Cancer treatment by combined use of immune checkpoint regulator and low-molecular-weight compound having Anti-fibrotic effect

Abstract

To provide a novel treatment method in which the effectiveness of cancer treatment is improved by using an immune checkpoint regulator in combination.SOLUTION: An anticancer drug of the present invention has, as an active ingredient, a compound that is N-(4-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-3-yl)-3-(piperidine-1-yl)benzamide, a pharmacologically acceptable salt thereof, or a solvate of the compound or the salt, and is used in combination with at least one immune checkpoint regulator. The immune checkpoint regulator is, for example, an immune checkpoint inhibitor such as an antagonistic anti-PD-1 antibody.SELECTED DRAWING: Figure 2

Description

[Technical Field]

[0001] The present invention relates to cancer therapy using N-(4-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-3-yl)-3-(piperidin-1-yl)benzamide in combination with an immune checkpoint regulator. [Background technology]

[0002] Immune checkpoint inhibitors (ICIs), which bind to inhibitory immune checkpoint receptors or their ligands and inhibit the transmission of immunosuppressive signals, have been clinically used, including anti-PD-1, anti-PD-L1, and anti-CTLA-4 antibodies, and have become a standard treatment for cancer. However, the response rate of ICIs is approximately 5-30%, and they are not effective for all cancers. To overcome this issue, combination therapies using ICIs or ICIs with other drugs have been investigated, and numerous clinical trials are being conducted.

[0003] Examples of anti-cancer combination therapies using ICIs that have been investigated include combination therapy between ICIs (e.g., Non-Patent Documents 1 to 3), combination therapy between an anti-VEGF / TKI and a PD-1 / PD-L1 inhibitor (Non-Patent Document 4), combination therapy between an MEK inhibitor such as cobimetinib and a PD-1 / PD-L1 inhibitor (Non-Patent Document 5), combination therapy between a TGF-β inhibitor such as galunisertib or vactosertib and a PD-1 / PD-L1 inhibitor (Non-Patent Documents 6 to 8), and combination therapy between an anti-CD4 antibody and an ICI (Patent Documents 1 and 2).Fusion protein molecules that simultaneously target immune checkpoints and other molecules, such as the bifunctional fusion protein Bintrafusp alfa that blocks TGF-β and PD-L1, have also been developed (Non-Patent Document 9).

[0004] Although these combination therapies have shown improved efficacy, more effective cancer therapies are desired.

[0005] Immune checkpoint molecules include not only inhibitory receptors and ligands, but also costimulatory receptors and their ligands that transmit immunostimulatory signals. Known costimulatory immune checkpoint molecules include CD28, ICOS, CD137 / 4-1BB, and OX40. Agonistic molecules that bind to costimulatory immune checkpoint receptors or their ligands and promote the transmission of immunostimulatory signals can be called immune checkpoint stimulators or activators.

[0006] Immune checkpoint activators have also been researched and developed as therapeutic agents for cancer and other conditions, but compared to ICIs, their practical application is scarce and appears to be facing difficulties. For example, an anti-CD28 antibody, which was being developed to target B-cell chronic lymphocytic leukemia, experienced a serious safety incident during clinical trials, resulting in multiple organ failure, leading to the revocation of clinical trial approval (Non-Patent Document 10). This incident raised concerns about the high risk of immune checkpoint overactivation. In clinical trials, anti-CD137 / 4-1BB antibodies have demonstrated antitumor activity but severe hepatotoxicity (Urelumab), while other antibodies have demonstrated high safety but low efficacy, and clinical trials are ongoing in combination with ICIs (anti-PD-L1 antibodies) (Utomilumab). Development of anti-human CD137 / 4-1BB antibodies that can exert high antitumor activity without inducing hepatotoxicity continues (Non-Patent Documents 11-13). [Prior art documents] [Patent documents]

[0007] [Patent Document 1] WO 2015 / 125652 A1 [Patent Document 2] WO 2015 / 120198 A1 [Non-patent literature]

[0008] [Non-Patent Document 1] ClinicalTrials.gov Identifier: NCT02477826, "An Investigational Immuno-therapy Trial of Nivolumab, or Nivolumab Plus Ipilimumab, or Nivolumab Plus Platinum-doublet Chemotherapy, Compared to Platinum Doublet Chemotherapy in Patients With Stage IV Non-Small Cell Lung Cancer (NSCLC) (CheckMate 227)." [https: / / clinicaltrials.gov / ct2 / show / NCT02477826] [Non-Patent Document 2] ClinicalTrials.gov Identifier: NCT01844505, "Phase 3 Study of Nivolumab or Nivolumab Plus Ipilimumab Versus Ipilimumab Alone in Previously Untreated Advanced Melanoma (CheckMate 067)." [https: / / clinicaltrials.gov / ct2 / show / NCT01844505] [Non-Patent Document 3] ClinicalTrials.gov Identifier: NCT02231749, "Nivolumab Combined With Ipilimumab Versus Sunitinib in Previously Untreated Advanced or Metastatic Renal Cell Carcinoma (CheckMate 214)." [https: / / clinicaltrials.gov / ct2 / show / NCT02231749] [Non-Patent Document 4] Masatoshi KUDO, Hepatobiliary Surg Nutr. 2021 Apr; 10(2): 241-245.

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Non-licensed literature 9

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[0009] The present invention aims to provide a new therapeutic method that improves the effectiveness of cancer treatment by using immune checkpoint control agents that target immune checkpoints, in particular in combination with immune checkpoint inhibitors that are being increasingly put into practical use. [Means for solving the problem]

[0010] The present inventors have conducted extensive research focusing on amide derivatives (WO 2014 / 003124) that were developed as compounds useful for the prevention and treatment of diseases involving collagen overproduction, such as pulmonary fibrosis. As a result, they have discovered that certain amide derivatives exhibit excellent anti-cancer effects when used in combination with immune checkpoint control agents, and have completed the present invention.

[0011] That is, the present invention is a cancer therapy using N-(4-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-3-yl)-3-(piperidin-1-yl)benzamide (hereinafter sometimes referred to as amide derivative A) in combination with an immune checkpoint control agent, and includes the following aspects. [1] An anticancer agent containing, as an active ingredient, a compound that is N-(4-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-3-yl)-3-(piperidin-1-yl)benzamide, a pharmaceutically acceptable salt thereof, or a solvate of said compound or said salt, which is used in combination with at least one immune checkpoint control agent. [2] The anticancer agent according to [1], wherein the dosage of the anticancer agent is 0.1 mg / kg to 10 mg / kg of body weight per day in terms of the amount of the active ingredient. [3] The anticancer agent according to [1] or [2], wherein the anticancer agent is an oral agent. [4] The anticancer agent according to any one of [1] to [3], wherein the immune checkpoint control agent is at least one immune checkpoint inhibitor selected from an antagonistic anti-PD-1 antibody, an anti-PD-L1 antibody, an anti-PD-L2 antibody, an antagonistic anti-LAG-3 antibody, an antagonistic anti-TIM-3 antibody, and an antagonistic anti-CTLA-4 antibody. [5] The anticancer agent according to [4], wherein the immune checkpoint control agent is at least one selected from an antagonistic anti-PD-1 antibody, an anti-PD-L1 antibody, and an anti-PD-L2 antibody. [Effects of the Invention]

[0012] The anticancer agents of the present invention contain as an active ingredient the free form of amide derivative A, a pharmaceutically acceptable salt thereof, or a solvate of amide derivative A or its salt (hereinafter, these may be collectively referred to as "amide derivative A" in this specification), and exhibit excellent anticancer activity when used in combination with an immune checkpoint regulator. Amide derivative A is a compound known to have antifibrotic activity, but it exhibits antitumor activity against cancer at concentrations far lower than those at which it exhibits antifibrotic activity, particularly when used in combination with an immune checkpoint regulator. It has been confirmed that tumor growth can be suppressed when used in combination with an immune checkpoint regulator, even at doses at which no effect on pulmonary fibrosis was observed when orally administered to pulmonary fibrosis model animals (data not shown). The effect on fibrosis is due to TGF-β inhibitory activity, and the fact that antitumor activity is achieved at low doses that are ineffective against pulmonary fibrosis suggests that the antitumor effect of amide derivative A is not due to TGF-β inhibitory activity. Even compared with the effective amount as an anticancer agent of Galunisertib, a known low-molecular-weight compound with similar activity, the effective amount of Amide Derivative A is much lower (see Examples below), and Amide Derivative A is considered to have superior efficacy to Galunisertib. Furthermore, for example, when formulated as oral tablets, Galunisertib requires the administration of a large number of tablets each time, whereas the anticancer agent of the present application only requires the administration of one tablet at a time, thereby reducing the burden of medication on cancer patients. [Brief explanation of the drawings]

[0013] [Figure 1] This is a graph showing the tumor volume measured over time for individual Colon 26 tumor-bearing mice administered the hydrochloride salt of amide derivative A (CFI2101) alone or in combination with an anti-PD-L1 antibody. [Figure 2] Tumor volume 19 days after tumor inoculation in Colon26 tumor-bearing mice treated with CFI2101 alone or in combination with an anti-PD-L1 antibody. Significant difference compared to the control group #: p<0.05 (Dunnett). Significant difference compared to the group treated with an anti-PD-1 antibody in combination with an anti-PD-L1 antibody **: p<0.01 (Dunnett). [Figure 3] In three animals, Colon26 solid tumors implanted in the right flank were eliminated and in one animal, tumor growth was partially suppressed by the combined use of CFI2101 and anti-PD-L1 antibody. A new Colon26 tumor was implanted in the left flank, and tumor growth on both sides was measured (changes in tumor volume for each individual). [Figure 4] This is a graph showing the tumor volume measured over time for individual mice bearing B16 melanoma that were administered CFI2101 alone or in combination with an anti-PD-L1 antibody. [Figure 5] Tumor volume 14 days after tumor inoculation in B16 melanoma-bearing mice treated with CFI2101 alone or in combination with an anti-PD-L1 antibody. Significant difference compared to the control group. *: p<0.05 (Dunnett). [Figure 6] This graph shows the tumor volume measured over time for individual LLC tumor-bearing mice administered CFI2101 alone or in combination with an anti-PD-L1 antibody. [Figure 7] Tumor volume 14 days after tumor inoculation in LLC tumor-bearing mice administered CFI2101 alone or in combination with an anti-PD-L1 antibody. Significant difference compared to the control group: * p<0.05, ** p<0.01 (Dunnett). Significant difference between the CFI2101 + anti-PD-L1 antibody combination group and the anti-PD-L1 antibody alone group: #: p<0.05, ## p<0.01 (Dunnett). [Figure 8] This figure shows the results of comparing the anti-cancer effects of CFI2101 and Galunisertib in Colon26 tumor-bearing mice. Tumor volumes were compared between each treatment group 19 days after tumor inoculation. Significant differences compared to the control group: * p< 0.05, ** p< 0.01 (Dunnett's). DETAILED DESCRIPTION OF THE INVENTION

[0014] The anticancer agent of the present invention contains, as an active ingredient, amide derivative A (free form) having the following structure, a pharmaceutically acceptable salt of amide derivative A, or a solvate of amide derivative A or a pharmaceutically acceptable salt thereof, and is used in combination with an immune checkpoint control agent.

[0015] [ka]

[0016] The terms "combined use" and "concomitant use" encompass both the use of amide derivative A and an immune checkpoint control agent as separate agents, and the use of a combined agent containing amide derivative A and an immune checkpoint control agent in the same formulation. The anticancer agent of the present invention typically employs the former embodiment, and the immune checkpoint control agent is generally prepared as a separate agent from the anticancer agent of the present invention. The same applies when multiple immune checkpoint control agents are used in combination; although a single formulation containing multiple immune checkpoint control agents may be used, it is generally preferable to combine multiple immune checkpoint control agents as separate agents. Combining each substance as a separate agent has the advantage that the administration site, administration timing, administration frequency, dosage, etc. of each substance can be individually optimized.

[0017] The terms "administered in combination" and "administered concomitantly" mean that multiple active ingredients (amide derivative A and immune checkpoint regulator) are administered to a patient simultaneously, sequentially, or separately. Sequential administration means that the administration of one active ingredient is completed followed immediately by the administration of the next active ingredient. Separate administration means that multiple active ingredients are administered at intervals, for example, at intervals of several hours or more on the same day, or on different days during a course of treatment. When administered simultaneously, active ingredients formulated as separate preparations may be administered simultaneously, or a preparation containing multiple ingredients in the same preparation may be administered.

[0018] In the field of cancer therapy, one course of treatment is a small unit of time that includes a period of medication and a period of rest. Whether it is monotherapy or a combination of multiple drugs, one course is defined as a period of administration of anticancer drugs for about one to several weeks, followed by a period of rest of about one week. The number of courses (usually several courses) is generally determined by the doctor depending on the patient's condition and the effect of shrinking the cancer.

[0019] Amide derivative A itself is a known compound disclosed in WO 2014 / 003124, and is one of a group of amide derivatives with collagen production inhibitory activity that were developed as compounds useful for the prevention and treatment of diseases involving collagen overproduction, such as pulmonary fibrosis. WO 2014 / 003124 makes no mention of amide derivative A having anticancer activity or being useful as an anticancer agent. Amide derivative A can be synthesized from N-(4-cyanobiphenyl-3-yl)-3-(piperidin-1-yl)benzamide (compound I) via N-(4-(hydroxyamidino)biphenyl-3-yl)-3-(piperidin-1-yl)benzamide (compound II) by the method described in WO 2014 / 003124, specifically, the method described in Example 62.

[0020] [ka]

[0021] The anticancer agent of the present invention may contain a pharmaceutically acceptable salt of amide derivative A. Examples of pharmaceutically acceptable salts include inorganic acid salts such as hydrochloride, sulfate, phosphate, and hydrobromide; organic acid salts such as oxalate, malonate, citrate, fumarate, lactate, malate, succinate, tartrate, acetate, trifluoroacetate, maleate, gluconate, benzoate, ascorbate, methanesulfonate, p-toluenesulfonate, and cinnamate; inorganic base salts such as sodium salt, potassium salt, calcium salt, magnesium salt, and ammonium salt; and organic base salts such as methylamine salt, diethylamine salt, trimethylamine salt, triethylamine salt, pyridinium salt, triethanolamine salt, ethylenediamine salt, and guanidine salt.

[0022] The anticancer agent of the present invention may contain a solvate of amide derivative A or a pharmaceutically acceptable salt thereof. Specific examples of the solvate include, but are not limited to, hydrates and ethanolates, and any solvate with a pharmaceutically acceptable solvent may be used.

[0023] In the present invention, the "immune checkpoint control agent" used in combination with the free form of amide derivative A, a salt thereof, or a solvate thereof is a substance that promotes the activation of immune cells by controlling the function of immune checkpoint molecules, and includes substances that act inhibitoryly against suppressive immune checkpoint molecules (immune checkpoint inhibitors) and substances that act stimulatoryly against costimulatory immune checkpoint molecules (immune checkpoint activators or immune checkpoint stimulators). The term "immune checkpoint molecule" includes both receptors and ligands that function as immune checkpoints.

[0024] Immune checkpoints are immune escape mechanisms that prevent the immune system from attacking the body itself. Immune checkpoint receptors exist on T cells and interact with ligands expressed on cancer cells and antigen-presenting cells. T cells recognize antigens presented on MHC molecules, become activated, and initiate an immune response, but T cell activation is regulated by immune checkpoint receptor-ligand interactions that occur in parallel. Immune checkpoint receptors are classified as costimulatory and inhibitory, and T cell activation and immune responses are regulated by the balance between the two.

[0025] "Immune checkpoint inhibitors" are antagonists to inhibitory immune checkpoint molecules, and include antibodies with antagonistic activity that bind to inhibitory immune checkpoint receptors and inhibit the binding of the receptor to its ligand; antibodies that bind to inhibitory immune checkpoint ligands and inhibit the binding of the ligand to its receptor; soluble polypeptides designed based on inhibitory immune checkpoint ligands that do not activate receptors; or vectors capable of expressing such polypeptides. Target inhibitory immune checkpoint molecules include receptors such as PD-1, CTLA-4, LAG-3, TIM-3, BTLA, and KIR, and ligands such as PD-L1 (PD-1 ligand), PD-L2 (PD-1 ligand), GAL9 (TIM-3 ligand), and HVEM (BTLA ligand). Specific examples of immune checkpoint inhibitors include antibodies with antagonistic activity that bind to inhibitory immune checkpoint receptors and inhibit the binding of the receptors to their ligands, such as antagonistic anti-PD-1 antibodies, antagonistic anti-CTLA-4 antibodies, antagonistic anti-LAG-3 antibodies, antagonistic anti-TIM-3 antibodies, antagonistic anti-BTLA antibodies, and antagonistic anti-KIR antibodies. Examples of antibodies that bind to inhibitory immune checkpoint ligands and inhibit the binding of the ligands to their receptors include, but are not limited to, anti-PD-L1 antibodies, anti-PD-L2 antibodies, anti-GAL9 antibodies, and anti-HVEM antibodies.

[0026] Cancer cells express ligands for inhibitory immune checkpoint receptors and use these receptors to escape destruction by cytotoxic T cells. Therefore, administration of immune checkpoint inhibitors that target inhibitory immune checkpoint molecules prevents cancer cells from utilizing the immune checkpoint mechanism, resulting in the suppression of CD8 + They can promote the killing of cancer cells by T cells. Immune checkpoint inhibitors, which have recently been put to practical use as anti-cancer drugs, are antibodies that target inhibitory immune checkpoint receptors or their ligands. Development of anti-PD-1 antibodies, anti-PD-L1 antibodies, anti-PD-L2 antibodies, anti-CTLA-4 antibodies, anti-LAG-3 antibodies, anti-TIM-3 antibodies, etc. is progressing for melanoma, lung cancer, leukemia, gastric cancer, lymphoma, kidney cancer, etc.

[0027] "Immune checkpoint activators" are agonists for costimulatory immune checkpoint molecules and include antibodies with agonistic activity that bind to costimulatory immune checkpoint receptors; soluble polypeptides designed based on costimulatory immune checkpoint ligands and capable of activating receptors; or vectors capable of expressing said polypeptides. Targeted costimulatory immune checkpoint molecules include receptors such as CD137 (also known as 4-1BB), OX40, and GITR, and ligands such as CD137L (a ligand for CD137), OX40L (a ligand for OX40), and TNFSF18 (a ligand for GITR). Administration of immune checkpoint activators targeting costimulatory immune checkpoint molecules promotes immune responses, thereby increasing CD8 +It is also possible to promote the killing of cancer cells by T cells. Specific examples of immune checkpoint activators include antibodies that bind to costimulatory immune checkpoint receptors and have agonistic activity, such as agonistic CD137 antibodies, agonistic anti-OX40 antibodies, and agonistic anti-GITR antibodies, but are not limited to these. As will be described later, examples of immune checkpoint activators being developed as pharmaceuticals are also known.

[0028] In one embodiment, the immune checkpoint control agent used in combination with the anticancer agent of the present invention is an immune checkpoint inhibitor. Specific examples of preferred immune checkpoint inhibitors include, but are not limited to, at least one selected from an antagonistic anti-PD-1 antibody, an anti-PD-L1 antibody, an anti-PD-L2 antibody, an antagonistic anti-LAG-3 antibody, an antagonistic anti-TIM-3 antibody, and an antagonistic anti-CTLA-4 antibody; at least one selected from an antagonistic anti-PD-1 antibody, an anti-PD-L1 antibody, an anti-PD-L2 antibody, an antagonistic anti-LAG-3 antibody, and an antagonistic anti-TIM-3 antibody; or at least one selected from an antagonistic anti-PD-1 antibody, an anti-PD-L1 antibody, and an anti-PD-L2 antibody.

[0029] Specific examples of immune checkpoint control agents, along with publicly known examples of pharmaceuticals currently under development or in practical use, include immune checkpoint inhibitors such as anti-CTLA-4 antibodies (e.g., ipilimumab (YERVOY (registered trademark), tremelimumab, AGEN-1884)), anti-PD-1 antibodies (e.g., nivolumab, cemiplimab (REGN-2810), pembrolizumab (MK-3475), spartalizumab (PDR-001), tislelizumab (BGB-A317), AMP-514 (MEDI0680), dostarlimab (ANB011, TSR-042), toripalimab (JS001), camrelizumab (SHR-1210), genolimzumab (CBT-501), sintilimab (IBI308), STI-A1110, ENUM 388D4, ENUM 244C8, GLS010, MGA012, AGEN2034, CS1003, HLX10, BAT-1306, AK105, AK103, BI754091, LZM009, CMAB819, Sym021, GB226, SSI-361, JY034, HX008, ABBV181, BCD-100, PF-06801591, CX-188, and JNJ-63723283), anti-PD-L1 antibodies (e.g., atezolizumab (RG7446, MPDL3280A), avelumab (PF-06834635, MSB0010718C), durvalumab (ME DI4736), BMS-936559, STI-1010, STI-1011, STI-1014, KN035, LY3300054, HLX20, SHR-1316, CS1001 (WBP3155), MSB2311, BGB-A333, KL-A167, CK-301, AK106, AK104, ZKAB001, FAZ053, CBT-502 (TQB2450), JS003 and CX-072, etc. PD-L2 antibodies (e.g., rHIgM12B7), PD-L1 fusion proteins, PD-L2 fusion proteins (e.g., AMP-224), anti-TIM-3 antibodies (e.g., MBG453), anti-LAG-3 antibodies (e.g., BMS-986016, LAG525), anti-KIR antibodies (e.g., lirilumab), PD-1 antagonists (e.g., AUNP-12, BMS-M1 to BMS-M10, BMS-1, BMS-2), Examples of immune checkpoint control agents include BMS-3, BMS-8, BMS-37, BMS-200, BMS-202, BMS-230, BMS-242, BMS-1001, BMS-1166, the compounds Incyte-1 to Incyte-6, CAMC-1 to CAMC-4, RG_1, and DPPA-1), PD-L1 / VISTA antagonists (e.g., CA-170), and PD-L1 / TIM3 antagonists (e.g., CA-327). Examples of immune checkpoint activators include anti-CD137 antibodies (e.g., urelumab, utomilumab, and LVGN6051) and anti-OX40 antibodies (e.g., PF-04518600). Antibodies containing the heavy and light chain complementarity-determining regions (CDRs) or variable regions (VRs) of the above-mentioned known antibodies are also embodiments of immune checkpoint control agents. For example, a further embodiment of the anti-PD-1 antibody includes an antibody comprising the heavy and light chain complementarity-determining regions (CDRs) or variable regions (VRs) of nivolumab.

[0030] The subjects to which the anticancer agent of the present invention is administered in combination with an immune checkpoint regulator are cancer patients, i.e., patients in need of cancer treatment, including patients who currently have cancer and patients who have undergone surgical resection of cancer lesions. Patients are typically mammals, particularly humans, but are not limited thereto.

[0031] In the present invention, the term "cancer treatment" encompasses various medical procedures performed for the purpose of treating cancer in patients. Specifically, it encompasses the treatment of primary cancer, recurrent cancer, and metastatic cancer, as well as the suppression of cancer recurrence and metastasis. For example, "cancer treatment" also encompasses the administration of the anticancer agent of the present invention to a patient after surgical resection of a cancer lesion for the purpose of preventing recurrence. The term "anticancer agent" encompasses therapeutic agents for cancer (primary cancer, recurrent cancer, and metastatic cancer), agents for suppressing cancer recurrence, and agents for suppressing cancer metastasis. As described above, the term "cancer patient" encompasses not only patients who currently have cancer, but also patients after surgical resection of a cancer lesion.

[0032] The type of cancer targeted by the anticancer agent of the present invention is not particularly limited, and the agent can be applied to various cancers, including solid cancers and blood cancers. Specific examples of solid cancers include malignant melanoma (e.g., malignant melanoma in the skin, oral mucosal epithelium, or orbit), lung cancer (e.g., non-small cell lung cancer such as squamous non-small cell lung cancer (squamous cell lung cancer) and non-squamous non-small cell lung cancer (adenocarcinoma, large cell lung cancer); small cell lung cancer), head and neck cancer, kidney cancer (e.g., clear cell renal cell carcinoma, multilocular cystic renal cell carcinoma, papillary renal cell carcinoma, chromophobe renal cell carcinoma, collecting duct carcinoma), breast cancer, ovarian cancer (e.g., serous adenocarcinoma, mucinous adenocarcinoma, clear cell adenocarcinoma), nasopharyngeal cancer, uterine cancer (e.g., cervical cancer, endometrial cancer, uterine body cancer), anal cancer (e.g., anal canal cancer), colorectal cancer / rectal cancer / colon cancer, and liver cancer (e.g., Examples of cancers that can be treated include hepatocellular carcinoma, cholangiocarcinoma, esophageal cancer (e.g., esophageal adenocarcinoma, esophageal squamous cell carcinoma), gastric cancer, esophagogastric junction cancer, small intestine cancer, pancreatic cancer, urothelial cancer (e.g., bladder cancer, upper urinary tract cancer, ureteral cancer, renal pelvis cancer, urethral cancer), prostate cancer, fallopian tube cancer, primary peritoneal cancer, pleural mesothelioma, gallbladder cancer, bile duct cancer, biliary tract cancer, skin cancer (e.g., Merkel cell carcinoma), testicular cancer (germ cell tumor), vaginal cancer, vulvar cancer, penile cancer, small intestine cancer, endocrine system cancer, thyroid cancer, parathyroid cancer, adrenal gland cancer, spinal tumor, brain tumor, glioblastoma, gliosarcoma, bone and soft tissue sarcoma (e.g., Ewing's sarcoma, childhood rhabdomyosarcoma, uterine corpus leiomyosarcoma), and Kaposi's sarcoma. Specific examples of blood cancer include malignant lymphoma, leukemia, and multiple myeloma. The anticancer agent of the present invention is typically preferably used against solid cancers.

[0033] The dose of the anticancer agent of the present invention may be an amount effective for treating cancer. The effective amount can be selected appropriately depending on the size and symptoms of the tumor, the age and body weight of the patient, and other factors. The dose of the anticancer agent of the present invention may be approximately 0.1 mg / kg to 50 mg / kg of body weight per day of the active ingredient to a cancer patient, for example, 0.1 mg / kg to 40 mg / kg, 0.1 mg / kg to 30 mg / kg, 0.1 mg / kg to 20 mg / kg, or 0.1 mg / kg to 10 mg / kg. The dose can also be reduced to, for example, 0.1 mg / kg to 7 mg / kg or 0.1 mg / kg to 5 mg / kg. The lower limit of these numerical ranges may be 0.2 mg / kg, 0.3 mg / kg, 0.4 mg / kg, or 0.5 mg / kg. The agent may be administered once a day or in divided doses. The anticancer agent of the present invention may be administered daily or every other day to every few days during the treatment period. Galunisertib, a low molecular weight compound known to have antifibrotic and anticancer effects similar to amide derivative A and undergoing clinical trials as an anticancer agent, is administered at 75 mg / kg body weight twice daily for a daily dose of 150 mg / kg body weight. However, the anticancer agent of the present invention can exert an anticancer effect equivalent to that of Galunisertib at a much lower dose, thereby reducing the burden of medication on patients.

[0034] The route of administration of the anticancer agent of the present invention is not particularly limited, and may be oral or parenteral. Parenteral administration may be any of intramuscular administration, subcutaneous administration, intravenous administration, intraarterial administration, transdermal administration, and nasal administration. Systemic administration or local administration may be used, and in the case of local administration, for example, administration may be into or near tumor tissue, or into lymph nodes near the tumor. The anticancer agent of the present invention can be preferably administered orally. That is, the dosage form of the anticancer agent of the present invention is preferably an oral formulation.

[0035] The free form of amide derivative A, its salts, and solvates thereof can be formulated by appropriately mixing with additives such as pharmaceutically acceptable carriers, diluents, excipients, binders, lubricants, disintegrants, sweeteners, suspending agents, emulsifiers, colorants, flavoring agents, and stabilizers suitable for each administration route. Examples of dosage forms include oral preparations such as tablets, soft capsules, hard capsules, granules, powders, and syrups, and parenteral preparations such as injections, suppositories, liquids, inhalants, and patches. Formulation methods and usable additives are well known in the field of pharmaceutical formulations, and any method and additive can be used.

[0036] The dosage of the immune checkpoint control agent used in combination with the anticancer agent of the present invention is also selected appropriately depending on the size and symptoms of the tumor, the age and weight of the patient, etc., but the dosage, administration route, and administration schedule normally used when the agent is administered alone or in combination with other drugs as an anticancer agent can also be used when the agent is used in combination with the anticancer agent of the present invention. Immune checkpoint control agents are generally administered to cancer patients daily or multiple times every few days during the treatment period. The administration route of the immune checkpoint control agent may be oral or parenteral, although parenteral administration such as intramuscular administration, subcutaneous administration, intravenous administration, or intra-arterial administration is generally preferred. Systemic or local administration may be used, although systemic administration is preferred. [Example]

[0037] The present invention will be described in more detail below with reference to examples, although the present invention is not limited to the following examples.

[0038] 1. Antitumor effect of CFI2101 in combination with immune checkpoint inhibitors in colon cancer cell-inoculated mice <Material> Tumor-bearing mice: Seven-week-old male BALB / c mice were used in groups of eight, and Colon26 mouse colon cancer cells were inoculated at 2 x 10 5 The cells were transplanted subcutaneously into the right flank of each mouse. antibody: Anti-mouse PD-L1 antibody (clone 10F.9G2) was purchased from BioXcell. Test compound: N-(4-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-3-yl)-3-(piperidin-1-yl)benzamide (amide derivative A) was synthesized by the method described in Example 62 of WO 2014 / 003124 A1. The hydrochloride salt of amide derivative A (hereinafter referred to as CFI2101) was used for administration to mice.

[0039] [ka]

[0040] <Methods and Results> In Colon26 tumor-bearing mice, CFI2101 was administered at doses of 0.02, 0.2, 2.0, and 20 mg / kg, and the efficacy and dose-response were investigated in combination with an anti-PD-L1 antibody (100 μg / mouse). Colon26 cells 2x10 5 Each tumor was subcutaneously implanted into the right flank of BALB / c mice, and an anti-PD-1 antibody was administered intraperitoneally (ip) on days 4, 8, and 12 after implantation. CFI2101 was suspended in 0.5% methylcellulose and administered orally (po) for 14 consecutive days starting on day 4 after implantation. The tumor volume of each mouse was measured over time starting on day 4 after implantation, and the tumor volume was calculated using the following formula. Tumor volume (mm 3 ) = (major diameter; mm) x (minor diameter; mm) 2 x 0.5236

[0041] Figure 1 shows the results of measuring tumor volume over time in individual mice starting on day 4 after tumor inoculation. Figure 2 also shows the results of comparing tumor volumes between treatment groups 19 days after tumor inoculation (significant difference vs. control group #: p<0.05 (Dunnett's); significant difference vs. anti-PD-L1 antibody group vs. anti-PD-1 antibody alone **: p<0.01 (Dunnett's)). CFI2101 alone did not exhibit significant inhibitory effects on solid tumors. However, the combination with anti-PD-L1 antibody demonstrated significant anti-tumor activity, with dose-responsiveness confirmed at 0.02, 0.2, and 2.0 mg / kg CFI2101. In particular, solid tumors were eliminated in 2 of 8 mice treated with CFI2101 at 2.0 mg / kg and anti-PD-L1. Some mice also exhibited elimination of solid tumors in the CFI2101 at 20 mg / kg and anti-PD-L1 combination group. These results confirmed that CFI2101 was dose-responsive in combination with an anti-PD-L1 antibody at 0.02 to 2 mg / kg, with the optimal dose being 2 mg / kg.

[0042] Next, to confirm the establishment of tumor immunity, three animals in which the Colon26 solid tumor had been eliminated and one animal in which the tumor had been partially suppressed were newly inoculated with 3x10 Colon26 tumor cells into the left flank. 5 The tumor volume in the right flank on day 33 after the first tumor transplantation, when the second tumor transplantation was performed, is shown in Table 1.

[0043] [Table 1]

[0044] The results of measuring tumor growth on the left and right sides are shown in Figure 3. In the three mice in which the tumors implanted in the right flank were rejected or almost completely suppressed, the tumor implanted on the left side did not grow into a solid tumor and was completely suppressed. On the other hand, in the mouse with a larger tumor on the right side, the growth of the tumor implanted on the left side was not suppressed and grew at the same rate as the tumor on the right side (CFI2101 2mg / αPD-L1 individual No. 6 in Figure 3). These results demonstrate that the combined administration of CFI2101 and anti-PD-L1 antibody establishes anti-tumor immunity that persists even after treatment has ended.

[0045] 2. Antitumor effect of CFI2101 in combination with immune checkpoint inhibitors in melanoma cell-inoculated mice <Material> Tumor-bearing mice: Seven-week-old female C57BL / 6 mice were used in groups of eight, and B16 mouse melanoma cells were inoculated at 5 x 10 5 The cells were transplanted subcutaneously into the right flank of each mouse. antibody: Anti-mouse PD-L1 antibody (clone 10F.9G2) was purchased from BioXcell. Test compound: The hydrochloride salt of amide derivative A (CFI2101) synthesized by the method described in Example 62 of WO 2014 / 003124 A1 was used.

[0046] <Methods and Results> The efficacy and dose-response of CFI2101 in combination with an anti-PD-L1 antibody (100 μg / mouse) was investigated in mice bearing B16 melanoma. 5 Each tumor was subcutaneously implanted into the right flank of C57BL / 6 mice, and an anti-PD-1 antibody was administered intraperitoneally on days 4, 8, and 12 after implantation. CFI2101 was suspended in 0.5% methylcellulose and administered orally for 13 consecutive days starting on day 4 after implantation. Starting on day 8 after implantation, the tumor volume of each mouse was measured over time, and the tumor volume was calculated using the following formula. Tumor volume (mm 3 ) = (major diameter; mm) x (minor diameter; mm) 2 x 0.5236

[0047] Figure 4 shows the results of measuring tumor volume over time in individual mice. Figure 5 shows the results of comparing tumor volumes between treatment groups 14 days after tumor inoculation (significant difference compared to the control group *: p<0.05 (Dunnett)). CFI2101 alone did not have an inhibitory effect in B16 tumor-bearing mice. The combination of CFI2101 and an anti-PD-L1 antibody did not result in tumor elimination, but did have an inhibitory effect on tumor growth. When combined with an anti-PD-L1 antibody, a dose-responsive response was observed at 0.4 and 2 mg / kg, with 2 mg / kg being the optimal dose.

[0048] 3. Antitumor effects of CFI2101 in combination with immune checkpoint inhibitors in lung cancer cell-inoculated mice <Material> Tumor-bearing mice: Seven-week-old female C57BL / 6 mice were used in groups of eight, and mouse Lewis lung carcinoma (LLC) cells were inoculated at 5 x 10 5 The cells were transplanted subcutaneously into the right flank of each mouse. antibody: Anti-mouse PD-L1 antibody (clone 10F.9G2) was purchased from BioXcell. Test compound: The hydrochloride salt of amide derivative A (CFI2101) synthesized by the method described in Example 62 of WO 2014 / 003124 A1 was used.

[0049] <Methods and Results> In LLC tumor-bearing mice, the efficacy and dose-response of CFI2101 in combination with an anti-PD-L1 antibody (100 μg / mouse) were investigated at doses of 0.02, 0.2, and 2.0 mg / kg. LLC tumor-bearing mice were treated with 5x10 LLC cells. 5 Each tumor was subcutaneously implanted into the right flank of a C57BL / 6 mouse, and an anti-PD-1 antibody was administered intraperitoneally on days 4 and 8 after implantation. CFI2101 was suspended in 0.5% methylcellulose and administered orally for 8 consecutive days starting on day 4 after implantation. The tumor volume of each mouse was measured over time starting on day 8 after implantation, and tumor volume was calculated using the following formula. Tumor volume (mm 3) = (major diameter; mm) x (minor diameter; mm) 2 x 0.5236

[0050] Figure 6 shows the results of measuring tumor volume over time in individual mice. Figure 7 shows the results of comparing tumor volumes between treatment groups 14 days after tumor inoculation (significant difference compared to the control group: * p<0.05, ** p<0.01 (Dunnett's). Significant difference between the CFI2101 + anti-PD-L1 antibody combination group and the anti-PD-L1 antibody alone group: # p<0.05, ## p<0.01 (Dunnett's)). CFI2101 alone significantly inhibited LLC solid tumor growth at 0.2 mg / kg, but not at 2 mg / kg. When combined with an anti-PD-L1 antibody, significant anti-tumor activity was observed at three doses: 0.02, 0.2, and 2 mg / kg. Significant combined effects were also observed at 0.02 and 2 mg / kg compared to the anti-PD-L1 antibody alone group. In particular, at a dose of 2 mg / kg, in combination with an anti-PD-L1 antibody, solid tumors completely regressed in one of eight cases, and almost completely regressed in three cases.

[0051] 4. Comparison of the antitumor effects of CFI2101 and Galunisertib Galunisertib is a drug with antifibrotic properties, but it has also been developed as an antitumor agent, and the results of its pharmacological efficacy tests and clinical trials have already been reported. In this example, a comparative study of the antitumor effects of CFI2101 and Galunisertib was conducted using a Colon26 tumor-bearing mouse model.

[0052] [ka]

[0053] In Colon26 tumor-bearing mice, CFI2101 was administered orally at a dose of 2 mg / kg once daily, and Galunisertib (MidChemExpress) was administered orally at two doses of 2 and 75 mg twice daily (4 and 150 mg / kg / day). 5The tumors were implanted subcutaneously into the right flank of BALB / c mice, and anti-PD-L1 antibodies were administered intraperitoneally at 100 μg / mouse on days 4, 8, and 12 after implantation. CFI2101 was administered orally for 14 consecutive days starting on day 4 of implantation. Galunisertib was administered orally for 15 days starting on day 4 of implantation. Tumor volume was measured over time in each mouse starting on day 5 of implantation. Tumor volumes 19 days after implantation were also shown and compared between treatment groups.

[0054] Figure 8 shows a comparison of tumor volume between treatment groups 19 days after tumor inoculation (significant difference compared to the control group: * p<0.05, ** p<0.01 (Dunnett's)). Galunisertib was administered at two doses: 2 mg / kg and 75 mg / kg (daily doses: 4 mg / kg and 150 mg / kg). At 2 mg / kg, galunisertib was less effective than the same dose of CFI2101, both alone and in combination with an anti-PD-L1 antibody. 75 mg / kg (150 mg / kg / day) is the reportedly effective dose for galunisertib, and this dose produced the same antitumor effect as CFI2101 2 mg / kg.

[0055] Galunisertib is being developed as an antitumor agent, and clinical trials are underway in combination with an anti-PD-1 antibody as well as a single agent (Non-Patent Document 7). Considering the effective dose, CFI2101 is thought to be more effective than Galunisertib.

Claims

1. An anticancer agent comprising, as an active ingredient, a compound which is N-(4-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-3-yl)-3-(piperidin-1-yl)benzamide, a pharmaceutically acceptable salt thereof, or a solvate of said compound or said salt, said anticancer agent being used in combination with at least one immune checkpoint control agent.

2. 2. The anticancer agent according to claim 1, wherein the dosage of the anticancer agent is 0.1 mg / kg to 10 mg / kg of body weight per day in terms of the amount of the active ingredient.

3. The anticancer drug according to claim 1, wherein the anticancer drug is an oral agent.

4. The anticancer agent according to any one of claims 1 to 3, wherein the immune checkpoint control agent is at least one immune checkpoint inhibitor selected from an antagonistic anti-PD-1 antibody, an anti-PD-L1 antibody, an anti-PD-L2 antibody, an antagonistic anti-LAG-3 antibody, an antagonistic anti-TIM-3 antibody, and an antagonistic anti-CTLA-4 antibody.

5. The anticancer agent according to claim 4, wherein the immune checkpoint control agent is at least one selected from the group consisting of an antagonistic anti-PD-1 antibody, an anti-PD-L1 antibody, and an anti-PD-L2 antibody.

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