- toxic parenterally acceptable diluent or solvent, for example as a solution in 1,3-butanediol.
- acceptable vehicles and solvents that may be employed are water, Ringer’s solution and isotonic sodium chloride solution.
- sterile, fixed oils are conventionally employed as a solvent or suspending medium.
- any bland fixed oil may be employed including synthetic mono- or di-glycerides.
- Fatty acids such as oleic acid and its glyceride derivatives are useful in the preparation of injectables, as are natural pharmaceutically acceptable oils, such as olive oil or castor oil, especially in their polyoxyethylated versions.
- These oil solutions or suspensions may also contain a long-chain alcohol diluent or dispersant, such as carboxymethyl cellulose or similar dispersing agents that are commonly used in the formulation of pharmaceutically acceptable dosage forms including emulsions and suspensions.
- Other commonly used surfactants such as Tweens, Spans and other emulsifying agents or bioavailabilify enhancers which are commonly used in the manufacture of pharmaceutically acceptable solid, liquid, or other dosage forms may also be used for the purposes of formulation.
- compositions of this invention may be orally administered in any orally acceptable dosage form including, but not limited to, capsules, tablets, aqueous suspensions or solutions.
- carriers commonly used include lactose and com starch.
- Lubricating agents such as magnesium stearate, are also typically added.
- useful diluents include lactose and dried cornstarch.
- aqueous suspensions are required for oral use, the active ingredient is combined with emulsifying and suspending agents. If desired, certain sweetening, flavoring or coloring agents may also be added.
- compositions of this invention may be administered in the form of suppositories for rectal administration.
- suppositories for rectal administration.
- suppositories can be prepared by mixing the agent with a suitable non-irritating excipient that is solid at room temperature but liquid at rectal temperature and therefore will melt in the rectum to release the drug.
- suitable non-irritating excipient include cocoa butter, beeswax and polyethylene glycols.
- compositions of this invention may also be administered topically, especially when the target of treatment includes areas or organs readily accessible by topical application, including diseases of the eye, the skin, or the lower intestinal tract. Suitable topical formulations are readily prepared for each of these areas or organs.
- Topical application for the lower intestinal tract can be effected in a rectal suppository' formulation (see above) or in a suitable enema formulation. Topically- transdermal patches may also be used.
- compositions may be formulated in a suitable ointment containing the active component suspended or dissolved in one or more carriers.
- Carriers for topical administration of compounds of this invention include, but are not limited to, mineral oil, liquid petrolatum, white petrolatum, propylene glycol, polyoxyethylene, polyoxypropylene compound, emulsifying wax and water.
- provided pharmaceutically acceptable compositions can be formulated in a suitable lotion or cream containing the active components suspended or dissolved in one or more pharmaceutically acceptable carriers.
- Suitable carriers include, but are not limited to, mineral oil, sorbitan monostearate, polysorbate 60, cetyl esters wax, cetearyl alcohol, 2-octyldodecanol, benzyl alcohol and water.
- compositions may be formulated as micronized suspensions in isotonic, pH adjusted sterile saline, or, preferably, as solutions in isotonic, pH adjusted sterile saline, either with or without a preservative such as benzylalkonium chloride.
- the pharmaceutically acceptable compositions may be formulated in an ointment such as petrolatum.
- compositions of this invention may also be administered by nasal aerosol or inhalation.
- Such compositions are prepared according to techniques well-known in the art of pharmaceutical formulation and may be prepared as solutions in saline, employing benzyl alcohol or other suitable preservatives, absorption promoters to enhance bioavailability, fluorocarbons, and/or other conventional solubilizing or dispersing agents.
- compositions of this invention are formulated for oral administration. Such formulations may be administered with or without food. In some embodiments, pharmaceutically acceptable compositions of this invention are administered without food. In other embodiments, pharmaceutically acceptable compositions of this invention are administered with food.
- compositions should be formulated so that a dosage of between 0.01 - 100 mg/kg body weight/day of the inhibitor can be administered to a patient receiving these compositions.
- a specific dosage and treatment regimen for any particular patient will depend upon a variety of factors, including the activity of the specific compound employed, the age, body weight, general health, sex, diet, time of administration, rate of excretion, drug combination, and the judgment of the treating physician and the severity of the particular disease being treated.
- the amount of a compound of the present invention in the composition will also depend upon the particular compound in the composition.
- the compounds and compositions, according to the method of the present invention may be administered using any amount and any route of administration effective for treating a cancer, such as those disclosed herein.
- the exact amount required will vary from subject to subject, depending on the species, age, and general condition of the subject, the severity of the cancer, the particular agent, its mode of administration, and the like.
- Compounds of the invention are preferably formulated in unit dosage form for ease of administration and uniformity of dosage.
- unit dosage form refers to a physically discrete unit of agent appropriate for the patient to be treated. It will be understood, however, that the total daily usage of the compounds and compositions of the present invention will be decided by the attending physician within the scope of sound medical judgment.
- the specific effective dose level for any particular patient or organism will depend upon a variety of factors including the cancer being treated and the severity of the cancer; the activity of the specific compound employed; the specific composition employed; the age, body weight, general health, sex and diet of the patient; the time of administration, route of administration, and rate of excretion of the specific compound employed; the duration of the treatment; drugs used in combination or coincidental with the specific compound employed, and like factors well known in the medical arts.
- the compounds of the invention may be administered orally or parenterally at dosage levels of about 0.01 mg/kg to about 50 mg/kg and preferably from about 1 mg/kg to about 25 mg/kg, of subject body weight per day, one or more times a day, to obtain the desired therapeutic effect.
- Liquid dosage forms for oral administration include, but are not limited to, pharmaceutically acceptable emulsions, microemulsions, solutions, suspensions, syrups and elixirs.
- the liquid dosage forms may contain inert diluents commonly used in the art such as, for example, water or other solvents, solubilizing agents and emulsifiers such as ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3-butylene glycol, dimethylformamide, oils (in particular, cottonseed, groundnut, com, germ, olive, castor, and sesame oils), glycerol, tetrahydrofurfuryl alcohol, polyethylene glycols and fatty acid esters of sorbitan, and mixtures thereof.
- the oral compositions can also
- Injectable preparations for example, sterile injectable aqueous or oleaginous suspensions may be formulated according to the known art using suitable dispersing or wetting agents and suspending agents.
- the sterile injectable preparation may also be a sterile injectable solution, suspension or emulsion in a nontoxic parenterally acceptable diluent or solvent, for example, as a solution in 1,3 -butanediol.
- the acceptable vehicles and solvents that may be employed are water, Ringer’s solution, U.S P and isotonic sodium chloride solution.
- sterile, fixed oils are conventionally employed as a solvent or suspending medium.
- any bland fixed oil can be employed including synthetic mono- or diglycerides.
- fatty acids such as oleic acid are used in the preparation of injectables.
- Injectable formulations can be sterilized, for example, by filtration through a bacterial-retaining filter, or by incorporating sterilizing agents in the form of sterile solid compositions which can be dissolved or dispersed in sterile water or other sterile injectable medium prior to use.
- a compound of the present invention In order to prolong the effect of a compound of the present invention, it is often desirable to slow the absorption of the compound from subcutaneous or intramuscular injection. This may be accomplished by the use of a liquid suspension of crystalline or amorphous material with poor water solubility. The rate of absorption of the compound then depends upon its rate of dissolution that, in turn, may depend upon crystal size and crystalline form. Alternatively, delayed absorption of a parenterally administered compound form is accomplished by dissolving or suspending the compound in an oil vehicle. Injectable depot forms are made by forming microencapsule matrices of the compound in biodegradable polymers such as polylactide-polyglycolide.
- the rate of compound release can be controlled.
- biodegradable polymers include poly (orthoesters) and poly (anhydrides). Depot injectable formulations are also prepared by entrapping the compound in liposomes or microemulsions that are compatible with body tissues.
- compositions for rectal or vaginal administration are preferably suppositories which can be prepared by mixing the compounds of this invention with suitable non-irritating excipients or carriers such as cocoa butter, polyethylene glycol or a suppository wax which are solid at ambient temperature but liquid at body temperature and therefore melt in the rectum or vaginal cavity and release the active compound.
- suitable non-irritating excipients or carriers such as cocoa butter, polyethylene glycol or a suppository wax which are solid at ambient temperature but liquid at body temperature and therefore melt in the rectum or vaginal cavity and release the active compound.
- Solid dosage forms for oral administration include capsules, tablets, pills, powders, and granules.
- the active compound is mixed with at least one inert, pharmaceutically acceptable excipient or carrier such as sodium citrate or dicalcium phosphate and/or a) fillers or extenders such as starches, lactose, sucrose, glucose, mannitol, and silicic acid, b) binders such as, for example, carboxymethylcellulose, alginates, gelatin, polyvinylpyrrolidinone, sucrose, and acacia, c) humectants such as glycerol, d) disintegrating agents such as agar-agar, calcium carbonate, potato or tapioca starch, alginic acid, certain silicates, and sodium carbonate, e) solution retarding agents such as paraffin, f) absorption accelerators such as quaternary ammonium compounds, g) wetting agents such as, for example, cetyl
- Solid compositions of a similar type may also be employed as fillers in soft and hard-filled gelatin capsules using such excipients as lactose or milk sugar as well as high molecular weight polyethylene glycols and the like.
- the solid dosage forms of tablets, dragees, capsules, pills, and granules can be prepared with coatings and shells such as enteric coatings and other coatings well known in the pharmaceutical formulating art. They may optionally contain opacifying agents and can also be of a composition that they release the active ingredient(s) only, or preferentially, in a certain part of the intestinal tract, optionally, in a delayed manner. Examples of embedding compositions that can be used include polymeric substances and waxes. Solid compositions of a similar type may also be employed as fillers in soft and hard-filled gelatin capsules using such excipients as lactose or milk sugar as well as high molecular weight polethylene glycols and the like.
- the active compounds can also be in micro-encapsulated form with one or more excipients as noted above.
- the solid dosage forms of tablets, dragees, capsules, pills, and granules can be prepared with coatings and shells such as enteric coatings, release controlling coatings and other coatings well known in the pharmaceutical formulating art.
- the active compound may be admixed with at least one inert diluent such as sucrose, lactose or starch.
- Such dosage forms may also comprise, as is normal practice, additional substances other than inert diluents, e.g., tableting lubricants and other tableting aids such a magnesium stearate and microcrystalline cellulose.
- the dosage forms may also comprise buffering agents. They may optionally contain opacifying agents and can also be of a composition that they release the active ingredient(s) only, or preferentially, in a certain part of the intestinal tract, optionally, in a delayed manner.
- buffering agents include polymeric substances and waxes.
- Dosage forms for topical or transdermal administration of a compound of this invention include ointments, pastes, creams, lotions, gels, powders, solutions, sprays, inhalants or patches.
- the active component is admixed under sterile conditions with a pharmaceutically acceptable carrier and any needed preservatives or buffers as may be required.
- Ophthalmic formulation, ear drops, and eye drops are also contemplated as being within the scope of this invention.
- the present invention contemplates the use of transdermal patches, which have the added advantage of providing controlled delivery of a compound to the body.
- Such dosage forms can be made by dissolving or dispensing the compound in the proper medium.
- Absorption enhancers can also be used to increase the flux of the compound across the skin. The rate can be controlled by either providing a rate controlling membrane or by dispersing the compound in a polymer matrix or gel.
- the present invention provides a pharmaceutical composition
- a pharmaceutical composition comprising mavorixafor or a pharmaceutically acceptable salt thereof, one or more diluents, a disintegrant, a lubricant, a flow aid, and a wetting agent.
- the present invention provides a composition comprising 10-1200 mg mavorixafor or a pharmaceutically acceptable salt thereof, microcrystalline cellulose, dibasic calcium phosphate dihydrate, croscarmellose sodium, sodium stearyl fumarate, colloidal silicon dioxide, and sodium lauryl sulfate.
- the present invention provides a unit dosage form wherein said unit dosage form comprises a composition comprising 10-200 mg mavorixafor, or a pharmaceutically acceptable salt thereof, microcrystalline cellulose, dibasic calcium phosphate dihydrate, croscarmellose sodium, sodium stearyl fumarate, colloidal silicon dioxide, and sodium lauryl sulfate.
- the present invention provides a unit dosage form comprising a composition comprising mavorixafor or a pharmaceutically acceptable salt thereof, present in an amount of about 10 mg, about 20 mg, about 25 mg, about 50 mg, about 75 mg, about 100 mg, about 125 mg, about 150 mg, about 200 mg, about 250 mg, about 300 mg, about 400 mg, about 450 mg, about 500 mg, about 600 mg, about 650 mg, about 700 mg, about 750 mg, about 800 mg, about 850 mg, about 900 mg, about 950 mg, about 1000 mg, about 1100 mg, about 1200 mg, about 1300 mg, about 1400 mg, about 1500 mg, or about 1600 mg.
- a provided composition is administered to the patient once per day, twice per day, three times per day, or four times per day. In some embodiments, a provided composition (or unit dosage form) is administered to the patient once per day or twice per day. In some embodiments, the unit dosage form comprises a capsule containing about 25 mg, about 50 mg, about 75 mg, about 100 mg, about 150 mg, or about 200 mg of mavorixafor or a pharmaceutically acceptable salt thereof.
- the present invention provides a unit dosage form comprising a pharmaceutical composition comprising:
- microcrystalline cellulose as about 20-25% by weight of the composition
- the present invention provides a unit dosage form comprising a composition comprising:
- microcrystalline cellulose as about 23% by weight of the composition
- the present invention provides a unit dosage form comprising a composition comprising:
- microcrystalline cellulose as about 10-15% by weight of the composition
- dibasic calcium phosphate dihydrate as about 15-20% by weight of the composition
- kits suitable for co-administration of the compositions may conveniently be combined in the form of a kit suitable for co-administration of the compositions.
- the kit of the invention includes two or more separate pharmaceutical compositions, at least one of which contains a compound of the invention, and means for separately retaining said compositions, such as a container, divided bottle, or divided foil packet.
- An example of such a kit is the familiar blister pack used for the packaging of tablets, capsules and the like.
- the kit of the invention is particularly suitable for administering different dosage forms, for example, oral and parenteral, for administering the separate compositions at different dosage intervals, or for titrating the separate compositions against one another.
- the kit typically includes directions for administration and may be provided with a memory aid.
- Example 1 Mavorixafor Enhances Efficacy of Bruton Tyrosine Kinase Inhibitors by Overcoming the Protective Effect of Bone Marrow Stroma on Tumor Cells in Waldenstrom’s Macroglobulinemia
- WM macroglobulinemia
- IgM monoclonal immunoglobulin M
- BM bone marrow
- CXCR4/CXCL12 axis is crucial for the homing/retention of WM cells in the BM.
- ibrutinib is less effective in treating relaps ed/refractory patients with double mutant WM; this is believed to be because CXCR4 mutations in WM patients cause greater adhesion of malignant B-cells to bone marrow stroma and initiate an IL-6-mediated survival response, thereby reducing efficacy of targeted chemotherapeutics.
- FIG. 1A ibrutinib is less effective in treating relaps ed/refractory patients with double mutant WM; this is believed to be because CXCR4 mutations in WM patients cause greater adhesion of malignant B-cells to bone marrow stroma and initiate an IL-6-mediated survival response, thereby reducing efficacy of targeted chemotherapeutics.
- IB shows reduced % of apoptotic cells when they are grown in the presence of BMSCs, indicating that bone marrow stroma cause a protective effect in WM cells.
- CXCL12 produced in bone marrow stroma BMSC
- CXCR4 chemotactic response through CXCR4 promoting homing of malignant WM cells to bone marrow (BM).
- mavorixafor with ibrutinib and other BTK inhibitors have not been evaluated.
- WM cells MWCL-1 cell line established from a WM patient, with IgM secretion > 1000 ng/mL, and MYD88 L265V CXCR4 WT> ) pretreated with mavorixafor and BTK inhibitors (ibrutinib, zanubrutinib, evobrutinib, LOXO-305, ARQ 531) were co-cultured with established BMSCs (HS27a cells; HPV16 E6/E7 transformed Fibroblast-like; they secrete CXCL12 and IL6). Cell viability, apoptosis, and IgM release were measured after 72 hours (48 hours for venetoclax).
- BTK inhibitors decreased tumor cell viability and increased apoptosis of WM cells in the absence of BMSCs.
- Co-culture with BMSCs enhanced CXCR4 expression and protected WM cells from the effects of BTK inhibitors.
- BMSCs also significantly increased IgM secretion 2- to 5-fold compared with WM cells grown in the absence of BMSCs.
- Mavorixafor alone inhibited CXCL12-stimulated Ca 21 mobilization and migration of WM cells and disrupted the adhesion of WM cells to BMSCs.
- Combination of mavorixafor with BTK inhibitors overcame the protective effect of BMSCs on tumor cells, decreasing cell viability and/or increasing apoptosis compared with BTK inhibitors alone.
- Mavorixafor also reduced IgM secretion, which was further decreased when combined with BTK inhibitors.
- Waldenstrom’s macroglobulinemia is a rare indolent B-cell lymphoma characterized by excess accumulation of malignant lymphoplasmacytic cells in the bone marrow (BM) and hypersecretion of monoclonal immunoglobulin M (IgM) by WM cells.
- BM bone marrow stromal cells
- IgM monoclonal immunoglobulin M
- BMSCs led to reduced apoptosis of WM cells treated with the tested B-cell-targeted inhibitors, suggesting BMSCs conferred drug resistance in WM cells.
- Blocking the CXCR4/CXLC12 axis with mavorixafor alone or in combination with tested B-cell-targeted inhibitors resulted in disruption of WM cell migration and adhesion to BMSCs, enhanced antitumor activity of B-cell-targeted inhibitors, overcame BMSC-induced drug resistance, and reduced BMSC- induced IgM hypersecretion.
- WM macroglobulinemia
- BM bone marrow
- IgM monoclonal immunoglobulin M
- MYD88 MYD88 innate immune signal transduction adaptor
- TLRs toll-like receptors
- BTK Bruton tyrosine kinase
- CXCR4 C-X-C chemokine receptor 4
- CXCL12 C-X-C chemokine ligand 12
- PI3K phosphoinositide 3-kinase
- CXCR4 mutation In WM, CXCR4 mutation generally occurs in the C terminal, intracellular domain of the protein — a region involved in signal transduction. Most CXCR4 C-temtinal mutations found in WM cause hyperactivation of the receptor and its downstream signaling pathways, resulting in decreased internalization of the receptor and increased chemotaxis (7, 11,12). Patients with MYD88 L265P CXCR4 Mvt WM typically present with higher serum IgM levels and greater BM involvement compared with those with MYD88 T 265P mutation alone (3,13).
- IL-6 directly contributes to IgM production in in vitro and in vivo models of WM, and in both models, treatment with an IL-6 receptor (IL-6R) antibody reduces IgM levels (26,27).
- IL-6 signaling links to signal transducer and activator of transcription 3 (STAT3) signaling, a pathway disrupted in many cancers.
- STAT3 signal transducer and activator of transcription 3
- BM microenvironment-mediated tumor progression and drug resistance involving CXCR4/CXCL12 and IL-6/STAT3 axis are also well recognized in various malignancies (e.g., ALL, chronic myelocytic leukemia [CML], chronic lymphocytic leukemia, multiple myeloma [MM], and diffuse large B-cell lymphoma [DLBCL]) (20,30-33).
- malignancies e.g., ALL, chronic myelocytic leukemia [CML], chronic lymphocytic leukemia, multiple myeloma [MM], and diffuse large B-cell lymphoma [DLBCL]
- the BTK inhibitor evobrutinib (# S8777) was provided by Selleck chemicals.
- MWCL-1 cells were provided by Dr Stephen M. Ansell (MAYO file number 2021-121; 200 First Street SW, Rochester, Minnesota) and the bone marrow stroma cell (BMSC) lines HS-27A and HS-5 were obtained from ATCC. All cell lines were cultured in RPMI-1640 medium (Fisher Scientific, # 32404-014) containing 10% fetal bovine serum (FBS) (Sigma-Aldrich, # F7524 or Takara Bio, # 631105), supplemented with 100 U/mL of Penicillin-Streptomycin (GibcoTM, Thermo Fisher Scientific, # 11548876) at 37 °C and 5% CO 2 .
- FBS fetal bovine serum
- BMSCs were cultured in 96-, 48-, or 24-well plates until 90% confluence.
- MWCL-1 cells density ⁇ 2 * 10 5 cells/mL
- mavorixa indicated concentration of mavorixafor together with indicated concentrations of B-cell-targeted inhibitors in medium containing 4% FBS for 1 hour and transferred to the BMSC monolayer.
- Cells were coincubated for 48 or 72 hours followed by measurement of cell viability, apoptosis, IgM, and IL-6 release.
- Cellular viability (as measured using metabolic activity) was determined using the CellTiter-Glo® assay (Promega, #G7570) according to the manufacturer’s instructions.
- IgM levels were quantitated using a human IgM Enzyme-linked immunosorbent assay (ELISA) kit (Abeam, # ab214568) according to the manufacturer’s instructions.
- IL-6 levels were quantitated using an IL-6 ELISA MAXTM kit (BioLegend, # 430515) per manufacturer’s recommendations.
- ELISA kits plates were developed with 3,3',5,5'-tetramethylbenzidine (TMB) development solution or a biotinylated antihuman IL-6 detection antibody/avidin horseradish peroxidase (HRP) solution. The reaction was stopped with the stop solution, and absorbance was read at 450 nm with a microplate reader (SynergyTM HT, BioTek Instruments). Calcium mobilization assay
- MWCL-1 cells (2 x io 5 cells/well) were seeded in transparent bottom, black 96- well plates coated with poly-L-lysine (BioCoat®, Coming) and serum-starved (medium with 1% FBS) for 24 hours. Medium was removed and cells were loaded with 100 pL of fluo-4 AM (3 pM, Invitrogen, # F14201) dye solution for 45 minutes at 37 °C. Subsequently, 100 pL of assay buffer alone or assay buffer with compound dilutions was added, and the plates were equilibrated in the plate reader for an additional 20 minutes at 37 °C.
- fluo-4 AM 3 pM, Invitrogen, # F14201
- the CXCL12 was injected with simultaneous measurement of fluorescent signal (FlexStation® 3 Multi-Mode Microplate Reader, Molecular Devices).
- Raw traces were analyzed in SoftMax®Pro 7 Software (Molecular Devices).
- SoftMax®Pro 7 Software Molecular Devices. The arbitrary units were calculated as the difference between maximal and minimal signal after treatment injection, normalized to the baseline signal before injection.
- MWCL-1 cells were stained with 500 nM Calcein AM (Invitrogen, # Cl 430) and premcubated with mavonxafor for 15 minutes before transfer (5 x 10 5 cells) to an upper well of a 5.0 pM pore size Transwell® (Coming, # 3421).
- the lower chamber contained either CXCL12 (10 nM) in medium supplemented with 1% FBS or a monolayer of HS-27A BMSCs seeded 72 hours prior and starved for 48 hours with 4% FBS medium.
- MWCL-1 mono- or cocultures were treated with mavorixafor and/or ibrutinib for 24 hours.
- Whole cells were lysed by radioimmunoprecipitation assay (RIP A) lysis buffer (Sigma-Aldrich, # R0278) with protease inhibitor cocktail (Roche Custom Biotech, # 11697498001). Lysates were separated by sodium dodecyl sulfate polyacrylamide gelelectrophoresis (SDS-PAGE) electrophoresis and transferred to Trans-Blot® TurboTM Mini PVDF Transfer Packs (Bio-Rad).
- RIP A radioimmunoprecipitation assay
- SDS-PAGE sodium dodecyl sulfate polyacrylamide gelelectrophoresis
- Membranes were incubated with primary antibodies: anti- poly adenosine diphosphate (ADP)-ribose polymerase (PARP) (1 :1000, Cell Signaling, # 9542); Anti-Caspase 3 (1: 1000, Cell Signaling, #9662) and antitubulin (1:5000, R&D, # MAB9344). Secondary HRP -conjugated antibodies (Abeam) were used at 1: 10.000 dilution. Membranes were developed with enhanced chemiluminescence reagent (AmershamTM ECL Prime Western Blotting Detection Reagent, GE Healthcare) on LAS4000 gel documentation system.
- MWCL-1 cells were labeled with 1 pM Calcein AM. After 10 minutes at 37 °C, cells were washed, resuspended in medium containing 1% FBS, and treated with compounds for 30 minutes (2.25 x io 5 cells/mL). MWCL-1 cells were transferred to the BMSC monolayer. After 4 hours, nonadherent cells were removed by gently washing with phosphate-buffered saline (PBS). Remaining cells were harvested, resuspended in flow buffer (Hanks balanced salt solution + 20 mM HEPES + 0.5% body surface area) and analyzed by flow cytometry.
- flow buffer Hanks balanced salt solution + 20 mM HEPES + 0.5% body surface area
- MWCL-1 cells were pretreated with tocilizumab, BP-1-102, or PF-06263276 for 20 minutes and stimulated with IL-6 for 24 hours. Cells were stained with CXCR4 antibody (BD Pharmigen, # 555976) and measured by flow cytometry.
- CXCR4 antibody BD Pharmigen, # 555976
- MWCL-1 cells were seeded in starvation medium in 96-well plate overnight. After stimulation with IL-6, the cells were fixed and permeabilized using BD PhosflowTM Fix Buffer I (BDBiosciences, # 557870) and BD PhosflowTM Perm Buffer III (BDBiosciences, # 558050) according to the manufacturer’s instructions.
- BMSC-derived IL-6 causes IgM hypersecretion by WM cells via IL-6R-JAK-STAT3
- WM is characterized by BM infiltration with malignant lymphoplasmacytic cells with increased synthesis of IgM (1,3)
- BMSCs affected IgM secretion by MWCL-1 WM cells.
- HS-27A BMSCs were cocultured with MWCL-1 cells for 72 hours, and IgM levels were measured in cell culture supernatants.
- IL-6-mediated IgM secretion in WM cells was inhibited by treatment with the IL-6R antibody tocilizumab, pan-JAK inhibitor PF- 06263276, or STAT3 inhibitor BP-1-102 (FIG. 13F).
- IL-6R antibody tocilizumab pan-JAK inhibitor PF- 06263276
- STAT3 inhibitor BP-1-102 STAT3 inhibitor BP-1-102
- BMSC-derived IL-6 increases CXCR4 cell surface expression in WM cells via IL-6R- JAK-STAT3 signaling and enhances WM cell adhesion to BMSCs
- CXCR4/CXCL12 axis plays an essential role in the homing of malignant cells to the protective niche of the BM (24,39,40), and CXCR4/CXCL12 axis expression is upregulated in malignant cells and BM of patients with WM (24,34,35).
- expression of CXCR4 in several publicly available gene expression data sets was analyzed (GSE171739 and GSE9656).
- CXCR4 expression was significantly upregulated in B cells derived from the BM of patients with WM compared with peripheral B cells from healthy donors (FIG. 14 A), suggesting that the BM microenvironment may have a direct impact on CXCR4 expression in WM cells.
- B-cell-targeted drugs in current use for treatment of patients with WM (BTK inhibitors ibrutinib and zanubrutinib) (14,15) or in/under review ongoing clinical trial for WM (BTK inhibitors evobrutinib, pirtobrutinib, nemtabrutinib; BCL-2 inhibitor venetoclax) (NCT03740529, NCT03162536, NCT02677324) were included in our study. All B-cell- targeted inhibitors tested led to a dose-dependent increase in apoptosis and decreased viability of MWCL-1 cells (FIG. 20A-F).
- MWCL-1 cells were premcubated with mavorixafor, an orally available CXCR4 antagonist that is currently being evaluated in clinical trials for patients with WHIM syndrome (NCT03995108), WM (NCT04274738) and SCN/CIN (NCT04154488), followed by the assessment of the percentage of MWCL-1 cells adhering to BMSCs.
- a dose-dependent decrease in adhesion of WM cells to BMSCs was observed after pretreatment with mavorixafor (FIG. 15A). The tested concentrations and durations (4 hours) were not sufficient to induce cytotoxicity in the MWCL-1 cells (data not shown).
- Mavorixafor enhances antitumor activity of B-cell-targeted inhibitors in WM cells and overcomes BMSC-induced drug resistance
- MWCL-1 cells were pretreated with mavorixafor alone or in combination with different B-cell-targeted inhibitors and cultured alone or together with HS-27A BMSCs. Apoptosis and viability were measured after 48 to 72 hours. Mavorixafor alone caused a minor increase in apoptosis of MWCL-1 cells (FIG. 16A-F). The combination of mavorixafor with B-cell-targeted inhibitors led to a further increase in apoptosis of MWCL-1 cells in monoculture (without stromal cells).
- MWCL-1 cells in the presence of BMSCs, showed resistance to apoptosis induced by all B-cell-targeted inhibitors tested.
- the addition of mavorixafor restored the sensitivity of MWCL-1 cells to all tested drugs (FIG. 17A-F).
- mavorixafor alone, at tested concentrations had much weaker effects on apoptosis of BMSCs in a WM cell-BMSC cocultured model (FIG. 23A-B).
- Mavorixafor as a single agent or in combination with B-cell-targeted therapies inhibits BMSC-induced IgM hypersecretion
- MWCL-1 cells were preincubated with mavorixafor, B-cell-targeted inhibitors, or both, and cultured with or without HS-27A BMSCs, followed by supernatant IgM measurements after 48 or 72 hours.
- IL-6 an important cytokine that is mainly secreted by stromal cells in the tumor microenvironment, plays a key role in promoting proliferation, angiogenesis, metastasis, and drug resistance of various malignant cells, including DLBCL, MM, and MCL (33,44,45).
- IL-6 levels are elevated in the BM and serum, and this increase is associated with increased IgM secretion by WM cells (22,25).
- Blockage of IL-6R by tocilizumab reduces IgM secretion and tumor growth in a WM mouse xenograft model (26).
- BMSCs upregulate IL-6 secretion when cocultured with WM cells.
- CXCR4 cell surface upregulation in WM cells to resistance to multiple B-cell-targeted inhibitors — those in use (BTK inhibitors ibrutinib and zanubrutinib) and those being studied for the treatment of WM (BTK inhibitors evobrutinib, pirtobrutinib, and nemtabrutinib; BCL-2 inhibitor venetoclax).
- IL-6 was previously suggested to boost CXCR4 cell surface expression and increase CXCL12-driven cell migration in astroglia (46).
- publicly available data sets confirm increased CXCR4 expression in BM-derived B-cells from patients with WM vs peripheral B-cells from healthy donors.
- Experimental overexpression of CXCR4 in WM cell lines increased tumor infiltration into BM and other organs, accelerated disease progression, decreased survival, and increased IgM secretion upon transplantation into severe combined immunodeficient (SCID)Zbeige (Bg) mice (41).
- SCID severe combined immunodeficient
- Bg severe combined immunodeficient mice
- monoclonal anti- CXCR4 antibody ulocuplumab reduced tumor infiltration in BM, spleen, and lymph nodes in a mouse xenograft model with human WM cells (41). Furthermore, similar in vitro cocultures using BMSCs and non-Hodgkin lymphoma or CML cells also showed increased CXCR4 surface expression, promoting growth, migration, and adhesion of malignant cells to BMSCs as well as resistance to anti-cancer drugs (31,40).
- CXCR4 cell surface expression in WM cells may prolong and sustain intracellular signaling via its ligand CXCL12, which is constitutively secreted by BMSCs. This intracellular signaling may promote the drug resistance observed in our WM cells-BMSC coculture model.
- CXCL12 was previously shown to enhance and sustain extracellular signal-regulated kinase and PI3K-Akt activation in WM cells expressing CXCR4 WWvl and protect cells against apoptosis caused by various anticancer drugs (i.e., ibrutinib, bendamustine, fludarabine, bortezomib, and idelalisib) (11,12).
- anticancer drugs i.e., ibrutinib, bendamustine, fludarabine, bortezomib, and idelalisib
- Complex crosstalk of the CXCL12/CXCR4 axis with other intracellular signaling pathways also promoted drug resistance in numerous cancers (47).
- our data underline the tight connection between WM cells and BMSCs and its importance in cell adhesion, IgM secretion, and resistance to therapeutic agents.
- mavorixafor blocked the CXCL12- induced calcium mobilization, homing of WM cells to CXCL12-secreted BMSCs, and adhesion of WM cells to BMSCs; it is also likely that mavorixafor enhanced PARP and caspase-3 cleavage caused by B-cell-targeted inhibitors in the presence of BMSCs. In contrast to WM cells, BMSCs were less sensitive to mavorixafor treatment, suggesting a potential therapeutic utility of mavorixafor in WM.
- Mavorixafor is well tolerated, with no treatment-related serious adverse events in patients with WHIM syndrome (NCT03005327). Mavorixafor was also reported to block stromal-induced migration of ALL cells, disrupt preestabhshed adhesion to stroma, and increase sensitivity' to chemotherapeutic drugs (vincristine) and targeted therapy (nilotinib) (20).
- BMSC-derived CXCL12 was shown to activate adhesion-related signaling (e.g., focal adhesion kinase [FAK], proto-oncogene non-receptor tyrosine [SRC] kinase) and enhance the expression of adhesion molecules (e.g., a4(31 integrins) in neoplastic and normal hematopoietic stem cells, facilitating homing and adhesion to BMSCs (21,48,49). Future studies are required to address whether mavorixafor inhibits BMSC-mediated upregulation of adhesion molecules, reducing their adhesion to BMSCs, and sensitizing them to therapeutic agents.
- adhesion-related signaling e.g., focal adhesion kinase [FAK], proto-oncogene non-receptor tyrosine [SRC] kinase
- adhesion molecules e.g., a4(31 integrins) in
- mavorixafor has several effects in WM cells: (1) mavorixafor synergizes with B-cell-targeted inhibitors to enhance apoptosis, (2) disrupts the crosstalk between WM cells and BMSCs and restores the sensitivity of WM cells to B-cell- targeted inhibitors, and (3) inhibits BMSC-induced IgM hypersecretion in WM and synergizes with B-cell-targeted drugs in this context.
- Our data provide strong experimental support for the potential use of mavorixafor as a single agent or in combination with B-cell- targeted drugs for the treatment of WM and possibly for other malignancies.
- Dimopoulos M Kastritis E, Owen R, et al. Treatment recommendations for patients with Waldenstrom macroglobulinemia (WM) and related disorders: 1WWM-7 consensus. Blood. 2014;124(9): 1404-11. Dimopoulos M, Trotman J, Tedeschi A, et al. Ibrutinib for patients with rituximabrefractory Waldenstrom’s macroglobulinaemia (INNOVATE): an open-label substudy of an international, multicentre, Phase 3 trial. Lancet Oncol. 2017;18(2):241-250. Dimopoulos M, Tedeschi A, Trotman J, et al.
- Hyperglycemia associated with targeted oncologic treatment mechanisms and management.
- Hassan S, Buchanan M, Jahan K, et al. CXCR4 peptide antagonist inhibits primary breast tumor growth, metastasis and enhances the efficacy of anti-VEGF treatment or docetaxel in a transgenic mouse model.
- Waldenstrom s macroglobulinaemia: an indolent B-cell lymphoma with distinct molecular and clinical features. Hematol Oncol. 2013;31 (1 ): 76-80. Treon S, Cao Y, Xu L, et al. Somatic mutations in MYD88 and CXCR4 are determinants of clinical presentation and overall survival in Waldenstrom macroglobulinemia. Blood. 2014;123(18):2791-6. Treon S, Tripsas C, Meid K, et al. Ibrutinib in previously treated Waldenstrom’s macroglobulinemia. N Engl J Med. 2015;372(15): 1430-40. [1] 60. Treon S, How I treat Waldenstrom macroglobulinemia. Blood. 2015;126(6):721-32. [2]
- Example 3 Mavorixafor enhances apoptosis of tumor cells treated with ibrutinib or venetoclax in diffuse large B-cell lymphoma, follicular lymphoma, mantle cell lymphoma, and chronic lymphocytic leukemia
- LCs lymphoma cells
- BMM bone marrow microenvironment
- CXCR4 WI and its ligand CXCL12 promote LC-BMM interactions, contributing to disease severity in lymphomas or leukemia such as diffuse large B-cell lymphoma (DLBCL), chronic lymphocytic leukemia (CLL), follicular lymphoma (FL), and mantle cell lymphoma (MCL).
- DLBCL diffuse large B-cell lymphoma
- CLL chronic lymphocytic leukemia
- FL follicular lymphoma
- MCL mantle cell lymphoma
- Mavorixafor is an investigational oral CXCR4 antagonist being evaluated in combination with the Bruton tyrosine kinase (BTK) inhibitor ibrutinib in patients with Waldenstrom’s macroglobulinemia (WM).
- BTK Bruton tyrosine kinase
- WM macroglobulinemia
- mavorixafor enhances apoptosis of lymphoma and leukemia cells when combined with venetoclax or ibrutinib.
- Panel (A) shows apoptosis of OCI-LY19 (DLBCL) cells and panel (B) shows D0HH2 (FL) cells treated with mavorixafor in combination with venetoclax.
- Panel (C) shows apoptosis of OCI-LY19 (DLBCL) cells, DOHH2 (FL) cells (Panel (D)), and MEC-1 (CLL) cells (Panel (E)) treated with mavorixafor in combination with ibrutinib.
- D DOHH2
- CLL MEC-1
- FIG. 29 shows apoptosis of lymphoma cells treated with venetoclax or ibrutinib with or without BMSC coculture.
- Apoptosis of OCI-LY19 (DLBCL) cells (A), DOHH2 (FL) cells (B) and MINO (MCL) cells (C) are shown with or without coculture with HS-27A BMSCs in response to venetoclax.
- P values ⁇ .05 are considered statistically significant and set as follows: ns, not significant; * — P ⁇ 05; ** — P ⁇ .01; *** — P ⁇ 001.
- FIG. 30 shows apoptosis of lymphoma cells after treatment with venetoclax or ibrutinib ⁇ mavorixafor with or without BMSC coculture. More specifically, the figure shows apoptosis of OCLLY19 (DLBCL) cells (A), DOHH2 (FL) cells (B), MINO (MCL) cells (C) with or without coculture with HS-27A BMSCs in the presence of venetoclax, and apoptosis of DOHH2 (FL) cells (D) with or without coculture with HS-27A BMSCs in the presence of ibrutinib.
- DLBCL OCLLY19
- DOHH2 FL
- MINO MINO
- P values ⁇ .05 are considered statistically significant and set as follows: ns, not significant; * — P ⁇ 05; ** — P ⁇ 01; *** — P ⁇ 001.
- FIG. 31 shows cell migration of lymphoma cells to CXCL12 with or without mavorixafor pretreatment. Effects of increasing concentrations of mavorixafor on migration of OCI-LY19 (DLBCL) cells (A), D0HH2 (FL) cells (B) toward CXCL12.
- P values ⁇ .05 are considered statistically significant and set as follows: ns, not significant; * — P ⁇ 05; ** — P ⁇ 01; ****— P ⁇ 0001.
- apoptosis of LCs was further enhanced by ⁇ 5% to 60% when treated with mavorixafor in combination with ibrutinib or venetoclax compared to ibrutinib or venetoclax alone.
- Coculture of LCs with BMSCs reduced the sensitivity of LCs to apoptosisinducing effects of ibrutinib and venetoclax.
- Combining mavorixafor with ibrutinib or venetoclax restored sensitivity of LCs to apoptosis-inducing effects of the tested B-cell targeted inhibitors.
- Mavorixafor also inhibited migration of LCs toward CXCL12, suggesting prevention of the homing of LCs to protective niche.
Abstract
The present invention relates to methods of treating cancer, in which a CXCR4 inhibitor such as mavorixafor (X4P-001) or a pharmaceutically acceptable salt thereof or pharmaceutical composition thereof is administered in combination with an additional therapeutic agent, such as a BTK or BCL-2 inhibitor or a BH3 mimetic.
Description
TREATMENTS FOR SINGLE-MUTANT WALDENSTROM’S
MACROGLOBULINEMIA
CROSS-REFERENCE TO RELATED APPLICATIONS
[0001] The present invention claims the benefit of U.S. Provisional Application Nos. 63/269.021, filed March 8, 2022; and 63/366,223, filed June 10, 2022; the entirety of each of which is hereby incorporated by reference.
FIELD OF THE INVENTION
[0002] The present invention relates to methods for treating cancer, such as combination therapies comprising a CXCR4 inhibitor and a BTK inhibitor. The cancer includes lymphomas such as Waldenstrom’s macroglobulinemia.
BACKGROUND OF THE INVENTION
[0003] Waldenstrom’s macroglobulinemia (WM) is a distinct B-cell lymphoproliferative disorder characterized by the proliferation of lymphoplasmacytic cells in the bone marrow in other organs, along with elevated serum levels of monoclonal immunoglobulin M (IgM) gammopathy (Owen 2003; Treon 2013). Waldenstrom’s macroglobulinemia represents a spectrum from early asymptomatic monoclonal gammopathy of undetermined significance (MGUS) (IgM-MGUS), where there are small numbers of lymphoplasmacytic cells in the bone marrow (< 10%), to active WM with anemia, hyperviscosity, and widespread disease (Kyle 2004; Kyle 2005). In a similar plasma-cell dyscrasia such as multiple myeloma, studies have demonstrated the presence of a small number of circulating plasma cells in over 70% of patients with multiple myeloma (Nowakowski 2005). The number of circulating cells in the peripheral blood increased with progression of the disease and was an independent unfavorable prognostic marker (Nowakowski 2005). This data implies that progression of these plasma cell dyscrasias occurs through the continuous trafficking of the malignant cells to new sites of the bone marrow (Nowakowski 2005).
[0004] WM is an indolent B-cell lymphoma characterized by accumulation of malignant lymphoplasmacytic cells in the bone marrow (BM). High levels of monoclonal immunoglobulin M (IgM) are secreted by WM cells, resulting in anemia, blood hyperviscosity syndrome, visual impairments, and neurological symptoms. Consequently, lowering serum IgM is a key end point in WM therapy and a common parameter to assess the success of any WM treatment.
[0005] Over the last decade, significant progress has been made in understanding the genetics underlying the pathogenesis of WM. Somatic mutations in clonal populations of cells lead to WM. The somatic L265P mutation in MYD88 innate immune signal transduction adaptor (MYD88) gene can be found in >90% of patients with WM. The MYD88 gene encodes a protein that is involved in signaling pathways, including activation of nuclear factor-kB upon stimulation of toll-like receptors (TLRs). Additionally, MYD88 anchors with phosphorylated Bruton tyrosine kinase (BTK), which itself is part of many signaling pathways, including toll-like, chemokine and B-cell receptors. MY/)88l-2,pp is thought to be an activating mutation that increases binding to BTK, promoting cell survival and proliferation.
[0006] A second, more diverse category of mutation in WM, detected in approximately 30% of patients, can be found in the gene encoding C-X-C chemokine receptor 4 (CXCR4). The G protein-coupled receptor CXCR4 binds its natural ligand' C-X-C chemokine ligand 12 (CXCL12), which is produced by the perivascular cells of the bone marrow stroma. Upon binding to CXCR4, CXCL12 induces downstream signaling activation of phosphoinositide 3- kmase (P13K), which controls lymphocyte trafficking, chemotaxis, and cell survival. In WM, CXCR4 mutation generally occurs in the C terminal, intracellular domain of the protein — a region involved in signal transduction. Most CXCR4 C-terminal mutations found in WM cause hyperactivation of the receptor and its downstream signaling pathways, resulting in decreased internalization of the receptor and increased chemotaxis. Patients with MYD88L26SP CXCR4Mat WM typically present with higher serum IgM levels and greater BM involvement compared with those wi th MYD88L265P mutation alone.
[0007] The World Health Organization classification defines WM as lymphoplasmacytic lymphoma with overexpression of a clone of IgM proteins, belonging to the category of non- Hodgkin B cell lymphomas with atypically indolent course.
[0008] Waldenstrom’s macroglobulinemia accounts for approximately 2% of all cases of non-Hodgkin lymphoma. It presents with distinctive clinical and laboratory features related to the presence of the monoclonal IgM (Mazzucchelli 2018).
[0009] Clinical manifestation of WM includes symptoms associated with anemia (e.g., pallor, weakness, fatigue), systemic complaints (e g., weight loss, fever, night sweats), organomegaly (e.g., enlarged lymph nodes, spleen, and/or liver), and/or symptoms related to the IgM monoclonal protein in the blood (e.g., hyperviscosity, peripheral neuropathy, and cryoglobulinemia) requiring various degrees of urgency in diagnosis and treatment to avoid secondary complications (Dimopoulos 2000).
[0010] These data underscore the significant, unmet need for study of therapies, including combination therapies, to treat rare cancers such as WM. The present invention addresses this need and provides certain other related advantages.
SUMMARY OF THE INVENTION
[0011] Il has now been found that CXCR4 inhibitors such as mavorixafor (X4P-001), in combination with a second therapeutic agent such as a BTK inhibitor, BTK degrader, BCL-2 inhibitor, BH3 mimetic, or proteasome inhibitor are useful in treating a variety of cellular proliferative disorders, such as those described herein.
[0012] In one aspect, the present invention provides a method of treating a cancer in a patient in need thereof, comprising administering to the patient an effective amount of mavorixafor, or a pharmaceutically acceptable salt thereof; in combination with an effective amount of BTK inhibitor, BTK degrader, BCL-2 inhibitor, BH3 mimetic, or proteasome inhibitor or a pharmaceutically acceptable salt thereof; and wherein the cancer includes a somatic mutation and is CXCR4WT (with WT indicating wild type). In some embodiments, the somatic mutation is a MYD88 mutation such as MYD88L265. In some embodiments, the cancer is MYD88W1CXCR4W1. In some embodiments, the cancer overexpresses CXCR4.
[0013] In another aspect, the present invention provides a method of treating Waldenstrom’s macroglobulinemia (WM) in a patient in need thereof, comprising administering to the patient an effective amount of mavorixafor, or a pharmaceutically acceptable salt thereof; in combination with an effective amount of a BTK inhibitor selected from ibruitinib, acalabrutinib, zanubrutinib, tirabrutinib, evobrutinib, fenebrutinib, poseltinib, vecabrutinib, spebrutinib, LCB 03-0110, LFM-A13, PCI 29732, PF 06465469, (-)-Terreic acid, BMX-IN-1, BI-BTK-1, BMS-986142, CGI-1746, GDC- 0834, olmutimb, PLS-123, PRN1008, RN-486, LOXO-305 (pirtobrutinib), and ARQ-531 (nemtabrutinib; MK-1026); or a pharmaceutically acceptable salt thereof; and wherein the WM has a CXCR4WT genomic status (with WT indicating wild type).
[0014] In another aspect, the present invention provides a method of treating Waldenstrom’s macroglobulinemia (WM) in a patient in need thereof, comprising administering to the patient an effective amount of mavorixafor, or a pharmaceutically acceptable salt thereof; in combination with an effective amount of a BCL-2 inhibitor or BH3-mimetic; or a pharmaceutically acceptable salt thereof; and wherein the WM has a CXCR4WT genomic status (with WT indicating wild type).
[0015] In another aspect, the present invention provides a method of treating Waldenstrom’s macroglobulinemia (WM) in a patient in need thereof, comprising administering to the patient an effective amount of mavorixafor, or a pharmaceutically acceptable salt thereof; in combination with an effective amount of a proteasome inhibitor; or a pharmaceutically acceptable salt thereof; and wherein the WM has a CXCR4WT genomic status (with WT indicating wild type).
BRIEF DESCRIPTION OF THE FIGURES
[0016] FIG. 1A shows median IgM levels of relapsed/refractory Waldenstrom’s patients by single mutant vs. double mutant status when treated with ibrutinib (420 mg QD). WM tumor cells have either elevated expression of CXCR4''V I (single-mutant WM) or mutated CXCR4MU I (double-mutant WM). Thus, “single mutant” refers to patients bearing a MYD88 mutation but not a CXCR4 mutation; “double mutant” refers to patients bearing a mutation in both MYD88 and CXCR4. This figure is a modification of Figure 2 from Supplement to: Dimopoulos MA, Trotman J, Tedeschi A, et al., on behalf of the INNOVATE Study Group and the European Consortium for Waldenstrom’s Macroglobulinemia. Ibrutinib for patients with rituximab-refractory Waldenstrom’s macroglobulinaemia (iNNOVATE): an open-label substudy of an international, multicentre, phase 3 trial. Lancet Oncol 2016; published online Dec 9, 2016. dx.doi. org/10.1016/S1470-2045(16)30632-5; hereby incorporated by reference. FIG. IB shows reduced % of apoptotic cells when they are grown in the presence of bone marrow stroma cells (BMSC), indicating that BMSC cause a protective effect in WM cells. Without wishing to be bound by theory, it is believed that CXCL12 produced in BMSC induce a chemotactic response through CXCR4 promoting homing of malignant WM cells to bone marrow (BM).
[0017] FIG. 2: B-Cell Agents in Development/Commercial Lose Anti-Tumor (Apoptosis) Efficacy in WM Cells Protected by Bone Marrow' Stroma. Without wishing to be bound by theory, it is believed that these data indicate that upregulated CXCR4 - CXCL12 - IL-6 axis is responsible for this BM-induced resistance.
[0018] FIG. 3: B-Cell Agents in Development/Commercial Lose IgM Reduction Efficacy in WM Cells Protected by Bone Marrow Stroma. Without washing to be bound by theory, it is believed that upregulated CXCR4 - CXCL12 - IL-6 axis is responsible for this BM-induced resistance.
[0019] FIG. 4: Co-culture of BMSC with MC cells Stroma Induces IL-6 Hypersecretion in BMSC and CXCR4 Overexpression in WM Cells.
[0020] FIG. 5: Mavorixafor Blocks CXCL12-Induced Migration and Adhesion of WM Cells to BM Stroma.
[0021] FIG. 6: Mavorixafor Reduces Cell Viability & Triggers Apoptosis in WM Cells.
[0022] FIG. 7: Mavorixafor Blocks BM Stroma-Induced IgM Hypersecretion in WM
Cells.
[0023] FIG. 8: Even in Absence of BMSC, Soluble IL-6 Upregulates CXCR4 Expression & IgM Secretion in WM Cells; which is Prevented by Blockade of IL-6/IL6R/STAT3 Axis.
[0024] FIG. 9: Mavorixafor-B Cell Agent Combinations Synergistically Enhance Antitumor Activity in Single-Mutant WM Cells.
[0025] FIG. 10: Mavorixafor-B Cell Agent Combinations Synergistically Enhance Antitumor Activity in WM Cells. Combination indices (CI) were generated with CalcuSyn software for each set of combination. CI <1, = 1, and >1 denote synergism, additive effect, and antagonism, respectively.
[0026] FIG. 11: Mavorixafor Overcomes BM Stroma-Induced Resistance to B Cell Agents.
[0027] FIG. 12: Mavorixafor Synergizes w/B Cell Agents to Inhibit BM Stroma-Induced IgM Hypersecretion in WM Cells.
[0028] FIG. 13: BMSC-derived IL-6 causes IgM hypersecretion in WM cells via IL-6R- JAK-STAT3. IgM (A) and IL-6 (B) were measured in the supernatants of HS-27A BMSCs cocultured for 72 hours with MWCL-1 cells. Viability (C), pathway activation (D), and IgM secretion (E) in starved MWCL-1 cells treated with IL-6 were measured by CellTiter-Glo, phosphoflow, and ELISA, respectively. Relative IgM release in the presence of exogenous IL-6 +/- tocilizumab (IL-6R antibody), PF-06263276 (pan-JAK inhibitor), or BP-1-102 (STAT3 inhibitor) was also measured (F). BMSC, bone marrow stromal cells; Ig, immunoglobulin; IL, interleukin; p-AKT, phosphor-PI3K-Akt; p-IKb, phosphor-nuclear factor of kappa light polypeptide gene enhancer in C-cells, inhibitor, alpha; p-JNK, phosphor-janus kinase; p-MAPK, phosphor-mitogen-activated protein kinase; p-STAT, signal transducer and activator of transcription; WM, Waldenstrom’s Macroglobulinemia. In this and other figures, P values <.05 were considered statistically significant and set as follows: ** — P< 01; *** — P< 001; **** — P< 0001.
[0029] FIG. 14: BMSC-derived IL-6 increases CXCR4 cell surface expression in WM cells via IL-6R-JAK-STAT3 signaling and enhances WM cell adhesion to BMSCs. Expression of CXCR4 was analyzed in publicly available gene expression data sets GSE171739 and GSE9656 (A). MWCL-1 cells were cocultured with HS-27A BMSCs +/-
tocilizumab (B) or pretreated with tocilizumab, BP-1-102, or PF-06263276 (C) and CXCR4 cell surface expression measured via flow cytometry. The effects of IL-6 pretreatment on BMSC adhesion of MWCL-1 cells to HS-27A cells (D) was visualized using Calcem AM. BMSC, bone marrow stromal cells; CXCR4, C-X-C chemokine receptor 4; IL, interleukin; FDR, false discovery rate; WM, Waldenstrom’s Macroglobulinemia.
[0030] FIG. 15: Mavorixafor causes disruption of WM cell migration and adhesion to BMSCs. The effects of mavorixafor pretreatment on BMSC adhesion to MWCL-1 cells cocultured with HS-27A BMSCs were visualized using Calcein AM (A). Migration of MWCL-1 cells toward CXCL12 with and without pretreatment with mavorixafor (B) and/or with and without HS-27A BMSCs coculture (C) was also measured by transwell migration assay. The effects of mavorixafor pretreatment on CXCL12-induced Ca2+ mobilization in MWCL-1 cells cocultured with HS-27A BMSCs were measured via Fluo-4 AM fluorescence (D). BMSC, bone marrow stromal cells; CXCR4, C-X-C chemokine receptor 4; CXCL12, C-X-C chemokine ligand 12; IL, interleukin; WM, Waldenstrom’s Macroglobulinemia.
[0031] FIG. 16: Mavorixafor enhances antitumor activity of B-cell-targeted therapies in WM cells. Apoptosis of MWCL-1 cells treated with mavonxafor in combination with B-cell- targeted inhibitors was measured via flow cytometry (A-F). Synergistic activity between mavorixafor and B-cell-targeted inhibitors was analyzed via Chou and Talalay analysis (A-F). Cleavage of apoptotic markers in the presence of mavorixafor and ibrutinib was measured via immunoblot (G). CF, cytoplasmic fraction; MAV, mavorixafor; PARP, poly [ADP-ribose] polymerase.
[0032] FIG. 17: Mavorixafor overcomes BMSC-induced drug resistance. Apoptosis of MWCL-1 cells treated with mavorixafor in combination with B-cell-targeted inhibitors in MWC-1 cells/HS-27A BMSCs coculture was measured via flow cytometry (A-F). Cleavage of apoptotic markers in the presence of mavonxafor and ibrutinib was measured via immunoblot (G). BMSC, bone marrow stromal cells; CF, cytoplasmic fraction; CXCR4, C- X-C chemokine receptor 4; Evo, evobrutinib; Ibr, ibrutinib; II, interleukin; PARP-1, poly [ADP-ribose] polymerase 1; Pir, pirtobrutinib; Mav, mavorixafor; Nem, nemtabrutinib; NS, not significant; Ven, venetoclax; WM, Waldenstrom’s Macroglobulinemia.
[0033] FIG. 18: Mavorixafor as a single agent or in combination with B-cell-targeted therapies inhibited BMSC-induced IgM hypersecretion. MWCL-1 cells were preincubated with mavorixafor, B-cell-targeted inhibitors, or both, and cocultured with or without HS-27A BMSCs, followed by supernatant IgM measurements after 48 or 72 hours (A-G). BMSC, bone marrow stromal cells; CXCR4, C-X-C chemokine receptor 4; Evo, evobrutinib; Ibr,
ibrutinib; Ig, immunoglobulin: II, interleukin; PARP-1, poly [ADP-ribose] polymerase 1; Pir, pirtobrutinib; Mav, mavorixafor; Nem, nemtabrutinib; NS, not significant; Ven, venetoclax; WM, Waldenstrom’s Macroglobulinerma.
[0034] FIG. 19: Viability of WM cells in the presence of IL-6R-JAK-STAT3 signaling inhibitors. Relative viability of MWCL-1 cells in the presence of tocilizumab (IL-6R antibody), BP-1-102 (STAT3 inhibitor), or PF-06263276 (pan-janus kinase inhibitor).
[0035] FIG. 20: BMSC-induced resistance of WM cells to B-cell-targeted therapies. Apoptosis and viability of MWCL-1 cells with and without coculture with HS-27A BMSCs in the presence of B-cell-targeted inhibitors (A-F).
[0036] FIG. 21: BMSC-induced IgM secretion by WM cells treated with B-cell-targeted therapies. IgM secretion by MWCL-1 cells with and without coculture with HS-27A BMSCs in the presence of B-cell-targeted inhibitors (A-F).
[0037] FIG. 22: HS-5 BMSCs reduced sensitivity of WM cells to B-cell-targeted therapies. Apoptosis of MWCL-1 cells (A,B) and IgM secretion by MWCL-1 cells (C,D) with and without coculture with HS-5 BMSCs in the presence of B-cell-targeted inhibitors, ibrutinib and zanubrutimb.
[0038] FIG. 23: Effect of mavorixafor on apoptosis of BMSCs in coculture with WM cells. Apoptosis of HS-27A (A) and HS-5 (B) BMSCs cocultured with WM cells in the presence of mavorixafor.
[0039] FIG. 24: IL-6 release in WM/BMSC coculture model. Effects of mavorixafor on IL-6 release in WM/BMSC coculture model.
[0040] FIG. 25: In vitro dose-response showing apoptosis of WM cells (not co-cultured with BMSC) that were treated with ixazomib with 0-10 micromolar mavorixafor. As can be seen, mavorixafor enhances the apoptosis efficacy of ixazomib. Timeframe of assay: 72 h.
[0041] FIG. 26: % apoptotic cells (WM cells cultured in absence or presence of BMSC) treated with ixazomib and 0-10 micromolar mavorixafor. Ixa = Ixazomib; Mav = Mavorixafor.
[0042] FIG. 27: Mavorixafor synergizes with ixazomib to inhibit BM stroma-induced IgM hypersecretion in WM cells. Ixa = Ixazomib; Mav = Mavorixafor.
[0043] FIG. 28: Mavorixafor enhances apoptosis of lymphoma and leukemia cells when combined with venetoclax or ibrutinib. Panel (A) shows apoptosis of OCI-LY19 (DLBCL) cells. Panel (B) shows DOHH2 (FL) cells treated with mavorixafor in combination with venetoclax. Panel (C) shows apoptosis of OCI-LY19 (DLBCL) cells, DOHH2 (FL) cells (Panel (D)), and MEC-1 (CLL) cells (Panel (E)) treated with mavorixafor in combination
with ibrutinib. Combination of mavorixafor with venetoclax or ibrutinib significantly increased apoptosis in lymphoma and leukemia cells compared to ibrutinib or venetoclax alone in the majority of dose combinations.
[0044] FIG. 29: Apoptosis of lymphoma cells treated with venetoclax or ibrutinib with or without BMSC coculture. Apoptosis of OCI-LY19 (DLBCL) cells (A), D0HH2 (FL) cells (B) and MINO (MCL) cells (C) are shown with or without coculture with HS-27A BMSCs in response to venetoclax. Apoptosis of DOHH2 (FL) cells with or without coculture with HS- 27 A BMSCs in response to ibrutinib (D). P values < 05 are considered statistically significant and set as follows: ns, not significant; * — P< 05; ** — P<.01; *** — P< 001.
[0045] FIG. 30: Apoptosis of lymphoma cells after treatment with venetoclax or ibrutinib ± mavorixafor with or without BMSC coculture. Apoptosis of OCI-LY19 (DLBCL) cells (A), D0HH2 (FL) cells (B), MINO (MCL) cells (C) with or without coculture with HS-27A BMSCs in the presence of venetoclax. Apoptosis of D0HH2 (FL) cells with or without coculture with HS-27A BMSCs in the presence of ibrutinib (D). These data show' that mavorixafor restores sensitivity of lymphoma cells to venetoclax and ibrutinib in BMSC cocultures. P values <.05 are considered statistically significant and set as follows: ns, not significant; * — P< 05; ** — P< 01; *** — P< 001.
[0046] FIG. 31: Cell migration of lymphoma cells to CXCL12 with or without mavorixafor pretreatment. Effects of increasing concentrations of mavorixafor on migration of OCI-LY19 (DLBCL) cells (A), D0HH2 (FL) cells (B) toward CXCL12. P values <.05 are considered statistically significant and set as follows: ns, not significant; * — P< 05; ** — p< 0i; **** — P< 0001. These data suggest that mavorixafor prevents the homing of lymphoma cells to protective niches.
[0047] FIG. 32: the top panel shows apoptosis of Waldenstrom’s Macroglobulinemia (WM) cells (MWCL-1; MYD88L265P-CXCR4WT) exposed to venetoclax with or without Compound 3. The botom panel shows apoptosis of WM cells exposed to venetoclax at 3.2 nM grown in the presence or absence of bone marrow stromal cells (BMSC) with or without Compound 3. Compound 3 successfully overcame BMSC-induced resistance of the WM cells to venetoclax to restore apoptotic efficacy. Venetoclax is not cytotoxic to BMSCs at concentrations tested. Compound 3 alone does not induce apoptosis at 5 pM. Vene: venetoclax. BMSC: Bone Marrow Stroma Cell line HS27A. Time frame of assay: 48 h.
[0048] FIG. 33: the top panel shows apoptosis of Waldenstrom’s Macroglobulinemia (WM) cells (MWCL-1; MYD88L265P-CXCR4WT) exposed to zanubrutinib wdth or without
Compound 3. The botom panel shows apoptosis of WM cells exposed to zanubrutinib
grown in the presence or absence of bone marrow stromal cells (BMSC) with or without Compound 3. Compound 3 successfully overcame BMSC-induced resistance of the WM cells to zanubrutinib to restore apoptotic efficacy. Zanubrutinib is not cytotoxic to BMSCs at concentrations tested. Compound 3 alone does not induce apoptosis at 5 pM. Zanub: zanubrutinib. BMSC: Bone Marrow Stroma Cell line HS27A. Time frame of assay: 72 h.
[0049] FIG. 34: the top panel shows inhibition of BMSC-induced IgM hypersecretion in WM cells (MWCL-1; MYD88L265P-CXCR4WT) by Compound 3. The bottom panel shows inhibition of BMSC-induced TgM hypersecretion in WM cells with or without zanubrutinib.
[0050] FIG. 35: inhibition of CXCL12-CXCR4 mediated migration in WM cells by Compound 3. WM: Waldenstrom’s Macroglobulinemia (MWCL-1; MYD88L265P- CXCR4WT). Time frame of assay: 4 h.
[0051] FIG. 36: the top panel shows that Compound 3 synergizes with ibrutinib to induce apoptosis in DLBCL cells (OCI-LY19). Higher concentrations of ibrutinib (8 pM) further synergizes with Compound 3 (2-5 pM) to induce 60% apoptosis in DLBCL cells (data not shown). The bottom panel shows that Compound 3 synergizes with venetoclax to induce apoptosis in DLBCL cells (OC1-LY19). Time frame of assays: 72 h.
[0052] FIG. 37: the top panel shows that Compound 3 overcomes BM stroma-induced resistance of DLBCL cells (OCI-LY19) to venetoclax. Compound 3 successfully overcame BMSC-induced resistance of the DLBCL cells to venetoclax to restore apoptotic efficacy. Compound 3 and Venetoclax are not cytotoxic to BMSCs at concentrations tested. Time frame of assay: 72 h. The bottom panel shows inhibition of CXCL12-CXCR4 mediated migration in DLBCL cells (OCI-LY19) by Compound 3. Time frame of assay: 4 h.
[0053] FIG. 38: the top panel shows that Compound 3 synergizes with ibrutinib to induce apoptosis in CLL cells (MEC-1). The bottom panel shows that Compound 3 synergizes with zanubrutinib to induce apoptosis in CLL cells (MEC-1). Time frame of assays: 72 h.
[0054] FIG. 39: Compound 3 synergizes with venetoclax to induce apoptosis in CLL cells (MEC-1). Time frame of assay: 72 h.
DETAILED DESCRIPTION OF CERTAIN EMBODIMENTS OF THE INVENTION
[0055] Waldenstrom’s macroglobulinemia (WM) is a distinct B-cell lymphoproliferative disorder characterized by the proliferation of lymphoplasmacytic cells in the bone marrow in other organs, along with elevated serum levels of monoclonal immunoglobulin M (IgM) gammopathy (Owen 2003; Treon 2013).
[0056] WM is sometimes referred to as a lymphoplasmacytic lymphoma (LPL) with an associated monoclonal IgM paraprotein. In WM, there is a malignant change to the B-cell in the late stages of maturing, and it continues to proliferate into a clone of identical cells, primarily in the bone marrow but also in the lymph nodes and other tissues and organs of the lymphatic system.
[0057] Under the microscope, WM cells have characteristics of both B-lymphocytes and plasma cells, and they are called lymphoplasmacytic cells. For that reason, WM is classified as a type of non-Hodgkin’s lymphoma called lymphoplasmacytic lymphoma (LPL). About 95% of LPL cases are WM; the remaining 5% do not secrete IgM and consequently are not classified as WM. WM is a very rare disease - only about 1,500 patients are diagnosed with it each year in the US. For reference, approximate normal levels of IgM are described, e.g., in Gonzalez-Quintela et al. (2007) Clinical and Experimental Immunology 151: 42-50. Normal levels are approximately: 70 mg/190 ml for males; and 80-250 mg/100 ml for females. See also “Range of normal serum immunoglobulin (IgG, IgA and IgM) values in Nigerians,” Oyeyinko et al., Afr J Med Med Sci 1984, Sep-Dec; 13(3-4): 169-76. Mean values of IgM varied from 65 to 132 mg/100 ml in the males and from 96 to 114 mg/100 ml in the females.
[0058] For men, normal hemoglobin levels are about 13.5 to 17.5 grams per deciliter; for women, 12.0 to 15.5 grams per deciliter.
[0059] As a result of proliferation in the bone marrow and other sites, the lymphoplasmacytic cells of WM may interfere with normal functioning. In the bone marrow where blood cells are produced, the WM cells “crowd out” the normal blood cells and may lead to a reduction in normal blood counts; in the lymph nodes and other organs, the WM cells may lead to enlargement of these structures and other complications.
[0060] Somatic mutation in myeloid differentiation primary response 88 (MYD88) is found in over 90% of patients with WM. Mutations in chemokine (C-X-C motif) receptor 4 (CXCR4) are the next most common mutations and found to be present in 43% of patients with WM (Xu 2016). Published pivotal clinical studies conducted with ibrutinib have reported MYD88 and CXCR4 mutation status affected responses to ibrutinib. In WM, three genomic groups have been delineated on the basis of clinical manifestations and survival: 1) MYD88L265 CXCR4WT [with WT indicating wild type], 2) MYD88L265PCXCR4WHIM [with WHIM indicating warts, hypogammaglobulinemia, infections, and myelokathexis], and 3) MYD88WTCXCR4WT. WHIM-like mutations result in a gain of function in CXCR4, which in turn decreases chemokine (C-X-C motif) 12 (CXCL12) mediated receptor down regulation
and ultimately inhibits egress of cells bearing the mutant CXCR4 from sequestered areas in bone marrow and lymph nodes (Lei 2016; Majumdar 2018). These findings affirm an important role for MYD88 and CXCR4 somatic mutations in the pathogenesis of tumors (Treon 2015 [2]). In the ibrutinib published studies in treatment-naive and previously treated WM patients, the very good partial response (VGPR) and major response (defined as complete response +VGPR + partial response) rates were highest among patients with MYD88L26’PCXCR4WT and significantly lower for those with MYD88L265PCXCR4WHIM. The CXCR4WHIM mutations have been associated with more aggressive disease features, such as higher IgM levels and bone marrow involvement.
[0061] Other somatic mutations associated with WM, although with substantially lower frequencies of about 3%-10%, have been identified. These include CD79B; HIST1HH1E; MYBPP1A, ARID1A; HIST1HH1B; TP53; and MLL2, as well as patients with more than one mutation, including TP53/CD79B; RAG2/ARID1A; IST1HH1E/IST1HH1B. Jiminez et al. (2015) Blood 126:2971; Poulain et al. (2016) Blood 128:4092; Hunter et al. (2014) Blood 123:1637; each of which is hereby incorporated by reference.
[0062] In some embodiments, the present invention provides a method of treating Waldenstrom’s macroglobulinemia (WM) that bears a somatic mutation and which is wild type in the CXCR4 receptor (CXCR4WT). Without wishing to be bound by theory, it is believed that WM having upregulation of wild type CXCR4 develops resistance to ibrutinib and that co-administration with a CXCR4 inhibitor such as mavorixafor will provide improved treatment outcomes for such patients.
[0063] Chemokines are major regulators of cell trafficking and adhesion. The chemokine CXCL12 (stromal cell-derived factor-la) is normally expressed on hematopoietic cells such as hematopoietic stem cells (HSCs), T cells, B cells, monocytes and macrophages, neutrophils, and eosinophils (Chatterjee 2014; Nagase 2000). CXCL12 has potent chemotactic activity for lymphocytes and myeloid-derived suppressor cells and is important in homing of HSCs to the bone marrow. When CXCL12 activates CXCR4, it enhances and sustains AKT, extracellular signal-regulated kinase, and Bruton’s tyrosine kinase (BTK) signaling pathways, as well as increases cell migration, adhesion, growth, and survival of WM cells (Cao 2014). The chemokine CXCL12 binds primarily to CXC receptor 4 (CXCR4; CD 184). The binding of CXCL12 to CXCR4 induces intracellular signaling through several divergent pathways initiating signals related to chemotaxis, cell survival and/or proliferation, increase in intracellular calcium, and gene transcription. CXCR4 is expressed on multiple cell types including lymphocytes, HSCs, endothelial and epithelial
cells, and cancer cells. The CXCL12/CXCR4 axis is involved in tumor progression, angiogenesis, metastasis, and survival. This pathway is a target for the development of therapeutic agents that can block the CXCL12/CXCR4 interaction or inhibit downstream intracellular signaling.
[0064] In WHIM syndrome, the gain-of-function mutation in CXCR4 results in decreased release of leukocytes into the bloodstream. Treatment with a CXCR4 antagonist has been shown to mobilize leukocytes to beneficially impact the characteristic lymphopenia and leukopenia observed in WHIM patients (Liu 2015; Dale 201 1).
[0065] At least 40 different nonsense and frameshift mutations in the C-terminal domain of CXCR4 have been described in WM (Poulain 2016; Xu 2016; Stone 2004) The nonsense mutations truncate the distal 15- to 20 amino acid region and the frameshift mutations comprise a region of up to 40 amino acids in the C-terminal domain (Hunter 2014). Nonsense and frameshift mutations are almost equally divided among WM patients. The most common CXCR4 mutation in WM is a nonsense mutation of S338X. The presence of CXCR4 somatic mutations can affect disease presentation in WM. Patients with CXCR4 mutations present with a significantly lower rate of adenopathy, and those with CXCR4 nonsense mutations have an increased bone marrow disease burden, serum IgM levels, and/or risk of symptomatic hyperviscosity (Stone 2004; Treon 2014).
[0066] Without wishing to be bound by theory, it is believed that WM develops resistance to BTK inhibitors and other therapeutics via association with bone marrow stroma cells (BMSCs). CXCL12 produced in BMSCs induce a chemotactic response through CXCR4 promoting homing of malignant WM cells to bone marrow (BM). Hypersecretion of CXCL12 and IL-6 in BM promotes survival and growth and confers resistance of WM cells to chemotherapeutic agents. Mavorixafor studies support the potential of CXCR4 antagonism to work synergistically with BTK inhibitors to overcome BMSC-induced resistance of WM cells to chemotherapeutics.
[0067] Accordingly, effective CXCR4 antagonism by mavorixafor provides a significant benefit in patients with WM.
[0068] The incidence of WM is approximately 3 per million people per year with 1400 new cases diagnosed in the United States (US) each year (Fonseca 2007; Groves 1998). The median age at the time of diagnosis is 70 years. Less than 10% of patients are under 50 years of age, and approximately 60% are males (Castillo 2015; Pophali 2018). Waldenstrom’s macroglobulinemia is much more common in Caucasians than in other ethnic groups.
Specifically, it is uncommon in blacks, who make up approximately 5% of cases, and those of Mexican descent (Fonseca 2007).
[0069] In a study published by Varettoni, the median treatment-free survival was significantly shorter in asymptomatic WM patients harboring a CXCR4 mutation at diagnosis (median 51 months) than in those with wild type CXCR4 (median not reached). In multivariate analysis, CXCR4 mutation was an independent prognostic factor for progression from asymptomatic to symptomatic WM requiring therapy (Varettoni 2017).
[0070] Waldenstrom’s macroglobulinemia patients are often treated with rituximab, an anti-CD20 antibody, as monotherapy or in combination with alkylating agents (bendamustine and cyclophosphamide) or nucleoside analogues (fludarabine and cladribine). Other novel therapies include BTK inhibitors (such as ibrutinib, acalabrutinib and zanubrutinib), proteasome inhibitors (ixazomib, bortezomib and carfilzomib), thalidomide, and everolimus (Buske 2013; Dimopoulos 2014; Treon 2015 [2]; Owen 2014; Dimopoulos 2007; Olszewski 2016). Even though these treatments show some activity, they are not curative, and a standard of care has not been established for WM (Dimopoulos 2017). Therefore, new and/or additional therapeutic options are needed.
[0071] Ibrutinib has been approved as a single agent to treat WM in both US and European Union (EU) (ibrutinib (IMBRUVICA®)). In the US, ibrutinib can be used in any line of treatment while in the EU, ibrutinib is approved for patients who have received at least one prior therapy, or in first-line treatment for patients unsuitable for chemo-immunotherapy. The ibrutinib monotherapy and rituximab combination pivotal trials have identified genetic mutation patients who have not benefited to the same extent of those patients without genetic mutations. One specific population identified with a remaining unmet medical need is the double mutation, MYD88L265P CXCR4WIIIM population, estimated at approximately 27% of the WM population (Treon 2015 [1], Treon 2018 [1]; Hunter 2014). Patients with the double mutations had a significantly reduced VGPR (9.5%) as compared with patients with the MYD88L265P CXC 4W I mutations (44.4%) (Treon 2015 [2]; Treon 2018 [2]).
[0072] X4P-001 (mavorixafor) is an orally bioavailable, small molecule inhibitor of
CXCR4. It has now been found that CXCR4 inhibitors such as mavorixafor (X4P-001), or a pharmaceutically acceptable salt thereof or pharmaceutical composition thereof, as described in greater detail below, is useful as a combination therapy with one or more other therapeutic agents described herein. Accordingly, in one aspect, the present invention provides a method of treating a cancer, such as those described herein, by administering to a patient in need thereof an effective amount of mavorixafor, or a pharmaceutically acceptable salt thereof or
pharmaceutical composition thereof, and comprising co-administering simultaneously or sequentially an effective amount of one or more additional therapeutic agents, such as those described herein. In some embodiments, the method includes co-administering one additional therapeutic agent. In some embodiments, the method includes co-administering two additional therapeutic agents. In some embodiments, the combination of mavorixafor and the additional therapeutic agent or agents acts synergistically to prevent or reduce immune escape and/or angiogenic escape of the cancer. In some embodiments, the patient has previously been administered another anticancer agent, such as an adjuvant therapy or immunotherapy. In some embodiments, the cancer is refractory.
[0073] In some embodiments, mavorixafor or a pharmaceutically acceptable salt thereof or pharmaceutical composition thereof is used in combination with an approved cancer therapy such as radiation, a chemotherapeutic, or an immunotherapy or targeted therapeutic. In some embodiments, the approved cancer therapy is chemotherapy, a targeted drug, a biological therapy, plasmapheresis (plasma exchange), stem cell transplant, or radiation therapy.
[0074] In some embodiments, the present invention provides a method of treating a cancer such as a B-cell disorder, wherein mavorixafor replaces the use of tocilizumab (anti- IL6 monoclocal antibody); and wherein mavorixafor is used for treatment of the B-cell disorder, comprising administering to a patient in need thereof an effective amount of mavorixafor, or a pharmaceutically acceptable salt thereof.
[0075] In one aspect, the present invention provides a method of treating a cancer in a patient in need thereof, comprising administering to the patient an effective amount of mavorixafor, or a pharmaceutically acceptable salt thereof; in combination with an effective amount of BTK inhibitor, BTK degrader, BCL-2 inhibitor, BH3 mimetic, or proteasome inhibitor or a pharmaceutically acceptable salt thereof; and wherein the cancer includes a somatic mutation and is CXCR4WT (with WT indicating wild type). In some embodiments, the somatic mutation is a MYD88 mutation such as MYD88L265. In some embodiments, the cancer is MYD88w rCXCR4w l . In some embodiments, the cancer overexpresses CXCR4.
[0076] In some embodiments, the BTK inhibitor is selected from ibruitinib, acalabrutinib, zanubrutinib, tirabrutinib, evobrutinib, fenebrutinib, poseltinib, vecabrutinib, spebrutinib, LCB 03-0110, LFM-A13, PCI 29732, PF 06465469, (-)- Terreic acid, BMX-IN-1, BI-BTK-1, BMS-986142, CGI-1746, GDC-0834, olmutinib, PLS-123, PRN1008, RN-486, LOXO-305 (pirtobrutinib), and ARQ-531 (nemtabrutinib; MK-1026).
[0077] In some embodiments, the BTK inhibitor is selected from tirabrutinib, evobrutinib, fenebrutinib, poseltinib, vecabrutinib, spebrutinib, LCB 03-0110, LFM-A13, PCI 29732, PF 06465469, (-)-Terreic acid, BMX-IN-1, BI-BTK-1, BMS-986142, CGI-1746, GDC-0834, olmutinib, PLS-123, PRN1008, RN-486, LOXO-305 (pirtobrutinib), and ARQ- 531 (nemtabrutinib; MK-1026).
[0078] In some embodiments, the cancer is a B-cell disorder such as WM.
[0079] In some embodiments, the patient has previously undergone treatment with a BTK inhibitor, BTK degrader, BCT-2 inhibitor, BH3 mimetic, or proteasome inhibitor. In some embodiments, the cancer is refractory or resistant to the BTK inhibitor, BTK degrader, BCL- 2 inhibitor, BH3 mimetic, or proteasome inhibitor. In some embodiments, the patient has undergone one previous treatment with a BTK inhibitor, BTK degrader, BCL-2 inhibitor, BH3 mimetic, or proteasome inhibitor, but has not been treated with a CXCR4 inhibitor, e.g., mavorixafor or a pharmaceutically acceptable salt thereof.
[0080] In some embodiments, the mavorixafor or pharmaceutically acceptable salt thereof is administered in an amount effective to reduce IL-6 overexpression in WM cells.
[0081] In some embodiments, the mavonxafor or pharmaceutically acceptable salt thereof is administered in an amount effective to reduce CXCL12-induced migration and adhesion of WM cells.
[0082] In some embodiments, the mavorixafor or pharmaceutically acceptable salt thereof is administered in an amount effective to increase apoptosis and decrease viability of WM cells.
[0083] In some embodiments, the mavorixafor or pharmaceutically acceptable salt thereof synergizes with a co-administered B cell agent to increase apoptosis and decrease viability of WM cells.
[0084] In some embodiments, the mavonxafor or pharmaceutically acceptable salt thereof is administered in an amount effective to decrease relative IgM release.
[0085] In some embodiments, the mavorixafor or pharmaceutically acceptable salt thereof is administered in an amount effective to overcome bone marrow stroma-induced resistance of WM cells to BTK inhibitor treatment.
[0086] In some embodiments, the mavorixafor or pharmaceutically acceptable salt thereof is administered in an amount effective to overcome bone marrow stroma-induced resistance due to IL6 overexpression and IgM hypersecretion.
[0087] In some embodiments, the cancer is refractory or relapsed.
[0088] In some embodiments, the cancer is refractory, relapsed, or resistant with respect to the BTK inhibitor, BTK degrader, BCL-2 inhibitor, BH3 mimetic, or proteasome inhibitor. [0089] In some embodiments, the cancer is a lymphoma. In some embodiments, the cancer is a Central Nervous System (CNS) lymphoma. In some embodiments, the cancer is a leukemia. In some embodiments, the leukemia is multiple myeloma (MM), acute lymphocytic leukemia (ALL), myeloid cell leukemia 1 (MCL-1), small lymphocytic lymphoma (SLL), or chronic lymphocytic leukemia (CLL).
[0090] In some embodiments, the cancer is non-Hodgkin’s lymphoma. In some embodiments, the cancer is Hodgkin’s lymphoma.
[0091] In some embodiments, the cancer is diffuse large B cell lymphoma (DLBCL), follicular lymphoma (FL), mantle cell lymphoma (MCL), marginal zone lymphoma (MZL), or chronic lymphocytic leukemia (CLL).
[0092] In one aspect, the present invention provides a method of treating Waldenstrom’s macroglobulinemia (WM) in a patient in need thereof, comprising administering to the patient an effective amount of mavorixafor, or a pharmaceutically acceptable salt thereof; in combination with an effective amount of BTK inhibitor, BTK degrader, BCL-2 inhibitor, BH3 mimetic, or proteasome inhibitor or a pharmaceutically acceptable salt thereof; and wherein the WM includes a somatic mutation and is CXCR4WT (with WT indicating wild type). In some embodiments, the somatic mutation is MYD88L2fi5. In some embodiments, the WM is MYD88WTCXCR4WT. In some embodiments, the WM overexpresses CXCR4.
[0093] Additional agents that may be co-administered with mavorixafor are described in WO 2018/237158, the entire contents of which are hereby incorporated by reference.
[0094] The BTK inhibitor, BTK degrader, BCL-2 inhibitor, BH3 mimetic, or proteasome inhibitor may be simultaneously or sequentially administered with the mavorixafor or a pharmaceutically acceptable salt thereof. In some embodiments, the mavonxafor and the BTK inhibitor, BTK degrader, BCL-2 inhibitor, BH3 mimetic, or proteasome inhibitor are co-administered, for example, as part of the same pharmaceutical composition. In some embodiments, the mavorixafor and the BTK inhibitor, BTK degrader, BCL-2 inhibitor, BH3 mimetic, or proteasome inhibitor are co-administered as part of separate pharmaceutical compositions.
[0095] In some embodiments, a BTK inhibitor is co-administered with mavorixafor or a pharmaceutically acceptable salt thereof. In some embodiments, the BTK inhibitor is ibrutinib, acalabrutinib, or zanubrutinib; or a pharmaceutically acceptable salt thereof.
[0096] The chemical name for ibrutinib is l-[(3R)-3-[4-amino-3-(4-phenoxyphenyl)- lHpyrazolo[3,4-d]pyrimidin-l-yl]-l-piperidinyl]-2-propen-l-one and has the following structure:
[0097] In the United States, IMBRUVICA® (ibrutinib) capsules for oral administration are available in the following dosage strengths: 70 mg and 140 mg. Each capsule contains ibrutinib (active ingredient) and the following inactive ingredients: croscarmellose sodium, magnesium stearate, microcrystalline cellulose, sodium lauryl sulfate. The capsule shell contains gelatin, titanium dioxide, yellow iron oxide (70 mg capsule only), and black ink. Ibrutinib tablets for oral administration are available in the following dosage strengths: 140 mg, 280 mg, 420 mg, and 560 mg. Each tablet contains ibrutinib (active ingredient) and the following inactive ingredients: colloidal silicon dioxide, croscarmellose sodium, lactose monohydrate, magnesium stearate, microcrystalline cellulose, povidone, and sodium lauryl sulfate. The film coating for each tablet contains ferrosoferric oxide (140 mg, 280 mg, and 420 mg tablets), polyvinyl alcohol, polyethylene glycol, red iron oxide (280 mg and 560 mg tablets), talc, titanium dioxide, and yellow iron oxide (140 mg, 420 mg, and 560 mg tablets).
[0098] Ibrutinib (Ibruvica® Pharmacyclics; AbbVie) is approved for:
• Treatment of mantle cell lymphoma in adult patients who have received at least one prior therapy.
• Treatment of chronic lymphocytic leukemia (CLL) or small lymphocytic lymphoma (SLL) [both including CLL and SLL with 17p deletion
• Treatment of Waldenstrom’s macroglobulinemia.
• Marginal zone lymphoma (MZL) who require systemic therapy and have received at least one prior anti-CD20-based therapy
• Chronic graft versus host disease (cGVHD) after failure of one or more lines of systemic therapy
[0099] Dosage:
• MCL and MZL: 560 mg taken orally once daily.
• CLL/SLL, WM, and cGVHD: 420 mg taken orally once daily.
[00100] Dose should be taken orally with a glass of water. Do not open, break, or chew the capsules. Do not cut, crush, or chew the tablets.
[00101] In the United States, acalabrutinib (Calquence® AstraZeneca Pharmaceuticals) is approved for:
• Treatment of mantle cell lymphoma in adult patients who have received at least one prior therapy:
• Treatment of chronic lymphocytic leukemia (CLL) or small lymphocytic lymphoma (SLL).
[00102] Recommended dose is 100 mg orally approximately every 12 hours; swallow whole with water and with or without food.
[00103] In the United States, zanubrutinib (Brukinsa® Beigene, USA) is approved for:
• Treatment of mantle cell lymphoma in adult patients who have received at least one prior therapy.
[00104] Recommended dose: 160 mg orally twice daily or 320 mg orally once daily; swallow whole with water and with or without food. Reduce dose in patients with severe hepatic impairment.
[00105] In one aspect, the present invention provides a method of treating Waldenstrom’s macroglobulinemia (WM) in a patient in need thereof, comprising administering to the patient an effective amount of mavorixafor, or a pharmaceutically acceptable salt thereof; in combination with an effective amount of a BTK inhibitor, or a pharmaceutically acceptable salt thereof; and wherein the WM bears one or more somatic mutations and is CXCR4WT.
[00106] In another aspect, the present invention provides a method of determining whether a patient’s WM will respond to treatment, comprising:
(a) testing a biological sample taken from the patient for a CXCR4 mutation and optionally a MYD88 mutation;
(b) if the patient’s WM does not bear a CXCR4 mutation, selecting the patient for treatment with a CXCR4 inhibitor.
[00107] In some embodiments, the method further comprises the step of treating the patient with a combination of an effective amount of mavorixafor, or a pharmaceutically
acceptable salt thereof; and an effective amount of a BTK inhibitor, BTK degrader, BCL-2 inhibitor, BH3 mimetic, or proteasome inhibitor.
[00108] In some embodiments, the BTK inhibitor is selected from ibruitinib, acalabrutinib, zanubrutinib, tirabrutinib, evobrutinib, fenebrutinib, poseltinib, vecabrutinib, spebrutinib, LCB 03-0110, LFM-A13, PCI 29732, PF 06465469, (-)-Terreic acid, BMX-IN- 1, BI-BTK-1, BMS-986142, CGI-1746, GDC-0834, olmutinib, PLS-123, PRN1008, RN-486, LOXO-305 (pirtobrutinib), and ARQ-531 (nemtabrutinib; MK-1026).
[00109] In some embodiments, the BTK inhibitor is selected from tirabrutinib, evobrutinib, fenebrutinib, poseltinib, vecabrutinib, spebrutinib, LCB 03-0110, LFM-A13, PCI 29732, PF 06465469, (-)-Terreic acid, BMX-IN-1, BI-BTK-1, BMS-986142, CGI-1746, GDC-0834, olmutinib, PLS-123, PRN1008, RN-486, LOXO-305 (pirtobrutinib), and ARQ- 531 (nemtabrutinib; MK-1026).
[00110] In some embodiments, the one or more somatic mutations do not comprise a CXCR4(S338X) somatic mutation.
[00111] In some embodiments, the WM further comprises a somatic MYD88 mutation and optionally a somatic deletion associated with B-cell lymphomagenesis.
[00112] In some embodiments, the MYD88 mutation is MYD88L265P.
[00113] In some embodiments, the BTK inhibitor is other than ibrutinib, acalabrutinib, or zanubrutinib, or a pharmaceutically acceptable salt thereof.
[00114] In some embodiments, the BTK inhibitor is other than ibrutinib or a pharmaceutically acceptable salt thereof.
[00115] In some embodiments, the patient has previously received at least one course of treatment with a BTK inhibitor, or a pharmaceutically acceptable salt thereof, before treatment with mavorixafor, or a pharmaceutically acceptable salt thereof.
[00116] In some embodiments, the patient is treatment naive, i.e., the patient has not received a previous treatment for WM. In some embodiments, the patient has not received previous treatment with a BTK inhibitor (such as ibrutinib), or a pharmaceutically acceptable salt thereof. In some embodiments, the patient has not received previous treatment with a BTK inhibitor (such as ibrutinib), or a pharmaceutically acceptable salt thereof, and has not received previous treatment with mavorixafor, or a pharmaceutically acceptable salt thereof.
[00117] In some embodiments, the patient’s WM is resistant to treatment with a BTK inhibitor.
[00118] In some embodiments, the patient has previously received at least one course of treatment with a BTK inhibitor, such as ibrutinib, acalabrutinib, or zanubrutinib, before treatment with mavorixafor or a pharmaceutically acceptable salt thereof.
[00119] In some embodiments, the patient’s WM has show n disease progression.
[00120] In another aspect, the present invention provides a method of treating Waldenstrom’s macroglobulinemia (WM) in a patient in need thereof, comprising administering to the patient an effective amount of mavorixafor, or a pharmaceutically acceptable salt thereof; in combination with an effective amount of a BTK inhibitor selected from ibrutinib, acalabrutinib, zanubrutinib, tirabrutinib, evobrutinib, fenebrutinib, poseltinib, vecabrutinib, spebrutinib, LCB 03-0110, LFM-A13, PCI 29732, PF 06465469, (-)-Terreic acid, BMX-IN-1, BI-BTK-1, BMS-986142, CGI-1746, GDC-0834, olmutinib, PLS-123, PRN1008, RN-486, LOXO-305 (pirtobrutinib), and ARQ-531 (nemtabrutinib; MK-1026); or a pharmaceutically acceptable salt thereof; and wherein the WM has a CXCR4WT genomic status (with WT indicating wild type).
[00121] In another aspect, the present invention provides a method of treating Waldenstrom’s macroglobulinemia (WM) in a patient in need thereof, comprising administering to the patient an effective amount of mavorixafor, or a pharmaceutically acceptable salt thereof; in combination with an effective amount of a BTK inhibitor selected from tirabrutinib, evobrutinib, fenebrutinib, poseltinib, vecabrutinib, spebrutinib, LCB 03- 0110, LFM-A13, PCI 29732, PF 06465469, (-)-Terreic acid, BMX-IN-1, BI-BTK-1, BMS-986142, CGI-1746, GDC-0834, olmutinib, PLS-123, PRN1008, RN-486, LOXO-30 (pirtobrutinib), and ARQ-531 (nemtabrutinib; MK-1026); or a pharmaceutically acceptable salt thereof; and wherein the WM has a CXCR4WT genomic status (with WT indicating wild type).
[00122] In some embodiments, the WM is selected from one of the following genomic groups: 1) MYD88L265 CXCR4WI (with WT indicating wild type), and 2)
MYD88WTCXCR4WT.
[00123] In some embodiments, the MYD88L265 mutation is MYD88L265P.
[00124] In some embodiments, the mavorixafor or a pharmaceutically acceptable salt thereof is co-administered with a BTK inhibitor selected from evobrutinib, LOXO-305, and ARQ-531, or a pharmaceutically acceptable salt thereof.
[00125] In some embodiments, the patient has previously received at least one course of treatment with a BTK inhibitor, or a pharmaceutically acceptable salt thereof, before treatment with mavorixafor, or a pharmaceutically acceptable salt thereof.
[00126] In some embodiments, the patient’s WM is resistant to treatment with a BTK inhibitor.
[00127] In some embodiments, the patient has previously received at least one course of treatment with ibrutinib before treatment with mavorixafor or a pharmaceutically acceptable salt thereof.
[00128] In some embodiments, the patient’s WM has shown disease progression.
[00129] In another aspect, the present invention provides a method of treating Waldenstrom’s macroglobulinemia (WM) in a patient in need thereof, comprising administering to the patient an effective amount of mavorixafor, or a pharmaceutically acceptable salt thereof; in combination with an effective amount of a BCL-2 inhibitor or BH3-mimetic; or a pharmaceutically acceptable salt thereof; and wherein the WM has a CXCR4WT genomic status (with WT indicating wild type).
[00130] In some embodiments, the BCL-2 inhibitor or BH3 mimetic is selected from venetoclax, BGB-11417, LOXO-338, LP-108, S55746, APG-2575, APG-1252 (pelcitoclax), AT-101, TQB3909, obatoclax, GDC-0199, ABT-737, and navitoclax (ABT-263); or a pharmaceutically acceptable salt thereof.
[00131] In some embodiments, the mavorixafor or pharmaceutically acceptable salt thereof is co-administered with venetoclax or a pharmaceutically acceptable salt thereof.
[00132] In some embodiments, the mavorixafor or pharmaceutically acceptable salt thereof is co-administered with ABT-737 or navitoclax (ABT-263); or a pharmaceutically acceptable salt thereof or a pharmaceutically acceptable salt thereof.
[00133] In some embodiments, the WM is selected from one of the following genomic groups: 1) MYD88L265 CXC 4W I (with WT indicating wild type), and 2) MYD88WTCXCR4WT.
[00134] In some embodiments, the MYD88L265 mutation is MYD88L265P.
[00135] In some embodiments, mavorixafor or a pharmaceutically acceptable salt thereof is administered to the patient in a dose of about 100 mg to about 1000 mg per day.
[00136] In some embodiments, mavorixafor or a pharmaceutically acceptable salt thereof is administered to the patient in a dose of about 200 mg to about 600 mg per day.
[00137] In some embodiments, mavorixafor or a pharmaceutically acceptable salt thereof is administered to the patient in a dose of about 200 mg, about 400 mg, or about 600 mg per day.
[00138] In some embodiments, mavorixafor or a pharmaceutically acceptable salt thereof is administered to the patient in a single daily dose (QD).
[00139] In some embodiments, the method provides about a 75-95% percent reduction in IgM from baseline.
[00140] In some embodiments, the method reduces IgM to within 2 times the normal range for a non-diseased adult human (non-WM patient).
[00141] In some embodiments, the mavorixafor, or a pharmaceutically acceptable salt thereof, and the BCL-2 inhibitor, BH3 mimetic, or a pharmaceutically acceptable salt thereof, act synergistically.
[00142] In some embodiments, the method further comprises the step of obtaining a biological sample from the patient and measuring the amount of a disease-related biomarker. [00143] In some embodiments, the biological sample is a blood sample.
[00144] In some embodiments, the disease-related biomarker is selected from circulating CD8+ T cells or the ratio of CD8+ T cells:Treg cells.
[00145] In some embodiments, the disease-related biomarker is IgM and/or Hgb.
[00146] In some embodiments, mavorixafor or a pharmaceutically acceptable salt thereof is administered to the patient in a dose of about 100 mg to about 1000 mg per day. In some embodiments, mavorixafor or a pharmaceutically acceptable salt thereof is administered to the patient in a dose of about 200 mg to about 800 mg per day.
[00147] In some embodiments, mavorixafor or a pharmaceutically acceptable salt thereof is administered to the patient in a dose of about 200 mg to about 600 mg per day.
[00148] In some embodiments, mavorixafor or a pharmaceutically acceptable salt thereof is administered to the patient in a dose of about 200 mg, about 400 mg, or about 600 mg per day.
[00149] In some embodiments, mavorixafor or a pharmaceutically acceptable salt thereof is administered to the patient in a single daily dose (QD).
[00150] In some embodiments, mavorixafor or a pharmaceutically acceptable salt thereof and the BTK inhibitor or a pharmaceutically acceptable salt thereof are administered to the patient in a fasted state.
[00151] In some embodiments, ibrutinib or a pharmaceutically acceptable salt thereof is administered to the patient in a dose of about 70 mg to about 840 per day.
[00152] In some embodiments, ibrutinib or a pharmaceutically acceptable salt thereof is administered to the patient in a dose of about 140 mg to about 420 mg per day.
[00153] In some embodiments, ibrutinib or a pharmaceutically acceptable salt thereof is administered to the patient in a dose of about 140 mg, about 280 mg, or about 420 mg per day.
[00154] In some embodiments, mavorixafor is administered to the patient in a dose of about 200 mg to about 600 mg per day in combination with ibrutinib in a dose of about 140 mg to about 420 mg per day.
[00155] In some embodiments, mavorixafor is administered to the patient in a dose of about 200 mg, about 400 mg, or about 600 mg per day in combination with ibrutinib in a dose of about 140 mg, about 280 mg, or about 420 mg per day.
[00156] In some embodiments, mavorixafor is administered to the patient in a dose of about 200 mg per day in combination with ibrutinib in a dose of about 140 mg, about 280 mg, or about 420 mg per day.
[00157] In some embodiments, mavorixafor is administered to the patient in a dose of about 400 mg per day in combination with ibrutinib in a dose of about 140 mg, about 280 mg, or about 420 mg per day.
[00158] In some embodiments, mavorixafor is administered to the patient in a dose of about 600 mg per day in combination with ibrutinib in a dose of about 140 mg, about 280 mg, or about 420 mg per day.
[00159] In some embodiments, mavorixafor is administered to the patient in a dose of about 200 mg per day in combination with ibrutinib in a dose of about 140 mg per day.
[00160] In some embodiments, mavorixafor is administered to the patient in a dose of about 400 mg per day in combination with ibrutinib in a dose of about 280 mg per day.
[00161] In some embodiments, mavorixafor is administered to the patient in a dose of about 600 mg per day in combination with ibrutinib in a dose of about 420 mg per day.
[00162] In some embodiments, the method provides at least a 50% percent decrease in IgM levels from baseline. In some embodiments, the method provides at least a 10%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 60%, 70%, 75%, 80%, 85%, 90%, 95%, or 98% decrease in IgM levels from baseline. In some embodiments, the method provides about a 50% decrease in IgM levels from baseline. In some embodiments, the method provides about a 10%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 60%, 70%, or 75% decrease in IgM levels from baseline. In some embodiments, the method provides about a 10-20%, 10-25%, 15- 30%, 15-35%, 20-40%, 20-45%, 25-50%, 30-60%, 35-70%, 50-60%, 50-75%, 60-90%, 70- 90%, 80-90%, 80-95%, 80-98%, 85-98%, 90-98%, or 95-98% decrease in IgM levels from baseline.
[00163] In some embodiments, the method reduces IgM and/or Hgb to within 2 times the normal range for a non-diseased adult human (non-WM patient), 1.5 times, 1.25 times, or to within the normal range for a non-diseased adult human.
[00164] In some embodiments, the method decreases Hgb to between 2 times the upper limit of normal (ULN) and the lower limit of normal.
[00165] In some embodiments, mavorixafor, or a pharmaceutically acceptable salt thereof, and the BTK inhibitor, or a pharmaceutically acceptable salt thereof, act synergistically.
[00166] In some embodiments, the dose of the BTK inhibitor, or a pharmaceutically acceptable salt thereof, required for effective treatment is decreased by at least 20% relative to the effective dose of the BTK inhibitor, or a pharmaceutically acceptable salt thereof, as a monotherapy.
[00167] In some embodiments, the method further comprises administering an additional therapeutic agent, such as rituximab or another described herein.
[00168] In some embodiments, the method further comprises the step of obtaining a biological sample from the patient and measuring the amount of a disease-related biomarker. [00169] In some embodiments, the biological sample is a blood sample.
[00170] In some embodiments, the disease-related biomarker is selected from circulating CD8+ T cells or the ratio of CD8+ T cells:Treg cells.
[00171] In some embodiments, the disease-related biomarker is IgM and/or Hgb. In some embodiments, the biomarker is absolute neutrophil count (ANC).
[00172] In some embodiments, the additional therapeutic agent is an immunostimulatory therapeutic compound.
[00173] In some embodiments, the immunostimulatory therapeutic compound is selected from elotuzumab, rmfamurtide, an agonist or activator of a toll-like receptor, or an activator of RORyt.
[00174] In some embodiments, the method further comprises administering to said patient an additional therapeutic agent, such as an immune checkpoint inhibitor. In some embodiments, the method comprises administering to the patient in need thereof three therapeutic agents selected from mavorixafor or a pharmaceutically acceptable salt thereof, a BTK inhibitor, and an immunostimulatory therapeutic compound or immune checkpoint inhibitor.
[00175] In some embodiments, the immune checkpoint inhibitor is selected from nivolumab, pembrolizumab, ipilimumab, avelumab, durvalumab, atezolizumab, or pidilizumab.
[00176] In some embodiments, the additional therapeutic agents are selected from an indoleamine (2,3)-dioxygenase (IDO) inhibitor, a Poly ADP ribose polymerase (PARP)
inhibitor, a histone deacetylase (HDAC) inhibitor, a CDK4/CDK6 inhibitor, or a phosphatidylinositol 3 kinase (PI3K) inhibitor.
[00177] In some embodiments, the IDO inhibitor is selected from epacadostat, mdoximod, capmanitib, GDC-0919, PF-06840003, BMS:F001287, Phy906/KD108, or an enzyme that breaks down kynurenine.
[00178] In some embodiments, the PARP inhibitor is selected from olaparib, rucaparib, or niraparib.
[00179] In some embodiments, the HDAC inhibitor is selected from vorinostat, romidepsin, panobinostat, belinostat, entinostat, or chidamide.
[00180] In some embodiments, the CDK 4/6 inhibitor is selected from palbociclib, ribociclib, abemaciclib or trilaciclib.
[00181] In some embodiments, the method further comprises administering to said patient a third therapeutic agent, such as an immune checkpoint inhibitor. In some embodiments, the method comprises administering to the patient in need thereof three therapeutic agents selected from mavorixafor or a pharmaceutically acceptable salt thereof, a BTK inhibitor, and a third therapeutic agent selected from an indoleamme (2,3)-dioxygenase (IDO) inhibitor, a Poly ADP ribose polymerase (PARP) inhibitor, a histone deacetylase (HDAC) inhibitor, a CDK4/CDK6 inhibitor, or a phosphatidylinositol 3 kinase (PI3K) inhibitor, and an immune checkpoint inhibitor. In some embodiments, the immune checkpoint inhibitor is selected from nivolumab, pembrolizumab, ipilimumab, avelumab, durvalumab, atezolizumab, or pidilizumab.
[00182] In some embodiments, the PI3K inhibitor is selected from idelalisib, alpelisib, taselisib, pictilisib, copanlisib, duvelisib, PQR309, or TGR1202.
[00183] In some embodiments, the method further comprises administering to said patient a platinum-based therapeutic, a taxane, a nucleoside inhibitor, or a therapeutic agent that interferes with normal DNA synthesis, protein synthesis, cell replication, or will otherwise inhibit rapidly proliferating cells.
[00184] In some embodiments, the platinum-based therapeutic is selected from cisplatin, carboplatin, oxaliplatin, nedaplatin, picoplatin, or satraplatin.
[00185] In some embodiments, the taxane is selected from paclitaxel, docetaxel, albuminbound paclitaxel, cabazitaxel, or SID530.
[00186] In some embodiments, the therapeutic agent that interferes with normal DNA synthesis, protein synthesis, cell replication, or will otherwise interfere with the replication of rapidly proliferating cells is selected from trabectedin, mechlorethamine, vincristine,
temozolomide, cytarabine, lomustine, azacitidine, omacetaxine mepesuccinate, asparaginase Erwinia chrysanthemi, eribulin mesylate, capacetrine, bendamustine, ixabepilone, nelarabine, clorafabine, trifluridine, or tipiracil.
[00187] In some embodiments, the patient has a solid tumor. Solid tumors generally comprise an abnormal mass of tissue that typically does not include cysts or liquid areas. In some embodiments, the cancer is Waldenstrom’s macroglobulinemia.
[00188] In some embodiments, the patient has a resectable solid tumor, meaning that the patient’s tumor is deemed susceptible to being removed by surgery. In other embodiments, the patient has an unresectable solid tumor, meaning that the patient’s tumor has been deemed not susceptible to being removed by surgery, in whole or in part.
[00189] In some embodiments, the present invention provides a method for treating refractory cancer in a patient in need thereof comprising administering to a patient in need thereof an effective amount of mavorixafor or a pharmaceutically acceptable salt thereof or pharmaceutical composition thereof, in combination with a BTK inhibitor and optionally further in combination with an additional therapeutic agent such as those described herein.
[00190] In certain embodiments, the patient completed a previous treatment. In some embodiments, the previous treatment is a protein kinase inhibitor. In some embodiments, the previous treatment is a VEGF-R antagonist. In certain embodiments, the previous treatment is an immune checkpoint inhibitor. In some embodiments, the previous treatment is an immune checkpoint inhibitor selected from nivolumab (Opdivo®, Bristol-Myers Squibb), pembrolizumab (Keytruda®, Merck), or ipilumumab (Yervoy®, Bristol-Myers Squibb).
[00191] In some embodiments, the patient experienced disease progression after the previous treatment. In some embodiments, the patient’s cancer, e.g., WM, is resistant or refractory to the previous treatment.
[00192] In some embodiments, mavorixafor, or a pharmaceutically acceptable salt thereof or pharmaceutical composition thereof, is administered to a patient in a fasted state.
CXCR4 Inhibitors
[00193] In certain embodiments, mavorixafor or a pharmaceutically acceptable salt thereof, or another CXCR4 antagonist, is administered in combination with an additional therapeutic agent. In some embodiments, mavorixafor or a pharmaceutically acceptable salt thereof, or another CXCR4 antagonist, is administered in combination with one additional therapeutic agent. In some embodiments, mavorixafor or a pharmaceutically acceptable salt thereof, or another CXCR4 antagonist, is administered in combination with two additional therapeutic agents. In some embodiments, mavorixafor or a pharmaceutically acceptable salt
thereof, or another CXCR4 antagonist, is administered in combination with three or more additional therapeutic agents.
[00194] In some embodiments, a CXCR4 inhibitor is co-administered in the combination therapies disclosed above. The CXCR4 may be administered prior to, concurrently with, or subsequent to administration of the targeted B-cell therapy and the IL-6 modulator.
[00195] In some embodiments, the CXCR4 inhibitor is selected from CXCR4 inhibitors disclosed in WO2017/223229 (including compounds 1-1 through 1-184 disclosed therein),
WO2017/223239 (including compounds 1-1 through 1-229 disclosed therein),
WO2017/223243 (including compounds 1-1 through 1-149 disclosed therein).
W02019/126106 (including compounds 1-1 through 1-69 disclosed therein).
WO2020/264292 (including compounds 1-1 through 1-31 disclosed therein), and
WO2021/263203 (including compounds 1-1 through 1-118 disclosed therein).
[00196] In other embodiments, the CXCR4 inhibitor is selected from the small molecule
CXCR4 inhibitors disclosed in US 7,291,631; US 7,332,605; US 7,354,932; US 7,354,934;
US 7,501,518; US 7,550,484; US 7,723,525; US 7,863,293; US 8,778,967; US 10,322,111; US 7,414,065; US 7,022,717; US 7,084,155; US 7,807,694; US 6,750,348; US 7,169,750; US 7,491,735; and US 7,790,747. The disclosures of the above documents are hereby specifically incorporated herein by reference.
[00197] In some embodiments, the CXCR4 inhibitor is selected from mavorixafor; plerixafor (AMD-3100; Sanofi); locuplumab (BMS-936564/MDX1338, Bristol Myers), a fully human anti-CXCR4 antibody, Kashyap et al. (2015) Oncotarget 7:2809-2822; Motixafortide (BL-8040; BKT-140; BiolineRx) Crees et al. (2021) Blood, 138 (Suppl):475 Abstract 711; POL6326 (balixafortide, Polyphor) Karpova et al. (2017) Journal of Translational Medicine 15:2; PRX177561 (Proximagen) Gravina et al. (2017) Tumor Biology, June 2017: 1-17; USL311 (Upsher-Smith Laboratories) NCT02765165; Burixafor hydrobromide (TG-0054, TaiGen Biotechnology) NCT02478125; LY2510924 (MEDI4736, Eli Lilly); NCT02737072, a CXCR4 Cyclic peptide antagonist; PF06747143 (Pfizer), a CXCR4 humanized IgGl antagonist; BGB— 11417, LOXO-338; LP-108; S55746; APG-257; APG-1252 (pelcitoclax); AT-101; TQB3909; obatoclax; GDC-0199; ABT-737; and navitoclax (ABT-263); or a pharmaceutically acceptable salt thereof.
[00198] In some embodiments, the CXCR4 inhibitor is mavorixafor, plerixafor, ulocuplumab, motixafortide, POL6326, PRX177561, USL311, burixafor (e.g., burixafor HBr), LY2510924, PF06747143, CX549, BPRCX807, TC14012, USL-311, FC131, CTCE- 9908, or GMI 1359; or a pharmaceutically acceptable salt thereof.
[00199] In some embodiments, the CXCR4 inhibitor is selected from one of the following:
Compound 13 or a pharmaceutically acceptable salt thereof.
Co-Administered Therapeutic Agents
[00200] In certain embodiments, mavorixafor or a pharmaceutically acceptable salt thereof, or another CXCR4 antagonist, is administered in combination with an additional therapeutic agent. In some embodiments, mavorixafor or a pharmaceutically acceptable salt thereof, or another CXCR4 antagonist, is administered in combination with one additional therapeutic agent. In some embodiments, mavorixafor or a pharmaceutically acceptable salt thereof, or another CXCR4 antagonist, is administered in combination with two additional therapeutic agents. In some embodiments, mavorixafor or a pharmaceutically acceptable salt thereof, or another CXCR4 antagonist, is administered in combination with three or more additional therapeutic agents.
Kinase Inhibitors
[00201] In some embodiments, the additional therapeutic agent is a kinase inhibitor or VEGF-R antagonist. Approved VEGF inhibitors and kinase inhibitors useful in the present invention include: bevacizumab (Avastin®, Genentech/Roche) an anti-VEGF monoclonal antibody: ramucirumab (Cyramza®, Eli Lilly), an anti-VEGFR-2 antibody and ziv- aflibercept, also known as VEGF Trap (Zaltrap®; Regeneron/Sanofi). VEGFR inhibitors, such as regorafenib (Stivarga®, Bayer); vandetanib (Caprelsa®, AstraZeneca); axitinib (Inlyta®, Pfizer); and lenvatimb (Lenvima®, Eisai); Raf inhibitors, such as sorafenib (Nexavar®, Bayer AG and Onyx); dabrafenib (Tafinlar®, Novartis); and vemurafenib (Zelboraf®, Genentech/Roche); MEK inhibitors, such as cobimetanib (Cotellic®, Exelexis/Genentech/Roche); trametinib (Mekinist®, Novartis); Bcr-Abl tyrosine kinase inhibitors, such as imatinib (Gleevec®, Novartis); nilotinib (Tasigna®, Novartis); dasatinib (Sprycel®, BnstolMyersSquibb); bosutinib (Bosulif®, Pfizer); and ponatinib (Inclusig®, Ariad Pharmaceuticals); Her2 and EGFR inhibitors, such as gefitinib (Iressa®, AstraZeneca); erlotinib (Tarceeva®, Genentech/Roche/ Astellas); lapatinib (Tykerb®, Novartis); afatinib (Gilotrif®, Boehringer Ingelheim); osimertinib (targeting activated EGFR, Tagrisso®, AstraZeneca); and bngatmib (Alunbng®, Anad Pharmaceuticals); c-Met and VEGFR2
inhibitors, such as cabozanitib (Cometriq®, Exelexis); and multikinase inhibitors, such as sunitinib (Sutent®, Pfizer); pazopanib (Votrient®, Novartis); ALK inhibitors, such as crizotinib (Xalkon®, Pfizer); ceritinib (Zykadia®, Novartis); and alectinib (Alecenza®, Genentech/Roche); Bruton’s tyrosine kinase inhibitors, such as ibrutinib (Imbruvica®, Pharmacyclics/Janssen); and Flt3 receptor inhibitors, such as midostaurin (Rydapt®, Novartis).
[00202] Other kinase inhibitors and VEGF-R antagonists that are in development and may be used in the present invention include tivozanib (Aveo Pharmaecuticals); vatalanib (Bayer/Novartis); lucitanib (Clovis Oncology); dovitinib (TKI258, Novartis); Chiauanib (Chipscreen Biosciences); CEP-11981 (Cephalon); linifanib (Abbott Laboratories); neratinib (HKI-272, Puma Biotechnology); radotinib (Supect®, IY5511, Il-Yang Pharmaceuticals, S. Korea); ruxolitinib (Jakafi®, Incyte Corporation); PTC299 (PTC Therapeutics); CP-547,632 (Pfizer); foretinib (Exelexis, GlaxoSmithKline); quizartinib (Daiichi Sankyo) and motesanib (Amgen/T akeda).
BTK Inhibitors
[00203] BTK inhibitors for use in the present invention include those described herein, such as ibruitinib, acalabrutinib, zanubrutinib, tirabrutinib, evobrutinib, fenebrutinib, poseltinib, vecabrutinib, spebrutinib, LCB 03-0110, LFM-A13, PCI 29732, PF 06465469, (-)- Terreic acid, BMX-IN-1, BI-BTK-1, BMS-986142, CGI-1746, GDC-0834, olmutinib, PLS- 123, PRN1008, RN-486, LOXO-305 (pirtobrutinib), and ARQ-531 (nemtabrutinib; MK- 1026); or a pharmaceutically acceptable salt thereof.
BTK Degraders
[00204] Degradation of Bruton’s tyrosine kinase mutants by proteolysis-targeting chimera (PROTAC) for a potential treatment of ibrutinib-resistant non-Hodgkin lymphomas has been reported. PROTAC is a novel strategy for the selective knockdow n of target proteins by small molecules, which utilizes the ubiquitin-protease system to target a specific protein and induce its degradation in the cell. The ubiquitin-protease system (UPS), also known as the ubiquitin- proteasome pathway (UPP), is a common post-translational regulation mechanism that is responsible for protein degradation in normal and pathological states. Ubiquitin, which is highly conserved in eukaryotic cells, is a modifier molecule, composed of 76 amino acids, that covalently binds to and labels target substrates via a cascade of enzymatic reactions involving El, E2, and E3 enzymes. Subsequently, the modified substrate is recognized by the 26S proteasome complex for ubiquitination-mediated degradation. Two El enzymes have been discovered, whereas ~40 E2 enzymes and more than 600 E3 enzymes offer the
functional diversity to govern the activity of many downstream protein substrates. A limited number of E3 ubiquitin ligases have been successfully hijacked for use by small-molecule PROTAC technology, including the Von Hippel-Lindau disease tumor suppressor protein (VHL), the Mouse Double Minute 2 homologue (MDM2), the Cellular Inhibitor of Apoptosis (cIAP), and cereblon.
[00205] As explored in a recent Phase 1 trial by Nurix Pharmaceuticals, NX-2127, a novel orally bioavailable degrader of the Bruton tyrosine kinase (BTK), demonstrated clinically meaning degradation of the BTK in patients with relapsed/refractory chronic lymphocytic leukemia (CLL) and other B-cell malignancies. NX-2127 carries the normal cellular protein degradation mechanism which allows it to catalyze degradation of BTK. This mechanism is important in B-cell malignancies because the BTK enzyme is present in the B-cell development, differentiation, and signaling that helps lymphoma and leukemia cells survive. The phase 1 clinical trial was designed to investigate the safety and tolerability of NX-2127 in patients with B-cell malignancies, including CLL, small lymphocytic lymphoma (SLL), mantle cell lymphoma, marginal zone lymphoma, Waldenstrom macroglobulinemia (WM), follicular lymphoma, and diffuse large B-cell lymphoma.
[00206] Accordingly, BTK degraders such as NX-2127, MT802, L18I, SPB5208, or RC-1 may be used in the present invention. See, e g., Yu, F., et al., Front. Chem, 30 June 2021, which is hereby incorporated by reference.
BCL-2 Inhibitors
[00207] The BCL-2 protein is the founding member of the BCL-2 family of apoptosis regulators and was the first apoptosis modulator to be associated with cancer. The recognition of the important role played by BCL-2 for cancer development and resistance to treatment made it a relevant target for therapy for many diseases, including solid tumors and hematological neoplasias. Among the different strategies that have been developed to inhibit BCL-2, BH3-mimetics have emerged as a novel class of compounds with favorable results in different clinical settings, including chronic lymphocytic leukemia (CLL). In April 2016, the first inhibitor of BCL-2, venetoclax, was approved by the US Food and Drug Administration for the treatment of patients with CLL who have 17p deletion and had received at least one prior therapy. The BCL-2 family’s members of this family can be grouped in three main categories. The anti-apoptotic subfamily is characterized by the presence of four BCL-2 homology (BH) domains (BH1, BH2, BH3, and BH4) and, in humans, includes the proteins BCL-2 (the founding member), BCL-XL, BCL-W, BCL-2-related protein Al (Bfl-l/Al), myeloid cell leukemia 1 (MCL-1), and BCLB/Boo. The pro-apoptotic members can be
divided in two subfamilies: the multi-domain pro-apoptotic ‘effectors’ (such as BAK and BAX) and those members known as ‘BH3-only proteins’ as they only have the short BH3 domain. The latter subfamily includes BAD, BID, BIK, BIM, BMF, HRK, PUMA, and NOXA
[00208] High levels of BCL-2 are observed in patients with FL, CLL, mantle-cell lymphoma (MCL), and Waldenstrom’s macroglobulinemia. A heterogeneous pattern of expression of BCL-2 is reported among other hematological neoplasms, such as diffuse large B-cell lymphoma (DLBCL), for which certain subtypes present low levels of this molecule; and multiple myeloma (MM), in which BCL-2 expression is especially elevated in patients harboring t(l 1 ;14).
[00209] The development of selective inhibitors for BCL-2 and BCL-XL is limited by the high degree of similarity shared by their BH3 domain [51], Using reverse engineering, a new compound was developed to overcome the unfavorable effect of navitoclax on platelets as the consequence of BCL-XL inhibition, while keeping its anti-tumor activity . Venetoclax is a potent and selective inhibitor of the BCL-2 protein that has demonstrated clinical efficacy in several hematological malignancies. Contrasting with navitoclax, which targets BCL-2 and BCL-XL, venetoclax has a distinct mode of action as it binds and neutralizes BCL-2 with subnanomolar affinity (Ki < 0.010 nM), while interacting only weakly with BCL-XL and BCL-W. By sparing BCL-XL, it exerts little effect on platelet numbers. In preclinical studies, this orally bioavailable inhibitor showed cell-killing activity' against a variety of cell lines, including cell lines derived from ALL, NHL, and AML. When investigated in xenografts models using hematological tumors, venetoclax promoted tumor growth inhibition in a dosedependent fashion. For those models in which venetoclax had little effect as single-agent, improved efficacy was achieved with the combination with other drugs. Venetoclax has been investigated for treatment of CLL and been tested in combination with numerous anticancer agents for cancers such as AML, MM, MCL, CLL/SLL, B-cell lymphoma, and DLBCL.
[00210] Exemplary BCL-2 inhibitors useful in the present invention include venetoclax (Velcade®), and navitoclax. Another useful BCL-2 inhibitor is AT-101. AT-101 is an orally active pan-Bcl-2 inhibitor that consists of gossypol, a natural compound derived from the cotton plant. AT-101 has shown potential efficacy in combinations with other drugs for treatment of solid tumors, such as in combination with docetaxel, topotecan, paclitaxel and carboplatin, cisplatin and etoposide. Other BCL-2 inhibitors include sabutoclax, S55746, HA-14-1 and gambogic acid (Han et al. (2019) BioMed Research International 2019:Article ID 1212369: Drugs and Clinical Approaches Targeting the Antiapoptotic Protein: A Review).
BI 13 Mimetics
[00211] BH3 mimetics comprise a novel class of BCL-2 inhibitors that have shown promising results in several hematological malignancies, both as single agents and in combination with other anti-cancer drugs. Among the BH3-mimetics, venetoclax (also known as ABT-199), a potent and selective inhibitor of BCL-2, was approved by the FDA in 2016 for treatment of relapsed/refractory chronic lymphocytic leukemia (CLL) with 17p deletion based on its favorable safety profile and high response rates.
[00212] This novel class of compounds is designed to selectively kill cancer cells by targeting the mechanism involved in their survival. These agents induce apoptosis by mimicking the activity of natural antagonists of BCL-2 and other related proteins. For example, ABT-737, developed by Abbott Laboratories (North Chicago, IL, USA), is considered the prototype of BH3 mimetics as it was the ’first- in-class' compound developed to mimic the function of BH3 -only -proteins. Discovered using a high-throughput nuclear magnetic resonance-based screening method to identify small molecules that bind to the BH3-binding groove of BCL-xL, ABT-737 binds with a much higher affinity (< 1 nmol/L) than previous compounds to anti-apoptotic proteins BCL-2, BCL-XL and BCL-w, blocking their function.
[00213] Navitoclax, a potent and selective inhibitor of BCL-2, is the second generation, orally bioavailable form of ABT-737. Like its predecessor, navitoclax interacts with high affinity and abrogates BCL-2, BCL-XL, and BCL-w, but has no activity against Al and MCL-1. Navitoclax showed in vitro activity against a broad panel of tumor cell lines both as single agent and in combination with chemotherapy. In in vivo experiments, treatment with this inhibitor induced rapid and complete tumor responses in multiple xenograft models developed using small-cell lung cancer and hematologic cell lines, with responses lasting several weeks in some models. Moreover, in B-cell malignant xenograft models, cotreatment with navitoclax significantly improved the efficacy of numerous approved anti-cancer agents. Navitoclax potentiated the activity of rituximab in the B-cell lymphoma flank xenograft model, of modified R-CHOP regimen in a flank xenograft model of MCL, and of bortezomib in an MM model.
[00214] BH3 Mimetics useful in the present invention include ABT-737, navitoclax and obatoclax mesylate (GX15-070).
Proteasome Inhibitors
[00215] Proteasome inhibitors useful in the present invention include ixazomib (Ninlaro®), bortezomib (Velcade®), carfilzomib (Kyprolis®), marizomib (NPI-0052), oprozomib
(ONX0912), ONX 0914 (an immunoproteasome selective inhibitor), and KZR-616 (an immunoproteas ome inhibitor).
Exemplary Standard of Care Therapies
Waldenstrom ’s Macroglobulinemia
[00216] In some embodiments, the present invention provides a method of treating Waldenstrom’s macroglobulinemia in a patient in need thereof, comprising administering to the patient an effective amount of mavorixafor in combination with an effective amount of a BTK inhibitor, and optionally further in combination with one or more standard of care treatments, or a combination thereof, for Waldenstrom’s macroglobulinemia.
[00217] Standard of care treatments for Waldenstrom’s macroglobulinemia are well known to one of ordinary skill in the art and include chemotherapy, or immunotherapy, or a combination thereof. In some embodiments, the standard of care chemotherapy is selected from chlorambucil, cladribine, cyclophosphamide, fludarabine, bendamustine, or a BTK inhibitor, such as ibrutinib, acalabrutinib, or zanubrutinib. In some embodiments, the additional therapeutic agent is ibrutinib (Imbruvica5) Pharmacychcs/Janssen/AbbVie).
[00218] In some embodiments, mavorixafor is administered to the patient as a monotherapy and as the first-line treatment for the Waldenstrom’s macroglobulinemia. In other embodiments, mavorixafor is administered to the patient as a first-line treatment in combination with a standard of care treatment for Waldenstrom’s macroglobulinemia (e.g., immunotherapy, or chemotherapy, or a combination thereof).
[00219] In some embodiments, when a standard of care treatment fails, such as when the Waldenstrom’s macroglobulinemia is partially resistant to a chemotherapy, a second-line treatment is used that can include a well-known second-line treatment to treat Waldenstrom’s macroglobulinemia. Accordingly, in some embodiments, the present invention provides a method of treating Waldenstrom’s macroglobulinemia in a patient wherein the cancer is resistant to a first-line therapy, said method comprising administering mavorixafor optionally in combination with a second-line treatment.
[00220] In some embodiments, the present invention provides a method of treating a resistant Waldenstrom’s macroglobulinemia comprising administering mavorixafor as the second-line treatment. In some embodiments, the present invention provides a method of treating a resistant Waldenstrom’s macroglobulinemia comprising administering mavorixafor in combination with another second-line treatment or standard of care second-line treatment for Waldenstrom’s macroglobulinemia (e.g., immunotherapy, chemotherapy, etc.). In some
embodiments, the second-line treatment is selected from a chemotherapy. For example, mavorixafor is administered as a second-line therapy in combination with a chemotherapy for the treatment of relapsed and refractory Waldenstrom’s macroglobulinemia.
[00221] In some instances when the first-line or second-line standard of care treatment fails, such as when chemotherapy continues to fail and remission occurs, a third-line treatment is administered to the patient that can include a well-known third-line treatment to treat Waldenstrom’s macroglobulinemia. In some embodiments, the present invention provides a method of treating a Waldenstrom’s macroglobulinemia resistant to both first-line therapy and second-line therapy comprising administering mavorixafor as the third-line treatment. In some embodiments, the present invention provides a method of treating a Waldenstrom’s macroglobulinemia resistant to both first-line therapy and second-line therapy comprising administering mavorixafor in combination with another third-line treatment or standard of care third-line treatment for Waldenstrom’s macroglobulinemia (e.g., immunotherapy, chemotherapy, etc.).
[00222] In some embodiments, mavorixafor is administered as a sensitizer for the treatment of Waldenstrom’s macroglobulinemia. Without wishing to be bound by any particular theory, it is believed that mavorixafor increases the efficacy of the standard of care, first-line, second-line, or third-line treatments for Waldenstrom’s macroglobulinemia, wherein the Waldenstrom’s macroglobulinemia comprises a CXCR4 mutation such as one of those described herein. In some embodiments, the present invention provides a method of treating a Waldenstrom’s macroglobulinemia in a patient in need thereof, comprising administering mavorixafor to the patient prior to administration of one or more of a standard of care, first-line, second-line, or third-line treatment. In some embodiments, administration of mavorixafor results in a more effective treatment of the Waldenstrom’s macroglobulinemia compared to treatment of Waldenstrom’s macroglobulinemia in the absence of administration of mavorixafor. In some embodiments, the present invention provides a method of treating a Waldenstrom’s macroglobulinemia in a patient in need thereof, comprising administering mavorixafor to the patient after administration of one or more of a standard of care, first-line, second-line, or third-line treatment.
[00223] In some embodiments, the present invention provides a method of treating a Waldenstrom’s macroglobulinemia in a patient in need thereof, comprising administering mavorixafor to the patient in combination with an additional therapeutic agent suitable for treating the Waldenstrom’s macroglobulinemia. In some embodiments, the additional therapeutic agent is a BTK inhibitor. In some embodiments, the additional therapeutic agent
is selected from chlorambucil, cladribine, cyclophosphamide, fludarabine, bendamustine, and ibrutinib. In some embodiments, the additional therapeutic agent is ibrutinib (Imbruvica®; Pharmacy clics/Janssen/AbbVie).
[00224] In some embodiments, the present invention provides a method of treating a cancer in a patient in need thereof, as described herein, comprising administering to the patient mavorixafor in combination with one or more additional therapies wherein the combination of mavorixafor and the one or more additional therapies acts synergistically. In some embodiments, the administration of mavorixafor in combination with an additional therapeutic agent results in a reduction of the effective amount of that additional therapeutic agent as compared to the effective amount of the additional therapeutic agent in the absence of administration in combination with mavorixafor. In some embodiments, the effective amount of the additional therapeutic agent administered in combination with mavorixafor is about 90%, about 80%, about 70%, about 60%, about 50%, about 40%, about 30%, about 20%, or about 10% of the effective amount of the additional therapeutic agent in the absence of administration in combination with mavorixafor.
[00225] In some embodiments, the mavonxafor or pharmaceutically acceptable salt thereof and additional therapy have a combination index (CI) of about 0.9 or less. In some embodiments, the mavorixafor or pharmaceutically acceptable salt thereof and additional therapy have a combination index (CI) of about 0.8 or less. In some embodiments, the mavorixafor or pharmaceutically acceptable salt thereof and additional therapy have a combination index (CI) of about 0.7 or less. In some embodiments, the mavorixafor or pharmaceutically acceptable salt thereof and additional therapy have a combination index (CI) of about 0.6 or less. In some embodiments, the mavorixafor or pharmaceutically acceptable salt thereof and additional therapy have a combination index (CI) of about 0.5 or less. In some embodiments, the mavonxafor or pharmaceutically acceptable salt thereof and additional therapy have a combination index (CI) of about 0.4 or less. In some embodiments, the mavorixafor or pharmaceutically acceptable salt thereof and additional therapy have a combination index (CI) of about 0.3 or less. In some embodiments, the mavorixafor or pharmaceutically acceptable salt thereof and additional therapy have a combination index (CI) of about 0.2 or less. In some embodiments, the mavorixafor or pharmaceutically acceptable salt thereof and additional therapy have a combination index (CI) of about 0.1 or less.
[00226] In some embodiments, the mavorixafor or pharmaceutically acceptable salt thereof and additional therapy have a combination index (CI) of about 0.1 to about 0.9. In
some embodiments, the mavorixafor or pharmaceutically acceptable salt thereof and additional therapy have a combination index (CI) of about 0.1 to about 0.8. In some embodiments, the mavorixafor or pharmaceutically acceptable salt thereof and additional therapy have a combination index (CI) of about 0. 1 to about 0.7. In some embodiments, the mavorixafor or pharmaceutically acceptable salt thereof and additional therapy have a combination index (CI) of about 0.1 to about 0.6. In some embodiments, the mavorixafor or pharmaceutically acceptable salt thereof and additional therapy have a combination index (CI) of about 0.1 to about 0.5. In some embodiments, the mavorixafor or pharmaceutically acceptable salt thereof and additional therapy have a combination index (CI) of about 0. 1 to about 0.4. In some embodiments, the mavorixafor or pharmaceutically acceptable salt thereof and additional therapy have a combination index (CI) of about 0.1 to about 0.3. In some embodiments, the mavorixafor or pharmaceutically acceptable salt thereof and additional therapy have a combination index (CI) of about 0.1 to about 0.2. In some embodiments, the mavorixafor or pharmaceutically acceptable salt thereof and additional therapy have a combination index (CI) of about 0.2 to about 0.9. In some embodiments, the mavorixafor or pharmaceutically acceptable salt thereof and additional therapy have a combination index (CI) of about 0.3 to about 0.9. In some embodiments, the mavorixafor or pharmaceutically acceptable salt thereof and additional therapy have a combination index (CI) of about 0.4 to about 0.9. In some embodiments, the mavorixafor or pharmaceutically acceptable salt thereof and additional therapy have a combination index (CI) of about 0.5 to about 0.9.
[00227] In some embodiments, the mavorixafor or pharmaceutically acceptable salt thereof and additional therapy have a combination index (CI) of about 0.01 to about 0.3. In some embodiments, the mavorixafor or pharmaceutically acceptable salt thereof and additional therapy have a combination index (CI) of about 0.05 to about 0.3. In some embodiments, the mavorixafor or pharmaceutically acceptable salt thereof and additional therapy have a combination index (CI) of about 0.8 to about 0.3.
[00228] As used herein, “about” means that the stated value or range may vary by up to 10% from the stated value or range. For example, “about” 5.0 means 5.0 ± 0.5, and “about 5.0-10.0” means 4.5-10.5.
Dosage and Formulations
[00229] Mavorixafor (X4P-001) is a CXCR4 antagonist, with molecular formula C21H27N5; molecular weight 349.48 amu; and appearance as a white to pale yellow solid.
Solubility: freely soluble in the pH range 3.0 to 8.0 (>100 mg/mL), sparingly soluble at pH 9.0 (10.7 mg/mL) and slightly soluble at pH 10.0 (2.0 mg/mL). Mavorixafor is only slightly soluble in water. Melting point: 108.9 °C.
X4P-001
[00231] In certain embodiments, a pharmaceutical composition containing mavorixafor or a pharmaceutically acceptable salt thereof is administered orally in an amount from about 200 mg to about 1200 mg daily. In certain embodiments, the dosage composition may be provided twice a day in divided dosage, approximately 12 hours apart. In other embodiments, the dosage composition may be provided once daily. The terminal half-life of mavorixafor has been generally determined to be between about 12 to about 24 hours, or approximately 14.5 hrs. Dosage for oral administration may be from about 100 mg to about 1200 mg once or twice per day. In certain embodiments, the dosage of mavorixafor or a pharmaceutically acceptable salt thereof useful in the invention is from about 200 mg to about 600 mg daily. In other embodiments, the dosage of mavorixafor or a pharmaceutically acceptable salt thereof useful in the invention may range from about 400 mg to about 800 mg, from about 600 mg to about 1000 mg or from about 800 mg to about 1200 mg daily. In certain embodiments, the invention comprises administration of an amount of mavorixafor or a pharmaceutically acceptable salt thereof of about 10 mg, about 20 mg, about 25 mg, about 50 mg, about 75 mg, about 100 mg, about 125 mg, about 150 mg, about 200 mg, about 250 mg, about 300 mg, about 400 mg, about 450 mg, about 500 mg, about 600 mg, about 650 mg, about 700 mg, about 750 mg, about 800 mg, about 850 mg, about 900 mg, about 950 mg, about 1000 mg, about 1100 mg, about 1200 mg, about 1300 mg, about 1400 mg, about 1500 mg, or about 1600 mg.
[00232] In some embodiments, a provided method comprises administering to the patient a pharmaceutically acceptable composition comprising mavorixafor or a pharmaceutically acceptable salt thereof wherein the composition is formulated for oral administration. In
certain embodiments, the composition is formulated for oral administration in the form of a tablet or a capsule. In some embodiments, the composition comprising mavorixafor or a pharmaceutically acceptable salt thereof is formulated for oral administration in the form of a capsule.
[00233] In certain embodiments, a provided method comprises administering to the patient one or more unit doses, such as capsules, comprising 100-1200 mg mavorixafor or a pharmaceutically acceptable salt thereof as an active ingredient; and one or more pharmaceutically acceptable excipients.
[00234] A composition according to the present invention comprises a compound for use in the invention or a pharmaceutically acceptable salt or derivative thereof and a pharmaceutically acceptable carrier, adjuvant, or vehicle. The amount of compound in compositions of this invention is an amount effective to measurably inhibit CXCR4, or a mutant thereof, in a biological sample or in a patient. In certain embodiments, a composition of this invention is formulated for administration to a patient in need of such a composition. In some embodiments, a composition of this invention is formulated for oral administration to a patient.
[00235] The term “patient,” as used herein, means an animal, preferably a mammal, and most preferably a human.
[00236] As used herein, the term “pharmaceutically acceptable salt” refers to those salts which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of humans and lower animals without undue toxicity, irritation, allergic response and the like, and are commensurate with a reasonable benefit/risk ratio. Pharmaceutically acceptable salts are well known in the art. For example, S. M. Berge et al., describe pharmaceutically acceptable salts in detail in J. Pharmaceutical Sciences, 1977, 66, 1-19, incorporated herein by reference. Pharmaceutically acceptable salts of the compounds of this invention include those derived from suitable inorganic and organic acids and bases. Examples of pharmaceutically acceptable, nontoxic acid addition salts are salts of an amino group formed with inorganic acids such as hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid and perchloric acid or with organic acids such as acetic acid, oxalic acid, maleic acid, tartaric acid, citric acid, succinic acid or malonic acid or by using other methods used in the art such as ion exchange. Other pharmaceutically acceptable salts include adipate, alginate, ascorbate, aspartate, benzenesulfonate, benzoate, bisulfate, borate, butyrate, camphorate, camphorsulfonate, citrate, cyclopentanepropionate, digluconate, dodecylsulfate, ethanesulfonate, formate, fumarate, glucoheptonate, glycerophosphate, gluconate,
hemisulfate, heptanoate, hexanoate, hydroiodide, 2-hydroxy-ethanesulfonate, lactobionate, lactate, laurate, lauryl sulfate, malate, maleate, malonate, methanesulfonate, 2- naphthalenesulfonate, nicotinate, nitrate, oleate, oxalate, palmitate, pamoate, pectinate, persulfate, 3-phenylpropionate, phosphate, pivalate, propionate, stearate, succinate, sulfate, tartrate, thiocyanate, p-toluenesulfonate, undecanoate, valerate salts, and the like.
[00237] Salts derived from appropriate bases include alkali metal, alkaline earth metal, ammonium and N+(Ci-4alkyl)4 salts. Representative alkali or alkaline earth metal salts include sodium, lithium, potassium, calcium, magnesium, and the like. Further pharmaceutically acceptable salts include, when appropriate, nontoxic ammonium, quaternary ammonium, and amine cations formed using counterions such as halide, hydroxide, carboxylate, sulfate, phosphate, nitrate, loweralkyl sulfonate and aryl sulfonate.
[00238] The term “pharmaceutically acceptable carrier, adjuvant, or vehicle” refers to a non-toxic carrier, adjuvant, or vehicle that does not destroy the pharmacological activity of the compound with which it is formulated. Pharmaceutically acceptable carriers, adjuvants or vehicles that may be used in the compositions of this invention include, but are not limited to, ion exchangers, alumina, aluminum stearate, lecithin, serum proteins, such as human serum albumin, buffer substances such as phosphates, glycine, sorbic acid, potassium sorbate, partial glyceride mixtures of saturated vegetable fatty acids, water, salts or electrolytes, such as protamine sulfate, disodium hydrogen phosphate, potassium hydrogen phosphate, sodium chloride, zinc salts, colloidal silica, magnesium trisilicate, polyvinyl pyrrolidone, cellulose- based substances, polyethylene glycol, sodium carboxymethylcellulose, polyacrylates, waxes, polyethylene-polyoxypropylene-block polymers, polyethylene glycol and wool fat.
[00239] A “pharmaceutically acceptable derivative” means any non-toxic salt, ester, salt of an ester or other derivative of a compound of this invention that, upon administration to a patient, is capable of providing, either directly or indirectly, a compound of this invention.
[00240] Compositions of the present invention may be administered orally, parenterally, by inhalation spray, topically (as by powders, ointments, or drops), rectally, nasally, buccally, intravaginally, intracisternally, or via an implanted reservoir. The term “parenteral” as used herein includes subcutaneous, intravenous, intramuscular, intra-articular, intra-synovial, intrastemal, intrathecal, intrahepatic, intralesional, and intracranial injection or infusion techniques. Preferably, the compositions are administered orally, intraperitoneally or intravenously. Sterile injectable forms of the compositions of this invention may be aqueous or oleaginous suspension. These suspensions may be formulated according to techniques known in the art using suitable dispersing or wetting agents and suspending agents. The
sterile injectable preparation may also be a sterile injectable solution or suspension in a non- toxic parenterally acceptable diluent or solvent, for example as a solution in 1,3-butanediol. Among the acceptable vehicles and solvents that may be employed are water, Ringer’s solution and isotonic sodium chloride solution. In addition, sterile, fixed oils are conventionally employed as a solvent or suspending medium.
[00241] For this purpose, any bland fixed oil may be employed including synthetic mono- or di-glycerides. Fatty acids, such as oleic acid and its glyceride derivatives are useful in the preparation of injectables, as are natural pharmaceutically acceptable oils, such as olive oil or castor oil, especially in their polyoxyethylated versions. These oil solutions or suspensions may also contain a long-chain alcohol diluent or dispersant, such as carboxymethyl cellulose or similar dispersing agents that are commonly used in the formulation of pharmaceutically acceptable dosage forms including emulsions and suspensions. Other commonly used surfactants, such as Tweens, Spans and other emulsifying agents or bioavailabilify enhancers which are commonly used in the manufacture of pharmaceutically acceptable solid, liquid, or other dosage forms may also be used for the purposes of formulation.
[00242] Pharmaceutically acceptable compositions of this invention may be orally administered in any orally acceptable dosage form including, but not limited to, capsules, tablets, aqueous suspensions or solutions. In the case of tablets for oral use, carriers commonly used include lactose and com starch. Lubricating agents, such as magnesium stearate, are also typically added. For oral administration in a capsule form, useful diluents include lactose and dried cornstarch. When aqueous suspensions are required for oral use, the active ingredient is combined with emulsifying and suspending agents. If desired, certain sweetening, flavoring or coloring agents may also be added.
[00243] Alternatively, pharmaceutically acceptable compositions of this invention may be administered in the form of suppositories for rectal administration. These can be prepared by mixing the agent with a suitable non-irritating excipient that is solid at room temperature but liquid at rectal temperature and therefore will melt in the rectum to release the drug. Such materials include cocoa butter, beeswax and polyethylene glycols.
[00244] Pharmaceutically acceptable compositions of this invention may also be administered topically, especially when the target of treatment includes areas or organs readily accessible by topical application, including diseases of the eye, the skin, or the lower intestinal tract. Suitable topical formulations are readily prepared for each of these areas or organs.
[00245] Topical application for the lower intestinal tract can be effected in a rectal suppository' formulation (see above) or in a suitable enema formulation. Topically- transdermal patches may also be used.
[00246] For topical applications, provided pharmaceutically acceptable compositions may be formulated in a suitable ointment containing the active component suspended or dissolved in one or more carriers. Carriers for topical administration of compounds of this invention include, but are not limited to, mineral oil, liquid petrolatum, white petrolatum, propylene glycol, polyoxyethylene, polyoxypropylene compound, emulsifying wax and water. Alternatively, provided pharmaceutically acceptable compositions can be formulated in a suitable lotion or cream containing the active components suspended or dissolved in one or more pharmaceutically acceptable carriers. Suitable carriers include, but are not limited to, mineral oil, sorbitan monostearate, polysorbate 60, cetyl esters wax, cetearyl alcohol, 2-octyldodecanol, benzyl alcohol and water.
[00247] For ophthalmic use, provided pharmaceutically acceptable compositions may be formulated as micronized suspensions in isotonic, pH adjusted sterile saline, or, preferably, as solutions in isotonic, pH adjusted sterile saline, either with or without a preservative such as benzylalkonium chloride. Alternatively, for ophthalmic uses, the pharmaceutically acceptable compositions may be formulated in an ointment such as petrolatum.
[00248] Pharmaceutically acceptable compositions of this invention may also be administered by nasal aerosol or inhalation. Such compositions are prepared according to techniques well-known in the art of pharmaceutical formulation and may be prepared as solutions in saline, employing benzyl alcohol or other suitable preservatives, absorption promoters to enhance bioavailability, fluorocarbons, and/or other conventional solubilizing or dispersing agents.
[00249] Most preferably, pharmaceutically acceptable compositions of this invention are formulated for oral administration. Such formulations may be administered with or without food. In some embodiments, pharmaceutically acceptable compositions of this invention are administered without food. In other embodiments, pharmaceutically acceptable compositions of this invention are administered with food.
[00250] The amount of compounds of the present invention that may be combined with the carrier materials to produce a composition in a single dosage form will vary depending upon the host treated and the particular mode of administration. Preferably, provided compositions should be formulated so that a dosage of between 0.01 - 100 mg/kg body weight/day of the inhibitor can be administered to a patient receiving these compositions.
[00251] It should also be understood that a specific dosage and treatment regimen for any particular patient will depend upon a variety of factors, including the activity of the specific compound employed, the age, body weight, general health, sex, diet, time of administration, rate of excretion, drug combination, and the judgment of the treating physician and the severity of the particular disease being treated. The amount of a compound of the present invention in the composition will also depend upon the particular compound in the composition.
[00252] The compounds and compositions, according to the method of the present invention, may be administered using any amount and any route of administration effective for treating a cancer, such as those disclosed herein. The exact amount required will vary from subject to subject, depending on the species, age, and general condition of the subject, the severity of the cancer, the particular agent, its mode of administration, and the like. Compounds of the invention are preferably formulated in unit dosage form for ease of administration and uniformity of dosage. The expression “unit dosage form” as used herein refers to a physically discrete unit of agent appropriate for the patient to be treated. It will be understood, however, that the total daily usage of the compounds and compositions of the present invention will be decided by the attending physician within the scope of sound medical judgment. The specific effective dose level for any particular patient or organism will depend upon a variety of factors including the cancer being treated and the severity of the cancer; the activity of the specific compound employed; the specific composition employed; the age, body weight, general health, sex and diet of the patient; the time of administration, route of administration, and rate of excretion of the specific compound employed; the duration of the treatment; drugs used in combination or coincidental with the specific compound employed, and like factors well known in the medical arts.
[00253] In certain embodiments, the compounds of the invention may be administered orally or parenterally at dosage levels of about 0.01 mg/kg to about 50 mg/kg and preferably from about 1 mg/kg to about 25 mg/kg, of subject body weight per day, one or more times a day, to obtain the desired therapeutic effect.
[00254] Liquid dosage forms for oral administration include, but are not limited to, pharmaceutically acceptable emulsions, microemulsions, solutions, suspensions, syrups and elixirs. In addition to the active compounds, the liquid dosage forms may contain inert diluents commonly used in the art such as, for example, water or other solvents, solubilizing agents and emulsifiers such as ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3-butylene glycol, dimethylformamide,
oils (in particular, cottonseed, groundnut, com, germ, olive, castor, and sesame oils), glycerol, tetrahydrofurfuryl alcohol, polyethylene glycols and fatty acid esters of sorbitan, and mixtures thereof. Besides inert diluents, the oral compositions can also include adjuvants such as wetting agents, emulsifying and suspending agents, sweetening, flavoring, and perfuming agents.
[00255] Injectable preparations, for example, sterile injectable aqueous or oleaginous suspensions may be formulated according to the known art using suitable dispersing or wetting agents and suspending agents. The sterile injectable preparation may also be a sterile injectable solution, suspension or emulsion in a nontoxic parenterally acceptable diluent or solvent, for example, as a solution in 1,3 -butanediol. Among the acceptable vehicles and solvents that may be employed are water, Ringer’s solution, U.S P and isotonic sodium chloride solution. In addition, sterile, fixed oils are conventionally employed as a solvent or suspending medium. For this purpose any bland fixed oil can be employed including synthetic mono- or diglycerides. In addition, fatty acids such as oleic acid are used in the preparation of injectables.
[00256] Injectable formulations can be sterilized, for example, by filtration through a bacterial-retaining filter, or by incorporating sterilizing agents in the form of sterile solid compositions which can be dissolved or dispersed in sterile water or other sterile injectable medium prior to use.
[00257] In order to prolong the effect of a compound of the present invention, it is often desirable to slow the absorption of the compound from subcutaneous or intramuscular injection. This may be accomplished by the use of a liquid suspension of crystalline or amorphous material with poor water solubility. The rate of absorption of the compound then depends upon its rate of dissolution that, in turn, may depend upon crystal size and crystalline form. Alternatively, delayed absorption of a parenterally administered compound form is accomplished by dissolving or suspending the compound in an oil vehicle. Injectable depot forms are made by forming microencapsule matrices of the compound in biodegradable polymers such as polylactide-polyglycolide. Depending upon the ratio of compound to polymer and the nature of the particular polymer employed, the rate of compound release can be controlled. Examples of other biodegradable polymers include poly (orthoesters) and poly (anhydrides). Depot injectable formulations are also prepared by entrapping the compound in liposomes or microemulsions that are compatible with body tissues.
[00258] Compositions for rectal or vaginal administration are preferably suppositories which can be prepared by mixing the compounds of this invention with suitable non-irritating
excipients or carriers such as cocoa butter, polyethylene glycol or a suppository wax which are solid at ambient temperature but liquid at body temperature and therefore melt in the rectum or vaginal cavity and release the active compound.
[00259] Solid dosage forms for oral administration include capsules, tablets, pills, powders, and granules. In such solid dosage forms, the active compound is mixed with at least one inert, pharmaceutically acceptable excipient or carrier such as sodium citrate or dicalcium phosphate and/or a) fillers or extenders such as starches, lactose, sucrose, glucose, mannitol, and silicic acid, b) binders such as, for example, carboxymethylcellulose, alginates, gelatin, polyvinylpyrrolidinone, sucrose, and acacia, c) humectants such as glycerol, d) disintegrating agents such as agar-agar, calcium carbonate, potato or tapioca starch, alginic acid, certain silicates, and sodium carbonate, e) solution retarding agents such as paraffin, f) absorption accelerators such as quaternary ammonium compounds, g) wetting agents such as, for example, cetyl alcohol and glycerol monostearate, h) absorbents such as kaolin and bentonite clay, and i) lubricants such as talc, calcium stearate, magnesium stearate, solid polyethylene glycols, sodium lauryl sulfate, and mixtures thereof. In the case of capsules, tablets and pills, the dosage form may also comprise buffering agents.
[00260] Solid compositions of a similar type may also be employed as fillers in soft and hard-filled gelatin capsules using such excipients as lactose or milk sugar as well as high molecular weight polyethylene glycols and the like. The solid dosage forms of tablets, dragees, capsules, pills, and granules can be prepared with coatings and shells such as enteric coatings and other coatings well known in the pharmaceutical formulating art. They may optionally contain opacifying agents and can also be of a composition that they release the active ingredient(s) only, or preferentially, in a certain part of the intestinal tract, optionally, in a delayed manner. Examples of embedding compositions that can be used include polymeric substances and waxes. Solid compositions of a similar type may also be employed as fillers in soft and hard-filled gelatin capsules using such excipients as lactose or milk sugar as well as high molecular weight polethylene glycols and the like.
[00261] The active compounds can also be in micro-encapsulated form with one or more excipients as noted above. The solid dosage forms of tablets, dragees, capsules, pills, and granules can be prepared with coatings and shells such as enteric coatings, release controlling coatings and other coatings well known in the pharmaceutical formulating art. In such solid dosage forms the active compound may be admixed with at least one inert diluent such as sucrose, lactose or starch. Such dosage forms may also comprise, as is normal practice, additional substances other than inert diluents, e.g., tableting lubricants and other tableting
aids such a magnesium stearate and microcrystalline cellulose. In the case of capsules, tablets and pills, the dosage forms may also comprise buffering agents. They may optionally contain opacifying agents and can also be of a composition that they release the active ingredient(s) only, or preferentially, in a certain part of the intestinal tract, optionally, in a delayed manner. Examples of embedding compositions that can be used include polymeric substances and waxes.
[00262] Dosage forms for topical or transdermal administration of a compound of this invention include ointments, pastes, creams, lotions, gels, powders, solutions, sprays, inhalants or patches. The active component is admixed under sterile conditions with a pharmaceutically acceptable carrier and any needed preservatives or buffers as may be required. Ophthalmic formulation, ear drops, and eye drops are also contemplated as being within the scope of this invention. Additionally, the present invention contemplates the use of transdermal patches, which have the added advantage of providing controlled delivery of a compound to the body. Such dosage forms can be made by dissolving or dispensing the compound in the proper medium. Absorption enhancers can also be used to increase the flux of the compound across the skin. The rate can be controlled by either providing a rate controlling membrane or by dispersing the compound in a polymer matrix or gel.
[00263] In certain embodiments, the present invention provides a pharmaceutical composition comprising mavorixafor or a pharmaceutically acceptable salt thereof, one or more diluents, a disintegrant, a lubricant, a flow aid, and a wetting agent. In some embodiments, the present invention provides a composition comprising 10-1200 mg mavorixafor or a pharmaceutically acceptable salt thereof, microcrystalline cellulose, dibasic calcium phosphate dihydrate, croscarmellose sodium, sodium stearyl fumarate, colloidal silicon dioxide, and sodium lauryl sulfate. In some embodiments, the present invention provides a unit dosage form wherein said unit dosage form comprises a composition comprising 10-200 mg mavorixafor, or a pharmaceutically acceptable salt thereof, microcrystalline cellulose, dibasic calcium phosphate dihydrate, croscarmellose sodium, sodium stearyl fumarate, colloidal silicon dioxide, and sodium lauryl sulfate. In certain embodiments, the present invention provides a unit dosage form comprising a composition comprising mavorixafor or a pharmaceutically acceptable salt thereof, present in an amount of about 10 mg, about 20 mg, about 25 mg, about 50 mg, about 75 mg, about 100 mg, about 125 mg, about 150 mg, about 200 mg, about 250 mg, about 300 mg, about 400 mg, about 450 mg, about 500 mg, about 600 mg, about 650 mg, about 700 mg, about 750 mg, about 800 mg, about 850 mg, about 900 mg, about 950 mg, about 1000 mg, about 1100 mg, about 1200 mg,
about 1300 mg, about 1400 mg, about 1500 mg, or about 1600 mg. In some embodiments, a provided composition (or unit dosage form) is administered to the patient once per day, twice per day, three times per day, or four times per day. In some embodiments, a provided composition (or unit dosage form) is administered to the patient once per day or twice per day. In some embodiments, the unit dosage form comprises a capsule containing about 25 mg, about 50 mg, about 75 mg, about 100 mg, about 150 mg, or about 200 mg of mavorixafor or a pharmaceutically acceptable salt thereof.
[00264] In some embodiments, the present invention provides a unit dosage form comprising a pharmaceutical composition comprising:
(a) mavorixafor, or a pharmaceutically acceptable salt thereof as about 30-40% by weight of the composition;
(b) microcrystalline cellulose as about 20-25% by weight of the composition;
(c) dibasic calcium phosphate dihydrate as about 30-35% by weight of the composition;
(d) croscarmellose sodium as about 5-10% by weight of the composition;
(e) sodium stearyl fumarate as about 0.5-2% by weight of the composition;
(f) colloidal silicon dioxide as about 0.1 -1.0 % by weight of the composition; and
(g) sodium lauryl sulfate as about 0. 1 -1.0 % by weight of the composition.
[00265] In some embodiments, the present invention provides a unit dosage form comprising a composition comprising:
(a) mavorixafor, or a pharmaceutically acceptable salt thereof as about 37% by weight of the composition;
(b) microcrystalline cellulose as about 23% by weight of the composition;
(c) dibasic calcium phosphate dihydrate as about 32% by weight of the composition;
(d) croscarmellose sodium as about 6% by weight of the composition;
(e) sodium stearyl fumarate as about 1% by weight of the composition;
(f) colloidal silicon dioxide as about 0.3 % by weight of the composition; and
(g) sodium lauryl sulfate as about 0.5 % by weight of the composition.
[00266] In some embodiments, the present invention provides a unit dosage form comprising a composition comprising:
(a) mavorixafor, or a pharmaceutically acceptable salt thereof as about 55-65% by weight of the composition;
(b) microcrystalline cellulose as about 10-15% by weight of the composition;
(c) dibasic calcium phosphate dihydrate as about 15-20% by weight of the composition;
(d) croscarmellose sodium as about 5-10% by weight of the composition;
(e) sodium stearyl fumarate as about 0.5-2% by weight of the composition;
(f) colloidal silicon dioxide as about 0.1 -1.0% by weight of the composition; and
(g) sodium lauryl sulfate as about 0. 1-1.0% by weight of the composition.
[00267] Inasmuch as it may be desirable to administer a combination of active compounds, for example, for the purpose of treating a particular disease or condition, it is within the scope of the present invention that two or more pharmaceutical compositions, at least one of which contains a compound in accordance with the invention, may conveniently be combined in the form of a kit suitable for co-administration of the compositions. Thus the kit of the invention includes two or more separate pharmaceutical compositions, at least one of which contains a compound of the invention, and means for separately retaining said compositions, such as a container, divided bottle, or divided foil packet. An example of such a kit is the familiar blister pack used for the packaging of tablets, capsules and the like.
[00268] The kit of the invention is particularly suitable for administering different dosage forms, for example, oral and parenteral, for administering the separate compositions at different dosage intervals, or for titrating the separate compositions against one another. To assist compliance, the kit typically includes directions for administration and may be provided with a memory aid.
[00269] The examples below explain the invention in more detail. The following preparations and examples are given to enable those skilled in the art to more clearly understand and to practice the present invention. The present invention, however, is not limited in scope by the exemplified embodiments, which are intended as illustrations of single aspects of the invention only, and methods which are functionally equivalent are within the scope of the invention. Indeed, various modifications of the invention in addition to those described herein will become apparent to those skilled in the art from the foregoing description and accompanying drawings. Such modifications are intended to fall within the scope of the appended claims.
[00270] The contents of each document cited in the specification are herein incorporated by reference in their entireties.
EXEMPLIFICATION
Example 1: Mavorixafor Enhances Efficacy of Bruton Tyrosine Kinase Inhibitors by
Overcoming the Protective Effect of Bone Marrow Stroma on Tumor Cells in Waldenstrom’s Macroglobulinemia
[00271] Waldenstrom’s macroglobulinemia (WM) is a rare B-cell malignancy characterized by monoclonal immunoglobulin M (IgM) hypersecretion and invasion of B cells in the bone marrow (BM) and lymphoid tissues. >90% of WM cases show mutations in MYD88 and 30-40% show mutations in the carboxyl terminus of CXCR4. The CXCR4/CXCL12 axis is crucial for the homing/retention of WM cells in the BM. Emerging clinical trial data (NCT04274738; ongoing) suggest that mavorixafor, a CXCR4 antagonist, in combination with ibrutinib results in clinically meaningful changes in levels of IgM and hemoglobin in patients with M//4S'<'L2,’ p CXCR4wajM WM. As shown in FIG. 1A, ibrutinib is less effective in treating relaps ed/refractory patients with double mutant WM; this is believed to be because CXCR4 mutations in WM patients cause greater adhesion of malignant B-cells to bone marrow stroma and initiate an IL-6-mediated survival response, thereby reducing efficacy of targeted chemotherapeutics. FIG. IB shows reduced % of apoptotic cells when they are grown in the presence of BMSCs, indicating that bone marrow stroma cause a protective effect in WM cells. Without wishing to be bound by theory, it is believed that CXCL12 produced in bone marrow stroma (BMSC) induce a chemotactic response through CXCR4 promoting homing of malignant WM cells to bone marrow (BM). However, the effects of mavorixafor with ibrutinib and other BTK inhibitors on WM cells harboring only the single mutation (MYD88L265P without CXCR4 mutation) have not been evaluated. This study was designed to test the ability of mavorixafor to sensitize WM cells carrying MYD88 265? (XCR4'v l to Bruton tyrosine kinase (BTK) inhibitors in a WM/BM stromal cell (BMSC) co-culture model. The effects of mavorixafor on Ca2+ mobilization, cell migration, and adhesion to BMSC were also measured.
[00272] WM cells (MWCL-1 cell line established from a WM patient, with IgM secretion > 1000 ng/mL, and MYD88L265VCXCR4WT>) pretreated with mavorixafor and BTK inhibitors (ibrutinib, zanubrutinib, evobrutinib, LOXO-305, ARQ 531) were co-cultured with established BMSCs (HS27a cells; HPV16 E6/E7 transformed Fibroblast-like; they secrete CXCL12 and IL6). Cell viability, apoptosis, and IgM release were measured after 72 hours (48 hours for venetoclax).
[00273] BTK inhibitors decreased tumor cell viability and increased apoptosis of WM cells in the absence of BMSCs. Co-culture with BMSCs enhanced CXCR4 expression and protected WM cells from the effects of BTK inhibitors. BMSCs also significantly increased IgM secretion 2- to 5-fold compared with WM cells grown in the absence of BMSCs. Mavorixafor alone inhibited CXCL12-stimulated Ca21 mobilization and migration of WM cells and disrupted the adhesion of WM cells to BMSCs. Combination of mavorixafor with BTK inhibitors overcame the protective effect of BMSCs on tumor cells, decreasing cell viability and/or increasing apoptosis compared with BTK inhibitors alone. Mavorixafor also reduced IgM secretion, which was further decreased when combined with BTK inhibitors.
[00274] This study is the first to show in vitro that the protection of WM cells against BTK inhibitors conferred by BMSCs can be overcome by inhibition of the CXCR4/CXCL12 axis. The observations and responses to mavorixafor suggest a contribution of CXCR4WY to the pathogenicity of WM cells carrying only the MYD88L265P mutation. Mavorixafor addition enhanced the efficacy of not only ibrutimb but the other BTK inhibitors tested, supporting the greater potential of this combination therapeutic strategy in WM patients with or without C -/WIIIM mutations. Further studies using additional WM cell lines and/or primary patient cells are warranted to support these findings.
Example 2: Mavorixafor disrupts the crosstalk between Waldenstrom’s Macroglobulinemia cells and the bone marrow stromal cells and enhances their sensitivity to B-cell-targeted therapies
[00275] Waldenstrom’s macroglobulinemia (WM) is a rare indolent B-cell lymphoma characterized by excess accumulation of malignant lymphoplasmacytic cells in the bone marrow (BM) and hypersecretion of monoclonal immunoglobulin M (IgM) by WM cells. Infiltration of BM by malignant cells and crosstalk with the BM microenvironment are thought to contribute to pathogenesis and resistance to therapy in WM. Here, we aimed to examine the crosstalk between WM cells and bone marrow stromal cells (BMSCs) in an in vitro coculture model.
[00276] Additionally, we sought to determine the effects of mavorixafor, an orally available CXCR4 antagonist, alone or in combination with B-cell-targeted drugs, including Bruton’s tyrosine kinase antagonists or a B-cell lymphoma 2 inhibitor on WM cells in coculture with BMSCs. Our results demonstrate that in cocultures of WM cells with BMSCs, BMSC-derived interleukin-6 (IL-6) upregulated IgM secretion and increased CXCR4 cell surface expression in WM cells via lL-6R-janus kmase-signal transducer and activator of transcription-3 signaling, and increased WM cells adhesion to BMSCs. In cocultures, BMSCs led to reduced apoptosis of WM cells treated with the tested B-cell-targeted inhibitors, suggesting BMSCs conferred drug resistance in WM cells. Blocking the CXCR4/CXLC12 axis with mavorixafor alone or in combination with tested B-cell-targeted inhibitors resulted in disruption of WM cell migration and adhesion to BMSCs, enhanced antitumor activity of B-cell-targeted inhibitors, overcame BMSC-induced drug resistance, and reduced BMSC- induced IgM hypersecretion. These results provide support for the potential use of mavorixafor alone or in combination with B-cell-targeted drugs for the treatment of WM and possibly for other malignancies.
[00277] Waldenstrom’s macroglobulinemia (WM) is an indolent B-cell lymphoma characterized by accumulation of malignant lymphoplasmacytic cells in the bone marrow (BM) (1). High levels of monoclonal immunoglobulin M (IgM) are secreted by WM cells, resulting in anemia, blood hy perviscosity syndrome, visual impairments, and neurological symptoms (2). Consequently, lowering serum IgM is a key end point in WM therapy and a common parameter to assess the success of any WM treatment.
[00278] Over the last decade, significant progress has been made in understanding the genetics underlying the pathogenesis of WM. Somatic mutations in clonal populations of cells lead to WM. The somatic L265P mutation in MYD88 innate immune signal
transduction adaptor (MYD88) gene can be found in >90% of patients with WM (3,4). The MYD88 gene encodes a protein that is involved in signaling pathways, including activation of nuclear factor-RB upon stimulation of toll-like receptors (TLRs). Additionally, MYD88 anchors with phosphorylated Bruton tyrosine kinase (BTK), which itself is part of many signaling pathways, including toll-like, chemokine and B-cell receptors (5). ATKD<?<SL265P is thought to be an activating mutation that increases binding to BTK, promoting cell survival and proliferation (3).
[00279] A second, more diverse category of mutation in WM, detected in approximately 30% of patients, can be found in the gene encoding C-X-C chemokine receptor 4 (CXCR4) (6-8). The G protein-coupled receptor CXCR4 binds its natural ligand C-X-C chemokine ligand 12 (CXCL12), which is produced by the perivascular cells of the bone marrow stroma. Upon binding to CXCR4, CXCL12 induces downstream signaling activation of phosphoinositide 3-kinase (PI3K), which controls lymphocyte trafficking, chemotaxis, and cell survival (9,10). In WM, CXCR4 mutation generally occurs in the C terminal, intracellular domain of the protein — a region involved in signal transduction. Most CXCR4 C-temtinal mutations found in WM cause hyperactivation of the receptor and its downstream signaling pathways, resulting in decreased internalization of the receptor and increased chemotaxis (7, 11,12). Patients with MYD88L265P CXCR4Mvt WM typically present with higher serum IgM levels and greater BM involvement compared with those with MYD88T 265P mutation alone (3,13).
[00280] Until recently, the typical therapeutic regimen for patients with WM consisted of chemotherapy, usually combined with targeted therapy such as rituximab (14,15). In 2015, the BTK inhibitor ibrutinib was the first drug to be approved by the US food and Drug Administration specifically for WM, followed by the next-generation BTK inhibitor zanubrutinib. Many more compounds with similar properties are currently being tested in clinical trials (14,15). Despite these advancements, it became clear that mutational status is a crucial determinant in the therapeutic management of WM (16-19). Patients harboring MYD88L265P and CXCR4 mutations have a lower response to BTK inhibitors and lower progression-free survival rates vs patients with the MYD88L265P mutation alone (16-19). This observation led to a recent clinical trial (NCT04274738) designed to test the effects of combination therapy with ibrutinib and mavorixafor. Mavorixafor is a noncyclam, orally available CXCR4 antagonist previously shown to effectively block the CXCL12-induced signaling pathway in acute lymphocytic leukemia (ALL) cells (20). Moreover, mavorixafor is currently under investigation in clinical trials for patients with Warts,
Hypogammaglobulinemia, Infections, and Myelokathexis (WHIM) syndrome (NCT03995108) and severe congenital neutropenia (SCN)/chronic idiopathic neutropenia (CN) (NCT04154488).
[00281] The interactions of malignant lymphoplasmacytic cells with the BM microenvironment (via cell-cell adhesion or secreted factors) are thought to contribute to the pathogenesis of disease and cause drug resistance in WM cells (21-24). Higher levels of cytokines and chemokines (primarily CXCL12) are detected in the BM of patients with WM compared with healthy controls (22). The elevated CXCL12 may be responsible for increased homing of lymphoplasmacytic cells to the BM (24). Additionally, higher levels of interleukin 6 (IL-6) are found in BM and sera of patients with WM (22,25). To note, IL-6 directly contributes to IgM production in in vitro and in vivo models of WM, and in both models, treatment with an IL-6 receptor (IL-6R) antibody reduces IgM levels (26,27). IL-6 signaling links to signal transducer and activator of transcription 3 (STAT3) signaling, a pathway disrupted in many cancers. Preclinical work in WM demonstrated upregulation of IL- 6/STAT3 signaling components, and a STAT3 inhibitor showed in vitro efficacy in WM cell lines (22,28,29). The BM microenvironment-mediated tumor progression and drug resistance involving CXCR4/CXCL12 and IL-6/STAT3 axis are also well recognized in various malignancies (e.g., ALL, chronic myelocytic leukemia [CML], chronic lymphocytic leukemia, multiple myeloma [MM], and diffuse large B-cell lymphoma [DLBCL]) (20,30-33).
[00282] Interestingly, recent data suggest that patients with MYD88 mutation but wild-type (WT) CXCR4 still exhibit CXCR4 dysregulation. A study comparing CXCR4 expression in samples from patients with MYD88L265P CXCR4WV and MYD88L265P CXCR4WHIM WM showed almost equally high increases in CXCR4 expression compared with healthy controls (34,35). The inventors theorized that that dysregulation of CXCR4, CXCL12, and subsequent downstream signaling events could contribute to disease pathogenesis, even in MYD88^6SP CXCR ^ WM and that administration of a CXCR4 inhibitor could help ameliorate such disease pathogenesis.
[00283] In the current study, we aimed to investigate the crosstalk between WM cell lines harboring MYD88lj265VCXCR4WT and bone marrow stromal cells in an in vitro coculture model. We also sought to evaluate the effect of mavorixafor with and without B-cell-targeted drugs, including BTK inhibitors or a B-cell lymphoma 2 inhibitor, on WM cells carrying only the MYI)88P2('P> mutation in coculture with BMSCs.
MATERIAL AND METHODS
Drugs and reagents
[00284] The BTK inhibitor evobrutinib (# S8777) was provided by Selleck chemicals. The BTK inhibitors ibrutinib (# HY-10997/CS), zanubrutinib (# HY-101474A), pirtobrutinib (# HY-131328), nemtabrutinib (# HY-112215), B-cell lymphoma 2 (BCL2) inhibitor venetoclax (# HY-15531), STAT3 inhibitor BP-1-102 (# HY-100493), pan-janus kinase (JAK) inhibitor PF-06263276 (# HY-101024), and IL-6R antibody tocilizumab (# HY-P9917) were purchased from MedChemExpress. Mavorixafor was synthesized by ChemPartner. Human CXCL12 (# 300-28A) and IL-6 (# 200-06) were purchased from PeproTech.
Cell lines
[00285] MWCL-1 cells were provided by Dr Stephen M. Ansell (MAYO file number 2021-121; 200 First Street SW, Rochester, Minnesota) and the bone marrow stroma cell (BMSC) lines HS-27A and HS-5 were obtained from ATCC. All cell lines were cultured in RPMI-1640 medium (Fisher Scientific, # 32404-014) containing 10% fetal bovine serum (FBS) (Sigma-Aldrich, # F7524 or Takara Bio, # 631105), supplemented with 100 U/mL of Penicillin-Streptomycin (Gibco™, Thermo Fisher Scientific, # 11548876) at 37 °C and 5% CO2.
Coculture experiments
[00286] BMSCs were cultured in 96-, 48-, or 24-well plates until 90% confluence. MWCL-1 cells (density ~2 * 105 cells/mL) were pretreated with indicated concentration of mavorixafor together with indicated concentrations of B-cell-targeted inhibitors in medium containing 4% FBS for 1 hour and transferred to the BMSC monolayer. Cells were coincubated for 48 or 72 hours followed by measurement of cell viability, apoptosis, IgM, and IL-6 release.
Cell viability assay
[00287] Cellular viability (as measured using metabolic activity) was determined using the CellTiter-Glo® assay (Promega, #G7570) according to the manufacturer’s instructions.
Enzyme-linked immunosorbent assays
[00288] The IgM levels were quantitated using a human IgM Enzyme-linked immunosorbent assay (ELISA) kit (Abeam, # ab214568) according to the manufacturer’s instructions. IL-6 levels were quantitated using an IL-6 ELISA MAX™ kit (BioLegend, # 430515) per manufacturer’s recommendations. For all ELISA kits, plates were developed with 3,3',5,5'-tetramethylbenzidine (TMB) development solution or a biotinylated antihuman IL-6 detection antibody/avidin horseradish peroxidase (HRP) solution. The reaction was stopped with the stop solution, and absorbance was read at 450 nm with a microplate reader (Synergy™ HT, BioTek Instruments).
Calcium mobilization assay
[00289] MWCL-1 cells (2 x io5 cells/well) were seeded in transparent bottom, black 96- well plates coated with poly-L-lysine (BioCoat®, Coming) and serum-starved (medium with 1% FBS) for 24 hours. Medium was removed and cells were loaded with 100 pL of fluo-4 AM (3 pM, Invitrogen, # F14201) dye solution for 45 minutes at 37 °C. Subsequently, 100 pL of assay buffer alone or assay buffer with compound dilutions was added, and the plates were equilibrated in the plate reader for an additional 20 minutes at 37 °C. The CXCL12 was injected with simultaneous measurement of fluorescent signal (FlexStation® 3 Multi-Mode Microplate Reader, Molecular Devices). Raw traces were analyzed in SoftMax®Pro 7 Software (Molecular Devices). The arbitrary units were calculated as the difference between maximal and minimal signal after treatment injection, normalized to the baseline signal before injection.
Transwell migration assay
[00290] Cell migration toward CXCL12 gradient or BMSC monolayer was determined using the Transwell migration assay. MWCL-1 cells were stained with 500 nM Calcein AM (Invitrogen, # Cl 430) and premcubated with mavonxafor for 15 minutes before transfer (5 x 105 cells) to an upper well of a 5.0 pM pore size Transwell® (Coming, # 3421). The lower chamber contained either CXCL12 (10 nM) in medium supplemented with 1% FBS or a monolayer of HS-27A BMSCs seeded 72 hours prior and starved for 48 hours with 4% FBS medium. Wells without CXCL12 were treated with 10 pM LIT-927 (Selleck Chemicals, # S8813), a neutraligand of CXCL12, to serve as background control. After 4 hours of incubation, cells that migrated to the lower chambers were collected and resuspended in Dulbecco’s phosphate-buffered saline (DPBS) containing Precision Count Beads™ (BioLegend, # 424902). Migrated cells and counting beads were counted by flow cytometry Immunoblotting
[00291] MWCL-1 mono- or cocultures were treated with mavorixafor and/or ibrutinib for 24 hours. Whole cells were lysed by radioimmunoprecipitation assay (RIP A) lysis buffer (Sigma-Aldrich, # R0278) with protease inhibitor cocktail (Roche Custom Biotech, # 11697498001). Lysates were separated by sodium dodecyl sulfate polyacrylamide gelelectrophoresis (SDS-PAGE) electrophoresis and transferred to Trans-Blot® Turbo™ Mini PVDF Transfer Packs (Bio-Rad). Membranes were incubated with primary antibodies: anti- poly adenosine diphosphate (ADP)-ribose polymerase (PARP) (1 :1000, Cell Signaling, # 9542); Anti-Caspase 3 (1: 1000, Cell Signaling, #9662) and antitubulin (1:5000, R&D, # MAB9344). Secondary HRP -conjugated antibodies (Abeam) were used at 1: 10.000 dilution.
Membranes were developed with enhanced chemiluminescence reagent (Amersham™ ECL Prime Western Blotting Detection Reagent, GE Healthcare) on LAS4000 gel documentation system.
Flow cytometry
[00292] Flow experiments were performed with the CytoFLEX S Flow Cytometer (Beckman Coulter). Samples were analyzed using FCS Express Software (De Novo Software).
Adhesion assay
[00293] MWCL-1 cells were labeled with 1 pM Calcein AM. After 10 minutes at 37 °C, cells were washed, resuspended in medium containing 1% FBS, and treated with compounds for 30 minutes (2.25 x io5 cells/mL). MWCL-1 cells were transferred to the BMSC monolayer. After 4 hours, nonadherent cells were removed by gently washing with phosphate-buffered saline (PBS). Remaining cells were harvested, resuspended in flow buffer (Hanks balanced salt solution + 20 mM HEPES + 0.5% body surface area) and analyzed by flow cytometry.
Apoptosis assay
[00294] Cells were washed with PBS, resuspended in Annexin V binding buffer (BioLegend, # 422201), and stained with Alexa Fluor® 647 Annexin V (BioLegend, # 640943), propidium iodide (BD Pharmingen, # 51-6621 IE), and CD45 antibody (BioLegend, # 368502) for 15 minutes at room temperature and analyzed by flow cytometry.
CXCR4 expression
[00295] MWCL-1 cells were pretreated with tocilizumab, BP-1-102, or PF-06263276 for 20 minutes and stimulated with IL-6 for 24 hours. Cells were stained with CXCR4 antibody (BD Pharmigen, # 555976) and measured by flow cytometry.
Phosphoflow
[00296] MWCL-1 cells were seeded in starvation medium in 96-well plate overnight. After stimulation with IL-6, the cells were fixed and permeabilized using BD Phosflow™ Fix Buffer I (BDBiosciences, # 557870) and BD Phosflow™ Perm Buffer III (BDBiosciences, # 558050) according to the manufacturer’s instructions. Cells were then stained with Brilliant Violet 421 Mouse Anti-Phospho STAT3 (pS727, BDBioscience, # 565416), Pacific Blue™ Mouse Anti-Phospho-STAT3 (pY705, BDBioscience, # 560312 ), Alexa Fluor® 647 Mouse Anti-STAT5 (pY694, BDBioscience, # 612599), AF488 Mouse Anti-Phospho-p38 MAPK (Thrl80/Tyrl82, Cell Signaling Technology, # 4551), Mouse Anti-Phospho-JNK (Thrl83/Tyrl85, Cell Signaling, #9275S), and PE Mouse Anti-Phospho-IkB (Ser32/Ser36,
Thermo Fisher, # 12-9035-42) for 1 hour at room temperature in darkness. Cells were then washed 2 times in BD Pharmingen™ Stain Buffer (BD Pharmingen, # 554656), resuspended in flow buffer, and measured by flow cytometry.
Statistical and bioinformatic analysis
[00297] For each experiment, independent biological replicates were performed; their numbers are indicated in the figure legends. Significance of differences between 2 independent groups was calculated using Student two-tailed t test; significance of differences between multiple groups was determined by 2-way analysis of variance (ANOVA) followed by Bonferroni post hoc test. Analyses were performed using GraphPad Prism 9 software (GraphPad Software). The combination index (CI) was calculated using Chou-Talalay method (36). A CI of 1 indicates an additive effect, a CI <1 a synergistic effect, and a CI >1 an antagonistic effect. To compare the expression of CXCR4 between B- cells derived from patients with WM and healthy donors, the data sets GSE171739 and GSE9656 were used. Statistical significance was assessed using the ImFit function of the R package Linear Models for Microarray (Limma) as previously described (37). False discovery rates <0.1 were considered significant.
RESULTS
BMSC-derived IL-6 causes IgM hypersecretion by WM cells via IL-6R-JAK-STAT3
[00298] Since WM is characterized by BM infiltration with malignant lymphoplasmacytic cells with increased synthesis of IgM (1,3), we tested whether BMSCs affected IgM secretion by MWCL-1 WM cells. HS-27A BMSCs were cocultured with MWCL-1 cells for 72 hours, and IgM levels were measured in cell culture supernatants. MWCL-1 cells, but not HS-27A BMSCs, secreted IgM into the supernatant, and coculture with HS-27A BMSCs led to an increase in IgM secretion (FIG. 13 A).
[00299] Since IL-6 signaling was previously linked to IgM production and secretion in WM cells (25,38), the cocultures were tested for the presence of the cytokine. HS-27A BMSCs, but not MWCL-1 cells, secreted IL-6, and coculture of these cells with WM cells increased IL-6 levels (FIG. 13B). In an analysis of its effects on WM cells, IL-6 showed minimal impact on the viability of MWCL-1 cells (FIG. 13C). However, IL-6 specifically caused phosphorylation of STAT3, and enhanced IgM secretion in MWCL-1 cells, whereas other pathways were much less affected (FIG. 13D, E). IL-6-mediated IgM secretion in WM cells was inhibited by treatment with the IL-6R antibody tocilizumab, pan-JAK inhibitor PF- 06263276, or STAT3 inhibitor BP-1-102 (FIG. 13F). Of note, viability of MWCL-1 cells was not affected by these inhibitors (FIG. 19). These findings suggest that the effects of these
inhibitors on IgM secretion in MWCL-1 cells were a direct result of activation of the intracellular signaling, independent of reduced cell viability.
[00300] These data suggest that BMSC-denved IL-6 upregulates IgM secretion in WM cells via the IL-6R-JAK-STAT3 pathway.
BMSC-derived IL-6 increases CXCR4 cell surface expression in WM cells via IL-6R- JAK-STAT3 signaling and enhances WM cell adhesion to BMSCs
[00301] The CXCR4/CXCL12 axis plays an essential role in the homing of malignant cells to the protective niche of the BM (24,39,40), and CXCR4/CXCL12 axis expression is upregulated in malignant cells and BM of patients with WM (24,34,35). To confirm and extend these findings, expression of CXCR4 in several publicly available gene expression data sets was analyzed (GSE171739 and GSE9656). CXCR4 expression was significantly upregulated in B cells derived from the BM of patients with WM compared with peripheral B cells from healthy donors (FIG. 14 A), suggesting that the BM microenvironment may have a direct impact on CXCR4 expression in WM cells.
[00302] Notably, whereas MWCL-1 cells alone expressed medium CXCR4 levels (MFI 1500-2000), coculture with HS-27A BMSCs significantly increased CXCR4 surface expression in MWCL-1 cells, with a more pronounced effect in the adherent cell population (MFI 8500 -10000) (FIG. 14B). This increase was inhibited with an IL-6R antibody, suggesting dependence on IL-6 signaling. CXCR4 surface expression was also increased in MWCL-1 cells stimulated with soluble IL-6 and this enhance can be blocked by tocilizumab, the pan-JAK inhibitor BP-1-102, and the STAT-3 inhibitor PF-06263276 (FIG. 14C).
[00303] As overexpression of CXCR4 in WM cells has been shown to increase cellular adhesion to BMSCs (41), and IL-6 enhances CXCR4 surface expression in WM cells, we explored whether increased IL-6 exposure would increase WM cell adhesion to BMSCs. Pretreatment of MWCL-1 cells with soluble IL-6 for 24 hours significantly promoted their adhesion to BMSCs (FIG. 14D). These findings indicate that BMSC-derived IL-6 enhances CXCR4 surface expression in WM cells via the IL-6R-JAK-STAT3 axis, increasing their adhesion to BMSCs.
BMSC-induced resistance of WM cells to B-cell- targeted therapies
[00304] The crosstalk between malignant cells and the BM microenvironment was previously reported to cause drug resistance in various malignant cells (21,30,32,39,40,42). We explored whether BMSCs also conferred resistance of WM cells to different B-cell- targeted drugs. MWCL-1 cells were treated with various B-cell-targeted inhibitors both in mono- and in coculture with BMSCs, and apoptosis, viability, and IgM secretion were
measured. B-cell-targeted drugs in current use for treatment of patients with WM (BTK inhibitors ibrutinib and zanubrutinib) (14,15) or in/under review ongoing clinical trial for WM (BTK inhibitors evobrutinib, pirtobrutinib, nemtabrutinib; BCL-2 inhibitor venetoclax) (NCT03740529, NCT03162536, NCT02677324) were included in our study. All B-cell- targeted inhibitors tested led to a dose-dependent increase in apoptosis and decreased viability of MWCL-1 cells (FIG. 20A-F). Coculture with HS-27A BMSCs significantly reduced apoptosis and preserved the viability of MWCL-1 cells treated with B-cell-targeted inhibitors (FIG. 20A-F). Additionally, all tested B-cell-targeted drugs decreased IgM secretion by MWCL-1 cells in a dose-dependent manner, whereas HS-27A BMSCs coculture significantly reduced the drug-induced reduction of IgM secretion (FIG. 21A-F). Similarly, HS-5 BMSCs also reduced the sensitivity of MWCL-1 cells to B-cell-targeted drugs (ibrutinib and zanubrutinib) (FIG. 22A-D).
[00305] Our data indicate that BMSCs confer resistance of WM cells to all tested B-cell- targeted inhibitors.
Mavorixafor causes disruption of WM cell migration and adhesion to BMSCs
[00306] Because BMSC coculture induced upregulation of CXCR4 surface expression in WM cells and conferred resistance to different B-cell-targeted inhibitors, we sought to test whether these 2 observations were connected. We speculated that pharmacological blockage of the CXCR4/CXCL12 axis could disrupt the communication between WM cells and BMSCs and enhance sensitivity to B-cell-targeted inhibitors. MWCL-1 cells were premcubated with mavorixafor, an orally available CXCR4 antagonist that is currently being evaluated in clinical trials for patients with WHIM syndrome (NCT03995108), WM (NCT04274738) and SCN/CIN (NCT04154488), followed by the assessment of the percentage of MWCL-1 cells adhering to BMSCs. A dose-dependent decrease in adhesion of WM cells to BMSCs was observed after pretreatment with mavorixafor (FIG. 15A). The tested concentrations and durations (4 hours) were not sufficient to induce cytotoxicity in the MWCL-1 cells (data not shown). The effects of mavorixafor on the migration of WM cells in response to exogenous CXCL12, as well as to CXCL12 constitutively secreted by HS-27A BMSCs, were also assessed. Pretreatment of MWCL-1 cells with mavorixafor significantly inhibited their migration toward a CXCL12 gradient or BMSC-secreted CXCL12 (-700- 1000 pg/mL) (FIG. 15B, C). Lastly, since CXCL12-induced Ca2+ mobilization was associated with cell migration (43), we tested the effect of mavorixafor on CXCL12-induced Ca2+ influx in MWCL-1 cells. Mavorixafor blocked CXCL12-mediated Ca2+ mobilization in MWCL-1 cells
in a dose-dependent manner (FIG. 15D). These findings indicate that mavorixafor disrupts the migration and adhesion of WM cells to BMSCs.
Mavorixafor enhances antitumor activity of B-cell-targeted inhibitors in WM cells and overcomes BMSC-induced drug resistance
[00307] Next, we asked whether the disruption of WM cell adhesion to BMSCs by mavorixafor restores sensitivity to B-cell-targeted inhibitors. MWCL-1 cells were pretreated with mavorixafor alone or in combination with different B-cell-targeted inhibitors and cultured alone or together with HS-27A BMSCs. Apoptosis and viability were measured after 48 to 72 hours. Mavorixafor alone caused a minor increase in apoptosis of MWCL-1 cells (FIG. 16A-F). The combination of mavorixafor with B-cell-targeted inhibitors led to a further increase in apoptosis of MWCL-1 cells in monoculture (without stromal cells). Chou and Talalay analysis confirmed synergistic activity in most of the dose combinations (CK1.0, FIG. 16A-F). These data suggest that mavorixafor enhances antitumor activity of all tested therapeutic agents. To further confirm this finding, MWCL-1 cells were cotreated with mavorixafor and ibrutinib, and the expression of proapoptotic proteins was analyzed by immunoblotting. Mavorixafor alone had minor effects on the cleavage of caspase-3 and PARP; however, combination with ibrutinib resulted in an increase in proteolytic cleavage of caspase-3 and PARP in MWCL-1 cells (FIG. 16G).
[00308] MWCL-1 cells, in the presence of BMSCs, showed resistance to apoptosis induced by all B-cell-targeted inhibitors tested. The addition of mavorixafor restored the sensitivity of MWCL-1 cells to all tested drugs (FIG. 17A-F). Of note, mavorixafor alone, at tested concentrations, had much weaker effects on apoptosis of BMSCs in a WM cell-BMSC cocultured model (FIG. 23A-B). To further explore the molecular mechanisms by which mavorixafor restored sensitivity to ibrutinib in the context of the BM microenvironment, we assessed the expression of proapoptotic proteins in MWCL-1 cells cultured with HS-27A BMSCs. As in monoculture, the combination of the 2 drugs led to a further enhanced proteolytic cleavage of caspase-3 and PARP in MWCL-1 BMSC cocultures (FIG. 17G).
[00309] Our data suggest that mavorixafor synergizes with B-cell-targeted inhibitors to enhance cytotoxicity in WM cells by inducing proapoptotic pathways and overcomes BMSC- mediated resistance to these drugs.
Mavorixafor as a single agent or in combination with B-cell-targeted therapies inhibits BMSC-induced IgM hypersecretion
[00310] Since lowering of serum IgM is a primary outcome of WM therapy, we next asked whether mavorixafor as a single agent or in combination with B-cell-targeted agents could
disrupt BMSC-mediated IgM hypersecretion by WM cells. MWCL-1 cells were preincubated with mavorixafor, B-cell-targeted inhibitors, or both, and cultured with or without HS-27A BMSCs, followed by supernatant IgM measurements after 48 or 72 hours. Mavorixafor alone inhibited BMSC-induced IgM hypersecretion in MWCL-1 cells in a dose-dependent fashion, while combination of mavorixafor with all tested B-cell-targeted inhibitors led to a further decreased BMSC-induced IgM hypersecretion in MWCL-1 cells (FIG. 18A-G).
[00311] Taken together, our data indicate that mavorixafor inhibits BMSC-mediated IgM hypersecretion and synergizes with all tested B-cell-targeted inhibitors to more effectively reduce IgM hypersecretion caused by BMSCs.
DISCUSSION
[00312] Despite significant advances in our understanding of the pathophysiology' and treatment of WM, it remains an incurable disease. Current therapeutic options for WM rely on the use of drugs targeting malignant cells directly, including BTK inhibitors (ibrutinib and zanubrutinib), anti-CD20 antibodies (rituximab), chemotherapeutic drugs, or combinations thereof (14,15). However, the infiltration of BM by malignant lymphoplasmacytic cells and crosstalk with the BM microenvironment is thought to strongly contribute to pathogenesis and resistance to therapy in WM (23-25,28). It is therefore important to develop a therapeutic strategy' that also disrupts the BM microenvironment. In this study, we aimed to decipher the crosstalk between WM cells and BMSCs in an in vitro coculture model. We also aimed to explore the effects of a novel combination therapy utilizing mavorixafor, an orally available CXCR4 antagonist, with various B-cell-targeted inhibitors to target WM cells in the BM milieu.
[00313] IL-6, an important cytokine that is mainly secreted by stromal cells in the tumor microenvironment, plays a key role in promoting proliferation, angiogenesis, metastasis, and drug resistance of various malignant cells, including DLBCL, MM, and MCL (33,44,45). In patients with WM, IL-6 levels are elevated in the BM and serum, and this increase is associated with increased IgM secretion by WM cells (22,25). Blockage of IL-6R by tocilizumab reduces IgM secretion and tumor growth in a WM mouse xenograft model (26). Here, we provide evidence that BMSCs upregulate IL-6 secretion when cocultured with WM cells. This interaction enhances CXCR4 cell surface expression in WM cells through JAK- STAT3 signaling, ultimately causing increased adhesion to the BMSCs and increased IgM secretion. Finally, we directly link CXCR4 cell surface upregulation in WM cells to resistance to multiple B-cell-targeted inhibitors — those in use (BTK inhibitors ibrutinib and
zanubrutinib) and those being studied for the treatment of WM (BTK inhibitors evobrutinib, pirtobrutinib, and nemtabrutinib; BCL-2 inhibitor venetoclax).
[00314] IL-6 was previously suggested to boost CXCR4 cell surface expression and increase CXCL12-driven cell migration in astroglia (46). In the context of WM, publicly available data sets confirm increased CXCR4 expression in BM-derived B-cells from patients with WM vs peripheral B-cells from healthy donors. Experimental overexpression of CXCR4 in WM cell lines increased tumor infiltration into BM and other organs, accelerated disease progression, decreased survival, and increased IgM secretion upon transplantation into severe combined immunodeficient (SCID)Zbeige (Bg) mice (41). Conversely, monoclonal anti- CXCR4 antibody ulocuplumab reduced tumor infiltration in BM, spleen, and lymph nodes in a mouse xenograft model with human WM cells (41). Furthermore, similar in vitro cocultures using BMSCs and non-Hodgkin lymphoma or CML cells also showed increased CXCR4 surface expression, promoting growth, migration, and adhesion of malignant cells to BMSCs as well as resistance to anti-cancer drugs (31,40). Besides its role in promoting the adhesion of WM cells to BMSCs, increased CXCR4 cell surface expression in WM cells may prolong and sustain intracellular signaling via its ligand CXCL12, which is constitutively secreted by BMSCs. This intracellular signaling may promote the drug resistance observed in our WM cells-BMSC coculture model. Supporting this assumption, CXCL12 was previously shown to enhance and sustain extracellular signal-regulated kinase and PI3K-Akt activation in WM cells expressing CXCR4WWvl and protect cells against apoptosis caused by various anticancer drugs (i.e., ibrutinib, bendamustine, fludarabine, bortezomib, and idelalisib) (11,12). Complex crosstalk of the CXCL12/CXCR4 axis with other intracellular signaling pathways also promoted drug resistance in numerous cancers (47). Collectively, our data underline the tight connection between WM cells and BMSCs and its importance in cell adhesion, IgM secretion, and resistance to therapeutic agents. These results also suggest that disruption of the WM cells-BMSC interaction — for example, by targeting the CXCR4/CXCL12 axis and disrupting the protective BM niche — is a promising therapeutic strategy for treating WM.
[00315] To test if targeting the CXCR4/CXCL12 axis disrupts the communication between WM cells and BMSCs to overcome drug resistance, we combined different B-cell-targeted inhibitors with mavorixafor in the presence and absence of BMSCs. Mavorixafor, a first-in- class, orally available small-molecule antagonist of CXCR4, is currently being studied in clinical trials for the treatment of patients with WHIM syndrome, WM, and SCN/CN. Our data showed that mavorixafor as a single agent directly induced apoptosis in WM cells and combining mavorixafor with B-cell-targeted inhibitors synergistically induced apoptosis in
WM cells, likely by inducing PARP and caspase-3. This synergy may be because these drugs target distinct pathways in WM cells: B-cell-targeted inhibitors used in our assay target BTK or BCL-2, while mavorixafor targets CXCR4. In line with our observation, high-affinity CXCR4 antagonist (BKT140) or monoclonal antibody anti-CXCR4 (ulocuplumab) directly inhibits proliferation, increases apoptosis, and enhances antitumor activity of several anticancer drugs in various lymphoma/leukemia cell lines (39-41). Our data provide evidence that blocking the CXCR4/CXCL12 axis with mavorixafor is an effective way to overcome BMSC-induced resistance to B-cell-targeted inhibitors and to target WM in the BM niche. Mechanistically, mavorixafor blocked the CXCL12- induced calcium mobilization, homing of WM cells to CXCL12-secreted BMSCs, and adhesion of WM cells to BMSCs; it is also likely that mavorixafor enhanced PARP and caspase-3 cleavage caused by B-cell-targeted inhibitors in the presence of BMSCs. In contrast to WM cells, BMSCs were less sensitive to mavorixafor treatment, suggesting a potential therapeutic utility of mavorixafor in WM.
[00316] Mavorixafor is well tolerated, with no treatment-related serious adverse events in patients with WHIM syndrome (NCT03005327). Mavorixafor was also reported to block stromal-induced migration of ALL cells, disrupt preestabhshed adhesion to stroma, and increase sensitivity' to chemotherapeutic drugs (vincristine) and targeted therapy (nilotinib) (20). BMSC-derived CXCL12 was shown to activate adhesion-related signaling (e.g., focal adhesion kinase [FAK], proto-oncogene non-receptor tyrosine [SRC] kinase) and enhance the expression of adhesion molecules (e.g., a4(31 integrins) in neoplastic and normal hematopoietic stem cells, facilitating homing and adhesion to BMSCs (21,48,49). Future studies are required to address whether mavorixafor inhibits BMSC-mediated upregulation of adhesion molecules, reducing their adhesion to BMSCs, and sensitizing them to therapeutic agents.
[00317] Since overproduction of IgM is a hallmark of WM (1,3), we investigated the effect of mavorixafor as a single agent or in combination with B-cell-targeted inhibitors on IgM secretion. In these studies, mavorixafor inhibited BMSC-induced IgM hypersecretion and synergized with tested therapeutic agents. In previous studies, IL-6 levels were elevated in the sera and BM of patients with WM, and it facilitated IgM secretion in WM cells (22,25). However, addition of mavorixafor had no significant effect on IL-6 release in our WM cell- BMSC coculture model (FIG. 24), suggesting that mavorixafor inhibited IgM hypersecretion independently of IL-6, potentially by disrupting cell-cell adhesion. BMSCs activated STAT3 signaling directly via cell-cell adhesion or indirectly through secreted factors (e.g., IL-6 or IL-21), facilitating IgM secretion in WM cells (21,25,28). Future experiments will have to
resolve the question whether mavorixafor reduces IgM hypersecretion via interference with BMSC-induced STAT3 activation.
[00318] Collectively, our data show that mavorixafor has several effects in WM cells: (1) mavorixafor synergizes with B-cell-targeted inhibitors to enhance apoptosis, (2) disrupts the crosstalk between WM cells and BMSCs and restores the sensitivity of WM cells to B-cell- targeted inhibitors, and (3) inhibits BMSC-induced IgM hypersecretion in WM and synergizes with B-cell-targeted drugs in this context. Our data provide strong experimental support for the potential use of mavorixafor as a single agent or in combination with B-cell- targeted drugs for the treatment of WM and possibly for other malignancies. Supporting this conclusion, cotreatment with mavorixafor and nilotinib prolonged the survival of C57BL6 mice transplanted with mouse Bcr/Abl+ ALL cells (20). Similarly, a combination of mavorixafor and vincristine significantly reduced the number of leukemic cells at extramedullary sites in a mouse xenograft model of a human ALL cells (20). A clinical trial evaluating the efficacy of mavorixafor in combination with ibrutinib in patients with WM with KD<8<8L265P and CXCR4wlSM mutations is currently ongoing (NCT04274738).
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Example 3: Mavorixafor enhances apoptosis of tumor cells treated with ibrutinib or venetoclax in diffuse large B-cell lymphoma, follicular lymphoma, mantle cell lymphoma, and chronic lymphocytic leukemia
[00319] Despite advances in therapies for B-cell lymphoma, patients may still develop resistance and often relapse. Contributing factors may include interactions between lymphoma cells (LCs) or leukemia cells and bone marrow microenvironment (BMM). Overexpression of CXCR4WI and its ligand CXCL12 promote LC-BMM interactions, contributing to disease severity in lymphomas or leukemia such as diffuse large B-cell lymphoma (DLBCL), chronic lymphocytic leukemia (CLL), follicular lymphoma (FL), and mantle cell lymphoma (MCL). Mavorixafor is an investigational oral CXCR4 antagonist being evaluated in combination with the Bruton tyrosine kinase (BTK) inhibitor ibrutinib in patients with Waldenstrom’s macroglobulinemia (WM). In preclinical models of A7}7J<SAL2fi5P CXCR4WV WM, mavorixafor restored sensitivity of WM cells to B-cell targeted therapies in coculture of WM cells and bone marrow stromal cells (BMSCs); however, the effects of mavorixafor on other lymphomas with CXCR4WIhave not been evaluated. We report here the effects of mavorixafor alone or in combination with B-cell targeted therapies on LCs in an in vitro preclinical model and assess the role of BMM in the pathogenesis of B-cell lymphomas in an in vitro coculture model of LCs and BMSCs.
[00320] As shown in FIG. 28, mavorixafor enhances apoptosis of lymphoma and leukemia cells when combined with venetoclax or ibrutinib. Panel (A) shows apoptosis of OCI-LY19 (DLBCL) cells and panel (B) shows D0HH2 (FL) cells treated with mavorixafor in combination with venetoclax. Panel (C) shows apoptosis of OCI-LY19 (DLBCL) cells, DOHH2 (FL) cells (Panel (D)), and MEC-1 (CLL) cells (Panel (E)) treated with mavorixafor in combination with ibrutinib. Combination of mavorixafor with venetoclax or ibrutinib significantly increased apoptosis in lymphoma and leukemia cells compared to ibrutinib or venetoclax alone in the majority of dose combinations.
[00321] FIG. 29 shows apoptosis of lymphoma cells treated with venetoclax or ibrutinib with or without BMSC coculture. Apoptosis of OCI-LY19 (DLBCL) cells (A), DOHH2 (FL) cells (B) and MINO (MCL) cells (C) are shown with or without coculture with HS-27A BMSCs in response to venetoclax. Apoptosis of D0HH2 (FL) cells with or without coculture with HS-27A BMSCs in response to ibrutinib (D). P values <.05 are considered statistically significant and set as follows: ns, not significant; * — P< 05; ** — P<.01; *** — P< 001.
[00322] FIG. 30 shows apoptosis of lymphoma cells after treatment with venetoclax or ibrutinib ± mavorixafor with or without BMSC coculture. More specifically, the figure shows apoptosis of OCLLY19 (DLBCL) cells (A), DOHH2 (FL) cells (B), MINO (MCL) cells (C) with or without coculture with HS-27A BMSCs in the presence of venetoclax, and apoptosis of DOHH2 (FL) cells (D) with or without coculture with HS-27A BMSCs in the presence of ibrutinib. These data show that mavorixafor restores sensitivity of lymphoma cells to venetoclax and ibrutinib in BMSC cocultures. P values <.05 are considered statistically significant and set as follows: ns, not significant; * — P< 05; ** — P< 01; *** — P< 001.
[00323] FIG. 31 shows cell migration of lymphoma cells to CXCL12 with or without mavorixafor pretreatment. Effects of increasing concentrations of mavorixafor on migration of OCI-LY19 (DLBCL) cells (A), D0HH2 (FL) cells (B) toward CXCL12. P values <.05 are considered statistically significant and set as follows: ns, not significant; * — P< 05; ** — P< 01; ****— P< 0001.
[00324] Bioinformatic analysis of publicly available gene expression datasets GSE11318 and GSE32918 showed patients with DLBCL and CXCR4^ have significantly inferior survival probability compared with those with CXCR4i(™ (P< 001 and P< 05, respectively). In vitro studies assessing effects of targeting CXCR4 with mavorixafor showed apoptosis of CXCR4+ LCs OCILY19 (DLBCL), MEC1 (CLL), MINO (MCL), and DOHH2 (FL) cells increased by ~10%— 60%. The apoptosis of LCs was further enhanced by ~5% to 60% when
treated with mavorixafor in combination with ibrutinib or venetoclax compared to ibrutinib or venetoclax alone. Coculture of LCs with BMSCs reduced the sensitivity of LCs to apoptosisinducing effects of ibrutinib and venetoclax. Combining mavorixafor with ibrutinib or venetoclax restored sensitivity of LCs to apoptosis-inducing effects of the tested B-cell targeted inhibitors. Mavorixafor also inhibited migration of LCs toward CXCL12, suggesting prevention of the homing of LCs to protective niche.
[00325] Overall, our findings suggest the contribution of CXCR4WT to pathogenicity of LCs. This is the first in vitro study to show that reduced sensitivity of LCs against B-cell- targeted therapies conferred by BMSCs can be overcome by inhibition of the CXCL12- CXCR4 axis with mavorixafor. Our study provides supporting evidence for further exploration of mavorixafor alone or in combination with other B-cell-targeted therapies in the treatment of lymphomas and leukemias. Further studies using additional LC lines and/or primary patient cells are warranted to support these findings.
Claims
1. A method of treating Waldenstrom's macroglobulinemia (WM) in a patient in need thereof, comprising administering to the patient an effective amount of mavorixafor, or a pharmaceutically acceptable salt thereof; in combination with an effective amount of a BTK inhibitor selected from tirabrutinib, evobrutinib, fenebrutinib, poseltinib, vecabrutinib, spebrutinib, LCB 03-0110, LFM-A13, PCI 29732, PF 06465469, (-)-Terreic acid, BMX-IN-
1. BI-BTK-1 , BMS-986142, CGT-1746, GDC-0834, olmutinib, PLS-123, PRN1008, RN-486, LOXO-305 (pirtobrutinib), and ARQ-531 (nemtabrutinib; MK-1026); or a pharmaceutically acceptable salt thereof; and wherein the WM has a CXCR4WI genomic status (with WT indicating wild type).
2. The method of claim 1, wherein the WM is selected from one of the following genomic groups: 1) MYD88L265 CXCR4W I (with WT indicating wild type), and 2) MYD88WTCXCR4WT.
3. The method of claim 1, wherein the MYD88L265 mutation is MYD88L265P
4. The method of any one of claims 1-3, wherein the mavorixafor or a pharmaceutically acceptable salt thereof is co-administered with a BTK inhibitor selected from evobrutinib, LOXO-305, and ARQ-531, or a pharmaceutically acceptable salt thereof.
5. The method of any one of claims 1-4, wherein the patient has previously received at least one course of treatment with a BTK inhibitor, or a pharmaceutically acceptable salt thereof, before treatment with mavorixafor, or a pharmaceutically acceptable salt thereof.
6. The method of any one of claims 1-5, wherein the patient's WM is resistant to treatment with a BTK inhibitor.
7. The method of claim 5 or 6, wherein the patient has previously received at least one course of treatment with ibrutinib before treatment with mavorixafor or a pharmaceutically acceptable salt thereof.
8. The method of claim 7, wherein the patient’s WM has shown disease progression.
9. A method of treating Waldenstrom's macroglobulinemia (WM) in a patient in need thereof, comprising administering to the patient an effective amount of mavorixafor, or a pharmaceutically acceptable salt thereof; in combination with an effective amount of a BCL- 2 inhibitor or BH3-mimetic; or a pharmaceutically acceptable salt thereof; and wherein the WM has a CXCR4WI genomic status (with WT indicating wild type).
10. The method of claim 9, wherein the BCL-2 inhibitor or BH3 mimetic is selected from venetoclax, BGB-11417, LOXO-338, LP-108, S55746, APG-2575, APG-1252 (pelcitoclax), AT-101, TQB3909, obatoclax, GDC-0199, ABT-737, and navitoclax (ABT-263); or a pharmaceutically acceptable salt thereof.
11. The method of claim 9, wherein the mavorixafor or pharmaceutically acceptable salt thereof is co-administered with venetoclax or a pharmaceutically acceptable salt thereof.
12. The method of claim 9, wherein the mavorixafor or pharmaceutically acceptable salt thereof is co-administered with ABT-737 or navitoclax (ABT-263); or a pharmaceutically acceptable salt thereof or a pharmaceutically acceptable salt thereof.
13. The method of any one of claims 9-12, wherein the WM is selected from one of the following genomic groups: 1) MYD88L265 CXCR4WT (with WT indicating wild type), and 2) MYDSS^CXCR ^.
14. The method of any one of claims 9-12, wherein the MYD88L265 mutation is MYD88L265P.
15. The method of any one of claims 1-14, wherein mavorixafor or a pharmaceutically acceptable salt thereof is administered to the patient in a dose of about 100 mg to about 1000 mg per day.
16. The method of any one of claims 1-14, wherein mavorixafor or a pharmaceutically acceptable salt thereof is administered to the patient in a dose of about 200 mg to about 600 mg per day.
17. The method of any one of claims 1-14, wherein mavorixafor or a pharmaceutically acceptable salt thereof is administered to the patient in a dose of about 200 mg, about 400 mg, or about 600 mg per day.
18. The method of any one of claims 1-17, wherein mavorixafor or a pharmaceutically acceptable salt thereof is administered to the patient in a single daily dose (QD).
19. The method of any one of claims 1 -18, wherein the method provides about a 75-95% percent reduction in IgM from baseline.
20. The method of any one of claims 1-19, wherein the method reduces IgM to within 2 times the normal range for a non-diseased adult human (non-WM patient).
21. The method of any one of claims 1-20, wherein the mavorixafor, or a pharmaceutically acceptable salt thereof, and the BCL-2 inhibitor, BH3 mimetic, or a pharmaceutically acceptable salt thereof, act synergistically.
22. The method of any one of claims 1-20, further comprising the step of obtaining a biological sample from the patient and measuring the amount of a disease-related biomarker.
23. The method of claim 22, wherein the biological sample is a blood sample.
24. The method of claim 23, wherein the disease-related biomarker is selected from circulating CD8+ T cells or the ratio of CD8+ T cells:Treg cells.
25. The method of claim 24, wherein the disease-related biomarker is IgM and/or Hgb.
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