WO2023285677A1 - Combinaisons pharmaceutiques pour le traitement du cancer - Google Patents

Combinaisons pharmaceutiques pour le traitement du cancer Download PDF

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WO2023285677A1
WO2023285677A1 PCT/EP2022/069908 EP2022069908W WO2023285677A1 WO 2023285677 A1 WO2023285677 A1 WO 2023285677A1 EP 2022069908 W EP2022069908 W EP 2022069908W WO 2023285677 A1 WO2023285677 A1 WO 2023285677A1
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tyr
cys
pro
xaa
inhibitor
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Johann Zimmermann
Francesco Bertoni
Jesus Alberto ARRIBAS CARMENA
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Spexis Ag
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides
    • A61K38/04—Peptides having up to 20 amino acids in a fully defined sequence; Derivatives thereof
    • 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
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents

Definitions

  • the present invention relates to pharmaceutical combinations comprising a peptidic CXCR4 inhibitor and a Bruton’s tyrosine kinase (BTK) inhibitor and their use in a method for the prevention, delay of progression or treatment of cancer in a subject.
  • BTK tyrosine kinase
  • chemotherapeutic agents include alkylating agents, nucleotide analogues such as gemcitabine and capecitabine, platinum agents such as cisplatin or oxaliplatin, topoisomerase I inhibitors such as camptothecin or irinotecan, topoisomerase II inhibitors such doxorubicin or mitoxanthrone, vinca alkaloids such as vinorelbine, and modulators of tubulins such as taxanes (I. Ojima et al. Exp. Opin. Ther. Patents 2016, 26, 1-20) and eribulin (U. Swami et al. Mar. Drugs 2015, 13, 5016-5058).
  • Chemotherapy can be effective, however, often there are severe side effects, e.g., vomiting, low white blood cells (WBC), loss of hair, loss of weight and other toxic effects. Because of the extremely toxic side effects, many cancer patients cannot successfully finish a complete chemotherapy therapy. Chemotherapy-induced side effects have a significant impact on the quality of life of patients affected by cancer and may dramatically influence individual compliance with treatment. Adverse side effects associated with chemotherapeutic agents are in many cases the major dose-limiting toxicity (DLT) in the administration of these drugs. Emerging tumor resistance during or after chemotherapy (N. Vasan et al.
  • DLT dose-limiting toxicity
  • one drug may inhibit, activate or induce the production of enzymes involved in a metabolic route of elimination of the other drug.
  • two drugs when two drugs are administered to treat the same condition, it is unpredictable whether each will complement, have no effect on, or interfere with, the therapeutic activity of the other in a subject.
  • the interaction between two drugs affect the intended therapeutic activity of each drug, but the interaction may increase the levels of toxic metabolites.
  • the interaction may also heighten or lessen the side effects of each drug.
  • it is unpredictable what change, either deterioration or improvement, will occur in the side effect profile of each drug. Additionally, it is difficult to accurately predict when the effects of the interaction between the two drugs will become manifest.
  • a combination comprising a peptidic CXCR4 inhibitor and a Bruton’s tyrosine kinase (BTK) inhibitor is useful for the prevention, delay of progression or treatment of cancer, in particular useful for the prevention, delay of progression or treatment of tumors of the hematopoietic and lymphoid tissues.
  • BTK Bruton’s tyrosine kinase
  • the present invention provides a pharmaceutical combination comprising: (a) a peptidic CXCR4 inhibitor; (b) a Bruton’s tyrosine kinase (BTK) inhibitor; and (c) optionally one or more pharmaceutically acceptable diluents, excipients or carriers.
  • a pharmaceutical combination as described herein for use as a medicament.
  • a pharmaceutical combination as described herein for use in a method for the prevention, delay of progression or treatment of cancer in a subject.
  • the present invention provides kit of parts comprising a first container, a second container and a package insert, wherein the first container comprises at least one dose of a medicament comprising a peptidic CXCR4 inhibitor; the second container comprises at least one dose of a medicament comprising a Bruton’s tyrosine kinase (BTK) inhibitor, and the package insert comprises optionally instructions for treating a subject for cancer using the medicaments.
  • BTK tyrosine kinase
  • Parental and resistant lines were derived from the VL51 splenic marginal zone lymphoma model. Cells were exposed (72h) to increasing doses of ibrutinib alone or in combination with increasing doses of POL5551 followed by MTT assay. Figure 2. Combination of the CXCR4 inhibitor POL6326 with BTK inhibitor ibrutinib. Anti-tumor activity of POL6236 was determined in parental lines and resistant lines (IBR-RES) to the BTK inhibitor ibrutinib (Ibru). Parental and resistant lines were derived from the VL51 splenic marginal zone lymphoma model.
  • the subject is a human.
  • pharmaceutically acceptable diluents, excipients or carriers refers to diluents, excipients or carriers that are suitable for use with humans and/or animals without undue adverse side effects (such as toxicity, irritation, and allergic response) commensurate with a reasonable benefit/risk ratio.
  • "Diluents” are agents which are added to the bulk volume of the active agent making up the solid composition. As a result, the size of the solid composition increases, which makes it easier to handle. Diluents are convenient when the dose of drug per solid composition is low and the solid composition would otherwise be too small.
  • Excipients can be binders, lubricants, glidants, coating additives or combinations thereof. Thus, excipients are intended to serve multiple purposes.
  • Carriers can be solvents, suspending agents or vehicles, for delivering the instant compounds to a subject.
  • dose refers to the total amount of an active ingredient (e.g., the peptidic CXCR4 inhibitor or Bruton’s tyrosine kinase (BTK) inhibitor) to be taken each time by a subject (e.g. a human).
  • ORR is a direct measure of drug antitumor activity, which can be evaluated in a single-arm study.
  • the ORR refers to the sum of complete response (CR) and partial response (PR).
  • CBR clinical benefit rate
  • PR partial response
  • SD stable disease
  • complete response CR as used herein in relation to target lesions refers to disappearance of all target lesions. Any pathological lymph nodes (whether target or non- target) must have reduction in short axis to ⁇ 10 mm.
  • CR complete response
  • PR partial response
  • PD progressive disease
  • the sum must also demonstrate an absolute increase of at least 5 mm.
  • the appearance of one or more new lesions is also considered progressions.
  • progressive disease (PD) as used herein in relation to non-target lesions refers to appearance of one or more new lesions and/or unequivocal progression of existing non-target lesions. Unequivocal progression should not normally trump target lesion status. It must be representative of overall disease status change, not a single lesion increase.
  • stable disease as used herein in relation to target lesions refers to neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for PD, taking as reference the smallest sum diameters while on study.
  • progression-free survival relates to the duration of time from start of treatment to time of progression or death, whichever occurs first.
  • cancer and “cancerous” as used herein refer to or describe the physiological condition in mammals that is typically characterized by unregulated cell growth.
  • a “tumor” comprises one or more cancerous cells. Examples of cancer include, but are not limited to, tumors of the hematopoietic and lymphoid tissues such as e.g.
  • SLL small lymphocytic leukemia
  • Waldenström's macroglobulinemia lymphoplasmacytic lymphoma
  • hairy cell leukaemia Burkitt lymphoma
  • MZL marginal zone lymphoma
  • SZL splenic marginal zone lymphoma
  • MCL mantle cell lymphoma
  • FL diffuse large B-cell lymphoma
  • CLL chronic lymphocytic leukemia
  • tumors of the hematopoietic and lymphoid tissues which is equivalent to the term “tumours of the haematopoietic and lymphoid malignancies” and is synonymously used herein means tumors that affect the blood, bone marrow, lymph, and lymphatic system.
  • matrix B-cell neoplasm refer to or describe biologically and clinically heterogeneous diseases of the B-lymphatic system. Mature B-cell neoplasms comprise over 90% of lymphoid neoplasms worldwide and there are 4% of new cancers each year.
  • FL follicular lymphoma
  • DLBCL diffuse large B-cell lymphoma
  • drug resistance drug resistance
  • cancer resistant to tumor resistant to
  • tumor of the hematopoietic and lymphoid tissues resistant to are used synonymously herein and refer to or describe a well-known phenomenon that results when cancers become tolerant to pharmaceutical treatments.
  • Cancer drug resistance is a complex phenomenon that is influenced by drug inactivation, drug target alteration, drug efflux, DNA damage repair, cell death inhibition, epithelial–mesenchymal transition (EMT), inherent cell heterogeneity, epigenetic effects, or any combination of these mechanisms (G.
  • Such salts include: (1) acid addition salts, formed with inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, and the like; or formed with organic acids such as acetic acid, propionic acid, hexanoic acid, cyclopentanepropionic acid, glycolic acid, pyruvic acid, lactic acid, malonic acid, succinic acid, malic acid, maleic acid, fumaric acid, citric acid, benzoic acid, 3-(4-hydroxy-benzoyl)benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, 1,2-ethane- disulfonic acid, 2-hydroxyethanesulfonic acid, benzenesulfonic acid, 4-chlorobenzenesulfonic acid, 2-naphthalenesulfonic acid, 4-toluenesulfonic acid, camphorsulfonic
  • the present invention provides a pharmaceutical combination comprising: (a) a peptidic CXCR4 inhibitor; b) a Bruton’s tyrosine kinase (BTK) inhibitor; and (c) optionally one or more pharmaceutically acceptable diluents, excipients or carriers.
  • a pharmaceutical combination comprising: (a) a peptidic CXCR4 inhibitor; b) a Bruton’s tyrosine kinase (BTK) inhibitor; and (c) optionally one or more pharmaceutically acceptable diluents, excipients or carriers.
  • peptidic CXCR4 inhibitor refers to a compound that binds to the CXCR4 receptor and generally antagonizes ligand (CXCL12)-induced signaling and can also act as an inverse agonist or a partial agonist of the CXCR4 receptor (W. Zhang et al., J Biol Chem. 2002, 277(27), 24515-24521).
  • the peptidic CXCR4 inhibitor is a backbone cyclized peptidic CXCR4 inhibitor.
  • the peptidic CXCR4 inhibitor is a backbone cyclized peptidic compound, built up from 16 amino acid residues.
  • the peptidic CXCR4 inhibitor is a backbone cyclized peptidic compound, built up from 16 amino acid residues, or pharmaceutically acceptable salts thereof, of the formula cyclo(-Tyr 1 -His 2 -Xaa 3 -Cys 4 -Ser 5 -Xaa 6 -Xaa 7 -Xaa 8 -Arg 9 -Tyr 10 -Cys 11 -Tyr 12 -Gln 13 -Xaa 14 - Xaa 15 -Pro 16 -) (Ia), in which Xaa 3 is Ala; Tyr; or Tyr(Me); Xaa 6 is Ala or Acc; Xaa 7 is D Pro; D Tyr; or D Tyr(Me); Xaa 8 is Dab; or Orn(iPr); Xaa 14 is Lys; or Lys(iPr); Xaa 15 is D Pro; or D Lys(iPr); wherein Tyr(M
  • the peptidic CXCR4 inhibitor is a backbone cyclized peptidic compound, built up from 16 amino acid residues, or pharmaceutically acceptable salts thereof, of the formula cyclo(-Tyr 1 -His 2 -Xaa 3 -Cys 4 -Ser 5 -Xaa 6 -Xaa 7 -Xaa 8 -Arg 9 -Tyr 10 -Cys 11 -Tyr 12 -Gln 13 -Xaa 14 - Xaa 15 -Pro 16 -) (Ia), in which Xaa 3 is Tyr; or Tyr(Me); Xaa 6 is Ala or Acc; Xaa 7 is D Pro; D Tyr; or D Tyr(Me); Xaa 8 is Dab; or Orn(iPr); Xaa 14 is Lys; or Lys(iPr); Xaa 15 is D Pro; or D Lys(iPr); wherein Tyr(Me
  • the peptidic CXCR4 inhibitor is a backbone cyclized peptidic compound, built up from 16 amino acid residues, or pharmaceutically acceptable salts thereof, of the formula cyclo(-Tyr 1 -His 2 -Xaa 3 -Cys 4 -Ser 5 -Ala 6 -Xaa 7 -Xaa 8 -Arg 9 -Tyr 10 -Cys 11 -Tyr 12 -Gln 13 -Xaa 14 -Xaa 15 -Pro 16 -) (I), in which Xaa 3 is Ala; Tyr; or Tyr(Me); Xaa 7 is D Pro; D Tyr; or D Tyr(Me); Xaa 8 is Dab; or Orn(iPr); Xaa 14 is Lys; or Lys(iPr); Xaa 15 is D Pro; or D Lys(iPr); wherein Tyr(Me) is (2S)-2-amino-3-
  • the peptidic CXCR4 inhibitor is a backbone cyclized peptidic compound, built up from 16 amino acid residues, or pharmaceutically acceptable salts thereof, of the formula cyclo(-Tyr 1 -His 2 -Xaa 3 -Cys 4 -Ser 5 -Ala 6 -Xaa 7 -Xaa 8 -Arg 9 -Tyr 10 -Cys 11 -Tyr 12 -Gln 13 -Xaa 14 -Xaa 15 -Pro 16 -) (I), in which Xaa 3 is Tyr; or Tyr(Me); Xaa 7 is D Pro; D Tyr; or D Tyr(Me); Xaa 8 is Dab; or Orn(iPr); Xaa 14 is Lys; or Lys(iPr); Xaa 15 is D Pro; or D Lys(iPr); wherein Tyr(Me) is (2S)-2-amino-3-(4-
  • the peptidic CXCR4 inhibitor is a backbone cyclized peptidic compound, built up from 16 amino acid residues, or pharmaceutically acceptable salts thereof, selected from the group consisting of cyclo(-Tyr-His-Ala-Cys-Ser-Ala- D Pro-Dab-Arg-Tyr-Cys-Tyr-Gln-Lys- D Pro-Pro-) having a disulfide bond between Cys 4 and Cys 11 , (SEQ ID NO:1) cyclo(-Tyr-His-Tyr-Cys-Ser-Ala- D Pro-Dab-Arg-Tyr-Cys-Tyr-Gln-Lys- D Pro-Pro-) having a disulfide bond between Cys 4 and Cys 11 , (SEQ ID NO:2) cyclo(-Tyr-His-Tyr-Cys-Ser-Ala- D Pro-Or
  • the peptidic CXCR4 inhibitor is selected from the group consisting of cyclo(-Tyr-His-Ala-Cys-Ser-Ala- D Pro-Dab-Arg-Tyr-Cys-Tyr-Gln-Lys- D Pro-Pro-) having a disulfide bond between Cys 4 and Cys 11 , (SEQ ID NO:1), and cyclo(-Tyr-His- Tyr-Cys-Ser-Ala- D Pro-Dab-Arg-Tyr-Cys-Tyr-Gln-Lys- D Pro-Pro-) having a disulfide bond between Cys 4 and Cys 11 , (SEQ ID NO:2), or pharmaceutically acceptable salts thereof.
  • the peptidic CXCR4 inhibitor is cyclo(-Tyr-His- Tyr-Cys-Ser-Ala- D Pro-Dab-Arg-Tyr-Cys-Tyr-Gln-Lys- D Pro-Pro-) having a disulfide bond between Cys 4 and Cys 11 , (SEQ ID NO:2), or pharmaceutically acceptable salts thereof.
  • POL6326 Cyclo(-Tyr-His-Ala-Cys-Ser-Ala- D Pro-Dab-Arg-Tyr-Cys-Tyr-Gln-Lys- D Pro-Pro-) having a disulfide bond between Cys 4 and Cys 11 , (SEQ ID NO:1), is also referred as POL6326 herein or balixafortide.
  • POL6326 is a cyclic synthetic peptide consisting of 16 amino acids and an antagonist of the highly conserved chemokine receptor CXCR4. In vitro receptor binding studies demonstrated a significant affinity of POL6326 for the human CXCR4 receptor, as well as a general lack of significant binding to other potential target receptors.
  • Particularly suitable pharmaceutically acceptable salts of the peptidic CXCR4 inhibitor to be useful in the context of the present invention include the acetates, carboxylic, phosphonic, sulfonic or sulfamic acids, for example acetic acid, propionic acid, octanoic acid, decanoic acid, dodecanoic acid, glycolic acid, lactic acid, fumaric acid, succinic acid, adipic acid, pimelic acid, suberic acid, azelaic acid, malic acid, citric acid, amino acids, such as glutamic acid or aspartic acid, maleic acid, hydroxymaleic acid, methylmaleic acid, cyclohexanecarboxylic acid, adamantanecarboxylic acid, benzoic acid, salicylic acid, 4-aminosalicylic acid, phthalic acid, phenylacetic acid, mandelic acid, cinnamic acid, methane- or ethane-sulfonic acid
  • Suitable inorganic acids are, for example, halogen acids, such as hydrochloric acid, sulfuric acid, or phosphoric acid.
  • BTK tyrosine kinase
  • BTK tyrosine kinase
  • BTK has diverse partner molecules which allows to transmit and amplify signals from a variety of surface molecules, including B-cell receptor (BCR, an antigen receptor), toll-like receptor (TLR; detection of DAMP, PAMP), growth factor and cytokine receptors, and GPCR’s such as chemokine receptors (for example CXCR4/CXCL12).
  • BCR B-cell receptor
  • TLR toll-like receptor
  • GPCR such as chemokine receptors (for example CXCR4/CXCL12).
  • BTK Upon activation, BTK triggers down stream signaling cascades (J. A. Burger; Cancer J.2019, 25 (6), 386 -393; C. Liang et al., Eur. J. Med. Chem.2018, 151, 315–326).
  • BTK (659 amino acids) consists of five domains: The N-terminal Pleckstrin homology (PH) domain, then the proline-rich TEC homology (TH) domain, the SRC homology domains SH3 and SH2 and the C-terminal catalytic kinase domain (T. Wen et al., Leukemia 2020, doi.org/10.1038/s41375-020-01072-6).
  • BTK is an important drug target for B-cell malignancies as well as autoimmune and inflammatory diseases.
  • the term “Bruton’s tyrosine kinase (BTK) inhibitor” relates to structurally diverse compounds which target BTK. Based on their mechanism of action there are three categories of BTK inhibitors: i.
  • the most well-known BTK inhibitors include Ibrutinib (PCI-32765; Imbruvica TM ), Acalabrutinib (ACP-196; Calquence TM ), Zanubrutinib (BGB-3111; Brukinsa TM ), Tirabrutinib (ONO/GS-4059; Velexbru TM ), and Orelabrutinib (ICP-022; Inokai TM ), which all belong to the group of irreversible, covalent inhibitors, binding to Cys481 due to the presence of an ⁇ , ⁇ -unsaturated amide function, and Dasatinib (Sprycel TM ), a kinase inhibitor used for the treatment of imatinib (Glivec)-resistant chronic myelogenous leukemia (CML).
  • PCI-32765 PCI-32765
  • Imbruvica TM Acalabrutinib
  • ACP-196 Calquence TM
  • Dasatinib targets Abl and Src kinases and potently inhibits also BTK at nanomolar concentrations in vitro in kinase assay and in cultured cells (O. Hantschel et al., PNAS 2007, 104 (33), 13283-13288).
  • BTK inhibitors are DTRMWXHS-12 (DTRM-12), CT-1530, TG-1701 (EBI-1449, SHR-1459), M-7583, TAS-5315, SN-1011 (XNW-1011), BIIB091, AS-0871, HWH-486, HZA-018, JNJ64264681, AS- 1763, FCN-647, ZXBT1055, ZXBT1058, PRN473, Pirtobrutinib (LOXO-305) and Abivertinib (AC0010).
  • a BTK inhibitor is selected from the group consisting of irreversible covalent inhibitors, reversible covalent- and reversible non-covalent inhibitors.
  • the BTK inhibitor is an irreversible covalent inhibitor.
  • the group of irreversible covalent BTK inhibitors consists of Ibrutinib (PCI-32765; Imbruvica TM ), Acalabrutinib (ACP-196; Calquence TM ), Zanubrutinib (BGB-3111; Brukinsa TM ), Tirabrutinib (ONO/GS-4059; Velexbru TM ), Olmutinib (BI1482694; HM-61713; Olita TM ), Spebrutinib (CC-292/AVL-292), Orelabrutinib (ICP-022; Inokai TM ), Poseltinib (HM-71224; LY- 3337641), Evobrutinib (M2951), Branebrutinib (BMS-986195), Remibrutinib (LOU064), AC- 0058TA, Tolebrutinib (PCI
  • the group of reversible covalent BTK inhibitors consists of Rilzabrutinib (PRN-1008).
  • the group of reversible non-covalent BTK inhibitors consists of MK-1026 (ARQ-531), Vecabrutinib (SNS-062), Fenebrutinib (GDC-0853), RN486, Luxeptinib (CG-806), Pirtobrutinib (LOXO-305), BMS-986142, TAK-020, BIIB068 and Dasatinib (Sprycel TM ).
  • a BTK inhibitor is selected from the group consisting of Ibrutinib (PCI-32765; Imbruvica TM ), Acalabrutinib (ACP-196; Calquence TM ), Zanubrutinib (BGB-3111; Brukinsa TM ), Tirabrutinib (ONO/GS-4059; Velexbru TM ), Olmutinib (BI1482694; HM-61713; Olita TM ), Spebrutinib (CC-292/AVL-292), Orelabrutinib (ICP-022; Inokai TM ), Poseltinib (HM- 71224; LY-3337641), Evobrutinib (M2951), Branebrutinib (BMS-986195), Remibrutinib (LOU064), AC-0058TA, and Tolebrutinib (SAR442168; PRN2246; BTK’168
  • a BTK inhibitor is selected from the group consisting of Ibrutinib (PCI-32765; Imbruvica TM ), Acalabrutinib (ACP-196; Calquence TM ), Zanubrutinib (BGB- 3111; Brukinsa TM ), Tirabrutinib (ONO/GS-4059; Velexbru TM ), Olmutinib (BI1482694; HM- 61713; Olita TM ), Spebrutinib (CC-292/AVL-292), Orelabrutinib (ICP-022; Inokai TM ), Poseltinib (HM-71224; LY-3337641), Evobrutinib (M2951), Branebrutinib (BMS-986195), Remibrutinib (LOU064), AC-0058TA, and Tolebrutinib (SAR442168; PRN2246; BTK
  • the BTK inhibitor is selected from the group consisting of Ibrutinib (PCI-32765; Imbruvica TM ), Acalabrutinib (ACP-196; Calquence TM ), Zanubrutinib (BGB-3111; Brukinsa TM ), Tirabrutinib (ONO/GS-4059; Velexbru TM ), Olmutinib (BI1482694; HM-61713; Olita TM ), Spebrutinib (CC-292/AVL-292), Orelabrutinib (ICP-022; Inokai TM ), Poseltinib (HM-71224; LY-3337641), Evobrutinib (M2951), Branebrutinib (BMS- 986195), Remibrutinib (LOU064), AC-0058TA, Tolebrutinib (SAR442168; PRN2246; BTK’168
  • the BTK inhibitor is selected from the group consisting of Ibrutinib (PCI-32765; Imbruvica TM ), Acalabrutinib (ACP-196; Calquence TM ), Zanubrutinib (BGB-3111; Brukinsa TM ), Tirabrutinib (ONO/GS-4059; Velexbru TM ), Spebrutinib (CC-292/AVL-292), Orelabrutinib (ICP-022; Inokai TM ), MK-1026 (ARQ-531), Vecabrutinib (SNS-062), Fenebrutinib (GDC-0853), Luxeptinib (CG-806), Pirtobrutinib (LOXO-305) and Dasatinib (Sprycel TM ).
  • the BTK inhibitor is selected from the group Ibrutinib (PCI- 32765; Imbruvica TM ), Acalabrutinib (ACP-196; Calquence TM ), Zanubrutinib (BGB-3111; Brukinsa TM ), Tirabrutinib (ONO/GS-4059; Velexbru TM ), Orelabrutinib (ICP-022; Inokai TM ), and Dasatinib (Sprycel TM ).
  • the BTK inhibitor is Ibrutinib (PCI- 32765; Imbruvica TM ).
  • Ibrutinib (PCI-32765; Imbruvica TM ), a covalent irreversible BTK inhibitor is described in SciFinder (CAS Registry Nr 936563-96-1), T. Wen et al., Leukemia 2020, doi.org/10.1038/s41375-020-01072-6, F. Musumeci et al., Expert Opin. Ther. Pat.2017, 27 (12), 1305-1318 and D. Zhao et al., Eur. J. Med. Chem.2017, 126, 444–455, and is represented by the structural formula indicated below: Acalabrutinib (ACP-196; Calquence TM ), a covalent irreversible BTK inhibitor (with improved selectivity) is described in C.
  • Zanubrutinib (BGB-3111; Brukinsa TM ), a covalent irreversible BTK inhibitor is described in SciFinder (CAS Registry Nr 1691249-45-2), in Y. Guo et al., J. Med. Chem.2019, 62, 7923-7940 and T. Wen et al., Leukemia 2020, doi.org/10.1038/s41375-020-01072-6, and is represented by the structural formula indicated below: Tirabrutinib (ONO/GS-4059; Velexbru TM ), a covalent irreversible BTK inhibitor is described in A. Liclican et al; BBA - General Subjects 2020, 1864, 129531 and D. Zhao et al., Eur. J. Med. Chem.2017, 126, 444–455, and is represented by the structural formula indicated below:
  • Olmutinib (BI1482694; HM-61713; Olita TM ), a covalent irreversible BTK inhibitor is described in C. Liang et al., Eur. J. Med. Chem.2018, 151, 315–326 and Y. Feng et al., Expert Opin. Ther. Pat.2019, 29 (4), 217-241, and is represented by the structural formula indicated below: Spebrutinib (CC-292/AVL-292), a covalent irreversible BTK inhibitor is described in A. Liclican et al; BBA - General Subjects 2020, 1864, 129531 and C. Liang et al., Eur. J. Med.
  • Remibrutinib (LOU064), an irreversible BTK inhibitor is described in D. Angst et al., J. Med. Chem.2020, 63, 5102-5118 and is represented by the structural formula indicated below: AC-0058TA, an irreversible BTK inhibitor is described in SciFinder (CAS Registry Nr 2242452- 37-3) and F. Musumeci et al., Expert Opin. Ther. Pat. 2017, 27 (12), 1305-1318 and is represented by the structural formula indicated below: Tolebrutinib (SAR442168; PRN2246; BTK’168), an irreversible BTK inhibitor, is described in K. Dahl et al., J. Label. Compd Radiopharm. 2020, 63, 482-487, and is represented by the structural formula indicated below:
  • Elsubrutinib (ABBV-105), an irreversible BTK inhibitor, is described in C. Goess et al., Mod. Rheumatol.2019, 29 (3), 510-522, and is represented by the structural formula indicated below:
  • Rilzabrutinib PRN-1008
  • SciFinder CAS Registry Nr 1575591-66-0
  • MK-1026 ARQ-531
  • Vecabrutinib SNS-062
  • SciFinder CAS Registry Nr 1510829-06-7
  • Y. Feng et al. Expert Opin. Ther. Pat.2019, 29 (4), 217-241
  • Fenebrutinib GDC-0853
  • a reversible non-covalent inhibitor is described in Y. Feng et al., Expert Opin. Ther. Pat.2019, 29 (4), 217-241 and J. J. Crawford et al., J. Med.
  • Chem.2018, 61, 2227-2245 is represented by the structural formula indicated below: RN486, a reversible non-covalent inhibitor, is described in C. Liang et al., Eur. J. Med. Chem. 2018, 151, 315–326 and Y. Feng et al., Expert Opin. Ther.
  • TAK-020 a reversible non-covalent inhibitor
  • BIIB068 a reversible non-covalent inhibitor
  • Chem.2020, 63, 12526-12541 is represented by the structural formula indicated below: Dasatinib (BMS-354825, Sprycel TM ), a kinase inhibitor used for the treatment of imatinib (Glivec)-resistant chronic myelogenous leukemia (CML), targets Abl and Src kinases and potently inhibits also BTK at nanomolar concentrations in vitro in kinase assay and in cultured cells (O. Hantschel et al., PNAS 2007, 104 (33), 13283-13288). It is described in J.S. Tokarski et al., Cancer Res.
  • the present invention provides a pharmaceutical combination comprising: a) a peptidic CXCR4 inhibitor; (b) a Bruton’s tyrosine kinase (BTK) inhibitor; and (c) optionally one or more pharmaceutically acceptable diluents, excipients or carriers.
  • a pharmaceutical combination comprising: a) a peptidic CXCR4 inhibitor; (b) a Bruton’s tyrosine kinase (BTK) inhibitor; and (c) optionally one or more pharmaceutically acceptable diluents, excipients or carriers.
  • a pharmaceutical combination according to the invention is for example a combined preparation or a pharmaceutical composition, for simultaneous, separate or sequential use.
  • the term “combined preparation” as used herein defines especially a “kit of parts” in the sense that said peptidic CXCR4 inhibitor and said Bruton’s tyrosine kinase (BTK) inhibitor can be dosed independently, either in separate form e.g. as separate tablets or by use of different fixed combinations with distinguished amounts of the active ingredients.
  • the ratio of the amount of peptidic CXCR4 inhibitor to the amount of Bruton’s tyrosine kinase (BTK) inhibitor to be administered in the combined preparation can be varied, e.g.
  • the individual parts of the combined preparation can be administered simultaneously or sequentially, i.e. chronologically staggered, e.g. at different time points and with equal or different time intervals for any part of the kit of parts.
  • pharmaceutical composition refers to a fixed-dose combination (FDC) that includes the peptidic CXCR4 inhibitor and the Bruton’s tyrosine kinase (BTK) inhibitor combined in a single dosage form, having a predetermined combination of respective dosages.
  • the pharmaceutical combination of the invention is a pharmaceutical composition and includes other medicinal or pharmaceutical agents, e.g., one or more pharmaceutically acceptable diluents, excipients or carriers.
  • the pharmaceutical combination further may be used as add-on therapy.
  • add-on or “add-on therapy” means an assemblage of reagents for use in therapy, the subject receiving the therapy begins a first treatment regimen of one or more reagents prior to beginning a second treatment regimen of one or more different reagents in addition to the first treatment regimen, so that not all of the reagents used in the therapy are started at the same time.
  • the pharmaceutical combination according to the invention is a combined preparation.
  • the amount of the peptidic CXCR4 inhibitor and the Bruton’s tyrosine kinase (BTK) inhibitor to be administered will vary depending upon factors such as the particular compound, disease condition and its severity, according to the particular circumstances surrounding the case, including, e.g., the specific peptidic CXCR4 inhibitor being administered, the route of administration, the condition being treated, the target area being treated, and the subject or host being treated.
  • the invention provides a pharmaceutical combination comprising a peptidic CXCR4 inhibitor and a Bruton’s tyrosine kinase (BTK) inhibitor, wherein said peptidic CXCR4 inhibitor and said Bruton’s tyrosine kinase (BTK) inhibitor are present in a therapeutically effective amount.
  • a pharmaceutical combination comprising a peptidic CXCR4 inhibitor and a Bruton’s tyrosine kinase (BTK) inhibitor, wherein said peptidic CXCR4 inhibitor and said Bruton’s tyrosine kinase (BTK) inhibitor are present in a therapeutically effective amount.
  • an amount capable of invoking one or more of the following effects in a subject receiving the combination of the present invention refers to an amount capable of invoking one or more of the following effects in a subject receiving the combination of the present invention: (i) increase of objective response rate (ORR); (ii) inhibition or arrest of tumor growth, including, reducing the rate of tumor growth or causing complete growth arrest; (iii) reduction in the number of tumor cells; (iv) reduction in tumor size; (v) reduction in tumor number; (vi) inhibition of metastasis (i.e.
  • a therapeutically effective amount of the peptidic CXCR4 inhibitor may (i) reduce the number of cancer cells; (ii) reduce tumor size; (iii) inhibit, retard, slow down to some extent, and preferably stop cancer cell infiltration into peripheral organs; (iv) inhibit (e.g., slow to some extent and preferably stop) tumor metastasis; (v) inhibit tumor growth; (vi) delay occurrence and/or recurrence of a tumor; and/or (vii) relieve to some extent one or more of the symptoms associated with the cancer.
  • the amount is sufficient to ameliorate, palliate, lessen, and/or delay one or more of symptoms of cancer.
  • the therapeutically effective amount may vary depending on the subject, and disease or condition being treated, the weight and age of the subject, the severity of the disease or condition, and the manner of administering, which can readily be determined by one ordinary skilled in the art.
  • the invention provides a pharmaceutical combination comprising a peptidic CXCR4 inhibitor and a Bruton’s tyrosine kinase (BTK) inhibitor, wherein said peptidic CXCR4 inhibitor and said Bruton’s tyrosine kinase (BTK) inhibitor produce an additive therapeutic effect i.e.
  • additive means that the effect achieved with the pharmaceutical combinations of this invention is approximately the sum of the effects that result from using the agents, namely the peptidic CXCR4 inhibitor and the Bruton’s tyrosine kinase (BTK) inhibitor, as a monotherapy.
  • the invention provides a pharmaceutical combination comprising a peptidic CXCR4 inhibitor and a Bruton’s tyrosine kinase (BTK) inhibitor, wherein said peptidic CXCR4 inhibitor and said Bruton’s tyrosine kinase (BTK) inhibitor produce a synergistic therapeutic effect, i.e. wherein said peptidic CXCR4 inhibitor and said Bruton’s tyrosine kinase (BTK) inhibitor are present in an amount producing a synergistic therapeutic effect.
  • a pharmaceutical combination comprising a peptidic CXCR4 inhibitor and a Bruton’s tyrosine kinase (BTK) inhibitor, wherein said peptidic CXCR4 inhibitor and said Bruton’s tyrosine kinase (BTK) inhibitor produce a synergistic therapeutic effect, i.e. wherein said peptidic CXCR4 inhibitor and said Bruton’s
  • the term “synergistic” means that the effect achieved with the pharmaceutical combinations of this invention is greater than the sum of the effects that result from using the agents, namely the peptidic CXCR4 inhibitor and the Bruton’s tyrosine kinase (BTK) inhibitor, as a monotherapy.
  • the synergistic effect of the pharmaceutical combination versus the single agents is referred to in the present application as synergism according to the Chou-Talalay combination index (Chou TC. Drug combination studies and their synergy quantification using the Chou-Talalay method. Cancer Res.
  • the invention provides a pharmaceutical combination comprising a Bruton’s tyrosine kinase (BTK) inhibitor and a peptidic CXCR4 inhibitor, wherein the amount of said peptidic CXCR4 inhibitor in the combination is is from about 0.3 to about 3500 mg, or from about 0.3 to about 2500 mg, or from about 0.3 to about 1600 mg, or from about 0.3 to about 1200 mg, or from about 0.3 to about 800 mg, or from about 1 to about 500 mg, preferably from about 1 to about 400 mg.
  • said peptidic CXCR4 inhibitor is in the form of a pharmaceutically acceptable salt
  • the amounts of peptidic CXCR4 inhibitor provided herein are calculated on the basis of the respective free base.
  • the invention provides a pharmaceutical combination comprising a Bruton’s tyrosine kinase (BTK) inhibitor and a peptidic CXCR4 inhibitor, wherein the amount of said Bruton’s tyrosine kinase (BTK) inhibitor in the combination is from about 0.1 to about 3500 mg, or from about 1 to about 1800 mg, or from about 5 to about 700 mg, preferably from about 5 to about 700 mg.
  • said Bruton’s tyrosine kinase (BTK) inhibitor is in the form of a pharmaceutically acceptable salt
  • the amounts of Bruton’s tyrosine kinase (BTK) inhibitor provided herein are calculated on the basis of the respective free base.
  • the invention provides a pharmaceutical combination comprising a Bruton’s tyrosine kinase (BTK) inhibitor and a peptidic CXCR4 inhibitor, wherein the amount of said peptidic CXCR4 inhibitor in the combination is from about 0.3 to about 3500 mg, or from about 0.3 to about 2500 mg, or from about 0.3 to about 1600 mg, or from about 0.3 to about 1200 mg, or from about 0.3 to about 800 mg, or from about 1 to about 500 mg, preferably from about 1 to about 400 mg, and wherein the amount of said Bruton’s tyrosine kinase (BTK) inhibitor in the combination is from about from about 0.1 to about 3500 mg, or from about 1 to about 1800 mg, or from about 5 to about 700 mg, preferably from about 5 to about 700 mg.
  • BTK Bruton’s tyrosine kinase
  • a pharmaceutical combination comprising: (a) a peptidic CXCR4 inhibitor; (b) a Bruton’s tyrosine kinase (BTK) inhibitor; and (c) optionally one or more pharmaceutically acceptable diluents, excipients or carriers, wherein said peptidic CXCR4 inhibitor is a backbone cyclized peptidic compound, built up from 16 amino acid residues, or pharmaceutically acceptable salts thereof, of the formula cyclo(-Tyr 1 -His 2 -Xaa 3 -Cys 4 -Ser 5 -Xaa 6 -Xaa 7 -Xaa 8 -Arg 9 -Tyr 10 -Cys 11 -Tyr 12 -Gln 13 -Xaa 14 - Xaa 15 -Pro 16 -) (Ia), in which Xaa 3 is Ala; Tyr; or Tyr(Me); Xaa 6 is Ala or
  • a pharmaceutical combination comprising: (a) a peptidic CXCR4 inhibitor; (b) a Bruton’s tyrosine kinase (BTK) inhibitor; and (c) optionally one or more pharmaceutically acceptable diluents, excipients or carriers, wherein said peptidic CXCR4 inhibitor is a backbone cyclized peptidic compound, built up from 16 amino acid residues, or pharmaceutically acceptable salts thereof, of the formula cyclo(-Tyr 1 -His 2 -Xaa 3 -Cys 4 -Ser 5 -Xaa 6 -Xaa 7 -Xaa 8 -Arg 9 -Tyr 10 -Cys 11 -Tyr 12 -Gln 13 -Xaa 14 - Xaa 15 -Pro 16 -) (Ia), in which Xaa 3 is Ala; Tyr; or Tyr(Me); Xaa 6 is Ala or
  • a pharmaceutical combination comprising: (a) a peptidic CXCR4 inhibitor; (b) a Bruton’s tyrosine kinase (BTK) inhibitor; and (c) optionally one or more pharmaceutically acceptable diluents, excipients or carriers, wherein said peptidic CXCR4 inhibitor is a backbone cyclized peptidic compound, built up from 16 amino acid residues, or pharmaceutically acceptable salts thereof, of the formula cyclo(-Tyr 1 -His 2 -Xaa 3 -Cys 4 -Ser 5 -Xaa 6 -Xaa 7 -Xaa 8 -Arg 9 -Tyr 10 -Cys 11 -Tyr 12 -Gln 13 -Xaa 14 - Xaa 15 -Pro 16 -) (Ia), in which Xaa 3 is Ala; Tyr; or Tyr(Me); Xaa 6 is Ala or
  • a pharmaceutical combination comprising: (a) a peptidic CXCR4 inhibitor; (b) a Bruton’s tyrosine kinase (BTK) inhibitor; and (c) optionally one or more pharmaceutically acceptable diluents, excipients or carriers, wherein said peptidic CXCR4 inhibitor is a backbone cyclized peptidic compound, built up from 16 amino acid residues, or pharmaceutically acceptable salts thereof, of the formula cyclo(-Tyr 1 -His 2 -Xaa 3 -Cys 4 -Ser 5 -Xaa 6 -Xaa 7 -Xaa 8 -Arg 9 -Tyr 10 -Cys 11 -Tyr 12 -Gln 13 -Xaa 14 - Xaa 15 -Pro 16 -) (Ia), in which Xaa 3 is Tyr; or Tyr(Me); Xaa 6 is Ala or Acc;
  • a pharmaceutical combination comprising: (a) a peptidic CXCR4 inhibitor; (b) a Bruton’s tyrosine kinase (BTK) inhibitor; and (c) optionally one or more pharmaceutically acceptable diluents, excipients or carriers, wherein said peptidic CXCR4 inhibitor is a backbone cyclized peptidic compound, built up from 16 amino acid residues, or pharmaceutically acceptable salts thereof, of the formula cyclo(-Tyr 1 -His 2 -Xaa 3 -Cys 4 -Ser 5 -Xaa 6 -Xaa 7 -Xaa 8 -Arg 9 -Tyr 10 -Cys 11 -Tyr 12 -Gln 13 -Xaa 14 - Xaa 15 -Pro 16 -) (Ia), in which Xaa 3 is Tyr; or Tyr(Me); Xaa 6 is Ala or Acc;
  • a pharmaceutical combination comprising: (a) a peptidic CXCR4 inhibitor; (b) a Bruton’s tyrosine kinase (BTK) inhibitor; and (c) optionally one or more pharmaceutically acceptable diluents, excipients or carriers, wherein said peptidic CXCR4 inhibitor is a backbone cyclized peptidic compound, built up from 16 amino acid residues, or pharmaceutically acceptable salts thereof, of the formula cyclo(-Tyr 1 -His 2 -Xaa 3 -Cys 4 -Ser 5 -Xaa 6 -Xaa 7 -Xaa 8 -Arg 9 -Tyr 10 -Cys 11 -Tyr 12 -Gln 13 -Xaa 14 - Xaa 15 -Pro 16 -) (Ia), in which Xaa 3 is Tyr; or Tyr(Me); Xaa 6 is Ala or Acc;
  • a pharmaceutical combination comprising: (a) a peptidic CXCR4 inhibitor; (b) a Bruton’s tyrosine kinase (BTK) inhibitor; and (c) optionally one or more pharmaceutically acceptable diluents, excipients or carriers, wherein said peptidic CXCR4 inhibitor is a backbone cyclized peptidic compound, built up from 16 amino acid residues, or pharmaceutically acceptable salts thereof, of the formula cyclo(-Tyr 1 -His 2 -Xaa 3 -Cys 4 -Ser 5 -Ala 6 -Xaa 7 -Xaa 8 -Arg 9 -Tyr 10 -Cys 11 -Tyr 12 -Gln 13 -Xaa 14 -Xaa 15 -Pro 16 -) (I), in which Xaa 3 is Ala; Tyr; or Tyr(Me); Xaa 7 is D Pro; D Tyr; or
  • a pharmaceutical combination comprising: (a) a peptidic CXCR4 inhibitor; (b) a Bruton’s tyrosine kinase (BTK) inhibitor; and (c) optionally one or more pharmaceutically acceptable diluents, excipients or carriers, wherein said peptidic CXCR4 inhibitor is a backbone cyclized peptidic compound, built up from 16 amino acid residues, or pharmaceutically acceptable salts thereof, of the formula cyclo(-Tyr 1 -His 2 -Xaa 3 -Cys 4 -Ser 5 -Ala 6 -Xaa 7 -Xaa 8 -Arg 9 -Tyr 10 -Cys 11 -Tyr 12 -Gln 13 -Xaa 14 -Xaa 15 -Pro 16 -) (I), in which Xaa 3 is Ala; Tyr; or Tyr(Me); Xaa 7 is D Pro; D Tyr; or
  • a pharmaceutical combination comprising: (a) a peptidic CXCR4 inhibitor; (b) a Bruton’s tyrosine kinase (BTK) inhibitor; and (c) optionally one or more pharmaceutically acceptable diluents, excipients or carriers, wherein said peptidic CXCR4 inhibitor is a backbone cyclized peptidic compound, built up from 16 amino acid residues, or pharmaceutically acceptable salts thereof, of the formula cyclo(-Tyr 1 -His 2 -Xaa 3 -Cys 4 -Ser 5 -Ala 6 -Xaa 7 -Xaa 8 -Arg 9 -Tyr 10 -Cys 11 -Tyr 12 -Gln 13 -Xaa 14 -Xaa 15 -Pro 16 -) (I), in which Xaa 3 is Ala; Tyr; or Tyr(Me); Xaa 7 is D Pro; D Tyr; or
  • a pharmaceutical combination comprising: (a) a peptidic CXCR4 inhibitor; (b) a Bruton’s tyrosine kinase (BTK) inhibitor; and (c) optionally one or more pharmaceutically acceptable diluents, excipients or carriers, wherein said peptidic CXCR4 inhibitor is a backbone cyclized peptidic compound, built up from 16 amino acid residues, or pharmaceutically acceptable salts thereof, of the formula cyclo(-Tyr 1 -His 2 -Xaa 3 -Cys 4 -Ser 5 -Ala 6 -Xaa 7 -Xaa 8 -Arg 9 -Tyr 10 -Cys 11 -Tyr 12 -Gln 13 -Xaa 14 -Xaa 15 -Pro 16 -) (I), in which Xaa 3 is Tyr; or Tyr(Me); Xaa 7 is D Pro; D Tyr; or D Tyr(
  • a pharmaceutical combination comprising: (a) a peptidic CXCR4 inhibitor; (b) a Bruton’s tyrosine kinase (BTK) inhibitor; and (c) optionally one or more pharmaceutically acceptable diluents, excipients or carriers, wherein said peptidic CXCR4 inhibitor is a backbone cyclized peptidic compound, built up from 16 amino acid residues, or pharmaceutically acceptable salts thereof, of the formula cyclo(-Tyr 1 -His 2 -Xaa 3 -Cys 4 -Ser 5 -Ala 6 -Xaa 7 -Xaa 8 -Arg 9 -Tyr 10 -Cys 11 -Tyr 12 -Gln 13 -Xaa 14 -Xaa 15 -Pro 16 -) (I), in which Xaa 3 is Tyr; or Tyr(Me); Xaa 7 is D Pro; D Tyr; or D Tyr(
  • a pharmaceutical combination comprising: (a) a peptidic CXCR4 inhibitor; (b) a Bruton’s tyrosine kinase (BTK) inhibitor; and (c) optionally one or more pharmaceutically acceptable diluents, excipients or carriers, wherein said peptidic CXCR4 inhibitor is a backbone cyclized peptidic compound, built up from 16 amino acid residues, or pharmaceutically acceptable salts thereof, of the formula cyclo(-Tyr 1 -His 2 -Xaa 3 -Cys 4 -Ser 5 -Ala 6 -Xaa 7 -Xaa 8 -Arg 9 -Tyr 10 -Cys 11 -Tyr 12 -Gln 13 -Xaa 14 -Xaa 15 -Pro 16 -) (I), in which Xaa 3 is Tyr; or Tyr(Me); Xaa 7 is D Pro; D Tyr; or D Tyr(
  • a pharmaceutical combination comprising: (a) a peptidic CXCR4 inhibitor; (b) a Bruton’s tyrosine kinase (BTK) inhibitor; and (c) optionally one or more pharmaceutically acceptable diluents, excipients or carriers, wherein the peptidic CXCR4 inhibitor is a backbone cyclized peptidic compound, built up from 16 amino acid residues, or pharmaceutically acceptable salts thereof, selected from the group consisting of cyclo(-Tyr-His-Ala-Cys-Ser-Ala- D Pro-Dab-Arg-Tyr-Cys-Tyr-Gln-Lys- D Pro-Pro-) having a disulfide bond between Cys 4 and Cys 11 , (SEQ ID NO:1), cyclo(-Tyr-His-Tyr-Cys-Ser-Ala- D Pro-Dab-Arg-Tyr-C
  • a pharmaceutical combination comprising: (a) a peptidic CXCR4 inhibitor; (b) a Bruton’s tyrosine kinase (BTK) inhibitor; and (c) optionally one or more pharmaceutically acceptable diluents, excipients or carriers, wherein the peptidic CXCR4 inhibitor is a backbone cyclized peptidic compound, built up from 16 amino acid residues, or pharmaceutically acceptable salts thereof, selected from the group consisting of cyclo(-Tyr-His-Ala-Cys-Ser-Ala- D Pro-Dab-Arg-Tyr-Cys-Tyr-Gln-Lys- D Pro-Pro-) having a disulfide bond between Cys 4 and Cys 11 , (SEQ ID NO:1), cyclo(-Tyr-His-Tyr-Cys-Ser-Ala- D Pro-Dab-Arg-Tyr-C
  • a pharmaceutical combination comprising: (a) a peptidic CXCR4 inhibitor; (b) a Bruton’s tyrosine kinase (BTK) inhibitor; and (c) optionally one or more pharmaceutically acceptable diluents, excipients or carriers, wherein the peptidic CXCR4 inhibitor is a backbone cyclized peptidic compound, built up from 16 amino acid residues, or pharmaceutically acceptable salts thereof, selected from the group consisting of cyclo(-Tyr-His-Ala-Cys-Ser-Ala- D Pro-Dab-Arg-Tyr-Cys-Tyr-Gln-Lys- D Pro-Pro-) having a disulfide bond between Cys 4 and Cys 11 , (SEQ ID NO:1), cyclo(-Tyr-His-Tyr-Cys-Ser-Ala- D Pro-Dab-Arg-Tyr-C
  • a pharmaceutical combination comprising: (a) a peptidic CXCR4 inhibitor; (b) a Bruton’s tyrosine kinase (BTK) inhibitor; and (c) optionally one or more pharmaceutically acceptable diluents, excipients or carriers, wherein said peptidic CXCR4 inhibitor is selected from the group consisting of cyclo(-Tyr-His-Ala-Cys-Ser-Ala- D Pro-Dab-Arg-Tyr-Cys-Tyr-Gln-Lys- D Pro-Pro-) having a disulfide bond between Cys 4 and Cys 11 , (SEQ ID NO:1), and cyclo(-Tyr-His-Tyr-Cys-Ser-Ala- D Pro-Dab-Arg-Tyr-Cys-Tyr-Gln-Lys- D Pro-Pro-) having a disulfide bond between Cys 4 and
  • a pharmaceutical combination comprising: (a) a peptidic CXCR4 inhibitor; (b) a Bruton’s tyrosine kinase (BTK) inhibitor; and (c) optionally one or more pharmaceutically acceptable diluents, excipients or carriers, wherein said peptidic CXCR4 inhibitor is selected from the group consisting of cyclo(-Tyr-His-Ala-Cys-Ser-Ala- D Pro-Dab-Arg-Tyr-Cys-Tyr-Gln-Lys- D Pro-Pro-) having a disulfide bond between Cys 4 and Cys 11 , (SEQ ID NO:1), and cyclo(-Tyr-His-Tyr-Cys-Ser-Ala- D Pro-Dab-Arg-Tyr-Cys-Tyr-Gln-Lys- D Pro-Pro-) having a disulfide bond between Cys 4 and
  • a pharmaceutical combination comprising: (a) a peptidic CXCR4 inhibitor; (b) a Bruton’s tyrosine kinase (BTK) inhibitor; and (c) optionally one or more pharmaceutically acceptable diluents, excipients or carriers, wherein said peptidic CXCR4 inhibitor is selected from the group consisting of cyclo(-Tyr-His-Ala-Cys-Ser-Ala- D Pro-Dab-Arg-Tyr-Cys-Tyr-Gln-Lys- D Pro-Pro-) having a disulfide bond between Cys 4 and Cys 11 , (SEQ ID NO:1), and cyclo(-Tyr-His-Tyr-Cys-Ser-Ala- D Pro-Dab-Arg-Tyr-Cys-Tyr-Gln-Lys- D Pro-Pro-) having a disulfide bond between Cys 4 and
  • a pharmaceutical combination comprising: (a) a peptidic CXCR4 inhibitor; (b) a Bruton’s tyrosine kinase (BTK) inhibitor; and (c) optionally one or more pharmaceutically acceptable diluents, excipients or carriers, wherein said peptidic CXCR4 inhibitor is cyclo(-Tyr-His-Tyr-Cys-Ser-Ala- D Pro-Dab-Arg-Tyr-Cys- Tyr-Gln-Lys- D Pro-Pro-) having a disulfide bond between Cys 4 and Cys 11 , (SEQ ID NO:2), or pharmaceutically acceptable salts thereof, and wherein the Bruton’s tyrosine kinase (BTK) inhibitor is selected from the group consisting of Ibrutinib (PCI-32765; Imbruvica TM ), Acalabrutinib (ACP-196; Cal
  • a pharmaceutical combination comprising: (a) a peptidic CXCR4 inhibitor; (b) a Bruton’s tyrosine kinase (BTK) inhibitor; and (c) optionally one or more pharmaceutically acceptable diluents, excipients or carriers, wherein said peptidic CXCR4 inhibitor is cyclo(-Tyr-His-Tyr-Cys-Ser-Ala- D Pro-Dab-Arg-Tyr-Cys- Tyr-Gln-Lys- D Pro-Pro-) having a disulfide bond between Cys 4 and Cys 11 , (SEQ ID NO:2), or pharmaceutically acceptable salts thereof, and the Bruton’s tyrosine kinase (BTK) inhibitor is Ibrutinib (PCI-32765; Imbruvica TM ), Acalabrutinib (ACP-196; Calquence TM ), Zan
  • a pharmaceutical combination comprising: (a) a peptidic CXCR4 inhibitor; (b) a Bruton’s tyrosine kinase (BTK) inhibitor; and (c) optionally one or more pharmaceutically acceptable diluents, excipients or carriers, wherein said peptidic CXCR4 inhibitor is cyclo(-Tyr-His-Tyr-Cys-Ser-Ala- D Pro-Dab-Arg-Tyr-Cys- Tyr-Gln-Lys- D Pro-Pro-) having a disulfide bond between Cys 4 and Cys 11 , (SEQ ID NO:2), or pharmaceutically acceptable salts thereof, and wherein the Bruton’s tyrosine kinase (BTK) inhibitor is an irreversible covalent inhibitor, preferably an irreversible covalent inhibitor selected from the group consisting of Ibrutinib (PCI-32765; Imbruvica
  • compositions or combined preparations of the invention may be administered in either single or multiple doses by any of the accepted modes of administration of agents having similar utilities, including rectal, buccal, intranasal, transmucosal, transdermal, by intra-arterial injection, intravenously, intraperitoneally, parenterally, intramuscularly, subcutaneously, orally, topically, as e.g. an inhalant via pulmonary adminstration, or via an impregnated or coated device such as a stent, for example, or an artery-inserted cylindrical polymer.
  • One mode for administration is administration by injection, preferably intravenous administration by injection.
  • the forms in which the peptidic CXCR4 inhibitor and/or Bruton’s tyrosine kinase (BTK) inhibitor, may be incorporated for administration by injection include aqueous or oil suspensions, or emulsions, with sesame oil, corn oil, cottonseed oil, peanut oil, or castor oil, or chemical modified derivatives of the aforesaid oils thereof, as for example Cremophor EL, as well as elixirs, mannitol, dextrose, or a sterile aqueous solution, and similar pharmaceutical vehicles.
  • Aqueous solutions in saline may also conventionally be used for injection, preferably physiologically compatible buffers such as Hank’s solution, Ringer’s solution, or physiological saline buffer are used as aqueous solutions.
  • physiologically compatible buffers such as Hank’s solution, Ringer’s solution, or physiological saline buffer are used as aqueous solutions.
  • Ethanol, glycerol, propylene glycol, liquid polyethylene glycol, and the like (and suitable mixtures thereof), cyclodextrin derivatives, and vegetable oils may also be employed.
  • the proper fluidity can be maintained, for example, by the use of a coating, such as lecithin, by the maintenance of the required particle size in the case of dispersion and by the use of surfactants.
  • the prevention of the action of microorganisms can be brought about by various antibacterial and antifungal agents, for example, parabens, chlorobutanol, phenol, sorbic acid, thimerosal, and the like.
  • Sterile injectable solutions are prepared by incorporating a compound according to the present disclosure in the required amount in the appropriate solvent with various other ingredients as enumerated above, as required, followed by filtered sterilization.
  • dispersions are prepared by incorporating the various sterilized active ingredients into a sterile vehicle which contains the basic dispersion medium and the required other ingredients from those enumerated above.
  • sterile injectable solutions are prepared containing a therapeutically effective amount, e.g., 0.3 to 3500 mg, of the peptidic CXCR4 inhibitor. It will be understood, however, that the amount of the compound actually administered usually will be determined by a physician, in the light of the relevant circumstances, including the condition to be treated, the chosen route of administration, the actual compound administered and its relative activity, the age, weight, and response of the individual patient, the severity of the patient's symptoms, and the like.
  • a pharmaceutical combination according to the invention is, preferably, suitable for oral administration and/or injection, e.g. subcutaneous, intravenous, intramuscular, intrathecal or intraperitoneal injection, and usually comprises a therapeutically effective amount of the active ingredients and one or more suitable pharmaceutically acceptable diluent, excipient or carrier, e.g. the Bruton’s tyrosine kinase (BTK) inhibitor is administered to the subject orally.
  • BTK Bruton’s tyrosine kinase
  • compositions or combined preparations in separate form comprising a peptidic CXCR4 inhibitor and Bruton’s tyrosine kinase (BTK) inhibitor may be manufactured by means of conventional mixing, dissolving, granulating, coated tablet-making, levigating, emulsifying, encapsulating, entrapping or lyophilizing processes.
  • Pharmaceutical compositions or combined preparations in separate form may be formulated in conventional manner using one or more physiologically acceptable carriers, diluents, excipients or auxilliaries which facilitate processing of the active ingredient into preparations which can be used pharmaceutically. Proper formulation depends upon the method of administration chosen.
  • the peptidic CXCR4 inhibitor and/or Bruton’s tyrosine kinase (BTK) inhibitor may be formulated as solutions, gels, ointments, creams, suspensions, etc. as are well-known in the art.
  • penetrants appropriate to the barrier to be permeated are used in the formulation as known in the art.
  • the compounds can be readily formulated by combining the peptidic CXCR4 inhibitor and/or Bruton’s tyrosine kinase (BTK) inhibitor with pharmaceutically acceptable carriers well known in the art.
  • Such carriers enable the peptidic CXCR4 inhibitor and/or Bruton’s tyrosine kinase (BTK) inhibitor to be formulated as tablets, pills, dragees, capsules, liquids, gels, syrups, slurries, suspensions etc., for oral ingestion by a patient to be treated.
  • BTK tyrosine kinase
  • suitable excipients include fillers such as sugars, e. g.
  • lactose sucrose, mannitol and sorbitol
  • cellulose preparations such as maize starch, wheat starch, rice starch, potato starch, gelatin, gum tragacanth, methyl cellulose, hydroxypropylmethyl cellulose, sodium carboxymethylcellulose; granulating agents; and binding agents.
  • desintegrating agents may be added, such as cross-linked polyvinylpyrrolidones, agar, or alginic acid or a salt thereof, such as sodium alginate.
  • solid dosage forms may be sugar-coated or enteric-coated using standard techniques.
  • suitable carriers, excipients or diluents include water, glycols, oils, alcohols, etc.
  • flavoring agents, preservatives, coloring agents and the like may be added.
  • buccal administration the composition may take the form of tablets, lozenges, etc. formulated as usual.
  • the peptidic CXCR4 inhibitor and/or Bruton’s tyrosine kinase (BTK) inhibitor are conveniently delivered in form of an aerosol spray from pressurized packs or a nebulizer, with the use of a suitable propellant, e.g.
  • the dose unit may be determined by providing a valve to deliver a metered amount.
  • Capsules and cartridges of e.g. gelatin for use in an inhaler or insufflator may be formulated containing a powder mix of the compounds of the invention and a suitable powder base such as lactose or starch.
  • the compounds may also be formulated in rectal or vaginal compositions such as suppositories together with appropriate suppository bases such as cocoa butter or other glycerides.
  • the peptidic CXCR4 inhibitor and/or Bruton’s tyrosine kinase (BTK) inhibitor may also be formulated as depot preparations. Such long acting formulations may be administered by implantation (e.g. subcutaneously or intramuscularly) or by intramuscular injection. For the manufacture of such depot preparations the peptidic CXCR4 inhibitor and/or Bruton’s tyrosine kinase (BTK) inhibitor may be formulated with suitable polymeric or hydrophobic materials (e.g. as an emulsion in an acceptable oil) or ion exchange resins, or as sparingly soluble salts.
  • peptidic CXCR4 inhibitor and/or Bruton’s tyrosine kinase (BTK) inhibitor may be delivered using a sustained-release system, such as semipermeable matrices of solid polymers containing the therapeutic agent.
  • sustained-release materials have been established and are well known by those skilled in the art. Sustained-release capsules may, depending on their chemical nature, release the compounds for a few weeks up to over 100 days. Depending on the chemical nature and the biological stability of the therapeutic agent, additional strategies for protein stabilization may be employed.
  • the present invention provides a pharmaceutical combination as described herein, for use as a medicament.
  • the present invention provides a pharmaceutical combination as described herein, for use in a method for the prevention, delay of progression or treatment of cancer in a subject, preferably for use in a method for the delay of progression or treatment of cancer in a subject, more preferably for use in a method for the treatment of cancer in a subject.
  • a pharmaceutical combination as described herein for the manufacture of a medicament for the prevention, delay of progression or treatment of cancer in a subject preferably for the manufacture of a medicament for the delay of progression or treatment of cancer in a subject, more preferably for the manufacture of a medicament for the treatment of cancer in a subject.
  • a pharmaceutical combination as described herein for the prevention, delay of progression or treatment of cancer in a subject preferably for the delay of progression or treatment of cancer in a subject, more preferably for the treatment of cancer in a subject.
  • a method for the prevention, delay of progression or treatment of cancer in a subject preferably a method for the delay of progression or treatment of cancer in a subject, more preferably a method for the treatment of cancer in a subject, comprising administering to said subject a pharmaceutical combination as described herein e.g. administering to said subject a therapeutically effective amount of a pharmaceutical combination as described herein.
  • prevention e.g. preventive treatments comprise prophylactic treatments.
  • the pharmaceutical combination of the invention is administered to a subject suspected of having, or at risk for developing cancer.
  • the term “delay of progression”/"delaying of progression” means increasing the time to appearance of a symptom of a cancer or a mark associated with a cancer or slowing the increase in severity of a symptom of a cancer. Further, “delay of progression” as used herein includes reversing or inhibition of disease progression. “Inhibition" of disease progression or disease complication in a subject means preventing or reducing the disease progression and/or disease complication in the subject.
  • treatment includes: (1) delaying the appearance of clinical symptoms of the state, disorder or condition developing in an animal, particularly a mammal and especially a human, that may be afflicted with or predisposed to the state, disorder or condition but does not yet experience or display clinical or subclinical symptoms of the state, disorder or condition; (2) inhibiting the state, disorder or condition (e.g. arresting, reducing or delaying the development of the disease, or a relapse thereof in case of maintenance treatment, of at least one clinical or subclinical symptom thereof; and/or (3) relieving the condition (i.e. causing regression of the state, disorder or condition or at least one of its clinical or subclinical symptoms).
  • the benefit to a patient to be treated is either statistically significant or at least perceptible to the patient or to the physician.
  • the outcome may not always be effective treatment.
  • the pharmaceutical combination is usually administered to a subject such as a patient already suffering from cancer, in an amount sufficient to cure or at least partially arrest the symptoms of the disease. Amounts effective for this use will depend on the severity and course of the disease, previous therapy, the subject's health status and response to the drugs, and the judgment of the treating physician.
  • the pharmaceutical combination of the invention may be administered chronically, which is, for an extended period of time, including throughout the duration of the subject's life in order to ameliorate or otherwise control or limit the symptoms of the subject's disease or condition.
  • the pharmaceutical combination may be administered continuously; alternatively, the dose of drugs being administered may be temporarily reduced or temporarily suspended for a certain length of time (i.e., a "drug holiday").
  • a maintenance dose of the pharmaceutical combination of the invention is administered if necessary.
  • a pharmaceutical combination according to the invention for use in a method for the prevention, delay of progression or treatment of cancer in a subject, preferably for use in a method for the delay of progression or treatment of a cancer in a subject, more preferably for use in a method for the treatment of cancer in a subject, wherein the cancer is a tumor of the hematopoietic and lymphoid tissues, even more preferably wherein the cancer is a mature B-cell neoplasm, in particular wherein the cancer is a non-Hodgkin lymphoma, more particular wherein the cancer is preferably selected from the group consisting of small lymphocytic leukemia (SLL), lymphoplasmacytic lymphoma (Waldenström's macroglobulinemia), hairy cell leukaemia, Burkitt lympho
  • SLL small lymphocytic leukemia
  • Waldenström's macroglobulinemia lymphoplasmacytic lymphoma
  • hairy cell leukaemia Burkitt lympho
  • a pharmaceutical combination according to the invention for use in a method for the prevention, delay of progression or treatment of cancer in a subject, preferably for use in a method for the delay of progression or treatment of a cancer in a subject, more preferably for use in a method for the treatment of cancer in a subject, wherein the cancer is selected from the group consisting of mantle cell lymphoma (MCL), chronic lymphocytic leukemia (CLL) and splenic marginal zone lymphoma (SMZL).
  • MCL mantle cell lymphoma
  • CLL chronic lymphocytic leukemia
  • SZL splenic marginal zone lymphoma
  • a pharmaceutical combination according to the invention for use in a method for the prevention, delay of progression or treatment of cancer in a subject, preferably for use in a method for the delay of progression or treatment of a cancer in a subject, more preferably for use in a method for the treatment of cancer in a subject, wherein the cancer is mantle cell lymphoma (MCL).
  • MCL mantle cell lymphoma
  • a pharmaceutical combination according to the invention for use in a method for the prevention, delay of progression or treatment of cancer in a subject, preferably for use in a method for the delay of progression or treatment of a cancer in a subject, more preferably for use in a method for the treatment of cancer in a subject, wherein the cancer is chronic lymphocytic leukemia (CLL).
  • CLL chronic lymphocytic leukemia
  • a pharmaceutical combination according to the invention for use in a method for the prevention, delay of progression or treatment of cancer in a subject, preferably for use in a method for the delay of progression or treatment of a cancer in a subject, more preferably for use in a method for the treatment of cancer in a subject, wherein the cancer is splenic marginal zone lymphoma (SMZL).
  • SSKL splenic marginal zone lymphoma
  • a pharmaceutical combination according to the invention for use in a method for the prevention, delay of progression or treatment of cancer in a subject, preferably for use in a method for the delay of progression or treatment of a cancer in a subject, more preferably for use in a method for the treatment of cancer in a subject, wherein the cancer is selected from the group consisting of mantle cell lymphoma (MCL), wherein the pharmaceutical combination according to the invention comprises POL5551 (cyclo(-Tyr-His-Tyr-Cys-Ser-Ala- D Pro-Dab-Arg-Tyr-Cys-Tyr-Gln- Lys- D Pro-Pro-) having a disulfide bond between Cys 4 and Cys 11 , (SEQ ID NO:2), and ibrutinib; chronic lymphocytic leukemia (CLL), wherein the pharmaceutical combination according to the invention comprises POL5551 (cyclo(-Tyr-His-Tyr-Cys-S
  • a pharmaceutical combination as described herein for the manufacture of a medicament for the prevention, delay of progression or treatment of cancer in a subject, preferably for the manufacture of a medicament for the delay of progression or treatment of a cancer in a subject, more preferably for the manufacture of a medicament for the treatment of cancer, wherein the cancer is a tumor of the hematopoietic and lymphoid tissues, even more preferably wherein the cancer is a mature B-cell neoplasm, in particular wherein the cancer is a non-Hodgkin lymphoma, more particular wherein the cancer is preferably selected from the group consisting of small lymphocytic leukemia (SLL), lymphoplasmacytic lymphoma (Waldenström's macroglobulinemia), hairy cell leukaemia, Burkitt lymphoma, marginal zone lymphoma (MZL), splenic marginal zone lymphoma (SMZL), mantle cell lymphoma (MCL), follicular lymphom
  • SLL small
  • a pharmaceutical combination as described herein for the manufacture of a medicament for the prevention, delay of progression or treatment of cancer in a subject, preferably for the manufacture of a medicament for the delay of progression or treatment of a cancer in a subject, more preferably for the manufacture of a medicament for the treatment of cancer, wherein the cancer is selected from the group consisting of mantle cell lymphoma (MCL), chronic lymphocytic leukemia (CLL) and splenic marginal zone lymphoma (SMZL).
  • MCL mantle cell lymphoma
  • CLL chronic lymphocytic leukemia
  • SZL splenic marginal zone lymphoma
  • a pharmaceutical combination as described herein for the manufacture of a medicament for the prevention, delay of progression or treatment of cancer in a subject, preferably for the manufacture of a medicament for the delay of progression or treatment of a cancer in a subject, more preferably for the manufacture of a medicament for the treatment of cancer, wherein the cancer is mantle cell lymphoma (MCL).
  • MCL mantle cell lymphoma
  • a pharmaceutical combination as described herein for the manufacture of a medicament for the prevention, delay of progression or treatment of cancer in a subject, preferably for the manufacture of a medicament for the delay of progression or treatment of a cancer in a subject, more preferably for the manufacture of a medicament for the treatment of cancer, wherein the cancer is chronic lymphocytic leukemia (CLL).
  • CLL chronic lymphocytic leukemia
  • a pharmaceutical combination as described herein for the manufacture of a medicament for the prevention, delay of progression or treatment of cancer in a subject, preferably for the manufacture of a medicament for the delay of progression or treatment of a cancer in a subject, more preferably for the manufacture of a medicament for the treatment of cancer, wherein the cancer is splenic marginal zone lymphoma (SMZL).
  • SSKL splenic marginal zone lymphoma
  • a pharmaceutical combination as described herein for the manufacture of a medicament for the prevention, delay of progression or treatment of cancer in a subject, preferably for the manufacture of a medicament for the delay of progression or treatment of a cancer in a subject, more preferably for the manufacture of a medicament for the treatment of cancer, wherein the cancer is selected from the group consisting of mantle cell lymphoma (MCL), wherein the pharmaceutical combination according to the invention comprises POL5551 (cyclo(-Tyr-His-Tyr-Cys-Ser-Ala- D Pro-Dab-Arg-Tyr-Cys-Tyr-Gln-Lys- D Pro-Pro-) having a disulfide bond between Cys 4 and Cys 11 ), (SEQ ID NO:2), and ibrutinib; chronic lymphocytic leukemia (CLL), wherein the pharmaceutical combination according to the invention comprises POL5551 (cyclo(-Tyr-His-Tyr-Cys-S
  • a pharmaceutical combination as described herein for the prevention, delay of progression or treatment of cancer in a subject, preferably for the delay of progression or treatment of a cancer in a subject, more preferably for the treatment of cancer, wherein the cancer is a tumor of the hematopoietic and lymphoid tissues, even more preferably wherein the cancer is a mature B-cell neoplasm, in particular wherein the cancer is a non-Hodgkin lymphoma, more particular wherein the cancer is preferably selected from the group consisting of small lymphocytic leukemia (SLL), lymphoplasmacytic lymphoma (Waldenström's macroglobulinemia), hairy cell leukaemia, Burkitt lymphoma, marginal zone lymphoma (MZL), splenic marginal zone lymphoma (SMZL), mantle cell lymphoma (MCL), follicular lymphoma (FL), diffuse large B-cell lymphoma (DLBCL), chronic lympho
  • SLL small
  • a pharmaceutical combination as described herein for the prevention, delay of progression or treatment of cancer in a subject, preferably for the delay of progression or treatment of a cancer in a subject, more preferably for the treatment of cancer, wherein the cancer is selected from the group consisting of mantle cell lymphoma (MCL), chronic lymphocytic leukemia (CLL) and splenic marginal zone lymphoma (SMZL).
  • MCL mantle cell lymphoma
  • CLL chronic lymphocytic leukemia
  • SZL splenic marginal zone lymphoma
  • a pharmaceutical combination as described herein for the prevention, delay of progression or treatment of cancer in a subject preferably for the delay of progression or treatment of a cancer in a subject, more preferably for the treatment of cancer, wherein the cancer is mantle cell lymphoma (MCL).
  • MCL mantle cell lymphoma
  • a pharmaceutical combination as described herein for the prevention, delay of progression or treatment of cancer in a subject preferably for the delay of progression or treatment of a cancer in a subject, more preferably for the treatment of cancer, wherein the cancer is chronic lymphocytic leukemia (CLL).
  • CLL chronic lymphocytic leukemia
  • a pharmaceutical combination as described herein for the prevention, delay of progression or treatment of cancer in a subject, preferably for the delay of progression or treatment of a cancer in a subject, more preferably for the treatment of cancer, wherein the cancer is splenic marginal zone lymphoma (SMZL).
  • SSKL splenic marginal zone lymphoma
  • a pharmaceutical combination as described herein for the prevention, delay of progression or treatment of cancer in a subject, preferably for the delay of progression or treatment of a cancer in a subject, more preferably for the treatment of cancer, wherein the cancer is selected from the group consisting of mantle cell lymphoma (MCL), wherein the pharmaceutical combination according to the invention comprises POL5551 (cyclo(-Tyr-His- Tyr-Cys-Ser-Ala- D Pro-Dab-Arg-Tyr-Cys-Tyr-Gln-Lys- D Pro-Pro-) having a disulfide bond between Cys 4 and Cys 11 , (SEQ ID NO:2), and ibrutinib; chronic lymphocytic leukemia (CLL), wherein the pharmaceutical combination according to the invention comprises POL5551 (cyclo(-Tyr-His- Tyr-Cys-Ser-Ala- D Pro-D
  • Also provided is a method for the prevention, delay of progression or treatment of cancer in a subject preferably a method for the delay of progression or treatment of cancer in a subject, more preferably a method for the treatment of a cancer in a subject, comprising administering to said subject a pharmaceutical combination as described herein e.g.
  • the cancer is a tumor of the hematopoietic and lymphoid tissues, even more preferably wherein the cancer is a mature B-cell neoplasm, in particular, wherein the cancer is a non-Hodgkin lymphoma, more particular, wherein the cancer is preferably selected from the group consisting of small lymphocytic leukemia (SLL), lymphoplasmacytic lymphoma (Waldenström's macroglobulinemia), hairy cell leukaemia, Burkitt lymphoma, marginal zone lymphoma (MZL), splenic marginal zone lymphoma (SMZL), mantle cell lymphoma (MCL), follicular lymphoma (FL), diffuse large B-cell lymphoma (DLBCL), chronic lymphocytic leukemia (CLL), more preferably selected from the group consisting of marginal zone lymphoma (MZL), sple
  • a method for the prevention, delay of progression or treatment of cancer in a subject preferably a method for the delay of progression or treatment of cancer in a subject, more preferably a method for the treatment of a cancer in a subject, comprising administering to said subject a pharmaceutical combination as described herein e.g. administering to said subject a therapeutically effective amount of a pharmaceutical combination as described herein, wherein the cancer is selected from the group consisting of mantle cell lymphoma (MCL), chronic lymphocytic leukemia (CLL) and splenic marginal zone lymphoma (SMZL).
  • MCL mantle cell lymphoma
  • CLL chronic lymphocytic leukemia
  • SZL splenic marginal zone lymphoma
  • a method for the prevention, delay of progression or treatment of cancer in a subject preferably a method for the delay of progression or treatment of cancer in a subject, more preferably a method for the treatment of a cancer in a subject, comprising administering to said subject a pharmaceutical combination as described herein e.g. administering to said subject a therapeutically effective amount of a pharmaceutical combination as described herein, wherein the cancer is mantle cell lymphoma (MCL).
  • MCL mantle cell lymphoma
  • a method for the prevention, delay of progression or treatment of cancer in a subject preferably a method for the delay of progression or treatment of cancer in a subject, more preferably a method for the treatment of a cancer in a subject, comprising administering to said subject a pharmaceutical combination as described herein e.g. administering to said subject a therapeutically effective amount of a pharmaceutical combination as described herein, wherein the cancer is chronic lymphocytic leukemia (CLL).
  • CLL chronic lymphocytic leukemia
  • a method for the prevention, delay of progression or treatment of cancer in a subject preferably a method for the delay of progression or treatment of cancer in a subject, more preferably a method for the treatment of a cancer in a subject, comprising administering to said subject a pharmaceutical combination as described herein e.g. administering to said subject a therapeutically effective amount of a pharmaceutical combination as described herein, wherein the cancer is splenic marginal zone lymphoma (SMZL).
  • SMF splenic marginal zone lymphoma
  • a method for the prevention, delay of progression or treatment of cancer in a subject preferably a method for the delay of progression or treatment of cancer in a subject, more preferably a method for the treatment of a cancer in a subject, comprising administering to said subject a pharmaceutical combination as described herein e.g.
  • the cancer is selected from the group consisting of mantle cell lymphoma (MCL), wherein the pharmaceutical combination according to the invention comprises POL5551 (cyclo(-Tyr-His-Tyr-Cys-Ser-Ala- D Pro-Dab-Arg-Tyr-Cys-Tyr-Gln-Lys- D Pro-Pro-) having a disulfide bond between Cys 4 and Cys 11 , (SEQ ID NO:2), and ibrutinib; chronic lymphocytic leukemia (CLL), wherein the pharmaceutical combination according to the invention comprises POL5551 (cyclo(-Tyr-His-Tyr-Cys-Ser-Ala- D Pro-Dab-Arg-Tyr-Cys-Tyr-Gln-Lys- D Pro-Pro-) having a disulfide bond between Cys 4
  • the subject who has cancer e.g. the subject who has a tumor of the hematopoietic and lymphoid tissues is resistant to at least one treatment with a BTK inhibitor.
  • the subject who has cancer e.g. the subject who has a tumor of the hematopoietic and lymphoid tissues is (i) refractory to at least one chemotherapy treatment e.g. refractory to at least one treatment with a BTK inhibitor, or (ii) is in relapse after treatment with chemotherapy, or a combination thereof.
  • the subject is refractory to at least two, at least three, or at least four anti-cancer therapy (including, for example, standard or experimental chemotherapies).
  • a subject who is refractory to at least one anti-cancer therapy and/or is in relapse after treatment with at least one anti-cancer therapy, as described above, may have undergone one or more prior therapies.
  • such subjects have undergone one, two, three, or four, or five, or at least one, at least two, at least three, at least four, or at least five, or between one and ten, between one and nine, between one and eight, between one and seven, between one and six, between one and five, or between one and four, or between one and three, between four and six or between seven and ten anti-cancer therapies prior to treatment using the methods described herein (e.g., prior to the administration of a peptidic CXCR4 inhibitor and a Bruton’s tyrosine kinase (BTK) inhibitor).
  • BTK Bruton’s tyrosine kinase
  • Dosing regimen of the peptidic CXCR4 inhibitor in combination with a Bruton’s tyrosine kinase (BTK) inhibitor in the methods provided herein may vary depending upon the indication, route of administration, and severity of the condition, for example. Depending on the route of administration, a suitable dose can be calculated according to body weight, body surface area, or organ size. The final dosing regimen can be determined by the attending physician in view of good medical practice, considering various factors that modify the action of drugs, e.g., the specific activity of the compound, the identity and severity of the disease state, the responsiveness of the patient, the age, condition, body weight, sex, and diet of the patient, and the severity of any infection.
  • Additional factors that can be taken into account include time and frequency of administration, drug combinations, reaction sensitivities, and tolerance/response to therapy. Further refinement of the doses appropriate for treatment involving any of the formulations mentioned herein is done routinely by the skilled practitioner without undue experimentation, especially in light of the dosing information and assays disclosed, as well as the pharmacokinetic data observed in human clinical trials. Appropriate doses can be ascertained through use of established assays for determining concentration of the agent in a body fluid or other sample together with dose response data. The amount, e.g. the therapeutically effective amount of the peptidic CXCR4 inhibitor may be provided in a single dose or multiple doses to achieve the desired treatment endpoint.
  • the frequency of dosing will depend on the pharmacokinetic parameters of the compound administered, the route of administration, and the particular disease treated.
  • the dose and frequency of dosing may also depend on pharmacokinetic and pharmacodynamic, as well as toxicity and therapeutic efficiency data.
  • pharmacokinetic and pharmacodynamic information about a peptidic CXCR4 inhibitor and a Bruton’s tyrosine kinase (BTK) inhibitor can be collected through preclinical in vitro and in vivo studies, later confirmed in humans during the course of clinical trials.
  • a therapeutically effective dose can be estimated initially from biochemical and/or cell-based assays. Then, dosage can be formulated in animal models to achieve a desirable circulating concentration range. As human studies are conducted further information will emerge regarding the appropriate dosage levels and duration of treatment for various diseases and conditions.
  • Toxicity and therapeutic efficacy of a peptidic CXCR4 inhibitor and a Bruton’s tyrosine kinase (BTK) inhibitor can be determined by standard pharmaceutical procedures in cell cultures or experimental animals, e.g., for determining the LD50 (the dose lethal to 50% of the population) and the ED50 (the dose therapeutically effective in 50% of the population).
  • the dose ratio between toxic and therapeutic effects is the "therapeutic index", which typically is expressed as the ratio LD50/ED50.
  • Compounds that exhibit large therapeutic indices, i.e. the toxic doses are substantially higher than the effective doses, are preferred.
  • the data obtained from such cell culture assays and additional animal studies can be used in formulating a range of dosage for human use.
  • a peptidic CXCR4 inhibitor may be administered to the subject (e.g. a human) within minutes or hours. In some embodiments, a peptidic CXCR4 inhibitor may be administered to the subject (e.g. a human) over about 1 to about 240 minutes, over about 1 to about 180 minutes, or over about 5 to about 150 minutes, or over about 5 to about 120 minutes, or over about 1 to 60 minutes, or over about 1 to 10 minutes, or over about 5 minutes.
  • a Bruton’s tyrosine kinase (BTK) inhibitor may be administered to the subject (e.g. a human) within minutes.
  • An exemplary treatment regime entails administration once daily, twice daily, three times daily, every day, every second day, every third day, every fourth day, every fifth day, every sixth day, twice per week, once per week.
  • the combination of the invention is usually administered on multiple occasions. Intervals between single dosages can be, for example, less than a day, a day, two days, three days, four days, five days, six days or a week.
  • the combination of the invention may be given as a continuous uninterrupted treatment.
  • the combination of the invention may also be given in a regime in which the subject receives cycles of treatment (administration cycles) interrupted by a drug holiday or period of non-treatment.
  • the combination of the invention may be administered according to the selected intervals above for a continuous period of one week or a part thereof, for two weeks, for three weeks for four weeks, for five weeks or for six weeks and then stopped for a period of one week, or a part thereof, for two weeks, for three weeks, for four weeks, for five weeks, or for six weeks or for even more weeks.
  • the combination of the treatment interval and the non- treatment interval is called a cycle.
  • the cycle may be repeated one or more times. Two or more different cycles may be used in combination for repeating the treatment one or more times.
  • the administration of the pharmaceutical combination according to the invention may start with a run-in cycle.
  • Exemplary doses of the peptidic CXCR4 inhibitor for a subject may be from about 0.1 to about 700 mg/kg, or from about 0.1 to about 500 mg/kg, or from about 0.1 to about 250 mg/kg.
  • Exemplary doses of Bruton’s tyrosine kinase (BTK) inhibitor, for a subject, preferably for a human subject may be from about 0.1 to about 50 mg/kg or from about 0.1 to about 25 mg/kg or from about 0.1 to about 12.5 mg/kg or from about 0.1 to about 10 mg/kg or from about 0.5 to about 8 mg/kg.
  • BTK tyrosine kinase
  • the invention provides a pharmaceutical combination comprising a peptidic CXCR4 inhibitor and Bruton’s tyrosine kinase (BTK) inhibitor, wherein the dose of said peptidic CXCR4 inhibitor in the combination from about 0.1 to about 700 mg/kg, or from about 0.1 to about 500 mg/kg, or from about 0.1 to about 250 mg kg and wherein the dose of said Bruton’s tyrosine kinase (BTK) inhibitor in the combination is from about 0.1 to about 50 mg/kg or from about 0.1 to about 25 mg/kg or from about 0.1 to about 12.5 mg/kg or from about 0.1 to about 10 mg/kg or from about 0.5 to about 8 mg/kg.
  • BTK Bruton’s tyrosine kinase
  • the invention provides a pharmaceutical combination comprising a peptidic CXCR4 inhibitor and Bruton’s tyrosine kinase (BTK) inhibitor, wherein the dose of said peptidic CXCR4 inhibitor in the combination is from about 0.1 to about 250 mg/kg; and wherein the dose of said Bruton’s tyrosine kinase (BTK) inhibitor in the combination is from about 0.1 to about 25 mg/kg.
  • BTK Bruton’s tyrosine kinase
  • the invention provides a pharmaceutical combination comprising a peptidic CXCR4 inhibitor and Bruton’s tyrosine kinase (BTK) inhibitor, wherein the peptidic CXCR4 inhibitor is administered to the subject at a dose from about 0.1 to about 700 mg/kg, or from about 0.1 to about 500 mg/kg, or from about 0.1 to about 250 mg/kg.
  • BTK Bruton’s tyrosine kinase
  • the invention provides a pharmaceutical combination comprising a peptidic CXCR4 inhibitor and Bruton’s tyrosine kinase (BTK) inhibitor, wherein Bruton’s tyrosine kinase (BTK) inhibitor is administered to the subject at a dose from about 0.1 to about 50 mg/kg or from about 0.1 to about 25 mg/kg or from about 0.1 to about 12.5 mg/kg or from about 0.1 to about 10 mg/kg or from about 0.5 to about 8 mg/kg Additional combination therapies Provided herein are also methods of treatment in which the peptidic CXCR4 inhibitor in combination with a Bruton’s tyrosine kinase (BTK) inhibitor, is administered to a subject (e.g.
  • the method for treating cancer in a subject comprises administering to the subject a therapeutically effective amount of a peptidic CXCR4 inhibitor and a Bruton’s tyrosine kinase (BTK) inhibitor, together with one or more additional therapies, which can be useful for treating the cancer.
  • the one or more additional therapies may involve the administration of one or more therapeutic agents, preferably therapeutic anti-cancer agents. Kit of parts A pharmaceutical combination e.g.
  • kits of parts also are contemplated.
  • a kit can comprise unit dosage forms of the peptidic CXCR4 inhibitor and the Bruton’s tyrosine kinase (BTK) inhibitor, and a package insert containing instructions for use of the composition in treatment of a medical condition.
  • kits comprises a unit dosage form of peptidic CXCR4 inhibitor and/or a Bruton’s tyrosine kinase (BTK) inhibitor.
  • the instructions for use in the kit may be for treating a cancer.
  • the present invention provides a kit of parts comprising a first container, a second container and a package insert, wherein the first container comprises at least one dose of a medicament comprising a peptidic CXCR4 inhibitor; the second container comprises at least one dose of a medicament comprising a Bruton’s tyrosine kinase (BTK) inhibitor, and the package insert comprises optionally instructions for treating a subject for cancer using the medicaments.
  • the cancer the instructions relate to are usually the cancers as described supra.
  • Example 1 Background Targeting downstream signaling to B-cell receptor (BCR) is one of the promising therapeutic approaches in lymphoma. Inhibition or BCR signaling is being extensively explored as a therapeutic approach for patients with lymphoid neoplasms.
  • the first-in-class BTK inhibitor ibrutinib has been approved by the FDA for different indications including the treatment of patients with MZL, who are in need of systemic therapy and have received at least one prior anti-CD20-based therapy (Noy A, de Vos S, Thieblemont C, et al.: Targeting Bruton tyrosine kinase with ibrutinib in relapsed/refractory marginal zone lymphoma, Blood 2017, 129(16), 2224-2232).
  • single treatment with BCR signaling inhibitors show limited success in complete response.
  • current treatments are initially effective, they are not curative, and their efficacy decreases upon repeated administrations leading to drug resistance and relapse.
  • VL51 lines José ⁇ ngel Martinez-Climent (Pamplona, ES) derived from splenic marginal zone lymphoma were used in all experiments.
  • VL51 resistant (ibrutinib-resistant) and parental lines were exposed to increasing doses of the CXCR4 inhibitors POL5551 (cyclo(-Tyr-His-Tyr- Cys-Ser-Ala- D Pro-Dab-Arg-Tyr-Cys-Tyr-Gln-Lys- D Pro-Pro-) having a disulfide bond between Cys 4 and Cys 11 , (SEQ ID NO:2), and POL6326 (cyclo(-Tyr-His-Ala-Cys-Ser-Ala- D Pro-Dab-Arg-Tyr- Cys-Tyr-Gln-Lys- D Pro-Pro-) having a disulfide bond between Cys 4 and Cys 11 , (SEQ
  • Synergistic Efficacy (MuSyC): synergistic: >1, additive: 0 ⁇ eff ⁇ 1, no effect: ⁇ 0, no benefit: ⁇ 0.
  • C ell type VL51 VL51 VL51 VL51 VL51 Example 2 Methods Various cell lines derived from mantle cell lymphoma (MCL) and chronic lymphocytic leukemia (CLL) (Table 2) were used in the experiments.

Abstract

La présente invention concerne des combinaisons pharmaceutiques comprenant un inhibiteur de CXCR4 peptidique et un inhibiteur de la tyrosine kinase de Bruton (BTK) pour une utilisation dans un procédé pour la prévention, le retardement de la progression ou le traitement du cancer.
PCT/EP2022/069908 2021-07-16 2022-07-15 Combinaisons pharmaceutiques pour le traitement du cancer WO2023285677A1 (fr)

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Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2008104090A1 (fr) 2007-02-28 2008-09-04 Polyphor Ag Peptidomimétiques fixés sur une matrice
WO2012168336A1 (fr) 2011-06-07 2012-12-13 Polyphor Ag Peptidomimétiques en épingle à cheveux bêta utilisés comme antagonistes de cxc4
WO2013182240A1 (fr) 2012-06-06 2013-12-12 Polyphor Ag Peptidomimétiques en épingle à cheveux beta
US20200368235A1 (en) * 2013-04-08 2020-11-26 Pharmacyclics Llc Ibrutinib combination therapy
WO2021127496A1 (fr) * 2019-12-18 2021-06-24 X4 Pharmaceuticals, Inc. Traitements combinés pour la macroglobulinémie de waldenstrom

Patent Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2008104090A1 (fr) 2007-02-28 2008-09-04 Polyphor Ag Peptidomimétiques fixés sur une matrice
WO2012168336A1 (fr) 2011-06-07 2012-12-13 Polyphor Ag Peptidomimétiques en épingle à cheveux bêta utilisés comme antagonistes de cxc4
WO2013182240A1 (fr) 2012-06-06 2013-12-12 Polyphor Ag Peptidomimétiques en épingle à cheveux beta
US20200368235A1 (en) * 2013-04-08 2020-11-26 Pharmacyclics Llc Ibrutinib combination therapy
WO2021127496A1 (fr) * 2019-12-18 2021-06-24 X4 Pharmaceuticals, Inc. Traitements combinés pour la macroglobulinémie de waldenstrom

Non-Patent Citations (37)

* Cited by examiner, † Cited by third party
Title
A. LICLICAN ET AL., BBA - GENERAL SUBJECTS, vol. 1864, 2020, pages 129531
A.R. MATO ET AL., LANCET, vol. 397, 2021, pages 892 - 901
ANONYMOUS: "History of Changes for Study: NCT03225716", 26 May 2021 (2021-05-26), XP055974363, Retrieved from the Internet <URL:https://clinicaltrials.gov/ct2/history/NCT03225716?V_9=View#StudyPageTop> [retrieved on 20221024] *
BOI MGAUDIO EBONETTI P ET AL.: "The BET Bromodomain Inhibitor OTX015 Affects Pathogenetic Pathways in Preclinical B-cell Tumor Models and Synergizes with Targeted Drugs", CLIN CANCER RES., vol. 21, no. 7, 2015, pages 1628 - 1638, XP055227481, DOI: 10.1158/1078-0432.CCR-14-1561
C. GOESS ET AL., MOD. RHEUMATOL., vol. 29, no. 3, 2019, pages 510 - 522
C. LIANG ET AL., EUR. J. MED. CHEM., vol. 151, 2018, pages 315 - 326
CAS , no. 1510829-06-7
CAS, no. 2242452-37-3
CHOU TC.: "Drug combination studies and their synergy quantification using the Chou-Talalay method", CANCER RES., vol. 70, no. 2, 2010, pages 440 - 446, XP055169871, DOI: 10.1158/0008-5472.CAN-09-1947
D. ANGST ET AL., J. MED. CHEM., vol. 63, 2020, pages 12526 - 12541
D. ZHAO ET AL., EUR. J. MED. CHEM., vol. 126, 2017, pages 444 - 455
F. MUSUMECI ET AL., EXPERT OPIN. THER. PAT., vol. 27, no. 12, 2017, pages 1305 - 1318
FEDERICA BARBIERI ET AL: "Drug design strategies focusing on the CXCR4/CXCR7/CXCL12 pathway in leukemia and lymphoma", EXPERT OPINION ON DRUG DISCOVERY, vol. 11, no. 11, 20 September 2016 (2016-09-20), London, GB, pages 1093 - 1109, XP055558199, ISSN: 1746-0441, DOI: 10.1080/17460441.2016.1233176 *
G. HOUSMAN ET AL., CANCERS, vol. 6, 2014, pages 1769 - 1792
I. OJIMA ET AL., EXP. OPIN. THER. PATENTS, vol. 26, 2016, pages 1 - 20
J. A. BURGER, CANCER J, vol. 25, no. 6, 2019, pages 386 - 393
J. K. PARK ET AL., ARTHRITIS RES. THER., vol. 18, 2016, pages 91
J.S. TOKARSKI ET AL., CANCER RES., vol. 66, no. 11, 2006, pages 5790 - 5797
K. DAHL ET AL., J. LABEL. COMPD RADIOPHARM., vol. 63, 2020, pages 482 - 487
KAISER LISA MARIE ET AL: "CXCR4 in Waldenström's Macroglobulinema: chances and challenges", LEUKEMIA, vol. 35, no. 2, February 2021 (2021-02-01), pages 333 - 345, XP037357186, ISSN: 0887-6924, DOI: 10.1038/S41375-020-01102-3 *
L. MAO ET AL., MED. DRUG DISCOVERY, vol. 6, 2020, pages 100035
M. C. BRYANN. S. RAJAPAKSA, J. MED. CHEM., vol. 61, 2018, pages 2227 - 2245
MARTIN MIGUEL ET AL: "At the bedside: Profiling and treating patients with CXCR4?expressing cancers", JOURNAL OF LEUKOCYTE BIOLOGY, 22 October 2020 (2020-10-22), GB, XP055798564, ISSN: 0741-5400, Retrieved from the Internet <URL:https://onlinelibrary.wiley.com/doi/full-xml/10.1002/JLB.5BT1219-714R> DOI: 10.1002/JLB.5BT1219-714R *
MEYER CTWOOTEN DJPAUDEL BB ET AL.: "Quantifying Drug Combination Synergy along Potency and Efficacy Axes", CELL SYST, vol. 8, no. 2, 2019, pages 97 - 108, XP055818860, DOI: 10.1016/j.cels.2019.01.003
N. VASAN ET AL., NATURE, vol. 575, 2019, pages 299 - 309
NOY ADE VOS STHIEBLEMONT C ET AL.: "Targeting Bruton tyrosine kinase with ibrutinib in relapsed/refractory marginal zone lymphoma", BLOOD, vol. 129, no. 16, 2017, pages 2224 - 2232
O. HANTSCHEL ET AL., PNAS, vol. 104, no. 33, 2007, pages 13283 - 13288
S. H. WATTERSON ET AL., J. MED. CHEM., vol. 59, 2016, pages 9173 - 9200
S. H. WATTERSON ET AL., J. MED. CHEM., vol. 62, 2019, pages 3228 - 3250
S.D. REIFF ET AL., CANCER DISCOVERY, vol. 8, no. 10, 2018, pages 1300 - 1315
T. BARF ET AL., J. PHARMACOL. EXP. THER., vol. 363, 2017, pages 240 - 252
T. WEN ET AL., LEUKEMIA, 2020
TARANTELLI CGAUDIO EARRIBAS AJ ET AL.: "PQR309 Is a Novel Dual PI3K/mTOR Inhibitor with Preclinical Antitumor Activity in Lymphomas as a Single Agent and in Combination Therapy", CLIN CANCER RES., vol. 24, no. 1, 2018, pages 120 - 129
TREON S. ET AL: "PRELIMINARY CLINICAL DATA FROM A PHASE 1B STUDY OF MAVORIXAFOR AND IBRUTINIB IN PATIENTS WITH WALDENSTRöM MACROGLOBULINEMIA WITH MYD88 AND CXCR4 MUTATIONS", HEMATOLOGICAL ONCOLOGY, vol. 39, no. S2, 1 June 2021 (2021-06-01), US, XP055974200, ISSN: 0278-0232, Retrieved from the Internet <URL:https://onlinelibrary.wiley.com/doi/full-xml/10.1002/hon.86_2881> DOI: 10.1002/hon.86_2881 *
U. SWAMI ET AL., MAR. DRUGS, vol. 13, 2015, pages 5016 - 5058
W. ZHANG ET AL., J BIOL CHEM., vol. 277, no. 27, 2002, pages 24515 - 24521
Y. FENG ET AL., EXPERT OPIN. THER. PAT., vol. 29, no. 4, 2019, pages 217 - 241

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