FUNAHASHI YASUHIRO (JP)
KATO YU (JP)
MERCK SHARP & DOHME (US)
MERCK INT GMBH (CH)
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WO2012115286A1 | 2012-08-30 |
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US20180185395A1 | 2018-07-05 |
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CLAIMS: What is claimed: 1. A method for treating a cancer in a human subject comprising administering to the individual a combination therapy which comprises: (i) an antagonist of a Programmed Death 1 protein (PD-1); (ii) lenvatinib having the structure: or a pharmaceutically acceptable salt thereof; and (iii) (6S,9aS)-N-benzyl-8-({6-[3-(4-ethylpiperazin-1-yl)azetidin-1-yl]pyridin-2- yl}methyl)-6-(2-fluoro-4-hydroxybenzyl)-4,7-dioxo-2-(prop-2-en-1-yl)hexahydro-2H- pyrazino[2,1-c][1,2,4]triazine-1(6H)-carboxamide (E7386) having the structure: or a pharmaceutically acceptable salt thereof, wherein the PD-1 antagonist is not atezolizumab. 2. The method of claim 1, wherein the cancer is a solid tumor. 3. The method of claim 1, wherein the cancer is selected from the group consisting of: a renal cell carcinoma (RCC), a colorectal cancer (CRC), a hepatocellular carcinoma (HCC), a melanoma, a bladder cancer a urothelial cancer, a breast cancer, a non-small cell lung cancer (NSCLC), an endometrial cancer, and a squamous cell carcinoma of head and neck. 4. The method of claim 1, wherein the cancer is a RCC. 5. The method of any one of claims 1 to 4, wherein the PD-1 antagonist is a monoclonal antibody, or an antigen binding fragment thereof. 6. The method of any of claims 1 to 5, wherein the PD-1 antagonist is an anti-PD- 1 antibody. 7. The method of any of claims 1 to 6, wherein the PD-1 antagonist is pembrolizumab or nivolumab . 8. The method of any of claims 1 to 7, wherein the PD-1 antagonist is pembrolizumab. 9. The method of any of claims 1 to 8, wherein lenvatinib or a pharmaceutically acceptable salt thereof is administered daily; and pembrolizumab is administered once every three weeks. 10. The method of claim 9, wherein lenvatinib or a pharmaceutically acceptable salt thereof is administered at a daily dose of 24 mg, 20 mg, 18 mg, 12 mg or 8 mg; and pembrolizumab is administered at a dose of 200 mg for an adult subject or 2 mg/kg (up to 200 mg) for a pediatric subject once every three weeks. 11. The method of any of claims 1 to 10, wherein lenvatinib or a pharmaceutically acceptable salt thereof is lenvatinib mesylate; and E7386 or a pharmaceutically acceptable salt thereof is E7386. 12. A pharmaceutical composition for treating a cancer, comprising (6S,9aS)-N- benzyl-8-({6-[3-(4-ethylpiperazin-1-yl)azetidin-1-yl]pyridin-2-yl}methyl)-6-(2-fluoro-4- hydroxybenzyl)-4,7-dioxo-2-(prop-2-en-1-yl)hexahydro-2H-pyrazino[2,1-c][1,2,4]triazine- 1(6H)-carboxamide (E7386)or a pharmaceutically acceptable salt thereof, wherein E7386 or a pharmaceutically acceptable salt thereof is administered in combination with (a) lenvatinib or a pharmaceutically acceptable salt thereof; and (b) an anti-PD-1 antibody. 13. A pharmaceutical composition for treating a cancer, comprising an anti-PD-1 antibody, wherein the anti-PD-1 antibody is administered in combination with (a) lenvatinib or a pharmaceutically acceptable salt thereof; and (b) (6S,9aS)-N-benzyl-8-({6-[3-(4- ethylpiperazin-1-yl)azetidin-1-yl]pyridin-2-yl}methyl)-6-(2-fluoro-4-hydroxybenzyl)-4,7- dioxo-2-(prop-2-en-1-yl)hexahydro-2H-pyrazino[2,1-c][1,2,4]triazine-1(6H)-carboxamide (E7386) or a pharmaceutically acceptable salt thereof. 14. A pharmaceutical composition for treating a cancer, comprising lenvatinib or a pharmaceutically acceptable salt thereof wherein lenvatinib or a pharmaceutically acceptable salt thereof is administered in combination with (a) (6S,9aS)-N-benzyl-8-({6-[3-(4- ethylpiperazin-1-yl)azetidin-1-yl]pyridin-2-yl}methyl)-6-(2-fluoro-4-hydroxybenzyl)-4,7- dioxo-2-(prop-2-en-1-yl)hexahydro-2H-pyrazino[2,1-c][1,2,4]triazine-1(6H)-carboxamide (E7386) or a pharmaceutically acceptable salt thereof; and (b) an anti-PD-1 antibody. 15. The pharmaceutical composition of any of claims 12 to 14, wherein lenvatinib or a pharmaceutically acceptable salt thereof is lenvatinib mesylate; and E7386 or a pharmaceutically acceptable salt thereof is E7386. 16. The pharmaceutical composition of any of claims 12 to 15, wherein the cancer is a solid tumor. 17. The pharmaceutical composition of any of claims 12 to 15, wherein the cancer is selected from the group consisting of: a renal cell carcinoma (RCC), a colorectal cancer (CRC), a hepatocellular carcinoma (HCC), a melanoma, a bladder cancer, a urothelial cancer, a breast cancer, a non-small cell lung cancer (NSCLC), ), an endometrial cancer, and a squamous cell carcinoma of head and neck. 18. The pharmaceutical composition of claim 17, wherein the cancer is a RCC. 19. The pharmaceutical composition of any of claims 12 to 18, wherein the PD-1 antagonist is a monoclonal antibody, or an antigen binding fragment thereof. 20. The pharmaceutical composition of any of claims 12 to 18, wherein the PD-1 antagonist is an anti-PD-1 antibody. 21. The pharmaceutical composition of any of claims 12 to 20, wherein the PD-1 antagonist is pembrolizumab or nivolumab. 22. The pharmaceutical composition of any of claims 12 to 21, wherein the PD-1 antagonist is pembrolizumab. 23. The pharmaceutical composition of any of claims 12 to 22, wherein lenvatinib or a pharmaceutically acceptable salt thereof is administered daily; and the PD-1 antagonist is pembrolizumab and is administered once every three weeks. 24. The pharmaceutical composition of claim 23, wherein lenvatinib or a pharmaceutically acceptable salt thereof is administered at a daily dose of 24 mg, 20 mg, 18 mg, 12 mg or 8 mg; and pembrolizumab is administered at a dose of 200 mg for an adult subject or 2 mg/kg (up to 200 mg) for a pediatric subject once every three weeks. 25. The pharmaceutical composition of any of claims 12 to 24, wherein lenvatinib or a pharmaceutically acceptable salt thereof is lenvatinib mesylate; and E7386 or a pharmaceutically acceptable salt thereof is E7386. 26. Use of the pharmaceutical composition of any of claims 12 to 25 for the manufacture of a medicament for a treatment of cancer. 27. The pharmaceutical composition of any of claims 12 to 25 for use in the treatment of a cancer. 28. The method, kit, or use of any one of claims 1-27. 29. The pharmaceutical composition of any of claims 12 to 22, wherein lenvatinib or a pharmaceutically acceptable salt thereof is administered daily; and the PD-1 antagonist is pembrolizumab and is administered once every six weeks. |
“PD-L1” or “PD-L2” expression as used herein means any detectable level of expression of the designated PD-L protein on the cell surface or of the designated PD-L mRNA within a cell or tissue. PD-L protein expression may be detected with a diagnostic PD- L antibody in an IHC assay of a tumor tissue section or by flow cytometry. Alternatively, PD- L protein expression by tumor cells may be detected by positron emission tomography (PET) imaging, using a binding agent (e.g., antibody fragment, affibody and the like) that specifically binds to the desired PD-L target, e.g., PD-L1 or PD-L2. Techniques for detecting and measuring PD-L mRNA expression include RT-PCR and real-time quantitative RT-PCR. Several approaches have been described for quantifying PD-L1 protein expression in IHC assays of tumor tissue sections. See, e.g., Thompson, R. H., et al., PNAS 101 (49): 17174- 17179 (2004); Thompson, R. H. et al., Cancer Res.66: 3381-3385 (2006); Gadiot, J., et al., Cancer 117: 2192-2201 (2011); Taube, J. M. et al., Sci Transl Med 4: 127-37 (2012); and Toplian, S. L. et al., New Eng. J Med.366(26): 2443-2454 (2012). One approach employs a simple binary end-point of positive or negative for PD-L1 expression, with a positive result defined in terms of the percentage of tumor cells that exhibit histologic evidence of cell-surface membrane staining. A tumor tissue section is counted as positive for PD-L1 expression is at least 1%, and preferably 5% of total tumor cells. In another approach, PD-L1 expression in the tumor tissue section is quantified in the tumor cells as well as in infiltrating immune cells, which predominantly comprise lymphocytes. The percentage of tumor cells and infiltrating immune cells that exhibit membrane staining are separately quantified as < 5%, 5 to 9%, and then in 10% increments up to 100%. For tumor cells, PD-L1 expression is counted as negative if the score is < 5% score and positive if the score is ≥ 5%. PD-L1 expression in the immune infiltrate is reported as a semi-quantitative measurement called the adjusted inflammation score (AIS), which is determined by multiplying the percent of membrane staining cells by the intensity of the infiltrate, which is graded as none (0), mild (score of 1, rare lymphocytes), moderate (score of 2, focal infiltration of tumor by lymphohistiocytic aggregates), or severe (score of 3, diffuse infiltration). A tumor tissue section is counted as positive for PD-L1 expression by immune infiltrates if the AIS is ≥ 5. The level of PD-L mRNA expression may be compared to the mRNA expression levels of one or more reference genes that are frequently used in quantitative RT-PCR, such as ubiquitin C. In some instances, a level of PD-L1 expression (protein and/or mRNA) by malignant cells and/or by infiltrating immune cells within a tumor is determined to be “overexpressed” or “elevated” based on comparison with the level of PD-L1 expression (protein and/ or mRNA) by an appropriate control. For example, a control PD-L1 protein or mRNA expression level may be the level quantified in nonmalignant cells of the same type or in a section from a matched normal tissue (i.e. non-malignant tissue). PD-L1 expression in a tumor sample is preferably determined to be elevated if PD-L1 protein (and/or PD-L1 mRNA) in the sample is at least 10%, 20%, or 30% greater than in the control. A “pembrolizumab biosimilar” means a biological product manufactured by an entity other than Merck & Co., Inc. d.b.a. Merck Sharp and Dohme (MSD) and which is approved by a regulatory agency in any country for marketing as a pembrolizumab biosimilar. A pembrolizumab biosimilar may include as the drug substance a pembrolizumab variant or an antibody with the same amino acid sequence as pembrolizumab. As used herein, a “pembrolizumab variant” means a monoclonal antibody which comprises heavy chain and light chain sequences that are identical to those in pembrolizumab, except for having three, two or one conservative amino acid substitutions at positions that are located outside of the light chain CDRs and six, five, four, three, two or one conservative amino acid substitutions that are located outside of the heavy chain CDRs, e.g, the variant positions are located in the FR regions and/or the constant region. In other words, pembrolizumab and a pembrolizumab variant comprise identical CDR sequences, but differ from each other due to having a conservative amino acid substitution at no more than three or six other positions in their full length light and heavy chain sequences, respectively. A pembrolizumab variant is substantially the same as pembrolizumab with respect to the following properties: binding affinity to PD-1 and ability to block the binding of each of PD- L1 and PD-L2 to PD-1. Patient / Cancer / Response Definitions. “RECIST 1.1 Response Criteria” as used herein means the definitions set forth in Eisenhauer et al., E.A. et al., Eur. J. Cancer 45: 228- 247 (2009) for target lesions or nontarget lesions, as appropriate based on the context in which response is being measured. “Responder patient” when referring to a specific anti-tumor response to treatment with a combination therapy described herein, means the patient exhibited the anti-tumor response. “Sustained response” means a sustained therapeutic effect after cessation of treatment with a therapeutic agent, or a combination therapy described herein. In some instances, the sustained response has a duration that is at least the same as the treatment duration, or at least 1.5, 2.0, 2.5 or 3 times longer than the treatment duration. "Tissue Section" refers to a single part or piece of a tissue sample, e.g., a thin slice of tissue cut from a sample of a normal tissue or of a tumor. "Treat" or "treating" a cancer as used herein means to administer a combination therapy of a PD-1 antagonist, lenvatinib or a pharmaceutically acceptable salt thereof, and E7386 or a pharmaceutically acceptable salt thereof to a subject having a cancer, or diagnosed with a cancer, to achieve at least one positive therapeutic effect, such as for example, reduced number of cancer cells, reduced tumor size, reduced rate of cancer cell infiltration into peripheral organs, or reduced rate of tumor metastasis or tumor growth. Positive therapeutic effects in cancer can be measured in a number of ways (see, W. A. Weber, J. Nucl. Med.50:1S-10S (2009)). For example, with respect to tumor growth inhibition, according to NCI standards, a T/C ≦42% is the minimum level of anti-tumor activity. A T/C < 10% is considered a high anti-tumor activity level, with T/C (%) = Median tumor volume of the treated/Median tumor volume of the control × 100. In some instances, response to a combination therapy described herein is assessed using RECIST 1.1 criteria or irRC (bidimensional or unidimensional) and the treatment achieved by a combination of lenvatinib or a pharmaceutically acceptable salt thereof, (6S,9aS)-N-benzyl-8-({6-[3-(4-ethylpiperazin-1-yl)azetidin-1 -yl]pyridin-2-yl}methyl)- 6-(2-fluoro-4-hydroxybenzyl)-4,7-dioxo-2-(prop-2-en-1-yl)hex ahydro-2H-pyrazino[2,1- c][1,2,4]triazine-1(6H)-carboxamide (E7386) or a pharmaceutically acceptable salt thereof, and a PD-1 antagonist is any of PR, CR, OR, PFS, DFS and OS. PFS, also referred to as “Time to Tumor Progression” indicates the length of time during and after treatment that the cancer does not grow, and includes the amount of time patients have experienced a CR or PR, as well as the amount of time patients have experienced SD. DFS refers to the length of time during and after treatment that the patient remains free of disease. OS refers to a prolongation in life expectancy as compared to naive or untreated individuals or patients. In some instances, response to a combination of a lenvatinib or a pharmaceutically acceptable salt thereof, (6S,9aS)-N-benzyl-8-({6-[3-(4-ethylpiperazin-1-yl)azetidin-1 -yl]pyridin-2-yl}methyl)-6-(2- fluoro-4-hydroxybenzyl)-4,7-dioxo-2-(prop-2-en-1-yl)hexahydr o-2H-pyrazino[2,1- c][1,2,4]triazine-1(6H)-carboxamide (E7386) or a pharmaceutically acceptable salt thereof, and a PD-1 antagonist is any of PR, CR, PFS, DFS, OR and OS that is assessed using RECIST 1.1 response criteria. The treatment regimen for the disclosed combination that is effective to treat a cancer patient may vary according to factors such as the disease state, age, and weight of the patient, and the ability of the therapy to elicit an anti-cancer response in the subject. The treatment methods, medicaments, and disclosed uses may not be effective in achieving a positive therapeutic effect in every subject, they should do so in a statistically significant number of subjects as determined by any statistical test known in the art such as the Student’s t-test, the chi 2 -test, the U-test according to Mann and Whitney, the Kruskal-Wallis test (H-test), Jonckheere-Terpstra-test and the Wilcoxon-test. The terms “treatment regimen”, “dosing protocol” and “dosing regimen” are used interchangeably to refer to the dose and timing of administration of each therapeutic agent in a combination of a lenvatinib or a pharmaceutically acceptable salt thereof, (6S,9aS)-N-benzyl-8- ({6-[3-(4-ethylpiperazin-1-yl)azetidin-1-yl]pyridin-2-yl}met hyl)-6-(2-fluoro-4- hydroxybenzyl)-4,7-dioxo-2-(prop-2-en-1-yl)hexahydro-2H-pyra zino[2,1-c][1,2,4]triazine- 1(6H)-carboxamide (E7386) or a pharmaceutically acceptable salt thereof, and a PD-1 antagonist. "Tumor" as it applies to a subject diagnosed with, or suspected of having, a cancer refers to a malignant or potentially malignant neoplasm or tissue mass of any size, and includes primary tumors and secondary neoplasms. A solid tumor is an abnormal growth or mass of tissue that usually does not contain cysts or liquid areas. Different types of solid tumors are named for the type of cells that form them. Examples of solid tumors are sarcomas, carcinomas, and lymphomas. "Tumor burden" also referred to as "tumor load", refers to the total amount of tumor material distributed throughout the body. Tumor burden refers to the total number of cancer cells or the total size of tumor(s), throughout the body, including lymph nodes and bone narrow. Tumor burden can be determined by a variety of methods known in the art, such as, e.g. by measuring the dimensions of tumor(s) upon removal from the subject, e.g., using calipers, or while in the body using imaging techniques, e.g., ultrasound, bone scan, computed tomography (CT) or magnetic resonance imaging (MRI) scans. The term "tumor size" refers to the total size of the tumor which can be measured as the length and width of a tumor. Tumor size may be determined by a variety of methods known in the art, such as, e.g. by measuring the dimensions of tumor(s) upon removal from the subject, e.g., using calipers, or while in the body using imaging techniques, e.g., bone scan, ultrasound, CT or MRI scans. “Unidimensional irRC refers to the set of criteria described in Nishino M, Giobbie- Hurder A, Gargano M, Suda M, Ramaiya NH, Hodi FS. “Developing a Common Language for Tumor Response to Immunotherapy: Immune-related Response Criteria using Unidimensional measurements,” Clin. Cancer Res.2013, 19(14): 3936–3943). These criteria utilize the longest diameter (cm) of each lesion. By a “multi-RTK inhibitor” means a small molecule compound that inhibits the receptor tyrokine kinase (RTK) activities of at least each of the following RTKs: (i) VEGFR2, and (ii) at least one FGFR selected from the group consisting of FGFR1, 2, 3 and 4. An exemplary multi-RTK inhibitor is lenvatinib or a pharmaceutically acceptable salt thereof. β-catenin functions as a mediator of Wnt signal transduction, binds to a transcription factor Tcf/Lef (T cell factor/Lymphocyte enhancing factor), promotes expression of various genes (cyclin D1, c-Myc etc.) involved in Wnt signal transduction, and controls proliferation and differentiation of cells (He et al., 1998 Science 281: 1509-1512; Kolligs et al., Mol. Cell. Biol.19: 5696-5706, 1999; Crawford et al., Oncogene 18: 2883-2891, 1999; Shtutman et al., Proc. Natl. Acad. Sci. USA, 11: 5522-5527, 1999; Tetsu and McCormick, 1999 Nature, 398: 422-426). CBP (cyclic AMP response element binding protein (CREB) binding protein) directly interacts with β-catenin in the CREB binding domain, and promotes transcription activation of Tcf/Lef (Ken-Ichi Takemaru and Randall T. Moon, 2000, J. Cell. Biol.149(2): 249-254). A CBP/β-catenin inhibitor is not particularly limited as long as it inhibits interaction between CBP and catenin, particularly β-catenin, and an embodiment in which binding of β-catenin and CBP is inhibited, as a result of which gene expression by β-catenin complex is suppressed is preferable. Inhibition of CBP/β-catenin can be measured by a binding assay (radiobinding assay etc.) known per se, a reporter assay method, and other in vitro and in vivo assays the like. Inhibition can be confirmed by measuring gene expression of Wnt signal transduction by the reporter assay method described in WO 2009/148192. The CBP/β-catenin inhibitor of the present invention is not particularly limited as long as it is as defined above. It is preferably an α-helix mimetic compound having a CBP/β- catenin inhibitory activity, and examples thereof include α-helix mimetic compounds, pharmaceutically acceptable salts thereof and the like as described in WO 2003/031448, WO 2004/093828, WO 2005/116032, WO 2009/148192, WO 2010/044485, WO 2010/128685, WO 2012/115286, and the like. An exemplary CBP/β-catenin inhibitor includes (6S,9aS)-N- benzyl-8-({6-[3-(4-ethylpiperazin-1-yl)azetidin-1-yl]pyridin -2-yl}methyl)-6-(2-fluoro-4- hydroxybenzyl)-4,7-dioxo-2-(prop-2-en-1-yl)hexahydro-2H-pyra zino[2,1-c][1,2,4]triazine- 1(6H)-carboxamide (E7386). Each of the PD-1 antagonist, lenvatinib and E7386 in the combination therapy disclosed herein may be administered either alone or in a medicament / formulation (also referred to herein as a pharmaceutical composition) which comprises the therapeutic agent and one or more pharmaceutically acceptable carriers, excipients and diluents, according to standard pharmaceutical practice. Each therapeutic agent may be prepared by formulating lenvatinib or its pharmaceutically acceptable salt, an anti-PD-1 antibody, and/or a E7386 or its pharmaceutically acceptable salt, may be administered either at the same time or separately. Further, the formulations may be placed in a single package, to provide the so called kit formulation. Lenvatinib or a pharmaceutically acceptable salt can be produced by the method described in Reference 17. Examples of the pharmaceutically acceptable salt include salts with inorganic acids, salts with organic acids, salts with inorganic bases, salts with organic bases, and salts with acidic or basic amino acids. Preferred examples of the salts with inorganic acids include salts with hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid and the like. Preferred examples of the salts with organic acids include salts with acetic acid, succinic acid, fumaric acid, maleic acid, tartaric acid, citric acid, lactic acid, stearic acid, benzoic acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid and the like. Preferred examples of the salts with inorganic bases include alkaline metal salts such as a sodium salt and a potassium salt; alkaline earth metal salts such as a calcium salt and a magnesium salt; an aluminum salt; and an ammonium salt. Preferred examples of the salts with organic bases include salts with diethylamine, diethanolamine, meglumine, N,N- dibenzylethylenediamine and the like. Preferred examples of the salts with acidic amino acids include salts with aspartic acid, glutamic acid and the like. Preferred examples of the salts with basic amino acids include salts with arginine, lysine, ornithine and the like. More preferred pharmaceutically acceptable salts are salts with organic acids and especially preferred pharmaceutically acceptable salts are salts with methanesulfonic acid. The PD-1 antagonist, lenvatinib or its pharmaceutically acceptable salt and E7386 or a pharmaceutically acceptable salt thereof in a combination therapy disclosed herein may be administered simultaneously (i.e., in the same medicament), concurrently (i.e., in separate medicaments administered one right after the other in any order) or sequentially in any order. Sequential administration is particularly useful when the therapeutic agents in the combination therapy are in different dosage forms (one agent is a tablet or capsule and another agent is a sterile liquid) and/or are administered on different dosing schedules, e.g., a chemotherapeutic that is administered at least daily and a biotherapeutic that is administered less frequently, such as once weekly, once every two weeks, or once every three weeks. In some instances, the lenvatinib or its pharmaceutically acceptable salt is administered before administration of the PD-1 antagonist and/or the CBP/β-catenin inhibitor, while in other instances, the multi-RTK inhibitor is administered after administration of the PD-1 antagonist and/or the E7386 or a pharmaceutically acceptable salt thereof. In some instances, at least one of the therapeutic agents in the combination therapy is administered using the same dosage regimen (dose, frequency and duration of treatment) that is typically employed when the agent is used as monotherapy for treating the same cancer. In other instances, the patient receives a lower total amount of at least one of the therapeutic agents in the combination therapy than when the agent is used as monotherapy, e.g., smaller doses, less frequent doses, and/or shorter treatment duration. Each small molecule therapeutic agent in a combination therapy disclosed herein can be administered orally in the form of a solid formulation such as a tablet, granule, fine granule, powder or capsule, or in the form of a liquid, jelly, syrup, or the like. Each small molecule therapeutic agent in a combination therapy disclosed herein may be administered parenterally, including the intravenous, intramuscular, intraperitoneal, subcutaneous, rectal, topical, and transdermal routes of administration. A combination therapy disclosed herein may be used prior to or following surgery to remove a tumor and may be used prior to, during or after radiation therapy. In some instances, a combination therapy disclosed herein is administered to a patient who has not been previously treated with a biotherapeutic or chemotherapeutic agent, i.e., is treatment-naïve. In other instances, the combination therapy is administered to a patient who failed to achieve a sustained response after prior therapy with a biotherapeutic or chemotherapeutic agent, i.e., is treatment-experienced. A combination therapy disclosed herein is typically used to treat a tumor that is large enough to be found by palpation or by imaging techniques well known in the art, such as magnetic resonance imaging (MRI), ultrasound, or computerized axial tomography (CAT) scan. A combination therapy disclosed herein is preferably administered to a human patient who has a cancer that tests positive for PD-L1 expression. PD-L1 expression is detected preferably using a diagnostic anti-human PD-L1 antibody, or antigen binding fragment thereof, in an IHC assay on an FFPE or frozen tissue section of a tumor sample removed from the patient. Typically, the patient’s physician would order a diagnostic test to determine PD-L1 expression in a tumor tissue sample removed from the patient prior to initiation of treatment with the PD-1 antagonist, the E7386 or a pharmaceutically acceptable salt thereof, and lenvatinib or its pharmaceutically acceptable salt, but it is envisioned that the physician could order the first or subsequent diagnostic tests at any time after initiation of treatment, such as for example after completion of a treatment cycle. Selecting a dosage regimen (also referred to herein as an administration regimen) for a combination therapy disclosed herein depends on several factors, including the serum or tissue turnover rate of the entity, the level of symptoms, the immunogenicity of the entity, and the accessibility of the target cells, tissue or organ in the individual being treated. Preferably, a dosage regimen maximizes the amount of each therapeutic agent delivered to the patient consistent with an acceptable level of side effects. Accordingly, the dose amount and dosing frequency of each biotherapeutic and chemotherapeutic agent in the combination depends in part on the particular therapeutic agent, the severity of the cancer being treated, and patient characteristics. Guidance in selecting appropriate doses of antibodies, cytokines, and small molecules are available. See, e.g., Wawrzynczak (1996) ANTIBODY THERAPY, Bios Scientific Pub. Ltd, Oxfordshire, UK; Kresina (ed.) (1991) MONOCLONAL ANTIBODIES, CYTOKINES AND ARTHRITIS, Marcel Dekker, New York, NY; Bach (ed.) (1993) MONOCLONAL ANTIBODIES AND P EPTIDE T HERAPY IN A UTOIMMUNE D ISEASES , Marcel Dekker, New York, NY; Baert et al. (2003) New Engl. J. Med.348: 601-608; Milgrom et al. (1999) New Engl. J. Med.341: 1966- 1973; Slamon et al. (2001) New Engl. J. Med.344: 783-792; Beniaminovitz et al. (2000) New Engl. J. Med.342: 613-619; Ghosh et al. (2003) New Engl. J. Med.348: 24-32; Lipsky et al. (2000) New Engl. J. Med.343: 1594-1602; P HYSICIANS ' D ESK R EFERENCE 2003 (Physicians' Desk Reference, 57th Ed.); Medical Economics Company; ISBN: 1563634457; 57th edition (November 2002). Determination of the appropriate dosage regimen may be made by the clinician, e.g., using parameters or factors known or suspected in the art to affect treatment or predicted to affect treatment, and will depend, for example, the patient's clinical history (e.g., previous therapy), the type and stage of the cancer to be treated and biomarkers of response to one or more of the therapeutic agents in the combination therapy. Biotherapeutic agents in a combination therapy disclosed herein (i.e., the PD-1 antagonist, lenvatinib or its pharmaceutically acceptable salt, and E7386 or its pharmaceutically acceptable salt) may be administered by continuous infusion, or by doses at intervals of, e.g., daily, every other day, three times per week, or one time each week, two weeks, three weeks, monthly, bimonthly, etc. A total weekly dose is generally at least 0.05 μg/kg, 0.2 μg/kg, 0.5 μg/kg, 1 μg/kg, 10 μg/kg, 100 μg/kg, 0.2 mg/kg, 1.0 mg/kg, 2.0 mg/kg, 10 mg/kg, 25 mg/kg, 50 mg/kg body weight or more. See, e.g., Yang et al. (2003) New Engl. J. Med.349: 427-434; Herold et al. (2002) New Engl. J. Med.346: 1692-1698; Liu et al. (1999) J. Neurol. Neurosurg. Psych.67: 451-456; Portielji et al. (2003) Cancer Immunol. Immunother.52: 133-144. Cemiplimab-rwlc (LIBTAYO®) is another PD-1 antagonist. It can be administered in intravenously wherein 350 mg is administered over 30 minutes once every 3 weeks (Q3W). The dose of lenvatinib or pharmaceutically acceptable salt thereof may be appropriately selected depending on the degrees of symptoms, age, sex, and body weight of the patient, difference in sensitivity, route, time of administration and interval of administration, type of pharmaceutical formulation, and/or the like. Typically, in cases where oral administration is carried out for an adult (60 kg body weight), the dose is 1 to 600 mg, preferably 5 to 400 mg, more preferably 5 to 200 mg per day. The dose may be administered at one time or divided into smaller doses provided 2 to 3 times per day. In some instances that employ an anti-human PD-1 mAb as the PD-1 antagonist in the combination therapy, the dosing regimen will comprise administering the anti-human PD-1 mAb at a dose of 1, 2, 3, 5 or 10 mg/kg at intervals of about 14 days (± 2 days) or about 21 days (± 2 days) or about 30 days (± 2 days) throughout the course of treatment. The dosage of an anti-PD-1 antibody can be appropriately selected in the same manner as above. Typically, in cases where intravenous administration is carried out for an adult (60 kg body weight), the dose can be 2 mg/kg on a schedule of once every 3 weeks on a 6-week cycle (a total of 2 doses). The antibody can be administered for 1 to 10 cycles at an appropriate interval. In other instances that employ an anti-human PD-1 mAb as the PD-1 antagonist in the combination therapy, the dosing regimen will comprise administering the anti-human PD-1 mAb at a dose of from about 0.005 mg/kg to about 10 mg/kg, with intra-patient dose escalation. The interval between doses can be progressively shortened, e.g., about 30 days (± 2 days) between the first and second dose, about 14 days (± 2 days) between the second and third doses. In certain embodiments, the dosing interval will be about 14 days (± 2 days), for doses subsequent to the second dose. In specific instances, a subject can be administered an intravenous (IV) infusion of a medicament comprising any of the PD-1 antagonists described herein. The PD-1 antagonist in the combination therapy is preferably nivolumab in some instances, which is administered intravenously at a dose selected from the group consisting of: 1 mg/kg Q2W, 2 mg/kg Q2W, 3 mg/kg Q2W, 5 mg/kg Q2W, 10 mg Q2W, 1 mg/kg Q3W, 2 mg/kg Q3W, 3 mg/kg Q3W, 5 mg/kg Q3W, and 10 mg Q3W. The PD-1 antagonist can also be cemiplimab-rwlc administered intravenously at a dose of 350 mg Q3W. The PD-1 antagonist in the combination therapy preferably is pembrolizumab, a pembrolizumab variant or a pembrolizumab biosimilar in some instances, which is administered in a liquid medicament at a dose selected from the group consisting of 1 mg/kg Q2W, 2 mg/kg Q2W, 3 mg/kg Q2W, 5 mg/kg Q2W, 10 mg Q2W, 1 mg/kg Q3W, 2 mg/kg Q3W, 3 mg/kg Q3W, 5 mg/kg Q3W, 10 mg Q3W and flat-dose equivalents of any of these doses, i.e., such as 200 mg Q3W and 400 mg Q6W. In some instances, pembrolizumab is provided as a liquid medicament which comprises 25 mg/ml pembrolizumab, 7% (w/v) sucrose, 0.02% (w/v) polysorbate 80 in 10 mM histidine buffer pH 5.5. In some instances, the selected dose of pembrolizumab is administered by IV infusion over a time period of between 25 and 40 minutes, or about 30 minutes. The optimal dose for pembrolizumab in combination with lenvatinib or a pharmaceutically acceptable salt thereof (e.g., lenvatinib mesylate) and a CBP/β-catenin inhibitor (e.g., E7386) may be identified by dose escalation or dose de-escalation of one or both of these agents. In some instances, the combination therapy comprises a 21 day treatment cycle in which pembrolizumab is administered at 200 mg Q3W by IV (or 400 mg Q6W by IV), a CBP/catenin inhibitor, the lenvatinib mesylate is administered at (a) 24 mg per day orally, (b) 20 mg per day orally or (c) 14 mg per day orally, each as lenvatinib. A patient can be treated first with a daily amount of a CBP/β-catenin inhibitor, 200 mg of pembrolizumab Q3W by IV (or 400 mg Q6W by IV) and 24 mg (as lenvatinib) of lenvatinib mesylate per day orally until at least one DLT is observed and then the dosage of lenvatinib mesylate can be reduced to 20 or 14 mg (each as lenvatinib) per day, while the pembrolizumab dose can be continued at 200 mg of pembrolizumab Q3W (or 400 mg Q6W by IV) and the CBP/β-catenin inhibitor can be continued at the same daily dosage or reduced. As an example dosing regimen, lenvatinib or a pharmaceutically acceptable salt thereof can be administered with water orally once a day, with or without food, in 21 day cycles at approximately the same time each day. Lenvatinib or a pharmaceutically acceptable salt thereof can be provided as 4 mg and 10 mg (each as lenvatinib) capsules. On Day one (D1) of each cycle, lenvatinib or a pharmaceutically acceptable salt thereof can be administered approximately within 1 hour after completion of pembrolizumab administration and/or E7386 or its pharmaceutically acceptable salt administration. Pembrolizumab may be provided as a sterile, preservative-free, white to off-white lyophilized powder in single-use vials. Each vial can be reconstituted and diluted for intravenous infusion. Each 2 mL of reconstituted solution may contain approximately 50 mg of pembrolizumab. In some instances, pembrolizumab may be provided as a sterile, preservative-free, clear to slightly opalescent, colorless to slightly yellow solution that requires dilution for intravenous infusion. Each vial may contain 100 mg of pembrolizumab in 4 mL of solution. Each 1 mL of solution may contain 25 mg of pembrolizumab. Pembrolizumab may be administered as a dose of 200 mg as a 30-minute intravenous infusion, Q3W (25 minutes to 40 minutes, for example). In cases where an oral solid formulation is prepared, a pharmaceutically acceptable vehicle, and, as required, a binder, disintegrator, lubricant, coloring agent, flavoring agent and/or the like may be added to the principal component, that is, a compound or pharmaceutically acceptable salt thereof represented by Formula (I), a CBP/β-catenin inhibitor, and/or an anti-PD-1 antibody, to prepare, thereafter, a tablet, granule, fine granule, powder, capsule or the like according to a conventional method. Examples of the vehicle include lactose, corn starch, white soft sugar, glucose, sorbitol, crystalline cellulose and silicon dioxide. Examples of the binder include polyvinyl alcohol, ethylcellulose, methylcellulose, gum arabic, hydroxypropylcellulose and hydroxypropylmethylcellulose. Examples of the lubricant include magnesium stearate, talc, and silica. Examples of the coloring agents include titanium oxide, iron sesquioxide, yellow iron sesquioxide, cochineal, carmine, and riboflavin. Examples of the flavoring agents include cocoa powder, ascorbic acid, tartaric acid, peppermint oil, borneol, and cinnamon powder. These tablets and granules may be coated as may be required. In some instances, the patient is treated with the combination therapy for at least 24 weeks, e.g., eight 3-week cycles. In some instances, treatment with the combination therapy continues until the patient exhibits evidence of PD or a CR. In some instances, the patient selected for treatment with the combination therapy disclosed herein if the patient has been diagnosed with a renal cell carcinoma (RCC), a colorectal cancer (CRC), a hepatocellular carcinoma (HCC), a melanoma, a bladder cancer, a urothelial cancer, a breast cancer, a non-small cell lung cancer (NSCLC), an endometrial cancer, or a squamous cell carcinoma of head and neck. A “therapeutic drug” or “combination therapy for a cancer comprises an immune checkpoint inhibitor (e.g., an anti-PD-1 antibody), lenvatinib or a pharmaceutically acceptable salt thereof, and E7386 or a pharmaceutically acceptable salt thereof. The drug may be formulated such that each of the 3 drugs is separate and administered separately or in a combination of two of the three drugs, or altogether by a method appropriate for desired administration, for example, oral, transnasal, mucous membrane, rectal, vaginal, topical, intravenously, intraperitoneal, intradermal, subcutaneous, and intramuscular administration and the like. Determination of the dose and so the timing of the administration of a therapeutically effective amount of a combination therapy for cancer containing a combination of an immune checkpoint inhibitor, lenvatinib or a pharmaceutically acceptable salt thereof, and E7386 or a pharmaceutically acceptable salt thereof is sufficiently within the knowledge of those of ordinary skill in the art. For example, the initial effective amount can be assumed from the cell culture or other in vitro assay. The dose can be set to create a circulation concentration or tissue concentration, such as IC50 concentration and the like, determined by cell culture assay and/or in an animal model. An administration method is selected relying on the condition under treatment and the therapeutic drug. An immune checkpoint inhibitor, lenvatinib or a pharmaceutically acceptable salt thereof, and E7386 or a pharmaceutically acceptable salt thereof can be administered by various methods. For example, one or more of the components can be administered to a subject via any of the following routes: subcutaneous, intravenous, intraperitoneal, intramuscular and systemic administrations and, in some cases, direct injection into a particular organ or tumor and the like. An immune checkpoint inhibitor, lenvatinib or a pharmaceutically acceptable salt thereof, and E7386 or a pharmaceutically acceptable salt thereof can be administered through a single pathway, or simultaneous several pathways at the same time or sequentially as described herein. E7386 or a pharmaceutically acceptable salt thereof may be administered once per day, twice per day, several times per day, or further, plural times per day, depending on, among other things, the treatment indication and the judgment of the prescribing physician. The amounts of an immune checkpoint inhibitor, lenvatinib or a pharmaceutically acceptable salt thereof, and E7386 or a pharmaceutically acceptable salt thereof necessary for affording a treatment effect can be empirically determined according to conventional procedures for a particular object. Generally, cells are given in a pharmacologically effective dose when administered for the object of treatment. The “pharmacologically effective amount” or “pharmacologically effective dose” refers to an amount sufficient for producing a desired physiological effect or capable of achieving a desired result, such as reducing or removing one or more symptoms or indications of a disorder or disease and the like, to treat a particular disorder or disease state. The combination therapy can be a combination of an immune checkpoint inhibitor, lenvatinib or a pharmaceutically acceptable salt thereof, and E7386 or a pharmaceutically acceptable salt thereof that can be further combined with other cancer treatments, for example, surgical resection, radiation therapy, chemotherapy, immunotherapy, and supporting therapy (e.g., analgesic, diuretic, antidiuretic, antiviral drug, antibiotic, nutritional supplement, anemia treatment, blood coagulation treatment, bone treatment, and psychopathological and psychological treatments) and the like. These and other aspects disclosed herein, including the exemplary specific treatment methods, medicaments, and uses listed below, will be apparent from the teachings contained herein. Specific Treatment Methods, Medicaments, and Uses [1]. A method for treating a cancer in a human subject comprising administering to the individual a combination therapy which comprises: (i) an antagonist of a Programmed Death 1 protein (PD-1); (ii) lenvatinib having the structure: or a pharmaceutically acceptable salt thereof; and (iii) (6S,9aS)-N-benzyl-8-({6-[3-(4-ethylpiperazin-1-yl)azetidin-1 -yl]pyridin-2- yl}methyl)-6-(2-fluoro-4-hydroxybenzyl)-4,7-dioxo-2-(prop-2- en-1-yl)hexahydro-2H- pyrazino[2,1-c][1,2,4]triazine-1(6H)-carboxamide (E7386) having the structure: or a pharmaceutically acceptable salt thereof, wherein the PD-1 antagonist is not atezolizumab. [2]. The method of [1], wherein the cancer is a solid tumor. [3]. The method of [1], wherein the cancer is selected from the group consisting of: a renal cell carcinoma (RCC), a colorectal cancer (CRC), a hepatocellular carcinoma (HCC), a melanoma, a bladder cancer, a breast cancer, and a non-small cell lung cancer (NSCLC). [4]. The method of [1], wherein the cancer is a RCC. [5]. The method of any one of [1]-[4], wherein the PD-1 antagonist is a monoclonal antibody, or an antigen binding fragment thereof. [6]. The method of any of [1]-[5], wherein the PD-1 antagonist is an anti-PD-1 antibody. [7]. The method of any of [1]-[6], wherein the PD-1 antagonist is pembrolizumab or nivolumab. [8]. The method of any one of [1]-[7], wherein the PD-1 antagonist is pembrolizumab. [9]. The method of any one of [1]-[8], wherein lenvatinib or a pharmaceutically acceptable salt thereof is administered daily; and pembrolizumab is administered once every three weeks. [10]. The method of [9], wherein lenvatinib or a pharmaceutically acceptable salt thereof is administered at a daily dose of 24 mg, 20 mg, 18 mg, 12 mg or 8 mg; and pembrolizumab is administered at a dose of 200 mg for adults or 2 mg/kg (up to 200 mg) for pediatrics once every three weeks. [11]. The method of any of [1]-[10], wherein lenvatinib or a pharmaceutically acceptable salt thereof is lenvatinib mesylate; and E7386 or a pharmaceutically acceptable salt thereof is E7386. [12]. A pharmaceutical composition for treating a cancer, comprising (6S,9aS)-N- benzyl-8-({6-[3-(4-ethylpiperazin-1-yl)azetidin-1-yl]pyridin -2-yl}methyl)-6-(2-fluoro-4- hydroxybenzyl)-4,7-dioxo-2-(prop-2-en-1-yl)hexahydro-2H-pyra zino[2,1-c][1,2,4]triazine- 1(6H)-carboxamide (E7386)or a pharmaceutically acceptable salt thereof, wherein E7386 or a pharmaceutically acceptable salt thereof is administered in combination with (a) lenvatinib or a pharmaceutically acceptable salt thereof; and (b) an anti-PD-1 antibody. [13]. A pharmaceutical composition for treating a cancer, comprising an anti-PD-1 antibody, wherein the an anti-PD-1 antibody is administered in combination with (a) lenvatinib or a pharmaceutically acceptable salt thereof; and (b) (6S,9aS)-N-benzyl-8-({6-[3-(4- ethylpiperazin-1-yl)azetidin-1-yl]pyridin-2-yl}methyl)-6-(2- fluoro-4-hydroxybenzyl)-4,7- dioxo-2-(prop-2-en-1-yl)hexahydro-2H-pyrazino[2,1-c][1,2,4]t riazine-1(6H)-carboxamide (E7386)or a pharmaceutically acceptable salt thereof. [14]. A pharmaceutical composition for treating a cancer, comprising lenvatinib or a pharmaceutically acceptable salt thereof wherein lenvatinib or a pharmaceutically acceptable salt thereof is administered in combination with (a) (6S,9aS)-N-benzyl-8-({6-[3-(4- ethylpiperazin-1-yl)azetidin-1-yl]pyridin-2-yl}methyl)-6-(2- fluoro-4-hydroxybenzyl)-4,7- dioxo-2-(prop-2-en-1-yl)hexahydro-2H-pyrazino[2,1-c][1,2,4]t riazine-1(6H)-carboxamide (E7386) or a pharmaceutically acceptable salt thereof; and (b) an anti-PD-1 antibody. [15]. The pharmaceutical composition of any of [12]-[14], wherein lenvatinib or a pharmaceutically acceptable salt thereof is lenvatinib mesylate; and E7386 or a pharmaceutically acceptable salt thereof is E7386. [16]. The pharmaceutical composition of any of [12]-[15], wherein the cancer is a solid tumor. [17]. The pharmaceutical composition of any of [12]-[15], wherein the cancer is selected from the group consisting of: a renal cell carcinoma (RCC), a colorectal cancer (CRC), a hepatocellular carcinoma (HCC), a melanoma, a bladder cancer, a urothelial cancer, a breast cancer, a non-small cell lung cancer (NSCLC), an endometrial cancer, and a squamous cell carcinoma of head and neck. [18]. The pharmaceutical composition of [17], wherein the cancer is a RCC. [19]. The pharmaceutical composition of any of [12]-[18], wherein the PD-1 antagonist is a monoclonal antibody, or an antigen binding fragment thereof. [20]. The pharmaceutical composition of any of [12]-[18], wherein the PD-1 antagonist is an anti-PD-1 antibody. [21]. The pharmaceutical composition of any of [12]-[20], wherein the PD-1 antagonist is pembrolizumab or nivolumab. [22]. The pharmaceutical composition of any of [12]-[21], wherein the PD-1 antagonist is pembrolizumab. [23]. The pharmaceutical composition of any of [12]-[22], wherein lenvatinib or a pharmaceutically acceptable salt thereof is administered daily; and the PD-1 antagonist is pembrolizumab and is administered once every three weeks. [24]. The pharmaceutical composition of [23], wherein lenvatinib or a pharmaceutically acceptable salt thereof is administered at a daily dose of 24 mg, 20 mg, 18 mg, 12 mg or 8 mg; and pembrolizumab is administered at a dose of 200 mg for adults or 2 mg/kg (up to 200 mg) for pediatrics once every three weeks. [25]. The pharmaceutical composition of any of [12]-[24], wherein lenvatinib or a pharmaceutically acceptable salt thereof is lenvatinib mesylate; and E7386 or a pharmaceutically acceptable salt thereof is E7386. [26]. Use of the pharmaceutical composition of any of [12]-[25] for the manufacture of a medicament for a treatment of cancer. [27]. The pharmaceutical composition of any of [12]-[25] for use in the treatment of a cancer. General Methods. Standard methods in molecular biology are described Sambrook, Fritsch and Maniatis (1982 & 19892 nd Edition, 20013 rd Edition) M OLECULAR C LONING , A LABORATORY MANUAL, Cold Spring Harbor Laboratory Press, Cold Spring Harbor, NY; Sambrook and Russell (2001) M OLECULAR C LONING , 3 rd ed., Cold Spring Harbor Laboratory Press, Cold Spring Harbor, NY; Wu (1993) RECOMBINANT DNA, Vol.217, Academic Press, San Diego, CA). Standard methods also appear in Ausbel, et al. (2001) Current Protocols in Molecular Biology, Vols.1-4, John Wiley and Sons, Inc. New York, NY, which describes cloning in bacterial cells and DNA mutagenesis (Vol.1), cloning in mammalian cells and yeast (Vol.2), glycoconjugates and protein expression (Vol. 3), and bioinformatics (Vol.4). Methods for protein purification including immunoprecipitation, chromatography, electrophoresis, centrifugation, and crystallization are described (Coligan, et al. (2000) CURRENT PROTOCOLS IN PROTEIN SCIENCE, Vol.1, John Wiley and Sons, Inc., New York). Chemical analysis, chemical modification, post-translational modification, production of fusion proteins, glycosylation of proteins are described (see, e.g., Coligan, et al. (2000) Current P ROTOCOLS IN P ROTEIN S CIENCE , Vol.2, John Wiley and Sons, Inc., New York; Ausubel, et al. (2001) CURRENT PROTOCOLS IN MOLECULAR BIOLOGY, Vol.3, John Wiley and Sons, Inc., NY, NY, pp.16.0.5-16.22.17; Sigma-Aldrich, Co. (2001) PRODUCTS FOR LIFE SCIENCE RESEARCH, St. Louis, MO; pp.45-89; Amersham Pharmacia Biotech (2001) BioDirectory, Piscataway, N.J., pp.384-391). Production, purification, and fragmentation of polyclonal and monoclonal antibodies are described (Coligan, et al. (2001) CURRENT P ROTCOLS IN I MMUNOLOGY , Vol.1, John Wiley and Sons, Inc., New York; Harlow and Lane (1999) USING ANTIBODIES, Cold Spring Harbor Laboratory Press, Cold Spring Harbor, NY; Harlow and Lane, supra). Standard techniques for characterizing ligand/receptor interactions are available (see, e.g., Coligan, et al. (2001) CURRENT PROTOCOLS IN IMMUNOLOGY, Vol.4, John Wiley, Inc., New York). Monoclonal, polyclonal, and humanized antibodies can be prepared (see, e.g., Sheperd and Dean (eds.) (2000) Monoclonal Antibodies, Oxford Univ. Press, New York, NY; Kontermann and Dubel (eds.) (2001) Antibody Engineering, Springer-Verlag, New York; Harlow and Lane (1988) Antibodies A Laboratory Manual, Cold Spring Harbor Laboratory Press, Cold Spring Harbor, NY, pp.139-243; Carpenter, et al. (2000) J. Immunol.165:6205; He, et al. (1998) J. Immunol.160:1029; Tang et al. (1999) J. Biol. Chem.274:27371-27378; Baca et al. (1997) J. Biol. Chem.272:10678-10684; Chothia et al. (1989) Nature 342:877-883; Foote and Winter (1992) J. Mol. Biol.224:487-499; U.S. Pat. No.6,329,511). An alternative to antibody humanization is to use human antibody libraries displayed on phage or human antibody libraries in transgenic mice (Vaughan et al. (1996) Nature Biotechnol.14: 309-314; Barbas (1995) Nature Medicine 1: 837-839; Mendez et al. (1997) Nature Genetics 15: 146-156; Hoogenboom and Chames (2000) Immunol. Today 21: 371-377; Barbas et al. (2001) Phage Display: A Laboratory Manual, Cold Spring Harbor Laboratory Press, Cold Spring Harbor, New York; Kay et al. (1996) Phage Display of Peptides and Proteins: A Laboratory Manual, Academic Press, San Diego, CA; de Bruin et al. (1999) Nature Biotechnol.17: 397-399). Purification of antigen is not necessary for the generation of antibodies. Animals can be immunized with cells bearing the antigen of interest. Splenocytes can then be isolated from the immunized animals, and the splenocytes can fused with a myeloma cell line to produce a hybridoma (see, e.g., Meyaard et al. (1997) Immunity 7: 283-290; Wright et al. (2000) Immunity 13: 233-242; Preston et al., supra; Kaithamana et al. (1999) J. Immunol.163:5157- 5164). Antibodies can be conjugated, e.g., to small drug molecules, enzymes, liposomes, polyethylene glycol (PEG). Antibodies are useful for therapeutic, diagnostic, kit or other purposes, and include antibodies coupled, e.g., to dyes, radioisotopes, enzymes, or metals, e.g., colloidal gold (see, e.g., Le Doussal et al. (1991) J. Immunol.146: 169-175; Gibellini et al. (1998) J. Immunol.160:3891-3898; Hsing and Bishop (1999) J. Immunol.162: 2804-2811; Everts et al. (2002) J. Immunol.168: 883-889). Methods for flow cytometry, including fluorescence activated cell sorting (FACS), are available (see, e.g., Owens, et al. (1994) Flow Cytometry Principles for Clinical Laboratory Practice, John Wiley and Sons, Hoboken, NJ; Givan (2001) Flow Cytometry, 2 nd ed.; Wiley- Liss, Hoboken, NJ; Shapiro (2003) Practical Flow Cytometry, John Wiley and Sons, Hoboken, NJ). Fluorescent reagents suitable for modifying nucleic acids, including nucleic acid primers and probes, polypeptides, and antibodies, for use, e.g., as diagnostic reagents, are available (Molecular Probesy (2003) Catalogue, Molecular Probes, Inc., Eugene, OR; Sigma-Aldrich (2003) Catalogue, St. Louis, MO). Standard methods of histology of the immune system are described (see, e.g., Muller- Harmelink (ed.) (1986) Human Thymus: Histopathology and Pathology, Springer Verlag, New York, NY; Hiatt, et al. (2000) Color Atlas of Histology, Lippincott, Williams, and Wilkins, Phila, PA; Louis, et al. (2002) Basic Histology: Text and Atlas, McGraw-Hill, New York, NY). Software packages and databases for determining, e.g., antigenic fragments, leader sequences, protein folding, functional domains, glycosylation sites, and sequence alignments, are available (see, e.g., GenBank, Vector NTI® Suite (Informax, Inc, Bethesda, MD); GCG Wisconsin Package (Accelrys, Inc., San Diego, CA); DeCypher® (TimeLogic Corp., Crystal Bay, Nevada); Menne, et al. (2000) Bioinformatics 16: 741-742; Menne, et al. (2000) Bioinformatics Applications Note 16: 741-742; Wren, et al. (2002) Comput. Methods Programs Biomed.68: 177-181; von Heijne (1983) Eur. J. Biochem.133: 17-21; von Heijne (1986) Nucleic Acids Res.14: 4683-4690). Table 3 provides a brief description of the sequences in the sequence listing. TABLE 3
EXAMPLES Example 1: Anti-tumor Effect by Triple combination of E7386, Lenvatinib and anti-PD-1 Antibody An Eagle’s minimal essential medium (E-MEM) containing 10% fetal bovine serum (FBS) and penicillin/streptomycin (100 unit/mL each) was used to culture a mouse Renal cell carcinoma cell line RAG (ATCC number: CCL-142). Logarithmic growing cells were collected from flasks using Trypsin-EDTA. The suspension of cells was centrifuged to remove the supernatant. Next, Hanks' Balanced Salt Solution (HBSS) was used to prepare a cell suspension having a concentration of 2.5 x 10 7 cells/mL. The cell suspension was subcutaneously transplanted at a dose of 0.1 mL on the right lateral side of the body of each of 7-week-old mice (BALB/cAnNCrlCrlj, female, Charles River Laboratories Japan Inc.). Eight (8) days after the transplantation, an electronic digital caliper (Digimatic (TM) Caliper; Mitutoyo Corporation) was used to measure the short and long diameters of a tumor of interest. The following equations were used to calculate the tumor volume TV and RTV. EQ.1: Tumor Volume TV (mm 3 ) = Long Diameter (mm) × Short Diameter (mm) × Short Diameter (mm) / 2. EQ.2: Relative Tumor Volume RTV= TV on day n / TV on day1. Based on the tumor volumes on the first day of administration, grouping was carried out such that the average values of the tumor volumes were almost the same. A 1 mg/ml solution of lenvatinib was prepared using 3 mM HCl and was orally administered at a dose of 0.2 mL/20 g mouse body weight once daily for 28 days. 0.2 mL of an administration sample containing 1.0 mg/mL of an anti-mouse-PD-1 antibody (Clone: RMP1-14, BioXCell, Catalog#: BE0146), which had been diluted with PBS, was intraperitoneally administered (at a dosage of 200 µg/mouse) twice a week a total of 8 times (day 1, day 4, day 8, day 11, day 15, day 18, day 22, and day 25, with the day of the grouping set to day 1). A 2.5 mg/ml solution of E7386 was prepared using 0.1 M HCl and was orally administered at a dose of 0.2 mL/20 g mouse body weight once daily for 28 days. To the control group, nothing was administered. Each group including 8 mice was used to conduct the experiment. Twice a week (day 1, day 4, day 8, day 11, day 15, day 18, day 22, day 25, and day29), the respective tumor volumes (TV) were determined for the control group, the lenvatinib administration group, the anti-mouse-PD- 1 antibody administration group, lenvatinib + anti-mouse-PD-1 antibody administration group, E7386 + lenvatinib administration group and triple combination group. The values obtained by logarithmically transforming the tumor volumes were used to carry out statistical analysis by repeated measured Dunnet’s multiple comparison. E7386 is (6S,9aS)-N-benzyl-8-({6-[3-(4- ethylpiperazin-1-yl)azetidin-1-yl]pyridin-2-yl}methyl)-6-(2- fluoro-4-hydroxybenzyl)-4,7- dioxo-2-(prop-2-en-1-yl)hexahydro-2H-pyrazino[2,1-c][1,2,4]t riazine-1(6H)-carboxamide. In the subcutaneous (s.c.) RAG transplantation model, the triple combination of E7386, lenvatinib and the anti-mouse-PD-1 antibody exhibited a significantly higher anti-tumor effect than either of the dual combinations (i.e., Lenvatinib + Anti PD-1 antibody combination or the lenvatinib + E7386 combination ) or each agent when administered alone as a monotherapy. For example, at day 29, the triple combination group had greater than 200 fold less tumor volume compared to the control group and the E7386 group. The triple combination had over 30 fold less and 120 fold less tumor volume compared to the lenvatinib group and anti PD-1 antibody group, respectively. In addition, the triple combination group had greater than 9 fold less and 17 fold less tumor volume compared to the lenvatinib + anti PD-1 antibody combination group and E7386 + lenvatinib combination group, respectively. In the aspect of CR rate, the rate observed with the triple combination group (lenvatinib, pembrolizumab and E7386) was superior to rates observed with the other treatment groups (CR rate: 0, 0, 2, 1, 4, 1, and 7 out of 8 mice in control group, lenvatinib group, anti- PD-1 antibody group, E7386 group, lenvatinib + Anti PD-1 antibody group, E7386 + lenvatinib group and Triple combination group, respectively). The daily change in the tumor volume is shown in Table 4. In addition, the time course of the tumor volumes change during administration and the relative tumor volume at day 29 of each group are shown in Figure 8 and Figure 9, respectively. TABLE 4 Example 2: Anti-tumor Effect by Triple combination of E7386, Lenvatinib and anti-PD-1 Antibody Various culture mediums were used to culture a mouse cell lines (see Figures 10A-10C, column A). Logarithmic growing cells were collected from flasks using Trypsin-EDTA. The suspension of cells was centrifuged to remove the supernatant. Next, Hanks' Balanced Salt Solution (HBSS) was used to prepare a cell suspension having a certain cell concentration (see Figures 10A-10C, column B). The cell suspension was subcutaneously transplanted at a dose of 0.1 mL on the right lateral side of the body of each of 7-week-old immune competent mice (see Figures 10A-10C, column C). Several days after the transplantation (see Figures 10A-10C, column D), an electronic digital caliper (Digimatic (TM) Caliper; Mitutoyo Corporation) was used to measure the short and long diameters of a tumor in the animal. The following equations were used to calculate the tumor volume TV and RTV. EQ.1: Tumor Volume TV (mm3) = Long Diameter (mm) × Short Diameter (mm) × Short Diameter (mm) / 2. EQ.2: Relative Tumor Volume RTV= TV on day n / TV on day1. Based on the tumor volumes on the first day of administration, grouping was carried out such that the average values of the tumor volumes were almost the same. A 1 mg/ml solution of lenvatinib was prepared using 3 mM HCl and was orally administered at a dose of 0.2 mL/20 g mouse body weight once daily for 28 days. 0.2 mL of an administration sample containing 1.0 mg/mL of an anti-mouse-PD-1 antibody (Clone: RMP1-14, BioXCell, Catalog#: BE0146), which had been diluted with PBS, was intraperitoneally administered (at a dosage of 200 µg/mouse) twice a week for 3 or 4 weeks (see Figures 10A-10C, column E). A 2.5 mg/ml solution of E7386 was prepared using 0.1 M HCl and was orally administered at a dose of 0.2 mL/20 g mouse body weight once daily for 3 or 4 weeks (see Figures 10A-10C, column E). To the control group, nothing was administered. Each group including 8 mice was used to conduct the experiment. Twice a week for 3 or 4 weeks (see Figures 10A-10C, column E), the respective tumor volumes (TV) were determined for the control group, the lenvatinib administration group, the anti-mouse-PD-1 antibody administration group, the lenvatinib + anti-mouse-PD-1 antibody administration group, the E7386 + lenvatinib administration group and the triple combination therapy group. The values obtained by logarithmically transforming the tumor volumes were used to carry out statistical analysis by repeated measured Dunnet’s multiple comparison. E7386 is (6S,9aS)-N-benzyl-8-({6-[3-(4-ethylpiperazin-1-yl)azetidin-1 - yl]pyridin-2-yl}methyl)-6-(2-fluoro-4-hydroxybenzyl)-4,7-dio xo-2-(prop-2-en-1- yl)hexahydro-2H-pyrazino[2,1-c][1,2,4]triazine-1(6H)-carboxa mide. As shown in Figure 11 and Figures 12A-12G, the triple combination therapy of E7386, lenvatinib and the anti-mouse-PD-1 antibody exhibited a higher anti-tumor effect than either of the dual combinations (i.e., Lenvatinib + Anti PD-1 antibody combination or the lenvatinib + E7386 combination ) or each agent when administered alone as a monotherapy. Relative tumor volume (RTV) at time t was calculated following formula: EQ.3: RTV= TVt/TVinitial x 100%. We defined the Best Average Response (BestAvgResponse) as the minimum value of the average of (RTV-100%) for t ≥ 8 d (EQ.4). This metric captures a combination of speed, strength and durability of response into a single value. The criteria for response (mRECIST) were adapted from RECIST criteria and defined as follows (applied in this order): mCR, BestAvgResponse < −95%; mPR, BestAvgResponse < −50%; mSD, BestAvgResponse < 30%; mPD, not otherwise categorized. REFERENCES 1. Sharpe, A.H, Wherry, E.J., Ahmed R., and Freeman G.J. 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Canadian Application No.3044658. 19. U.S. Patent 9,174,998. 20. U.S. Patent 10,259,817. 21. Keiichi Tamai, et al., “Suppressive expression of CD274 increases tumorigenesis and cancer stem cell phenotypes in cholangiocarcinoma,” Cancer Sci.105(6): 667-674, 2014. Anthony B. El-Khoueiry, et al., “A phase I first-in-human study of PRI-724 in patients (pts) with advanced solid tumors,” J. Clin. Oncol.31(15_supple(May 20,2013)): abstr 2501. 22. Renée van Amerongen, et al., “Break the loop, escape the cycle?” The EMBO Journal 2013, 32: 1977-1989. All references cited herein are incorporated by reference to the same extent as if each individual publication, database entry (e.g. Genbank sequences or GeneID entries), patent application, or patent, was specifically and individually indicated to be incorporated by reference. This statement of incorporation by reference is intended by Applicants, pursuant to 37 C.F.R. §1.57(b)(1), to relate to each and every individual publication, database entry (e.g. Genbank sequences or GeneID entries), patent application, or patent, each of which is clearly identified in compliance with 37 C.F.R. §1.57(b)(2), even if such citation is not immediately adjacent to a dedicated statement of incorporation by reference. The inclusion of dedicated statements of incorporation by reference, if any, within the specification does not in any way weaken this general statement of incorporation by reference. Citation of the references herein is not intended as an admission that the reference is pertinent prior art, nor does it constitute any admission as to the contents or date of these publications or documents.
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