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WO2020202005A1 - Association d'un inhibiteur de la kinase fak et d'un agent ciblant des récepteurs co-stimulateurs des cellules t - Google Patents

Association d'un inhibiteur de la kinase fak et d'un agent ciblant des récepteurs co-stimulateurs des cellules t Download PDF

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Publication number
WO2020202005A1
WO2020202005A1 PCT/IB2020/053046 IB2020053046W WO2020202005A1 WO 2020202005 A1 WO2020202005 A1 WO 2020202005A1 IB 2020053046 W IB2020053046 W IB 2020053046W WO 2020202005 A1 WO2020202005 A1 WO 2020202005A1
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Prior art keywords
cancer
cell
lymphoma
tumor
leukemia
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English (en)
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Alan SERRELS
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Inxmed Shanghai Co Ltd
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Inxmed Shanghai Co Ltd
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/506—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim not condensed and containing further heterocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents

Definitions

  • the present invention belongs to the field of cancer treatment.
  • the present invention discloses a combination of the FAK kinase inhibitor BI853520 or the pharmaceutical acceptable salts thereof and an agent targeting T-cell co-stimulatory receptors selected from 0X40 and41BB, and the CD80 based stratification method of cancer patients for treatment with FAK kinase inhibitor.
  • FAK Focal Adhesion Kinase
  • FAKi FAK kinase inhibitors
  • the inventors identify that endogenous expression of the T-cell co-stimulatory ligand CD80 on the surface of cancer cells correlates with the response of tumors to the FAK kinase inhibitor BI 853520, and that exogenous expression of CD80 into cancer cells that do not normally express this ligand renders them sensitive to the anti-tumor activity of BI 853520.
  • the inventors demonstrate that FAK kinase inhibitor BI 853520 has virtually no antitumor activity against tumor cells without CD80 expression, in contrast to the remarkable antitumor activities of BI 853520 against tumor cells with high expression of CD80.
  • GITR glucocorticoid-induced TNFR-related protein
  • TNFRSF18 Tumor necrosis factor receptor superfamily member 18
  • CD40 also known as TNFRSF5
  • 4 IBB also known as tumor necrosis factor receptor superfamily member 9 (TNFRSF9) and CD137
  • 0X40 also known as Tumor necrosis factor receptor superfamily member 4 (TNFRSF4) and CD134
  • BI853520 and anti-OX40 treatment both reduce the number of Regulatory T-cells (Tregs) in SCC tumors, while anti-OX40 drives elevated CD8 T-cell infiltration.
  • BI853520 also significantly downregulates PDL2 expression on tumor associated macrophages, monocytic-myeloid derived suppressor cells (M-MDSCs) and cancer cells, establishing a novel role for FAK in the regulation of immune checkpoint signaling.
  • M-MDSCs monocytic-myeloid derived suppressor cells
  • this invention relates to the treatment of cancer by using the FAK kinase inhibitor BI853520 or the pharmaceutical acceptable salts thereof in combination with an agent targeting T-cell co-stimulatory receptors selected from 0X40 and 41BB.
  • this invention relates to a combination comprising the FAK kinase inhibitor BI853520 or the pharmaceutical acceptable salts thereof and an agent targeting T-cell co-stimulatory receptors selected from 0X40 and 41BB.
  • this invention relates to a pharmaceutical composition
  • a pharmaceutical composition comprising the FAK kinase inhibitor BI853520 or the pharmaceutical acceptable salts thereof and an agent targeting T-cell co-stimulatory receptors selected from 0X40 and 41BB.
  • this invention relates to a kit comprising a first composition including the FAK kinase inhibitor BI853520 or the pharmaceutical acceptable salts thereof, and a second composition including an agent targeting T-cell co-stimulatory receptors selected from 0X40 and 41BB.
  • this invention relates to a method for treating cancer comprising administrating the FAK kinase inhibitor BI853520 or the pharmaceutical acceptable salts thereof in combination with an agent targeting T-cell co-stimulatory receptors selected from 0X40 and 41BB.
  • this invention relates to the FAK kinase inhibitor BI853520 or the pharmaceutical acceptable salts thereof for use in the above methods.
  • this invention relates to an agent targeting T-cell co-stimulatory receptors selected from 0X40 and 4 IBB for use in the above methods.
  • this invention relates to a use of the FAK kinase inhibitor BI853520 or the pharmaceutical acceptable salts thereof and an agent targeting T-cell co stimulatory receptors selected from 0X40 and 4 IBB in the preparation of medicament for treating cancer.
  • this invention relates to a medicament comprising the FAK kinase inhibitor BI853520 or the pharmaceutical acceptable salts thereof for use in treating cancer in a subject, wherein the FAK kinase inhibitor is for use in combination with an agent targeting T-cell co-stimulatory receptors selected from 0X40 and 41BB.
  • this invention relates to a use of medicament comprising an agent targeting T-cell co-stimulatory receptors selected from 0X40 and 4 IBB for use in treating cancer in a subject, wherein the agent targeting T-cell co-stimulatory receptors selected from 0X40 and 4 IBB is for use in combination with an agent directed to a FAK kinase inhibitor.
  • this invention relates to use of CD80 as a biomarker for identifying a subject with cancer that could benefit from treatment with the FAK kinase inhibitor BI853520 or the pharmaceutical acceptable salts thereof, wherein the subject is identified when CD80 expression (preferable high CD80 expression) is detected on the cancer cell.
  • this invention relates to use of the FAK kinase inhibitor BI853520 or the pharmaceutical acceptable salts thereof in the preparation of medicament for treating cancer with CD80 expression (preferable with high CD80 expression) or the FAK kinase inhibitor BI853520 or the pharmaceutical acceptable salts thereof for treating cancer with CD80 expression (preferable with high CD80 expression) in a subject.
  • this invention relates to a method for treating a cancer with CD80 expression (preferable with high CD80 expression) in a subject, comprising administering the FAK kinase inhibitor BI853520 or the pharmaceutical acceptable salts thereof to the subject.
  • this invention relates to a method for identifying a subject with cancer that could benefit from treatment with the FAK kinase inhibitor BI853520 or the pharmaceutical acceptable salts thereof, comprising detecting CD80 expression on the cancer cell, the subject is identified when CD80 expression (preferable with high CD80 expression) is detected.
  • FIG. 1 Treatment of a range of tumor models with the FAK kinase inhibitor BI 853520 identifies a spectrum of responses.
  • H and I Subcutaneous tumor growth of SCC7.1 and MetOl cells treated with either vehicle or BI 853520 and Isotype control antibody (IgG) or anti-CD8 T-cell depleting antibody.
  • FIG. 2 CD80 expression on cancer cells correlates with response of tumors to BI 853520.
  • A Flow cytometry analysis of CD8+ T-cell infiltration in SCC7.1, MetOl, SCC6.2, Panc43, Panc47, and Panel 17 tumors.
  • B Flow cytometry quantification of the percentage of CD8+ T-cells expressing PD1 in SCC7.1, MetOl, SCC6.2, Panc43, Panc47, and Panel 17 tumors.
  • C Flow cytometry analysis of PDL1 expression on SCC7.1, MetOl, SCC6.2, Panc43, Panc47, and Panel 17 cells following stimulation with 10 ng/ml IFNy for 24 hours under normal culture conditions.
  • FIG. 3 Expression of the immune costimulatory ligand CD80 in SCC6.2 cells renders tumors responsive to BI 853520.
  • A Nanostring gene expression analysis of Major Histocompatibility Complex (MHC) genes in SCC7.1 and SCC6.2 cells.
  • B Comparison of CD80 surface expression between SCC7.1 cells and SCC6.2 cells transfected with a pcDNA3-CD80 vector. Left - Flow cytometry analysis of the percentage of cells expressing CD80, Right - mean fluorescent intensity (MFI) of CD80 cell surface expression.
  • C Left - Subcutaneous tumor growth of SCC6.2 cells transfected with either pcDNA3 empty vector or pcDNA3-CD80 vector and treated once daily with either vehicle or 50 mg/kg BI 853520. Right - Comparison of tumor volume on day 17 post-implantation of tumor cells. Graph represents mean +/- s.e.m. P ⁇ 0.01, one-way ANOVA with Dunnett’s multiple comparison.
  • Figure 4 - Genomics analysis identifies a subset of hematological malignancies that co-express high levels of CD80 and FAK.
  • A Analysis of CD80 expression in genomics datasets derived from human cancer cell lines. The number of cell lines from each tumor type is listed below along with the percentage positive for expression.
  • B Analysis of FAK expression in the same genomics datasets from human cancer cell lines.
  • C Scatter plot of CD80 expression against FAK expression in all cell lines.
  • D Analysis of CD80 expression in genomics datasets derived from human cancer cell lines from different types of hematological malignancies.
  • Figure 6 - 0X40 and BI 853520 display overlapping and distinct immune modulatory activity.
  • A-C Flow cytometry quantification of tumor infiltrating Tregs, CD4 (non-Treg) T-cells, and CD8eff T-cells.
  • D Flow cytometry quantification of the percentage of CD8eff T-cells positive for expression of PD1 / LAG3 (left) and PD1 / Tim3 (right).
  • E Flow cytometry quantification of tumor infiltrating macrophages.
  • F Flow cytometry quantification of the percentage of macrophages expressing PDL1 (left), and the mean fluorescent intensity of PDL1 expression (right).
  • G Flow cytometry quantification of the percentage of macrophages expressing PDL2 (left), and the mean fluorescent intensity of PDL2 expression (right).
  • H Representative histogram of PDL2 fluorescent intensity in a control sample stained with all antibodies except for PDL2 (FMO), cancer cells, G-MDSCs, M-MDSCs, Macrophages, and CDl lb+ Dendritic cells.
  • I Flow cytometry quantification of the percentage of M- MDSCs, G-MDSCs, cancer cells, and dendritic cells positive for expression of PDL2. Statistical analysis performed using an ordinary one-way ANOVA with Tukey’s multiple comparison.
  • FIG. 7 Treatment with BI 853520 renders Panc47 tumors responsive to treatment with agonistic antibodies targeting the immune co-stimulatory molecules 41BB and 0X40.
  • a - D Left - Subcutaneous growth of Panc47 tumors treated with either vehicle or 50 mg/kg BI 853520 in combination with either lOOug GITR, CD40, 4 IBB, or 0X40 agonistic antibodies.
  • Graph represents individual tumor measurements together with the mean +/- s.e.m. Dosing schedule identical to Fig. 4A.
  • Figure 8 Frequency of immune cell populations in SCC6.2 tumors treated with either vehicle, 0X40, BI 853520 or 0X40 + BI 853520.
  • the articles “a” and “an” refer to one or to more than one (e.g., at least one) of the grammatical object of the article.
  • ABSOR and “approximately” shall generally mean an acceptable degree of error for the quantity measured given the nature or precision of the measurements. Exemplary degrees of error are within 20 percent (%), typically, within 10%, and more typically, within 5% of a given value or range of values.
  • the term "pharmaceutically acceptable,” refers to a compound or carrier (e.g., excipient) that may be administered to a subject, together with a compound described herein, and which does not destroy the pharmacological activity thereof and is nontoxic when administered in doses sufficient to deliver a therapeutic amount of the compound.
  • administering refers to contact of an exogenous pharmaceutical, therapeutic, diagnostic agent, or composition to the animal, human, subject, cell, tissue, organ, or biological fluid.
  • Treatment of a cell encompasses contact of a reagent to the cell, as well as contact of a reagent to a fluid, where the fluid is in contact with the cell.
  • administering also means in vitro and ex vivo treatments, e.g., of a cell, by a reagent, diagnostic, binding compound, or by another cell.
  • the term "agent targeting T-cell co-stimulatory receptors selected from 0X40 and 4 IBB” means any chemical compound or biological molecule capable of binding to 0X40 or 41BB.
  • the agent targeting T-cell co stimulatory receptors selected from 0X40 and 4 IBB is an 0X40 agonist or a 4 IBB agonist.
  • the agent targeting T-cell co-stimulatory receptors selected from 0X40 and 41BB is an 0X40 binding protein or a 41BB binding protein.
  • 0X40 binding protein refers to antibodies and other protein constructs, such as domains, which are capable of binding to 0X40. In some instances, the 0X40 is human 0X40.
  • 0X40 binding protein can be used interchangeably with "0X40 antigen binding protein.”
  • anti-OX40 antibodies and/or 0X40 antigen binding proteins would be considered 0X40 binding proteins.
  • anti-OX40 antibody means an antibody, as defined herein, capable of binding to human 0X40 receptor.
  • antigen binding protein is any protein, including but not limited to antibodies, domains and other constructs described herein, that binds to an antigen, such as 0X40.
  • antigen binding portion of an 0X40 binding protein would include any portion of the 0X40 binding protein capable of binding to 0X40, including but not limited to, an antigen binding antibody fragment.
  • 41BB binding protein refers to antibodies and other protein constructs, such as domains, which are capable of binding to 41BB.
  • the 41BB is human 41BB.
  • 4 IBB binding protein can be used interchangeably with “4 IBB antigen binding protein.”
  • anti-4 IBB antibodies and/or 4 IBB antigen binding proteins would be considered 4 IBB binding proteins.
  • anti-41BB antibody means an antibody, as defined herein, capable of binding to human 41BB receptor.
  • antigen binding protein is any protein, including but not limited to antibodies, domains and other constructs described herein, that binds to an antigen, such as 41BB.
  • antigen binding portion of a 4 IBB binding protein would include any portion of the 4 IBB binding protein capable of binding to 4 IBB, including but not limited to, an antigen binding antibody fragment.
  • the term "antagonist” refers to an antigen binding protein including but not limited to an antibody, which upon contact with a co-signaling receptor causes one or more of the following (1) attenuates, blocks or inactivates the receptor and/or blocks activation of a receptor by its natural ligand, (2) reduces, decreases or shortens the activity, function or presence of the receptor and/or (3) reduces, decrease, abrogates the expression of the receptor.
  • Antagonist activity can be measured in vitro by various assays know in the art such as, but not limited to, measurement of an increase or decrease in cell signaling, cell proliferation, immune cell activation markers, cytokine production.
  • Antagonist activity can also be measured in vivo by various assays that measure surrogate end points such as, but not limited to the measurement of T cell proliferation or cytokine production.
  • cross competes for binding refers to any agent such as an antibody that will compete for binding to a target with any of the agents of the present invention. Competition for binding between two antibodies can be tested by various methods known in the art including Flow Cytometry, Meso Scale Discovery and ELISA. Binding can be measured directly, meaning two or more binding proteins can be put in contact with a co-signaling receptor and bind may be measured for one or each. Alternatively, binding of molecules or interest can be tested against the binding or natural ligand and quantitatively compared with each other.
  • binding protein refers to antibodies and other protein constructs, such as domains, which are capable of binding to an antigen.
  • antibody is used herein in the broadest sense to refer to molecules with an immunoglobulin-like domain (for example IgG, IgM, IgA, IgD or IgE) and includes monoclonal, recombinant, polyclonal, chimeric, human, humanized, multispecific antibodies, including bispecific antibodies, and heteroconjugate antibodies, a single variable domain (e.g., VH, VHH, VL, domain antibody (dAbTM)), antigen binding antibody fragments, Fab, F(ab')2, Fv, disulphide linked Fv, single chain Fv, disulphide-linked scFv, diabodies, TANDABSTM, etc. and modified versions of any of the foregoing.
  • immunoglobulin-like domain for example IgG, IgM, IgA, IgD or IgE
  • a single variable domain e.g., VH, VHH, VL, domain antibody (dAbTM)
  • Fab fragment antigen binding antibody fragments
  • Alternative antibody formats include alternative scaffolds in which the one or more CDRs of the antigen binding protein can be arranged onto a suitable non- immunoglobulin protein scaffold or skeleton, such as an affibody, a SpA scaffold, an LDL receptor class A domain, an avimer or an EGF domain.
  • a suitable non- immunoglobulin protein scaffold or skeleton such as an affibody, a SpA scaffold, an LDL receptor class A domain, an avimer or an EGF domain.
  • domain refers to a folded protein structure which retains its tertiary structure independent of the rest of the protein. Generally, domains are responsible for discrete functional properties of proteins and in many cases may be added, removed or transferred to other proteins without loss of function of the remainder of the protein and/or of the domain.
  • single variable domain refers to a folded polypeptide domain comprising sequences characteristic of antibody variable domains. It therefore includes complete antibody variable domains such as VH, VHH and VL and modified antibody variable domains, for example, in which one or more loops have been replaced by sequences which are not characteristic of antibody variable domains, or antibody variable domains which have been truncated or comprise N- or C-terminal extensions, as well as folded fragments of variable domains which retain at least the binding activity and specificity of the full-length domain.
  • a single variable domain is capable of binding an antigen or epitope independently of a different variable region or domain.
  • a "domain antibody” or “dAb (1M)" may be considered the same as a "single variable domain”.
  • a single variable domain may be a human single variable domain, but also includes single variable domains from other species such as rodent nurse shark and Camelid VHH dAbsTM
  • Camelid VHH are immunoglobulin single variable domain polypeptides that are derived from species including camel, llama, alpaca, dromedary, and guanaco, which produce heavy chain antibodies naturally devoid of light chains.
  • Such VHH domains may be humanized according to standard techniques available in the art, and such domains are considered to be "single variable domains".
  • VH includes camelid VHH domains.
  • An antigen binding fragment may be provided by means of arrangement of one or more CDRs on non-antibody protein scaffolds.
  • Protein Scaffold as used herein includes but is not limited to an immunoglobulin (Ig) scaffold, for example an IgG scaffold, which may be a four chain or two chain antibody, or which may comprise only the Fc region of an antibody, or which may comprise one or more constant regions from an antibody, which constant regions may be of human or primate origin, or which may be an artificial chimera of human and primate constant regions.
  • Ig immunoglobulin
  • the protein scaffold may be an Ig scaffold, for example an IgG, or IgA scaffold.
  • the IgG scaffold may comprise some or all the domains of an antibody (i.e. CHI, CH2, CH3, VH, VL).
  • the antigen binding protein may comprise an IgG scaffold selected from IgGl, IgG2, IgG3, IgG4 or IgG4PE.
  • the scaffold may be IgGl.
  • the scaffold may consist of, or comprise, the Fc region of an antibody, or is a part thereof.
  • Affinity is the strength of binding of one molecule, e.g. an antigen binding protein of the invention, to another, e.g. its target antigen, at a single binding site.
  • the binding affinity of an antigen binding protein to its target may be determined by equilibrium methods (e.g. enzyme-linked immunoabsorbent assay (ELISA) or radioimmunoassay (RIA)), or kinetics (e.g. BIACORETM analysis).
  • Avidity is the sum total of the strength of binding of two molecules to one another at multiple sites, e.g. taking into account the valency of the interaction.
  • the term "Patient” or “subject” refers to any single subject for which therapy is desired or that is participating in a clinical trial, epidemiological study or used as a control, including humans and mammalian veterinary patients such as cattle, horses, dogs, and cats.
  • cancer refers to or describe the physiological condition in mammals that is typically characterized by unregulated cell growth.
  • cancer include but are not limited to, carcinoma, lymphoma, leukemia, blastoma, and sarcoma.
  • cancers include squamous cell carcinoma, myeloma, small-cell lung cancer, non-small cell lung cancer, glioma, hodgkin's lymphoma, non-hodgkin's lymphoma, acute myeloid leukemia (AML), multiple myeloma, gastrointestinal (tract) cancer, renal cancer, ovarian cancer, liver cancer, lymphoblastic leukemia, lymphocytic leukemia, colorectal cancer, endometrial cancer, kidney cancer, prostate cancer, thyroid cancer, melanoma, chondrosarcoma, neuroblastoma, pancreatic cancer, glioblastoma multiforme, cervical cancer, brain cancer, stomach cancer, bladder cancer, hepatoma, breast cancer, colon carcinoma, and head and neck cancer.
  • Another particular example of cancer includes renal cell carcinoma.
  • this invention relates to a combination comprising aFAK kinase inhibitor and an agent targeting T-cell co-stimulatory receptors selected from 0X40 and 41BB.
  • the FAK kinase inhibitor is BI853520 or the pharmaceutical acceptable salts thereof, preferable BI853520 tartaric acid salt.
  • the agent targeting T-cell co-stimulatory receptors selected from 0X40 and 4 IBB is an 0X40 agonist or a 4 IBB agonist.
  • the agent targeting T-cell co-stimulatory receptors selected from 0X40 and 41BB is an 0X40 binding protein or a 41BB binding protein.
  • the agent targeting T-cell co-stimulatory receptors selected from 0X40 and 4 IBB is an anti-OX40 antibody or antigen binding portion thereof, or an anti-4 IBB antibody or antigen binding portion thereof.
  • the anti- 0X40 antibody is PF-04518600, MEDI0562, INCAGN1949, GSK3174998, MOXR0916, BMS-986178, ABBV-368, IBI101 or ATOR-1015
  • the anti-41BB antibody is utomilumab (PF-05082566) or urelumab (BMS-663513).
  • the combination further comprises an additional therapeutic agent.
  • the additional therapeutic agent is selected from: Alkylating agents, Anti-metabolites, Antibiotics, Hormonal therapy agents, Plant derived anti-tumor substances, Cytotoxic topoisomerase inhibiting agents, Immunological s, Biological response modifiers, Other anticancer agents, Other anti- angiogenic compounds, Platinum-coordinated compounds, Tyrosine kinase inhibitors, Antibodies, and Interferons.
  • the therapeutic agent is Anti metabolites or Plant derived anti-tumor substances, preferable gemcitabine or paclitaxel.
  • this invention relates to a pharmaceutical composition
  • a pharmaceutical composition comprising the FAR kinase inhibitor BI853520 or the pharmaceutical acceptable salts thereof and an agent targeting T-cell co-stimulatory receptors selected from 0X40 and 41BB.
  • the pharmaceutical acceptable salts are preferably BI853520 tartaric acid salt.
  • the agent targeting T-cell co-stimulatory receptors selected from 0X40 and 4 IBB is an 0X40 agonist or a 4 IBB agonist.
  • the agent targeting T-cell co-stimulatory receptors selected from 0X40 and 4 IBB is an 0X40 binding protein or a 4 IBB binding protein.
  • the agent targeting T-cell co-stimulatory receptors selected from 0X40 and 4 IBB is an anti-OX40 antibody or antigen binding portion thereof, or an anti-4 IBB antibody or antigen binding portion thereof.
  • the anti-OX40 antibody is PF- 04518600, MEDI0562, INCAGN1949, GSK3174998, MOXR0916, BMS-986178, ABBV-368, IBIIOI or ATOR-1015
  • the anti-41BB antibody is utomilumab (PF- 05082566) or urelumab (BMS-663513).
  • the pharmaceutical composition further comprises an additional therapeutic agent.
  • the additional therapeutic agent is selected from: Alkylating agents, Anti-metabolites, Antibiotics, Hormonal therapy agents, Plant derived anti-tumor substances, Cytotoxic topoisomerase inhibiting agents, Immunological s, Biological response modifiers, Other anticancer agents, Other anti- angiogenic compounds, Platinum-coordinated compounds, Tyrosine kinase inhibitors, Antibodies, and Interferons.
  • the therapeutic agent is Anti-metabolites or Plant derived anti-tumor substances, preferable gemcitabine or paclitaxel.
  • this invention relates to a kit comprising a first composition including a FAK kinase inhibitor, and a second composition including an agent targeting T-cell co-stimulatory receptors selected from 0X40 and 41BB.
  • the agent targeting T-cell co-stimulatory receptors selected from 0X40 and 4 IBB is an 0X40 agonist or a 4 IBB agonist.
  • the agent targeting T-cell co stimulatory receptors selected from 0X40 and 4 IBB is an 0X40 binding protein or a 4 IBB binding protein.
  • the agent targeting T-cell co-stimulatory receptors selected from 0X40 and 41BB is an anti-OX40 antibody or antigen binding portion thereof, or an anti-41BB antibody or antigen binding portion thereof.
  • the anti-OX40 antibody is PF-04518600, MEDI0562, INCAGN1949, GSK3174998, MOXR0916, BMS-986178, ABBV-368, IBI101 or ATOR-1015
  • the anti-41BB antibody is utomilumab (PF-05082566) or urelumab (BMS-663513).
  • the kit further comprises a third composition including an additional therapeutic agent.
  • the additional therapeutic agent is selected from: Alkylating agents, Anti-metabolites, Antibiotics, Hormonal therapy agents, Plant derived anti-tumor substances, Cytotoxic topoisomerase inhibiting agents, Immunological s, Biological response modifiers, Other anticancer agents, Other anti- angiogenic compounds, Platinum-coordinated compounds, Tyrosine kinase inhibitors, Antibodies, and Interferons.
  • the therapeutic agent is Anti metabolites or Plant derived anti-tumor substances, preferable gemcitabine or paclitaxel.
  • the kit further comprising a package insert
  • the package insert comprises instructions for treating cancer in a subject by using them.
  • this invention relates to a method for treating cancer comprising administrating the FAK kinase inhibitor BI853520 or the pharmaceutical acceptable salts thereof in combination with an agent targeting T-cell co-stimulatory receptors selected from 0X40 and 41BB.
  • the pharmaceutical acceptable salts are preferably BI853520 tartaric acid salt.
  • the agent targeting T-cell co-stimulatory receptors selected from 0X40 and 4 IBB is an 0X40 agonist or a 4 IBB agonist.
  • the agent targeting T-cell co-stimulatory receptors selected from 0X40 and 4 IBB is an 0X40 binding protein or a 4 IBB binding protein.
  • the agent targeting T-cell co-stimulatory receptors selected from 0X40 and 4 IBB is an anti-OX40 antibody or antigen binding portion thereof, or an anti-4 IBB antibody or antigen binding portion thereof.
  • the anti-OX40 antibody is PF- 04518600, MEDI0562, INCAGN1949, GSK3174998, MOXR0916, BMS-986178, ABBV-368, IBIIOI or ATOR-1015
  • the anti-41BB antibody is utomilumab (PF- 05082566) or urelumab (BMS-663513).
  • the method further comprises administration of an additional therapeutic agent.
  • the additional therapeutic agent is selected from: Alkylating agents, Anti-metabolites, Antibiotics, Hormonal therapy agents, Plant derived anti-tumor substances, Cytotoxic topoisomerase inhibiting agents, Immunological s, Biological response modifiers, Other anticancer agents, Other anti- angiogenic compounds, Platinum-coordinated compounds, Tyrosine kinase inhibitors, Antibodies, and Interferons.
  • the therapeutic agent is Anti metabolites or Plant derived anti-tumor substances, preferable gemcitabine or paclitaxel.
  • the cancer is a solid tumor.
  • the cancer is renal cell carcinoma (RCC), bladder cancer, breast cancer, kidney cancer, head/neck squamous cell carcinoma (SCCHN), lung squamous cell carcinoma, malignant melanoma, non-small-cell lung cancer (NSCLC), ovarian cancer, pancreatic cancer, prostate cancer, small-cell lung cancer (SCLC) or breast cancer.
  • RCC renal cell carcinoma
  • SCCHN head/neck squamous cell carcinoma
  • NSCLC non-small-cell lung cancer
  • SCLC small-cell lung cancer
  • the cancer is Chondrosarcoma, Ewing's sarcoma, Malignant fibrous histiocytoma of bone/osteosarcoma, Osteosarcoma, Rhabdomyosarcoma, Heart cancer, Astrocytoma, Brainstem glioma, Pilocytic astrocytoma, ependymoma, Primitive neuroectodermal tumor, Cerebellar astrocytoma, Cerebral astrocytoma, Glioma, Medulloblastoma, Neuroblastoma, Oligodendroglioma, Pineal astrocytoma, Pituitary adenoma, Visual pathway and hypothalamic glioma, Breast cancer, Invasive lobular carcinoma, Tubular carcinoma, Invasive cribriform carcinoma, Medullary carcinoma, Male breast cancer, Phyllodes tumor, Inflammatory Breast Cancer, Adrenocortical carcinoma, Islet
  • the cancer is hematological malignancies or lymphomas.
  • the cancer is selected from acute lymphoblastic leukemia (ALL), acute myeloid leukemia (AML), chronic lymphocytic leukemia (CLL), chronic myeloid leukemia (CML), diffuse large B-cell lymphoma (DLBCL), EBV-positive DLBCL, primary mediastinal large B-cell lymphoma, T-cell/histocyte-rich large B-cell lymphoma, follicular lymphoma, Hodgkin's lymphoma (HL), mantle cell lymphoma (MCL), multiple myeloma (MM), myeloid cell leukemia- 1 protein (Mcl-1), myelodysplastic syndrome (MDS), non-Hodgkin's lymphoma (NHL), or small lymphocytic lymphoma (SLL).
  • ALL acute lymphoblastic leukemia
  • AML acute myeloid leukemia
  • CLL chronic lymphoc
  • the cancer is Acute biphenotypic leukemia, Acute eosinophilic leukemia, Acute lymphoblastic leukemia, Acute myeloid leukemia, Acute myeloid dendritic cell leukemia, AIDS-related lymphoma, Anaplastic large cell lymphoma, Angioimmunoblastic T-cell lymphoma, B-cell prolymphocytic leukemia, Burkitt's lymphoma, Chronic lymphocytic leukemia, Chronic myelogenous leukemia, Cutaneous T-cell lymphoma, Diffuse large B-cell lymphoma, Follicular lymphoma, Hairy cell leukemia, Hepatosplenic T-cell lymphoma, Hodgkin's lymphoma, Hairy cell leukemia, Intravascular large B-cell lymphoma, Large granular lymphocytic leukemia, Lymphoplasmacytic lymphoma, Lymphomatoid
  • the FAK kinase inhibitor is administered orally. In some embodiments, the FAK kinase inhibitor is administered at least once a day. In some embodiments, the FAK kinase inhibitor is administered once a day. In some embodiments, the FAK kinase inhibitor is administered twice a day. In some embodiments, the FAK kinase inhibitor is administered at about 100 mg to about 2000 mg. In some embodiments, the FAK kinase inhibitor is administered before the agent targeting T-cell co-stimulatory receptors selected from 0X40 and 4 IBB is administered.
  • the FAK kinase inhibitor is administered after the agent targeting T-cell co-stimulatory receptors selected from 0X40 and 4 IBB is administered. In some embodiments, the FAK kinase inhibitor is administered concurrently with the agent targeting T-cell co-stimulatory receptors selected from 0X40 and 4 IBB is administered.
  • this invention relates to the FAK kinase inhibitor BI853520 or the pharmaceutical acceptable salts thereof for use in the above methods.
  • this invention relates to an agent targeting T-cell co-stimulatory receptors selected from 0X40 and 4 IBB for use in the above methods.
  • the pharmaceutical acceptable salts are preferably BI853520 tartaric acid salt.
  • the agent targeting T-cell co-stimulatory receptors selected from 0X40 and 4 IBB is an 0X40 agonist or a 4 IBB agonist.
  • the agent targeting T-cell co-stimulatory receptors selected from 0X40 and 4 IBB is an 0X40 binding protein or a 4 IBB binding protein.
  • the agent targeting T-cell co-stimulatory receptors selected from 0X40 and 4 IBB is an anti-OX40 antibody or antigen binding portion thereof, or an anti-4 IBB antibody or antigen binding portion thereof.
  • the anti-OX40 antibody is PF- 04518600, MEDI0562, INCAGN1949, GSK3174998, MOXR0916, BMS-986178, ABBV-368, IBIIOI or ATOR-1015
  • the anti-41BB antibody is utomilumab (PF- 05082566) or urelumab (BMS-663513).
  • this invention relates to a use of the FAK kinase inhibitor BI853520 or the pharmaceutical acceptable salts thereof and an agent targeting T-cell co stimulatory receptors selected from 0X40 and 4 IBB in the preparation of medicament for treating cancer.
  • the pharmaceutical acceptable salts are preferably BI853520 tartaric acid salt.
  • the agent targeting T-cell co-stimulatory receptors selected from 0X40 and 4 IBB is an 0X40 agonist or a 4 IBB agonist.
  • the agent targeting T-cell co-stimulatory receptors selected from 0X40 and 4 IBB is an 0X40 binding protein or a 4 IBB binding protein.
  • the agent targeting T-cell co-stimulatory receptors selected from 0X40 and 4 IBB is an anti-OX40 antibody or antigen binding portion thereof, or an anti-4 IBB antibody or antigen binding portion thereof.
  • the anti-OX40 antibody is PF- 04518600, MEDI0562, INCAGN1949, GSK3174998, MOXR0916, BMS-986178, ABBV-368, IBIIOI or ATOR-1015
  • the anti-41BB antibody is utomilumab (PF- 05082566) or urelumab (BMS-663513).
  • the medicament is further used in combination with an additional therapeutic agent.
  • the additional therapeutic agent is selected from: Alkylating agents, Anti-metabolites, Antibiotics, Hormonal therapy agents, Plant derived anti-tumor substances, Cytotoxic topoisomerase inhibiting agents, Immunological s, Biological response modifiers, Other anticancer agents, Other anti- angiogenic compounds, Platinum-coordinated compounds, Tyrosine kinase inhibitors, Antibodies, and Interferons.
  • the therapeutic agent is Anti metabolites or Plant derived anti-tumor substances, preferable gemcitabine or paclitaxel.
  • the cancer is a solid tumor.
  • the cancer is renal cell carcinoma (RCC), bladder cancer, breast cancer, kidney cancer, head/neck squamous cell carcinoma (SCCHN), lung squamous cell carcinoma, malignant melanoma, non-small-cell lung cancer (NSCLC), ovarian cancer, pancreatic cancer, prostate cancer, small-cell lung cancer (SCLC) or breast cancer.
  • the cancer is hematological malignancies and lymphomas.
  • the cancer is Acute biphenotypic leukemia, Acute eosinophilic leukemia, Acute lymphoblastic leukemia, Acute myeloid leukemia, Acute myeloid dendritic cell leukemia, AIDS-related lymphoma, Anaplastic large cell lymphoma, Angioimmunoblastic T-cell lymphoma, B-cell prolymphocytic leukemia, Burkitt's lymphoma, Chronic lymphocytic leukemia, Chronic myelogenous leukemia, Cutaneous T-cell lymphoma, Diffuse large B-cell lymphoma, Follicular lymphoma, Hairy cell leukemia, Hepatosplenic T-cell lymphoma, Hodgkin's lymphoma, Hairy cell leukemia, Intravascular large B-cell lymphoma, Large granular lymphocytic leukemia, Lymphoplasmacytic lymphoma, Lymphomatoid
  • the cancer is selected from acute lymphoblastic leukemia (ALL), acute myeloid leukemia (AML), chronic lymphocytic leukemia (CLL), chronic myeloid leukemia (CML), diffuse large B-cell lymphoma (DLBCL), EBV-positive DLBCL, primary mediastinal large B-cell lymphoma, T-cell/histiocyte-rich large B-cell lymphoma, follicular lymphoma, Hodgkin's lymphoma (HL), mantle cell lymphoma (MCL), multiple myeloma (MM), myeloid cell leukemia- 1 protein (Mcl-1), myelodysplastic syndrome (MDS), non-Hodgkin's lymphoma (NHL), or small lymphocytic lymphoma (SLL).
  • ALL acute lymphoblastic leukemia
  • AML acute myeloid leukemia
  • CLL chronic lymphocytic leukemia
  • CML chronic myeloid leukemia
  • the cancer is Acute biphenotypic leukemia, Acute eosinophilic leukemia, Acute lymphoblastic leukemia, Acute myeloid leukemia, Acute myeloid dendritic cell leukemia, AIDS-related lymphoma, Anaplastic large cell lymphoma, Angioimmunoblastic T-cell lymphoma, B-cell prolymphocytic leukemia, Burkitt's lymphoma, Chronic lymphocytic leukemia, Chronic myelogenous leukemia, Cutaneous T-cell lymphoma, Diffuse large B-cell lymphoma, Follicular lymphoma, Hairy cell leukemia, Hepatosplenic T-cell lymphoma, Hodgkin's lymphoma, Hairy cell leukemia, Intravascular large B-cell lymphoma, Large granular lymphocytic leukemia, Lymphoplasmacytic lymphoma, Lymphomatoid
  • this invention relates to the use of the FAK kinase inhibitor BI853520 or the pharmaceutical acceptable salts thereof in the preparation of medicament for treating cancer, wherein the medicament is used in combination with an agent targeting T-cell co-stimulatory receptors selected from 0X40 and 4 IBB.
  • this invention relates to a use of an agent targeting T-cell co-stimulatory receptors selected from 0X40 and 4 IBB in the preparation of medicament for treating cancer, wherein the medicament is used in combination with a FAR kinase inhibitor.
  • the pharmaceutical acceptable salts are preferably BI853520 tartaric acid salt.
  • the agent targeting T-cell co-stimulatory receptors selected from 0X40 and 4 IBB is an 0X40 agonist or a 4 IBB agonist.
  • the agent targeting T-cell co-stimulatory receptors selected from 0X40 and 4 IBB is an 0X40 binding protein or a 4 IBB binding protein.
  • the agent targeting T-cell co-stimulatory receptors selected from 0X40 and 4 IBB is an anti-OX40 antibody or antigen binding portion thereof, or an anti-4 IBB antibody or antigen binding portion thereof.
  • the anti-OX40 antibody is PF- 04518600, MEDI0562, INCAGN1949, GSK3174998, MOXR0916, BMS-986178, ABBV-368, IBIIOI or ATOR-1015
  • the anti-41BB antibody is utomilumab (PF- 05082566) or urelumab (BMS-663513).
  • the medicament is further used in combination with an additional therapeutic agent.
  • the additional therapeutic agent is selected from: Alkylating agents, Anti-metabolites, Antibiotics, Hormonal therapy agents, Plant derived anti-tumor substances, Cytotoxic topoisomerase inhibiting agents, Immunological s, Biological response modifiers, Other anticancer agents, Other anti- angiogenic compounds, Platinum-coordinated compounds, Tyrosine kinase inhibitors, Antibodies, and Interferons.
  • the therapeutic agent is Anti metabolites or Plant derived anti-tumor substances, preferable gemcitabine or paclitaxel.
  • the cancer is a solid tumor.
  • the cancer is renal cell carcinoma (RCC), bladder cancer, breast cancer, kidney cancer, head/neck squamous cell carcinoma (SCCHN), lung squamous cell carcinoma, malignant melanoma, non-small-cell lung cancer (NSCLC), ovarian cancer, pancreatic cancer, prostate cancer, small-cell lung cancer (SCLC) or breast cancer.
  • RCC renal cell carcinoma
  • SCCHN head/neck squamous cell carcinoma
  • NSCLC non-small-cell lung cancer
  • SCLC small-cell lung cancer
  • the cancer is Acute biphenotypic leukemia, Acute eosinophilic leukemia, Acute lymphoblastic leukemia, Acute myeloid leukemia, Acute myeloid dendritic cell leukemia, AIDS-related lymphoma, Anaplastic large cell lymphoma, Angioimmunoblastic T-cell lymphoma, B-cell prolymphocytic leukemia, Burkitt's lymphoma, Chronic lymphocytic leukemia, Chronic myelogenous leukemia, Cutaneous T-cell lymphoma, Diffuse large B-cell lymphoma, Follicular lymphoma, Hairy cell leukemia, Hepatosplenic T-cell lymphoma, Hodgkin's lymphoma, Hairy cell leukemia, Intravascular large B-cell lymphoma, Large granular lymphocytic leukemia, Lymphoplasmacytic lymphoma, Lymphomatoid
  • the cancer is hematological malignancies or lymphomas.
  • the cancer is selected from acute lymphoblastic leukemia (ALL), acute myeloid leukemia (AML), chronic lymphocytic leukemia (CLL), chronic myeloid leukemia (CML), diffuse large B-cell lymphoma (DLBCL), EBV-positive DLBCL, primary mediastinal large B-cell lymphoma, T-cell/histiocyte-rich large B-cell lymphoma, follicular lymphoma, Hodgkin's lymphoma (HL), mantle cell lymphoma (MCL), multiple myeloma (MM), myeloid cell leukemia- 1 protein (Mcl-1), myelodysplastic syndrome (MDS), non-Hodgkin's lymphoma (NHL), and small lymphocytic lymphoma (SLL).
  • ALL acute lymphoblastic leukemia
  • AML acute myeloid leukemia
  • CLL chronic lympho
  • the cancer is Acute biphenotypic leukemia, Acute eosinophilic leukemia, Acute lymphoblastic leukemia, Acute myeloid leukemia, Acute myeloid dendritic cell leukemia, AIDS-related lymphoma, Anaplastic large cell lymphoma, Angioimmunoblastic T-cell lymphoma, B-cell prolymphocytic leukemia, Burkitt's lymphoma, Chronic lymphocytic leukemia, Chronic myelogenous leukemia, Cutaneous T-cell lymphoma, Diffuse large B-cell lymphoma, Follicular lymphoma, Hairy cell leukemia, Hepatosplenic T-cell lymphoma, Hodgkin's lymphoma, Hairy cell leukemia, Intravascular large B-cell lymphoma, Large granular lymphocytic leukemia, Lymphoplasmacytic lymphoma, Lymphomatoid
  • this invention relates to a medicament comprising the FAK kinase inhibitor BI853520 or the pharmaceutical acceptable salts thereof for use in treating cancer in a subject, wherein the FAK kinase inhibitor is for use in combination with an agent targeting T-cell co-stimulatory receptors selected from 0X40 and 41BB.
  • this invention relates to a use of medicament comprising an agent targeting T-cell co-stimulatory receptors selected from 0X40 and 4 IBB for use in treating cancer in a subject, wherein the agent targeting T-cell co-stimulatory receptors selected from 0X40 and 41BB is for use in combination with an agent directed to the FAK kinase inhibitor BI853520 or the pharmaceutical acceptable salts thereof.
  • the pharmaceutical acceptable salts are preferably BI853520 tartaric acid salt.
  • the agent targeting T-cell co-stimulatory receptors selected from 0X40 and 4 IBB is an 0X40 agonist or a 4 IBB agonist.
  • the agent targeting T-cell co-stimulatory receptors selected from 0X40 and 4 IBB is an 0X40 binding protein or a 4 IBB binding protein.
  • the agent targeting T-cell co-stimulatory receptors selected from 0X40 and 4 IBB is an anti-OX40 antibody or antigen binding portion thereof, or an anti-4 IBB antibody or antigen binding portion thereof.
  • the anti-OX40 antibody is PF- 04518600, MEDI0562, INCAGN1949, GSK3174998, MOXR0916, BMS-986178, ABBV-368, IBIIOI or ATOR-1015
  • the anti-41BB antibody is utomilumab (PF- 05082566) or urelumab (BMS-663513).
  • the medicament is further used in combination with an additional therapeutic agent.
  • the additional therapeutic agent is selected from: Alkylating agents, Anti-metabolites, Antibiotics, Hormonal therapy agents, Plant derived anti-tumor substances, Cytotoxic topoisomerase inhibiting agents, Immunological s, Biological response modifiers, Other anticancer agents, Other anti- angiogenic compounds, Platinum-coordinated compounds, Tyrosine kinase inhibitors, Antibodies, and Interferons.
  • the therapeutic agent is Anti metabolites or Plant derived anti-tumor substances, preferable gemcitabine or paclitaxel.
  • the cancer is a solid tumor.
  • the cancer is renal cell carcinoma (RCC), bladder cancer, breast cancer, kidney cancer, head/neck squamous cell carcinoma (SCCHN), lung squamous cell carcinoma, malignant melanoma, non-small-cell lung cancer (NSCLC), ovarian cancer, pancreatic cancer, prostate cancer, small-cell lung cancer (SCLC) or breast cancer.
  • RCC renal cell carcinoma
  • SCCHN head/neck squamous cell carcinoma
  • NSCLC non-small-cell lung cancer
  • SCLC small-cell lung cancer
  • the cancer is Acute biphenotypic leukemia, Acute eosinophilic leukemia, Acute lymphoblastic leukemia, Acute myeloid leukemia, Acute myeloid dendritic cell leukemia, AIDS-related lymphoma, Anaplastic large cell lymphoma, Angioimmunoblastic T-cell lymphoma, B-cell prolymphocytic leukemia, Burkitt's lymphoma, Chronic lymphocytic leukemia, Chronic myelogenous leukemia, Cutaneous T-cell lymphoma, Diffuse large B-cell lymphoma, Follicular lymphoma, Hairy cell leukemia, Hepatosplenic T-cell lymphoma, Hodgkin's lymphoma, Hairy cell leukemia, Intravascular large B-cell lymphoma, Large granular lymphocytic leukemia, Lymphoplasmacytic lymphoma, Lymphomatoid
  • the cancer is hematological malignancies or lymphomas.
  • the cancer is selected from acute lymphoblastic leukemia (ALL), acute myeloid leukemia (AML), chronic lymphocytic leukemia (CLL), chronic myeloid leukemia (CML), diffuse large B-cell lymphoma (DLBCL), EBV-positive DLBCL, primary mediastinal large B-cell lymphoma, T-cell/histiocyte-rich large B-cell lymphoma, follicular lymphoma, Hodgkin's lymphoma (HL), mantle cell lymphoma (MCL), multiple myeloma (MM), myeloid cell leukemia- 1 protein (Mcl-1), myelodysplastic syndrome (MDS), non-Hodgkin's lymphoma (NHL), and small lymphocytic lymphoma (SLL).
  • ALL acute lymphoblastic leukemia
  • AML acute myeloid leukemia
  • CLL chronic lympho
  • the cancer is Acute biphenotypic leukemia, Acute eosinophilic leukemia, Acute lymphoblastic leukemia, Acute myeloid leukemia, Acute myeloid dendritic cell leukemia, AIDS-related lymphoma, Anaplastic large cell lymphoma, Angioimmunoblastic T-cell lymphoma, B-cell prolymphocytic leukemia, Burkitt's lymphoma, Chronic lymphocytic leukemia, Chronic myelogenous leukemia, Cutaneous T-cell lymphoma, Diffuse large B-cell lymphoma, Follicular lymphoma, Hairy cell leukemia, Hepatosplenic T-cell lymphoma, Hodgkin's lymphoma, Hairy cell leukemia, Intravascular large B-cell lymphoma, Large granular lymphocytic leukemia, Lymphoplasmacytic lymphoma, Lymphomatoid
  • this invention relates to use of the FAK kinase inhibitor BI853520 or the pharmaceutical acceptable salts thereof in the preparation of medicament for treating cancer with CD80 expression, preferably with high CD80 expression.
  • the pharmaceutical acceptable salts are preferably BI853520 tartaric acid salt.
  • the cancer is a solid tumor.
  • the cancer is Chondrosarcoma, Ewing's sarcoma, Malignant fibrous histiocytoma of bone/osteosarcoma, Osteosarcoma, Rhabdomyosarcoma, Heart cancer, Astrocytoma, Brainstem glioma, Pilocytic astrocytoma, ependymoma, Primitive neuroectodermal tumor, Cerebellar astrocytoma, Cerebral astrocytoma, Glioma, Medulloblastoma, Neuroblastoma, Oligodendroglioma, Pineal astrocytoma, Pituitary adenoma, Visual pathway and hypothalamic glioma, Breast cancer, Invasive lobular carcinoma, Tubular carcinoma, Invasive cri
  • the cancer is hematological malignancies or lymphomas.
  • the cancer is Acute biphenotypic leukemia, Acute eosinophilic leukemia, Acute lymphoblastic leukemia, Acute myeloid leukemia, Acute myeloid dendritic cell leukemia, AIDS-related lymphoma, Anaplastic large cell lymphoma, Angioimmunoblastic T-cell lymphoma, B-cell prolymphocytic leukemia, Burkitt's lymphoma, Chronic lymphocytic leukemia, Chronic myelogenous leukemia, Cutaneous T-cell lymphoma, Diffuse large B-cell lymphoma, Follicular lymphoma, Hairy cell leukemia, Hepatosplenic T-cell lymphoma, Hodgkin's lymphoma, Hairy cell leukemia, Intravascular large B-cell lymphoma, Large granular lymphocytic leukemia, Acute biphen
  • this invention relates to the FAK kinase inhibitor BI853520 or the pharmaceutical acceptable salts thereof for treating cancer with CD80 expression, preferable with high CD80 expression, in a subject.
  • the pharmaceutical acceptable salts are preferably BI853520 tartaric acid salt.
  • the cancer is a solid tumor.
  • the cancer is Chondrosarcoma, Ewing's sarcoma, Malignant fibrous histiocytoma of bone/osteosarcoma, Osteosarcoma, Rhabdomyosarcoma, Heart cancer, Astrocytoma, Brainstem glioma, Pilocytic astrocytoma, ependymoma, Primitive neuroectodermal tumor, Cerebellar astrocytoma, Cerebral astrocytoma, Glioma, Medulloblastoma, Neuroblastoma, Oligodendroglioma, Pineal astrocytoma, Pituitary adenoma, Visual pathway and hypothalamic glioma, Breast cancer, Invasive lobular carcinoma, Tubular carcinoma, Invasive cri
  • the cancer is hematological malignancies or lymphomas.
  • the cancer is Acute biphenotypic leukemia, Acute eosinophilic leukemia, Acute lymphoblastic leukemia, Acute myeloid leukemia, Acute myeloid dendritic cell leukemia, AIDS-related lymphoma, Anaplastic large cell lymphoma, Angioimmunoblastic T-cell lymphoma, B-cell prolymphocytic leukemia, Burkitt's lymphoma, Chronic lymphocytic leukemia, Chronic myelogenous leukemia, Cutaneous T-cell lymphoma, Diffuse large B-cell lymphoma, Follicular lymphoma, Hairy cell leukemia, Hepatosplenic T-cell lymphoma, Hodgkin's lymphoma, Hairy cell leukemia, Intravascular large B-cell lymphoma, Large granular lymphocytic leukemia, Acute biphen
  • this invention relates to a method for treating a cancer with CD80 expression, preferable with high CD80 expression, in a subject, comprising administering the FAK kinase inhibitor BI853520 or the pharmaceutical acceptable salts thereof to the subject.
  • the subject is human.
  • the pharmaceutical acceptable salts are preferably BI853520 tartaric acid salt.
  • the cancer is a solid tumor.
  • the cancer is Chondrosarcoma, Ewing's sarcoma, Malignant fibrous histiocytoma of bone/osteosarcoma, Osteosarcoma, Rhabdomyosarcoma, Heart cancer, Astrocytoma, Brainstem glioma, Pilocytic astrocytoma, ependymoma, Primitive neuroectodermal tumor, Cerebellar astrocytoma, Cerebral astrocytoma, Glioma, Medulloblastoma, Neuroblastoma, Oligodendroglioma, Pineal astrocytoma, Pituitary adenoma, Visual pathway and hypothalamic glioma, Breast cancer, Invasive lobular carcinoma
  • the cancer is hematological malignancies or lymphomas.
  • the cancer is Acute biphenotypic leukemia, Acute eosinophilic leukemia, Acute lymphoblastic leukemia, Acute myeloid leukemia, Acute myeloid dendritic cell leukemia, AIDS-related lymphoma, Anaplastic large cell lymphoma, Angioimmunoblastic T-cell lymphoma, B-cell prolymphocytic leukemia, Burkitt's lymphoma, Chronic lymphocytic leukemia, Chronic myelogenous leukemia, Cutaneous T-cell lymphoma, Diffuse large B-cell lymphoma, Follicular lymphoma, Hairy cell leukemia, Hepatosplenic T-cell lymphoma, Hodgkin's lymphoma, Hairy cell leukemia, Intravascular large B-cell lymphoma, Large granular lymphocytic leukemia, Acute biphen
  • this invention relates to a method for identifying a subject with cancer that could benefit from treatment with the FAK kinase inhibitor BI853520 or the pharmaceutical acceptable salts thereof, comprising detecting CD80 expression on the cancer cell, the subject is identified when CD80 expression, preferable high CD80 expression, is detected.
  • the subject is human.
  • the pharmaceutical acceptable salts are preferably BI853520 tartaric acid salt.
  • the cancer is a solid tumor.
  • the cancer is Chondrosarcoma, Ewing's sarcoma, Malignant fibrous histiocytoma of bone/osteosarcoma, Osteosarcoma, Rhabdomyosarcoma, Heart cancer, Astrocytoma, Brainstem glioma, Pilocytic astrocytoma, ependymoma, Primitive neuroectodermal tumor, Cerebellar astrocytoma, Cerebral astrocytoma, Glioma, Medulloblastoma, Neuroblastoma, Oligodendroglioma, Pineal astrocytoma, Pituitary adenoma, Visual pathway and hypothalamic glioma, Breast cancer, Invasive lobular carcinoma
  • the cancer is hematological malignancies or lymphomas.
  • the cancer is Acute biphenotypic leukemia, Acute eosinophilic leukemia, Acute lymphoblastic leukemia, Acute myeloid leukemia, Acute myeloid dendritic cell leukemia, AIDS-related lymphoma, Anaplastic large cell lymphoma, Angioimmunoblastic T-cell lymphoma, B-cell prolymphocytic leukemia, Burkitt's lymphoma, Chronic lymphocytic leukemia, Chronic myelogenous leukemia, Cutaneous T-cell lymphoma, Diffuse large B-cell lymphoma, Follicular lymphoma, Hairy cell leukemia, Hepatosplenic T-cell lymphoma, Hodgkin's lymphoma, Hairy cell leukemia, Intravascular large B-cell lymphoma, Large granular lymphocytic leukemia, Acute biphen
  • this invention relates to use of CD80 as a biomarker for identifying a subject with cancer that could benefit from treatment with the FAK kinase inhibitor BI853520 or the pharmaceutical acceptable salts thereof, wherein the subject is identified when CD80 expression, preferable high CD80 expression, is detected on the cancer cell.
  • the subject is human.
  • the pharmaceutical acceptable salts are preferably BI853520 tartaric acid salt.
  • the cancer is a solid tumor.
  • the cancer is Chondrosarcoma, Ewing's sarcoma, Malignant fibrous histiocytoma of bone/osteosarcoma, Osteosarcoma, Rhabdomyosarcoma, Heart cancer, Astrocytoma, Brainstem glioma, Pilocytic astrocytoma, ependymoma, Primitive neuroectodermal tumor, Cerebellar astrocytoma, Cerebral astrocytoma, Glioma, Medulloblastoma, Neuroblastoma, Oligodendroglioma, Pineal astrocytoma, Pituitary adenoma, Visual pathway and hypothalamic glioma, Breast cancer, Invasive lobular carcinoma
  • the cancer is hematological malignancies or lymphomas.
  • the cancer is Acute biphenotypic leukemia, Acute eosinophilic leukemia, Acute lymphoblastic leukemia, Acute myeloid leukemia, Acute myeloid dendritic cell leukemia, AIDS-related lymphoma, Anaplastic large cell lymphoma, Angioimmunoblastic T-cell lymphoma, B-cell prolymphocytic leukemia, Burkitt's lymphoma, Chronic lymphocytic leukemia, Chronic myelogenous leukemia, Cutaneous T-cell lymphoma, Diffuse large B-cell lymphoma, Follicular lymphoma, Hairy cell leukemia, Hepatosplenic T-cell lymphoma, Hodgkin's lymphoma, Hairy cell leukemia, Intravascular large B-cell lymphoma, Large granular lymphocytic leukemia, Acute biphen
  • the agent targeting T-cell co-stimulatory receptor 0X40 that can be used in the present invention is any chemical compound or biological molecule capable of binding to 0X40.
  • the agent targeting T-cell co-stimulatory receptor 0X40 can be an 0X40 agonist. In one embodiment, the agent targeting T-cell co-stimulatory receptor 0X40 can be an 0X40 binding protein. In one embodiment, the agent targeting T-cell co-stimulatory receptor 0X40 can be an anti-OX40 antibody or antigen binding portion thereof.
  • Examples of mAbs that bind to human 0X40, and useful in the treatment method, medicaments and uses of the present invention, are described in, for example, U.S. Patent No. 7,960,515, PCT Patent Application Publication Nos. WO2013028231 and W02013/119202, and U.S. Patent Application Publication No. 20150190506.
  • Examples of an anti-OX40 antibody used in the present invention are PF-04518600, MEDI0562, INCAGN1949, GSK3174998, MOXR0916, BMS-986178, ABBV-368, IBI101 or ATOR-1015.
  • the agent targeting T-cell co-stimulatory receptor 4 IBB that can be used in the present invention is any chemical compound or biological molecule capable of binding to 41BB.
  • the agent targeting T-cell co-stimulatory receptor 4 IBB can be a 4 IBB agonist. In one embodiment, the agent targeting T-cell co-stimulatory receptor 4 IBB can be a 4 IBB binding protein. In one embodiment, the agent targeting T-cell co stimulatory receptor 4 IBB can be an anti-4 IBB antibody or antigen binding portion thereof.
  • Examples of mAbs that bind to human 4 IBB, and useful in the treatment method, medicaments and uses of the present invention, are described in, for example, US Patent Nos. 7,288,638 and 8,962,804.
  • Examples of an anti-41BB antibody used in the present invention are utomilumab (PF-05082566) or urelumab (BMS-663513).
  • Potent inhibitors of the FAK protein tyrosine kinases may be adapted to therapeutic use as antiproliferative agents (e.g., anticancer), antitumor (e.g., effective against solid tumors), antiangiogenesis (e.g., stop or prevent proliferation of blood vessels) in mammals, particularly in humans.
  • antiproliferative agents e.g., anticancer
  • antitumor e.g., effective against solid tumors
  • antiangiogenesis e.g., stop or prevent proliferation of blood vessels
  • the compound described herein, BI853520 or the pharmaceutical acceptable salts thereof may be useful in the prevention and treatment of a disease or disorder described herein (e.g., abnormal cell growth, e.g., cancer (e.g., a cancer described herein)).
  • the compounds described herein, or pharmaceutically acceptable salts thereof are present in a composition in the amount of 5, 10, 11, 12, 12.5, 13, 14, 15, 20, 25, 30, 35, 40, 45, 50, 55, 60% w/w or greater. In some embodiments, the compounds described herein, or pharmaceutically acceptable salts thereof, is present in a composition in the amount from about 5% to 60%, 5% to 50%, 10% to 50%, 10% to 40% w/w.
  • Exemplary FAK kinase inhibitors that can be used in the present invention include the compounds disclosed in W02010058032A.
  • the FAK kinase inhibitor is BI 853520, which has the following structure:
  • the methods of the present invention may be administered in combination with an additional agent (e.g., therapeutic agent).
  • the additional agent can include but are not limited to, an anti-tumor or anti-cancer agent, e.g., an anti-tumor agent selected from the group consisting of mitotic inhibitors, alkylating agents, anti-metabolites, intercalating antibiotics, growth factor inhibitors, cell cycle inhibitors, enzymes, topoisomerase inhibitors, biological response modifiers, antibodies, cytotoxics, anti hormones, and anti-androgens.
  • the methods and compositions described herein e.g., a FAK kinase inhibitor in combination with an agent targeting T-cell co-stimulatory receptors selected from 0X40 and 41BB
  • an additional therapy e.g., cancer treatment
  • a mixture of one or more compounds or pharmaceutical compositions may be administered with the combination described herein, e.g., a FAK kinase inhibitor in combination with an agent targeting T-cell co stimulatory receptors selected from 0X40 and 4 IBB, to a subject in need thereof.
  • one or more compounds or compositions may be administered with the combination described herein, e.g., a FAK kinase inhibitor in combination with an agent targeting T-cell co-stimulatory receptors selected from 0X40 and 4 IBB, for the treatment or avoidance of disease relates to abnormal cell growth.
  • a FAK kinase inhibitor in combination with an agent targeting T-cell co-stimulatory receptors selected from 0X40 and 4 IBB, for the treatment or avoidance of disease relates to abnormal cell growth.
  • combination therapies comprising a compound or pharmaceutical composition described herein may refer to (1) pharmaceutical compositions that comprise one or more compounds in combination with the combination described herein, e.g., the FAK kinase inhibitor BI853520 or the pharmaceutical acceptable salts thereof in combination with an agent targeting T-cell co-stimulatory receptors selected from 0X40 and 4 IBB, and (2) co-administration of one or more compounds or pharmaceutical compositions described herein with the combination described herein, e.g., the FAK kinase inhibitor BI853520 or the pharmaceutical acceptable salts thereof in combination with an agent targeting T-cell co-stimulatory receptors selected from 0X40 and 4 IBB, wherein the compound or pharmaceutical composition described herein have not been formulated in the same compositions.
  • pharmaceutical compositions that comprise one or more compounds in combination with the combination described herein, e.g., the FAK kinase inhibitor BI853520 or the pharmaceutical acceptable salts thereof in combination with an agent targeting T-cell co-stimulatory receptors selected from
  • the combinations described herein are administered with an additional treatment (e.g., an additional cancer treatment).
  • an additional treatment e.g., an additional cancer treatment
  • the additional treatment e.g., an additional cancer treatment
  • Sequential administration refers to administration of one treatment before (e.g., immediately before, less than 5, 10, 15, 30, 45, 60 minutes, 1, 2, 3, 4, 6, 8, 10, 12, 16, 20, 24, 48, 72, 96 or more hours, 4, 5, 6, 7, 8, 9 or more days, 1, 2, 3, 4, 5, 6, 7, 8 or more weeks before) administration of an additional treatment (e.g., a compound or therapy).
  • an additional treatment e.g., a compound or therapy.
  • the order of administration of the first and secondary compound or therapy can also be reversed.
  • the methods of the invention may be used or administered in combination with one or more additional therapies (e.g., cancer treatment, e.g., surgery, additional drug(s) or therapeutic agents) for the treatment of the disorder/diseases mentioned.
  • additional therapies e.g., cancer treatment, e.g., drug(s) or therapeutic agents described herein
  • methods of the invention may be administered either simultaneously (as a combined preparation) or sequentially in order to achieve a desired effect. This is especially desirable where the therapeutic profile of each compound is different such that the combined effect of the two drugs provides an improved therapeutic result.
  • Exemplary cancer treatments include, for example: chemotherapy, targeted therapies such as antibody therapies, immunotherapy, and hormonal therapy. Examples of each of these treatments are provided below. Chemotherapy
  • the methods of the invention are administered with a chemotherapy.
  • “Chemotherapy” usually refers to cytotoxic drugs which affect rapidly dividing cells in general, in contrast with targeted therapy. Chemotherapy drugs interfere with cell division in various possible ways, e.g., with the duplication of DNA or the separation of newly formed chromosomes. Most forms of chemotherapy target all rapidly dividing cells and are not specific for cancer cells, although some degree of specificity may come from the inability of many cancer cells to repair DNA damage, while normal cells generally can.
  • the methods of the invention may be used with antitumor agents, alkylating agents, antimetabolites, antibiotics, plant-derived antitumor agents, camptothecin derivatives, tyrosine kinase inhibitors, antibodies, interferons, and/or biological response modifiers.
  • additional agents e.g., additional therapeutic agents that may be used with the methods of the invention.
  • Alkylating agents include, but are not limited to, nitrogen mustard N-oxide, cyclophosphamide, ifosfamide, melphalan, busulfan, mitobronitol, carboquone, thiotepa, ranimustine, nimustine, temozolomide, AMD-473, altretamine, AP-5280, apaziquone, brostallicin, bendamustine, carmustine, estramustine, fotemustine, glufosfamide, ifosfamide, KW-2170, mafosfamide, and mitolactol
  • platinum- coordinated alkylating compounds include but are not limited to, cisplatin, carboplatin, eptaplatin, lobaplatin, nedaplatin, oxaliplatin or satrplatin,
  • Antimetabolites include but are not limited to, methotrexate, 6-mercaptopurine riboside, mercaptopurine, 5-fluorouracil (5-FU) alone or in combination with leucovorin, tegafur, UFT, doxifluridine, carmofur, cytarabine, cytarabine ocfosfate, enocitabine, S-l, gemcitabine, fludarabin, 5-azacitidine, capecitabine, cladribine, clofarabine, decitabine, eflornithine, ethynylcytidine, cytosine arabinoside, hydroxyurea, TS-1, melphalan, nelarabine, nolatrexed, ocfosfate, disodium premetrexed, pentostatin, pelitrexol, raltitrexed, triapine, trimetrexate, vidarabine, vin
  • Antibiotics include but are not limited to: aclarubicin, actinomycin D, amrubicin, annamycin, bleomycin, daunorubicin, doxorubicin, elsamitrucin, epirubicin, galarubicin, idarubicin, mitomycin C, nemorubicin, neocarzinostatin, peplomycin, pirarubicin, rebeccamycin, stimalamer, streptozocin, valrubicin or zinostatin,
  • Hormonal therapy agents e.g., exemestane (Aromasin), Lupron, anastrozole (Arimidex), doxercalciferol, fadrozole, formestane, anti-estrogens such as tamoxifen citrate (Nolvadex) and fulvestrant, Trelstar, toremifene, raloxifene, lasofoxifene, letrozole (Femara), or anti-androgens such as bicalutamide, flutamide, mifepristone, nilutamide, Casodex® (4'-cyano-3-(4- fluorophenylsulphonyl)-2-hydroxy-2-methyl-3'-(trifluoromethyl)propionanilide) and combinations thereof.
  • Plant derived anti-tumor substances include for example those selected from mitotic inhibitors, for example vinblastine, docetaxel (Taxotere) and paclitaxel
  • Cytotoxic topoisomerase inhibiting agents include one or more agents selected from the group consisting of aclarubicin, amonafide, belotecan, camptothecin, 10- hydroxycamptothecin, 9- aminocamptothecin, diflomotecan, irinotecan HC1 (Camptosar), edotecarin, epirubicin (Ellence), etoposide, exatecan, gimatecan, lurtotecan, mitoxantrone, pirarubicin, pixantrone, rubitecan, sobuzoxane, SN-38, tafluposide, and topotecan, and combinations thereof.
  • Immunological s include but are not limited to, interferons and numerous other immune enhancing agents.
  • Interferons include but are not limited to, interferon alpha, interferon alpha-2a, interferon, alpha-2b, interferon beta, interferon gamma- la or interferon gamma- nl.
  • agents include but are not limited to, filgrastim, lentinan, sizofilan, TheraCys, ubenimex, WF-10, aldesleukin, alemtuzumab, BAM-002, dacarbazine, daclizumab, denileukin, gemtuzumab ozogamicin, ibritumomab, imiquimod, lenograstim, lentinan, melanoma vaccine (Corixa), molgramostim, OncoVAX-CL, sargramostim, tasonermin, tecleukin, thymalasin, tositumomab, Virulizin, Z-100, epratuzumab, mitumomab, oregovomab, pemtumomab, and Provenge.
  • Biological response modifiers are agents that modify defense mechanisms of living organisms or biological responses, such as survival, growth, or differentiation of tissue cells to direct them to have anti-tumor activity.
  • agents include but are not limited to, krestin, lentinan, sizofiran, picibanil, or ubenimex.
  • anticancer agents include but are not limited to, alitretinoin, ampligen, atrasentan, bexarotene, bortezomib, Bosentan, calcitriol, exisulind, finasteride, fotemustine, ibandronic acid, miltefosine, mitoxantrone, 1 -asparaginase, procarbazine, dacarbazine, hydroxycarbamide, pegaspargase, pentostatin, tazarotne, TLK-286, Velcade, Tarceva, or tretinoin.
  • anti-angiogenic compounds include but are not limited to, acitretin, fenretinide, thalidomide, zoledronic acid, angiostatin, aplidine, cilengtide, combretastatin A-4, endostatin, halofuginone, rebimastat, removab, Revlimid, squalamine, ukrain and Vitaxin.
  • Platinum-coordinated compounds include but are not limited to, cisplatin, carboplatin, nedaplatin, or oxaliplatin.
  • Camptothecin derivatives include but are not limited to camptothecin, 10- hydroxycamptothecin, 9-aminocamptothecin, irinotecan, SN-38, edotecarin, and topotecan.
  • the chemotherapy agents can be used in combination with the methods described herein.
  • the methods of the invention are administered with a targeted therapy.
  • Targeted therapy constitutes the use of agents specific for the deregulated proteins of cancer cells.
  • Small molecule targeted therapy drugs are generally inhibitors of enzymatic domains on mutated, overexpressed, or otherwise critical proteins within the cancer cell.
  • Prominent examples are the tyrosine kinase inhibitors such as Axitinib, Bosutinib, Cediranib, desatinib, erolotinib, imatinib, gefitinib, lapatinib, Lestaurtinib, Nilotinib, Semaxanib, Sorafenib, Sunitinib, Iressa, SU5416 and Vandetanib, and also cyclin-depdendent kinase inhibitors such as Alvocidib and Seliciclib.
  • Monoclonal antibody therapy is another strategy in which the therapeutic agent is an antibody which specifically binds to a protein on the surface of the cancer cells.
  • Examples include but are not limited to, the anti-HER2/neu antibody trastuzumab (HERCEPTIN®) typically used in breast cancer, and the anti-CD20 antibody rituximab and Tositumomab typically used in a variety of B-cell malignancies.
  • Other exemplary antibodies include but are not limited to, Ctuximab, Panitumumab, Trastuzumab, Alemtuzumab, Bevacizumab, Edrecolomab, and Gemtuzumab.
  • Exemplary fusion proteins include but are not limited to, Aflibercept and Denileukin diftitox.
  • Targeted therapy can also involve small peptides as "homing devices" which can bind to cell surface receptors or affected extracellular matrix surrounding the tumor. Radionuclides which are attached to these peptides (e.g., RGDs) eventually kill the cancer cell if the nuclide decays in the vicinity of the cell.
  • RGDs Radionuclides which are attached to these peptides
  • An example of such therapy includes BEXXAR®.
  • the targeted therapy can be used in combination with the methods of the invention.
  • the methods of the invention are can be used in combination with directed energy or particle, or radioisotope treatments, e.g., radiation therapies, e.g., radiation oncology, for the treatment of proliferative disease, e.g., cancer, e.g., cancer associated with cancer stem cells.
  • the methods of the invention may be administered to a subject simultaneously or sequentially along with the directed energy or particle, or radioisotope treatments.
  • the methods of the invention may be administered before, during, or after the directed energy or particle, or radioisotope treatment, or a combination thereof.
  • the directed energy or particle therapy may comprise total body irradiation, local body irradiation, or point irradiation.
  • the directed energy or particle may originate from an accelerator, synchrotron, nuclear reaction, vacuum tube, laser, or from a radioisotope.
  • the therapy may comprise external beam radiation therapy, teletherapy, brachytherapy, sealed source radiation therapy, systemic radioisotope therapy, or unsealed source radiotherapy.
  • the therapy may comprise ingestion of, or placement in proximity to, a radioisotope, e.g., radioactive iodine, cobalt, cesium, potassium, bromine, fluorine, carbon.
  • External beam radiation may comprise exposure to directed alpha particles, electrons (e.g., beta particles), protons, neutrons, positrons, or photons (e.g., radiowave, millimeter wave, microwave, infrared, visible, ultraviolet, X-ray, or gamma-ray photons).
  • the radiation may be directed at any portion of the subject in need of treatment.
  • the methods of the invention can be used in combination with surgery, e.g., surgical exploration, intervention, biopsy, for the treatment of proliferative disease, e.g., cancer, e.g., cancer associated with cancer stem cells.
  • the methods of the invention may be administered to a subject simultaneously or sequentially along with the surgery.
  • the methods of the invention may be administered before (pre -operative), during, or after (post-operative) the surgery, or a combination thereof.
  • the surgery may be a biopsy during which one or more cells are collected for further analysis.
  • the biopsy may be accomplished, for example, with a scalpel, a needle, a catheter, an endoscope, a spatula, or scissors.
  • the biopsy may be an excisional biopsy, an incisional biopsy, a core biopsy, or a needle biopsy, e.g., a needle aspiration biopsy.
  • the surgery may involve the removal of localized tissues suspected to be or identified as being cancerous.
  • the procedure may involve the removal of a cancerous lesion, lump, polyp, or mole.
  • the procedure may involve the removal of larger amounts of tissue, such as breast, bone, skin, fat, or muscle.
  • the procedure may involve removal of part of, or the entirety of, an organ or node, for example, lung, throat, tongue, bladder, cervix, ovary, testicle, lymph node, liver, pancreas, brain, eye, kidney, gallbladder, stomach, colon, rectum, or intestine.
  • the cancer is breast cancer, e.g., triple negative breast cancer
  • the surgery is a mastectomy or lumpectomy. Examples
  • BI 853520 was provided by Boehringer Ingelheim GmbH or synthesized according to W02010058032A.
  • pcDNA3 construct encoding the ORF for murine CD80 was synthetized by GeneArt (Invitrogen). All flow cytometry antibodies used are listed in Tables 1 and 2.
  • Table 1 T-cell flow cytometry panel
  • Table 3 Markers used to identify tumor infiltrating cell populations
  • a selection of murine tumor derived cell lines were used in this study, namely, Squamous Cell Carcinoma cell lines (SCC7.1 and SCC6.2), an MMTV-PyMT mammary tumor cell line (MetOl), and LSL-Kras G12D/+ , LSL-Trp53 R172H/+ , Pdx-l-Cre derived pancreatic cancer cell lines (Panc43, Panc47, Panel 17). Cells were pathogen tested in September 2016 using the Impactlll test (Idex Bioresearch) and were negative for all pathogens. Cell lines were routinely tested for mycoplasma every 2-3 months in- house and were never found to be mycoplasma positive.
  • SCC cell lines were cultured for no more than 3 months following freeze thawing. SCC cell lines were generated and cultured as previously described [Serrels, A., et al. Nuclear FAK controls chemokine transcription, Tregs, and evasion of anti-tumor immunity. Cell 163, 160-173 (2015); Serrels, A., et al. The role of focal adhesion kinase catalytic activity on the proliferation and migration of squamous cell carcinoma cells. Int J Cancer 131, 287-297 (2012)]. SCC6.2 cells stably expressing pcDNA3-CD80 were generated by transfection using Lipofectamine 2000 (Invitrogen) and selection with 0.6mg/ml geneticin. MetOl and Pane cell lines were cultured in DMEM supplemented with 4500 mg/L glucose, L- glutamine, sodium pyruvate, sodium bicarbonate, and 10% FBS.
  • BI 853520 drug was prepared in 0.5% carboxymethyl cellulose (Vehicle) (Sigma-Aldrich), and mice were treated at 50 mg/kg QD by oral gavage.
  • Isotype control, anti-GITR (clone DTA-1), anti-CD40 (clone FGK4.5), anti- 41BB (clone LOB12.3), anti-OX40 (clone OX-86), and anti-CD28 (clone 37.51) antibodies were dosed twice weekly by intraperitoneal injection at a concentration of 100 pg/mouse diluted in PBS (BioXcell). Animals were visually monitored for signs of toxicity and weighed prior to each dose of BI 853520 or antibody.
  • mice were injected into both flanks of FVB/N mice and treatment administered as above. Following tumor regression, mice were maintained without treatment for 5 weeks prior to re-challenge with 5 x 10 5 SCC6.2 cells per flank. Tumor growth was measured twice-weekly as described above. At the time of re-challenge, an age-matched control cohort of mice that had not previously been challenged with tumor cells were injected on both flanks using the same cell preparation and tumor growth monitored as above. Tumor volume was calculated as described above.
  • mice were treated with 150 pg of antibody administered by intraperitoneal injection for 3 consecutive days, followed by a rest period of 3 days. Following this, SCC or MetOl cells were injected subcutaneously into both flanks and T-cell depletion maintained by further administration of 150 pg depleting antibody at 3 -day intervals for the remainder of the experiment. Tumor growth was measured twice-weekly as described above.
  • Tumors established following subcutaneous injection of cells into mice were removed at day 12 into DMEM (Sigma-Aldrich). Tumor tissue was mashed using a scalpel and re-suspended in DMEM (Sigma-Aldrich) supplemented with 2 mg/ml collagenase D (Roche) and 40 units/ml DNasel (Roche). Samples were incubated for 30 minutes at 37°C, 5% C02 on an orbital shaker set at 120 rpm, and then pelleted by centrifugation at 1300 rpm for 5 min at 4°C.
  • the resulting cell pellet was re-suspended in PBS containing Zombie NIR viability dye [1 : 1000 dilution (BioLegend)] and incubated at 4°C for 30 minutes then pelleted by centrifugation at 1300 rpm for 5 min at 4°C. Cells were resuspended in FACS buffer and pelleted by centrifugation at 1300 rpm for 5 min at 4°C. This step was repeated twice. Cell pellets were resuspended in 100 pi of Fc block [1 :200 dilution ofFc antibody (eBioscience) in FACS buffer] and incubated for 15 min.
  • Adhered cells were dissociated from tissue culture flasks by incubating them in enzyme free cell dissociation solution (Millipore) for 10 minutes at 37°C, 5% C02, and then scraping with a cell scraper. Cells were pelleted by centrifugation at 1300 rpm for 5 min at 4°C and washed with PBS. This step was repeated twice. Cells were then resuspended in viability dye and stained as above.
  • enzyme free cell dissociation solution Millipore
  • RNA extracts were obtained using a RNeasy kit (Qiagen), following manufacturer’s instructions. 100 ng of RNA was analyzed using a mouse nanostring PanCancer Immune Profiling panel as per the manufacturer’s instructions. Hybridization was performed for 18 hours at 65°C and samples processed using the nanostring prep station set on high sensitivity. Images were analyzed at maximum (555 fields of view). Data was normalized using nSolver 4.0 software.
  • CD80 expression in human cancer cell line data The expression of CD80 and FAR were assessed across the panels of cell lines from the Cancer Cell Line Encyclopedia (https://www.ncbi.nlm.nih.gov/pubmed/22460905) using data downloaded from The Broad Institute portal (https://portals.broadinstitute.org/ccle).
  • Example 1 Endogenous expression of the T-cell co-stimulatory ligand CD80 on the surface of cancer cells correlates with the response of tumors to the FAK, and may potentially serve as a biomarker for patient stratification
  • CCL2 recruits inflammatory monocytes to facilitate breast-tumour metastasis. Nature 475, 222-225 (2011)]; (3) Pancreatic Ductal Adenocarcinoma (PD AC) arising on the LSL-Kras GI2D/+ ; LSL-Trp53 R172H/+ ; Pdx-l-Cre (KPC) GEM model of pancreatic cancer (Pane cell lines) [Hingorani, S. R. et al., Trp53R172H and KrasG12D cooperate to promote chromosomal instability and widely metastatic pancreatic ductal adenocarcinoma in mice. Cancer Cell 7, 469-483 (2005)].
  • PD AC Pancreatic Ductal Adenocarcinoma
  • KPC Pdx-l-Cre
  • SCC7.1 cells are the parental population from which the SCC FAK-wt and FAK-/- cell model was developed, hence the similarity of response to FAK kinase inhibition.
  • CD8 T-cells are required for tumor regression / stable disease in response to BI 853520 treatment.
  • mice treated with a CD8 T-cell depleting antibody SCC7.1 and MetOl tumors exhibited only a modest growth delay in response to treatment with BI 853520 when compared to vehicle treated controls, while in mice treated with an isotype control antibody all SCC7.1 tumors underwent complete regression and all MetOl tumors exhibited stable disease following treatment with BI 853520 (Figs. 1H and II).
  • FAK kinase inhibition elicits CD8 T-cell mediated anti-tumor immunity that is required for SCC7.1 tumor regression and MetOl stable disease.
  • FAK kinase inhibitors including BI 853520, are now in early-phase (I/II) clinical trials as experimental cancer therapies [Shapiro, I. M. et. al. Merlin deficiency predicts FAK inhibitor sensitivity: a synthetic lethal relationship. Sci Trans Med , 6, (237):237ra68 (2014); Hirt, U. A. et. al. Efficacy of the highly selective focal adhesion kinase inhibitor BI 853520 in adenocarcinoma xenograft models is linked to a mesenchymal tumor phenotype. Oncogenesis , 7, 21, (2018)].
  • CD8 T-cell function can be regulated in a number of ways, including through coinhibitory and costimulatory receptors expressed on the surface of CD8 T-cells (REF).
  • REF costimulatory receptors expressed on the surface of CD8 T-cells
  • CD80 was expressed into a cell line that showed a poor response to BI 853520 when grown as a tumor in a syngeneic host (Fig. 1).
  • SCC6.2 cell line was selected as these are most similar to the SCC7.1 cells that when grown as tumors undergo complete CD8 T-cell mediated regression in response to treatment with BI 853520 (Fig. IB).
  • MHC Major Histocompatibility Complex
  • SCC6.2 pcDNA3 or SCC6.2 pcDNA-CD80 cells were injected subcutaneously into FVB/N mice and tumor growth monitored in response to either treatment with vehicle or BI 853520 (Fig. 3C).
  • Expression of CD80 had no impact on SCC6.2 tumor growth.
  • SCC6.2 pcDNA3-CD80 tumors showed a significantly improved response to BI 853520 in comparison to either vehicle treated controls or SCC6.2 pcDNA3 tumors treated with BI 853520.
  • CD80 expression sensitizes SCC6.2 tumors to BI 853520.
  • Example 2 Combination of FAK inhibition with agonistic antibodies targeting T- cell co-stimulatory receptors in cancer models that do not express CD80 results in enhanced antitumor activities
  • FAK inhibition enhances the response of SCC6.2 tumors to agonistic antibodies targeting T-cell costimulatory receptors.
  • GITR glucocorticoid- induced TNFR-related protein
  • CD40 also known as TNFRSF5
  • 4 IBB also known as tumor necrosis factor receptor superfamily member 9 (TNFRSF9) and CD137
  • 0X40 also known as Tumor necrosis factor receptor superfamily member 4 (TNFRSF4) and CD 134
  • 0.5 x 106 SCC6.2 cells were injected subcutaneously into FVB/N mice and mice treated with either Vehicle, Vehicle + 100 pg/mouse anti-GITR, Vehicle + 100 pg/mouse CD40, Vehicle + 100 pg/mouse 4- IBB, Vehicle + 100 pg/mouse 0X40, BI 853520 + 100 pg/mouse anti-GITR, BI 853520 + 100 pg/mouse CD40, BI 853520 + 100 pg/mouse 4-1BB or BI 853520 + 100 pg/mouse 0X40 (treatment schedule shown in Fig. 5A).
  • Flow cytometry was used to profile the tumor immune cell infiltrate and its regulation in response to treatment with either Vehicle, anti-OX40 (clone OX-86), BI 853520, or BI 853520 + anti-OX40 (clone OX-86).
  • BI 853520 treatment either alone or in combination with anti-OX40 was also found to result in a reduction in PD-L2 + cancer cells and M-MDSCs (Fig. 61). Therefore, BI 853520 treatment broadly depletes the availability of PD-L2 within the tumor microenvironment, likely impacting on PD-L2 - PD-1 signaling and ultimately CD8 T-cell exhaustion.
  • SCC6.2 cancer cells were generated using the DMBA / TPA chemical carcinogenesis protocol that results in a large number of somatic mutations, and therefore likely increased immunogenicity. Hence, one would predict that these will respond better to immunotherapy than poorly immunogenic tumor models such as those derived from the KPC GEM model of pancreatic cancer.
  • Panc47 cells were injected subcutaneously into C57BL/6 mice and mice treated with either Vehicle, 100 ug/mouse anti-GITR, CD40, 4- IBB or 0X40, or BI 853520 + anti-GITR, CD40, 4- IBB or 0X40 (treatment schedule shown in Fig. 5A).
  • Anti-GITR alone had no effect on the growth of Panc47 tumors, while in combination with BI 853520 we observed a small growth delay (Fig. 7A).
  • treatment with an anti-CD40 agonistic antibody resulted in a significant delay in the growth of Panc47 tumors, and this was not improved when used in combination with BI 853520 (Fig. 7B).
  • Gemcitabine treatment of Panc47 tumors resulted in a significant growth delay that was not further improved by combination with either BI 853520 or anti-OX40.
  • the triple combination of Gemcitabine + BI 853520 + anti-OX40 did show a significant improvement in response when compared to Gemcitabine alone, Gemcitabine + BI 853520, or Gemcitabine + 0X40, and tumors were also smaller than corresponding measurements for BI 853520 + anti-OX40 (Fig. 7D). Therefore, Gemcitabine exhibits anti-tumor efficacy that can further add to that of BI 853520 + anti-OX40.

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Abstract

La présente invention concerne des méthodes de traitement du cancer chez un patient, comprenant l'administration de BI853520, un inhibiteur de la kinase FAK, ou de ses sels pharmaceutiquement acceptables, et d'un agent ciblant des récepteurs co-stimulateurs des cellules T choisis entre OX40 et 41BB, par exemple anti-OX 40 ou anti-41BB, et la méthode de stratification de patients atteints d'un cancer reposant sur CD80 en vue d'un traitement par un inhibiteur de la kinase FAK.
PCT/IB2020/053046 2019-04-02 2020-03-31 Association d'un inhibiteur de la kinase fak et d'un agent ciblant des récepteurs co-stimulateurs des cellules t Ceased WO2020202005A1 (fr)

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