WO2023172640A1 - Traitements pour la macroglobulinémie de waldenström mutante unique - Google Patents

Traitements pour la macroglobulinémie de waldenström mutante unique Download PDF

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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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mavorixafor
cells
pharmaceutically acceptable
acceptable salt
cxcr4
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Chi Nguyen
Art Taveras
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X4 Pharmaceuticals, Inc.
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/415—1,2-Diazoles
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/47—Quinolines; Isoquinolines
    • A61K31/4709—Non-condensed quinolines and containing further heterocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/506—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim not condensed and containing further heterocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/63—Compounds containing para-N-benzenesulfonyl-N-groups, e.g. sulfanilamide, p-nitrobenzenesulfonyl hydrazide
    • A61K31/635—Compounds containing para-N-benzenesulfonyl-N-groups, e.g. sulfanilamide, p-nitrobenzenesulfonyl hydrazide having a heterocyclic ring, e.g. sulfadiazine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • 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

La présente invention concerne des méthodes de traitement du cancer, dans lesquelles un inhibiteur de CXCR4 tel que le mavorixafor (X4P-001) ou un sel pharmaceutiquement acceptable de celui-ci ou une composition pharmaceutique de celui-ci est administré en combinaison avec un agent thérapeutique supplémentaire, tel qu'un inhibiteur de BTK ou BCL-2 ou un mimétique de BH3.
PCT/US2023/014834 2022-03-08 2023-03-08 Traitements pour la macroglobulinémie de waldenström mutante unique WO2023172640A1 (fr)

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WO2023240258A1 (fr) * 2022-06-10 2023-12-14 X4 Pharmaceuticals, Inc. Polythérapies pour le traitement de troubles hyperprolifératifs

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Publication number Priority date Publication date Assignee Title
US20200138804A1 (en) * 2017-06-21 2020-05-07 X4 Pharmaceuticals, Inc. Methods for treating cancer
WO2021127496A1 (fr) * 2019-12-18 2021-06-24 X4 Pharmaceuticals, Inc. Traitements combinés pour la macroglobulinémie de waldenstrom
WO2022031330A1 (fr) * 2020-08-03 2022-02-10 Curis, Inc. Compositions et méthodes de traitement de maladies et de troubles

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Publication number Priority date Publication date Assignee Title
US20200138804A1 (en) * 2017-06-21 2020-05-07 X4 Pharmaceuticals, Inc. Methods for treating cancer
WO2021127496A1 (fr) * 2019-12-18 2021-06-24 X4 Pharmaceuticals, Inc. Traitements combinés pour la macroglobulinémie de waldenstrom
WO2022031330A1 (fr) * 2020-08-03 2022-02-10 Curis, Inc. Compositions et méthodes de traitement de maladies et de troubles

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2023240258A1 (fr) * 2022-06-10 2023-12-14 X4 Pharmaceuticals, Inc. Polythérapies pour le traitement de troubles hyperprolifératifs

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