Combination therapy of IOA-244, PD-1 or PD-L1 inhibitors, and chemotherapy agents for cancer treatment.

Abstract

A compound of formula (I) or a pharmaceutically acceptable salt thereof for use in the treatment of cancer in a subject, wherein the treatment comprises administering to the subject separately, sequentially, or simultaneously: i) a pharmaceutically acceptable salt thereof of compound 1 or thereof, ii) a PD-1 or PD-L1 inhibitor or a pharmaceutically acceptable salt thereof, and iii) a chemotherapeutic agent or a pharmaceutically acceptable salt thereof. [Formula 1] JPEG2026521174000025.jpg73164

Description

[Technical Field]

[0001] This disclosure relates to a method for treating solid tumors and hematological malignancies that are refractory or recurrent after checkpoint blocker therapy. [Background technology]

[0002] Checkpoint blockers are a leading form of immunotherapy that has revolutionized the field of cancer treatment.

[0003] The immune system has built-in checkpoints, which are regulatory mechanisms that prevent the overactivation of immune cells and maintain self-tolerance. Cancer cells can use these checkpoints to evade immune detection and attack. Checkpoint inhibitors are designed to block these suppressive signals and restore the immune system's ability to recognize and eliminate cancer cells. The most widely studied and utilized checkpoint inhibitors target two major immune checkpoint proteins: cytotoxic T lymphocyte antigen (CTLA-4) and programmed cell death protein (PD-1), as well as their ligand, programmed cell death ligand (PD-L1). When these checkpoint proteins bind to their respective ligands, they transmit suppressive signals that inhibit the immune response against cancer cells.

[0004] Checkpoint inhibitor therapy works by blocking the interaction between checkpoint proteins and their ligands, thus liberating the immune system and initiating a powerful attack against cancer cells. In doing so, these therapies can enhance the body's innate ability to recognize and destroy cancer cells.

[0005] There are several checkpoint inhibitors approved for the treatment of various cancers. Some examples include: 1. Ipilimumab: A monoclonal antibody targeting CTLA-4, and the first checkpoint inhibitor approved by the FDA. It is primarily used to treat advanced melanoma. 2. Pembrolizumab and nivolumab: These drugs target PD-1 and are approved for the treatment of a variety of cancers, including melanoma, non-small cell lung cancer, renal cell carcinoma, bladder cancer, and Hodgkin lymphoma. 3. Atezolizumab, durvalumab, and avelumab: These drugs target PD-L1 and are approved for the treatment of certain cancers, including non-small cell lung cancer, bladder cancer, and Merkel cell carcinoma.

[0006] Checkpoint inhibitors, both as monotherapy and / or in combination with chemotherapy, have shown remarkable success in some patients, leading to longer response rates and improved survival in various cancers. However, not all patients respond to these treatments, and most importantly, some types of tumors do not respond at all to immunotherapy. Resistance to checkpoint inhibitors can arise through multiple mechanisms, including: 1. Absence of tumor-infiltrating lymphocytes (TILs): Checkpoint inhibitors rely on the presence of TILs, which are immune cells that recognize and attack cancer cells. Some tumors have a low number of TILs or lack specific TILs necessary to initiate an effective immune response, which leads to resistance. 2. Upregulation of surrogate immune checkpoints: Tumors can upregulate surrogate immune checkpoint molecules such as TIM-3, LAG-3, and VISTA, which may counteract the effects of checkpoint inhibitors. These surrogate checkpoints provide additional suppressive signals to immune cells, thereby suppressing the immune response. 3. Loss of antigen presentation: Cancer cells may downregulate major histocompatibility complex (MHC) molecules or components of the antigen presentation mechanism, making it difficult for immune cells to recognize and attack the tumor. Without effective antigen presentation, the effectiveness of checkpoint inhibitors may be reduced. 4. Tumor Microenvironment Factors: The tumor microenvironment can create an immunosuppressive environment that hinders the effectiveness of checkpoint inhibitors. Tumor-associated fibroblasts, regulatory T cells, myeloid-derived suppressor cells, and cytokines, such as transforming growth factor-beta (TGF-β), can contribute to immunosuppression and resistance. 5. Genetic changes: Genetic changes within tumors can lead to resistance. For example, mutations in the JAK1 / JAK2 or beta-2-microglobulin (B2M) genes may impair the interferon signaling pathway essential for checkpoint inhibitor activity.

[0007] Overcoming resistance to checkpoint inhibitors is an active area of ​​research. Several strategies being considered include combination therapies with other immunotherapies, targeted therapies, chemotherapy, and radiotherapy.

[0008] This invention was devised in light of the above considerations. [Overview of the Initiative]

[0009] The present invention relates to a novel treatment for cancer. In some embodiments, a method for treating cancer in a subject requiring cancer treatment, wherein the subject is given a first amount of formula I: [ka] A method is disclosed comprising administering a compound (compound 1) or a pharmaceutically acceptable salt thereof, a second amount of a PD1 or PD-L1 inhibitor or a pharmaceutically acceptable salt thereof, and a third amount of a chemotherapeutic agent or a pharmaceutically acceptable salt thereof, wherein the first, second, and third amounts together constitute a therapeutically effective dose.

[0010] In some embodiments, a pharmaceutically acceptable salt of compound 1 or a pharmaceutically acceptable salt thereof is provided for use in the treatment of cancer in a subject, wherein the treatment comprises administering to the subject separately, sequentially, or simultaneously, i) compound 1 or a pharmaceutically acceptable salt thereof, ii) a PD-1 or PD-L1 inhibitor or a pharmaceutically acceptable salt thereof, and iii) a chemotherapeutic agent or a pharmaceutically acceptable salt thereof.

[0011] In some embodiments, a PD-1 or PD-L1 inhibitor or a pharmaceutically acceptable salt thereof is provided for use in the treatment of cancer in a subject, wherein the treatment comprises administering to the subject separately, sequentially, or simultaneously, i) the PD-1 or PD-L1 inhibitor or a pharmaceutically acceptable salt thereof, ii) compound 1 or a pharmaceutically acceptable salt thereof, and iii) a chemotherapeutic agent or a pharmaceutically acceptable salt thereof.

[0012] In some embodiments, there are provided uses of compound 1 or a pharmaceutically acceptable salt thereof in the manufacture of a drug for use in the treatment of cancer, wherein the treatment comprises administering to a subject separately, sequentially, or simultaneously: i) the drug comprising compound 1 or a pharmaceutically acceptable salt thereof, ii) a PD-1 or PD-L1 inhibitor or a pharmaceutically acceptable salt thereof, and iii) a chemotherapeutic agent or a pharmaceutically acceptable salt thereof.

[0013] In some of the embodiments described above, the PD-1 or PD-L1 inhibitor is a PD-1 inhibitor.

[0014] In addition to the embodiments described above, the PD-1 or PD-L1 inhibitor is a PD-L1 inhibitor.

[0015] In some of the embodiments described above, only a single chemotherapeutic agent is present, i.e., no further chemotherapeutic agents are present. Therefore, treatment may consist of administering i) the compound 1 or a pharmaceutically acceptable salt thereof, ii) a PD-1 or PD-L1 inhibitor or a pharmaceutically acceptable salt thereof, and iii) the single chemotherapeutic agent or a pharmaceutically acceptable salt thereof separately, sequentially, or simultaneously.

[0016] In the embodiments described above, cancer can be breast cancer, bladder cancer, cervical cancer, colon cancer, head and neck cancer, hematological cancer, liver cancer, lung cancer, kidney cancer, skin cancer including melanoma, uveal melanoma, gastric cancer, rectal cancer, mesothelioma, endometrial cancer, small intestine cancer, biliary tract cancer, ovarian cancer, brain cancer, testicular cancer, pancreatic cancer, bone cancer, and any solid tumor that cannot repair errors in its DNA that occur when it is copied.

[0017] In the embodiments described above, cancer may be breast cancer, bladder cancer, cervical cancer, colon cancer, head and neck cancer, hematological cancer, liver cancer, lung cancer, kidney cancer, skin cancer including melanoma, uveal melanoma, gastric cancer, rectal cancer, mesothelioma, endometrial cancer, small intestine cancer, biliary tract cancer, ovarian cancer, brain cancer, testicular cancer, pancreatic cancer, or bone cancer.

[0018] In the embodiments described above, the cancer may be a malignant tumor that is refractory to treatment with a checkpoint inhibitor administered in combination with another chemotherapeutic agent at the discretion of the party, or that recurs after such treatment.

[0019] In the embodiments described above, the subjects may have previously been treated with chemotherapy agents and / or PD-1 or PD-L1 inhibitors, and the cancer is refractory or resistant to these treatments. In some embodiments, the subjects may have previously been treated with chemotherapy agents and / or PD-1 or PD-L1 inhibitors and have not responded to treatment or are resistant to treatment. In some embodiments, the subjects are patients with malignancies that are refractory to checkpoint inhibitors plus chemotherapy or that recur after checkpoint inhibitors plus chemotherapy.

[0020] In some embodiments, a pharmaceutical product is disclosed comprising i) compound 1 or a pharmaceutically acceptable salt thereof, ii) a PD-1 or PD-L1 inhibitor or a pharmaceutically acceptable salt thereof, and iii) a chemotherapeutic agent or a pharmaceutically acceptable salt thereof.

[0021] In some embodiments, a kit is disclosed comprising a first pharmaceutical composition comprising compound 1 or a pharmaceutically acceptable salt thereof, a second pharmaceutical composition comprising a PD-1 or PD-L1 inhibitor or a pharmaceutically acceptable salt thereof, a third pharmaceutical composition comprising a chemotherapeutic agent or a pharmaceutically acceptable salt thereof, and instructions for using the first and second pharmaceutical compositions in combination.

[0022] Inhibition of PI3Kδ via treatment with compound 1 reconstitutes the tumor's immunosuppressive microenvironment, increasing the antitumor immune response and responsiveness to combination therapy with checkpoint inhibitors and chemotherapy. This helps to meet a high unmet clinical need in the field of immunotherapy.

[0023] Surprisingly, the combination of compound 1 with checkpoint inhibitors and chemotherapy has been found to have a synergistic effect in enhancing the antitumor immune response and cytotoxicity against tumor cells. Therefore, improved antitumor activity may be achieved in combination therapy. Surprisingly, these synergistic effects are already present at sub-therapeutic doses. Therefore, improved tolerability of combination therapy may be achieved.

[0024] Furthermore, remarkably, the synergistic antitumor activity of compound 1 in combination with checkpoint inhibitors and chemotherapy has been found to be not limited to specific malignancies. Therefore, it is possible to provide combination therapies with improved cross-reactivity against multiple malignancies.

[0025] Furthermore, remarkably, the combination of compound 1 with a checkpoint inhibitor and chemotherapy leads to the killing of tumor cells, which is not observed with any of the inhibitors alone. Therefore, a tripartite combination therapy that can reduce tumor burden can be provided.

[0026] Furthermore, surprisingly, the combination of compound 1 with checkpoint inhibitors and chemotherapy has been found to treat patients with malignancies that are refractory to treatment with checkpoint inhibitors plus other chemotherapy agents, or that recur after treatment with checkpoint inhibitors plus other chemotherapy agents.

[0027] Therefore, the present invention is an improved method for treating cancer.

[0028] The present invention includes combinations of the described embodiments and preferred features, except where such combinations are clearly unacceptable or expressly avoided.

[0029] The embodiments and experiments illustrating the principle of the present invention will be described below with reference to the attached drawings. [Brief explanation of the drawing]

[0030] [Figure 1] This shows the immunophenotypic changes driven by the combined use of compound 1 with immunotherapy and chemotherapy in mesothelioma. [Figure 2] This shows the immunophenotypic changes driven by the combined use of compound 1 with immunotherapy and chemotherapy in NSCLC patients. [Modes for carrying out the invention]

[0031] The embodiments and aspects of the present invention will be described below with reference to the accompanying drawings. Further embodiments and aspects will be apparent to those skilled in the art. All documents referenced herein are incorporated herein by reference.

[0032] Compound 1 is Example 339 of WO2011 / 058149, which is incorporated herein by reference in its entirety. Its structure is given by Formula I. [ka]

[0033] In IUPAC nomenclature, compound 1 above may be called 6-fluoro-3-(morpholine-4-ylcarbonyl)-1-[4-(morpholine-4-ylmethyl)phenyl]-1,4-dihydrothiochromeno[4,3-c]pyrazole 5,5-dioxide. Alternatively, the above structural formula may be written as [6-fluoro-1-(4-morpholine-4-ylmethylphenyl)-5,5-dioxo-4,5-dihydro-1H-5λ6-thiochromeno[4,3-C]pyrazole-3-yl]morpholine-4-ylmethanone.

[0034] Compound 1 can be prepared and characterized as described in published patent application WO 2011 / 058149 A1 (see Compound 339 on page 69, Preparation on pages 303-307, and Characterization on pages 481 and 414-418). This information is incorporated herein by reference.

[0035] Based on the process disclosed in WO2011 / 058149A1, the author Haselmayer, 2014, describes a five-step procedure for the preparation of the compound. This procedure begins with the reaction of 8-fluoro-2,3-dihydro-4Hthiochromen-4-one with diethyl oxalate in the presence of sodium ethoxide. The intermediate is cyclized with 4-(4-hydrazinylbenzyl)morpholine to form a pyrazole ring. The thioether is then oxidized to the corresponding sulfone by reaction with meta-chloroperbenzoic acid, followed by saponification of the ethyl ester to the corresponding acid, and then coupling with morpholine to obtain the compound of formula I.

[0036] Alternatively, the intermediate of the reaction between 8-fluoro-2,3-dihydro-4H-thiochromen-4-one and diethyl oxalate in the presence of sodium ethoxide is cyclized with 4-hydrazinobenzoic acid. This benzoic acid is reduced using a borane-THF complex, and the resulting thioether is oxidized to the corresponding sulfone by reaction with meta-chloroperbenzoic acid. The ethyl ester is saponified to the corresponding acid, and both the acid and alcohol are chlorinated with excess thionyl chloride in the presence of dimethylformamide, followed by coupling with morpholine to obtain compound 1.

[0037] Compound 1 may be provided as a pharmaceutically acceptable salt. Suitable pharmaceutically acceptable salts are known in the art. Several pharmaceutically acceptable salts of Compound 1 are described in WO2014 / 121901, which is incorporated as a whole by reference.

[0038] When used herein, compound 1 is provided as hemi-fumarate anhydride (formula shown). Its synthesis and characterization are described in WO2014 / 121901 (page 4). This is referred to as solid form A1. Hemi-fumarate hydrate (H1) has also been identified. The hemi-fumarate anhydride used is crystalline and has the powder X-ray peak list described in WO2014 / 121901. The discoveries of the present invention are not limited to the use of this solid form, but it will be understood that it is preferred.

[0039] Therefore, in some cases, compound 1 is administered as hemi-fumarate (formula Ia). However, it should be understood that the present invention is not limited thereto, and other solid forms (e.g., other pharmaceutically acceptable salts) are also conceivable. [ka]

[0040] Haselmayer 2014 also describes the characterization of the compound as a highly selective PI3Kδ inhibitor. Johnson 2023 describes the use of the compound in the treatment of solid tumor cell lines and refers to ongoing clinical trials.

[0041] Compound 1 can be used to treat cancer.

[0042] PD-1 and PD-L1 inhibitors PD-1 inhibitors and PD-L1 inhibitors are a group of checkpoint inhibitor anticancer drugs that block the activity of PD-1 and PD-L1 immune checkpoint proteins present on the surface of cells. Immune checkpoint inhibitors have emerged as treatments for several types of cancer.

[0043] PD-1 and PD-L1 inhibitors work by inhibiting the association between programmed cell death ligand 1 (PD-L1) and its receptor, programmed cell death protein 1 (PD-1). The interaction of these cell surface proteins is involved in the suppression of the immune system, which occurs post-infection and limits the killing of bystander host cells, thereby preventing autoimmune diseases.

[0044] Immune checkpoint inhibitors can be used to treat a wide variety of cancers, including breast cancer, bladder cancer, cervical cancer, colon cancer, head and neck cancer, Hodgkin lymphoma, liver cancer, lung cancer, renal cell carcinoma, skin cancers including melanoma, uveal melanoma, gastric cancer, rectal cancer, and any solid tumors that cannot repair the errors in their DNA that occur when they are copied.

[0045] Approved checkpoint inhibitors that block PD-1 include nivolumab (Opdivo), pembrolizumab (Keytruda), semiprimab (Libtayo), dostallimab (Jemperli), retifanlimab (Zynyz), and tripalimab (Loqtorzi). Approved checkpoint inhibitors that block PD-L1 include atezolizumab (Tecentriq), avelumab (Bavencio), and durvalumab (Imfinzi).

[0046] In some embodiments, the PD-1 or PD-L1 inhibitor is a PD-1 inhibitor.

[0047] In some embodiments, the PD-1 inhibitor is an antibody, such as a monoclonal antibody.

[0048] In some embodiments, the PD-1 or PD-L1 inhibitor is a PD-L1 inhibitor.

[0049] In some embodiments, the PDL-1 inhibitor is an antibody, such as a monoclonal antibody.

[0050] In some embodiments, the PDL-1 inhibitor is a peptide or a macrocycle.

[0051] In some embodiments, the PD-1 or PD-L1 inhibitor is selected from nivolumab, pembrolizumab, semiprimab, dostallimab, retifanlimab, tripalimab, atezolizumab, avelumab, and durvalumab.

[0052] In some embodiments, the PD-1 or PD-L1 inhibitor is selected from nivolumab, pembrolizumab, atezolizumab, avelumab, durvalumab, and semiprimab.

[0053] In some embodiments, the PD-1 inhibitor is nivolumab. Nivolumab (marketed under the name Opdivo) is a PD-1 inhibitor used to treat a variety of cancers, including advanced melanoma, melanoma, non-small cell lung cancer, malignant pleural mesothelioma, renal cell carcinoma, classical Hodgkin lymphoma, adult head and neck cancer, advanced urothelial carcinoma (bladder and urinary tract cancer), urothelial carcinoma, advanced colorectal cancer (colon or rectal cancer), advanced esophageal (gullet) cancer, esophageal (oesophageal or gullet) cancer or gastroesophageal junction cancer, advanced gastric cancer, gastroesophageal junction or esophageal adenocarcinoma (gastric or esophageal cancer).

[0054] Nivolumab is a monoclonal antibody, a type of protein designed to recognize and bind to specific target substances in the body. Nivolumab binds to a target protein called programmed death-1 receptor (PD-1), which can turn off the activity of T cells. By binding to PD-1, nivolumab blocks its action, preventing PD-1 from turning off T cells. This helps increase the activity of melanoma, lung cancer, kidney cancer, lymphoma, head and neck cancer, bladder cancer, colon cancer, rectal cancer, gastric cancer, esophageal cancer, or gastroesophageal junction cancer cells. Nivolumab can be used in combination with other anticancer drugs and radiation therapy.

[0055] In some embodiments, the PD-1 inhibitor is pembrolizumab. Pembrolizumab (also marketed as Keytruda) is a PD-1 inhibitor used to treat a variety of cancers, including melanoma, non-small cell lung cancer, classical Hodgkin lymphoma, bladder cancer (urothelial carcinoma), head and neck squamous cell carcinoma, renal cell carcinoma, colorectal cancer, uterus (endometrial cancer), stomach (gastric cancer), small intestine (small intestinal cancer), or bile duct or gallbladder (biliary tract cancer), esophageal cancer, triple-negative breast cancer, endometrial cancer, and cervical cancer.

[0056] Pembrolizumab is a humanized monoclonal antibody that binds to the programmed cell death-1 (PD-1) receptor and blocks its interaction with ligands PD-L1 and PD-L2. Pembrolizumab enhances T cell responses, including antitumor responses, by blocking PD-1 binding to PD-L1 and PD-L2, which are expressed on antigen-presenting cells and may be expressed by tumors or other cells within the tumor microenvironment. Pembrolizumab can be used in combination with other anticancer drugs and radiotherapy.

[0057] In some embodiments, the PD-1 inhibitor is cemiprimab (marketed under the name Libtayo). Cemiprimab is a monoclonal antibody used to treat cutaneous squamous cell carcinoma, basal cell carcinoma, lung cancer, or cervical cancer.

[0058] In some embodiments, the PD-1 inhibitor is dostallimab. Dostallimab (marketed under the name Jemperli) is a PD-1 inhibitor used to treat endometrial cancer. Dostallimab is used in particular for the treatment of adults with mismatch repair deficiency (dMMR) recurrent or advanced endometrial cancer. Dostallimab is described in US9815897 and US10738117, and its use, including dosage, is described in US11407830.

[0059] In some embodiments, the PD-1 inhibitor is retifan limab. Retifan limab (marketed under the name Zynyz and also known as INCMGA00012) is a PD-1 inhibitor used to treat Merkel cell carcinoma. Retifan limab is a humanized IgG4 monoclonal antibody developed by Incyte and MacroGenics.

[0060] In some embodiments, the PD-1 inhibitor is tripalimab. Tripalimab (marketed under the name Loqtorzi and also known as JS001) is a PD-1 inhibitor used to treat metastatic or recurrent locally advanced nasopharyngeal cancer. Tripalimab is a humanized IgG4 monoclonal antibody against PD-1.

[0061] Currently, many other PD-1 inhibitors are under development, including the following: Voplaterimab (JTX-4014) by Jounce Therapeutics entered Phase I trials as of 2020. Spartalizumab (PDR001) is a PD-1 inhibitor developed by Novartis to treat both solid tumors and lymphomas, and as of 2018, it was in Phase III trials. Camrelizumab (SHR1210) is an anti-PD-1 monoclonal antibody introduced by Jiangsu HengRui Medicine Co., Ltd.; it was recently conditionally approved in China for the treatment of relapsed or refractory classical Hodgkin lymphoma; Scintilimab (IBI308) is a human anti-PD-1 antibody developed by Innovent and Eli Lilly for patients with non-small cell lung cancer (NSCLC). Tislerizumab (BGB-A317) is a humanized IgG4 anti-PD-1 monoclonal antibody currently undergoing pivotal Phase 3 and Phase 2 clinical trials in solid tumors and hematological malignancies; Pizilizumab (CT-011) by Medication; Cetrelimab (JNJ-63723283) by Johnson and Johnson; Cellulimab (HLX10) by Shanghai Henlius Biotech; Sasanlimab (PF-06801591) by Pfizer; Zimberelimab (GLS-010) by Arcus Biosciences, Gloria Pharmaceuticals, and WuXi Biologics Penprimab (ANNIKO) by Akeso Biopharma / SinoBiopharm; Innovent Biologics' scintillimab (IBI308); Geptanolimab (APL-501, GB226) by Genor BioPharma / Apolomics AMP-110 by AstraZeneca; AMP-224 by AstraZeneca / MedImmune and GlaxoSmithKline; AMP-514 (MEDI0680) by AstraZeneca; Acryxolimab (YBL-006) by Y-Biologics.

[0062] In some embodiments, the PD-L1 inhibitor is atezolizumab (Tecentriq). Atezolizumab is a monoclonal antibody drug used to treat urothelial carcinoma, lung cancer, breast cancer, or hepatocellular carcinoma. It is a fully humanized, engineered monoclonal antibody against PD-L1 using the IgG1 isotype.

[0063] In some embodiments, the PD-L1 inhibitor is avelumab (Bavencio). Avelumab is a fully human monoclonal antibody drug used to treat Merkel cell carcinoma, urothelial carcinoma, and renal cell carcinoma.

[0064] In some embodiments, the PD-L1 inhibitor is durvalumab (Imfinzi). Durvalumab is a human immunoglobulin G1 kappa (IgG1κ) monoclonal antibody that blocks the interaction of programmed cell death ligand 1 (PD-L1) and is an approved immunotherapy for the treatment of cancer. Durvalumab is used to treat lung cancer, bladder cancer, or biliary tract cancer.

[0065] Currently, many other PDL-1 inhibitors are under development, including the following: Alphamab, 3DMed emvafolimab (KN035); Sugemalimab (Cejemly, CS1001) by CStone Pharmaceuticals; BAT-1306 by BioThera Solutions; Kosiberimab (CK-301) by Dana Farber; AUNP12 (29-mer peptide) by Aurigene and Laboratoires Pierre Fabre; CA-170 (PD-L1 and VISTA SMI antagonist) by Aurigene / Curis; and BMS-986189 (macrocyclic peptide) by Bristol-Myers Squibb.

[0066] Some of these are documented in Guzik 2019.

[0067] Chemotherapy agents Chemotherapy agents can be selected from those currently considered standard treatments for certain types of cancer.

[0068] Various types of chemotherapeutic agents exist, including DNA damaging agents, folate antagonists, alkylating agents, nitrosourea, plant alkaloids and natural products, antitumor antibiotics, hormones, or biological response modifiers. In some embodiments, the chemotherapeutic agent is a DNA damaging agent.

[0069] In some embodiments, the chemotherapeutic agent may be selected from carboplatin, gemcitabine, cisplatin, docetaxel, doxorubicin, mitoxantrone, 5-fluorouracil (5-FU), capecitabine, irinotecan, oxaliplatin, pemetrexed, trifluridine, and tipiracil.

[0070] In some embodiments, the chemotherapeutic agent may be selected from carboplatin, gemcitabine, cisplatin, doxorubicin, mitoxantrone, 5-fluorouracil (5-FU), capecitabine, irinotecan, oxaliplatin, pemetrexed, trifluridine, and tipiracil.

[0071] In some embodiments, the chemotherapeutic agent is carboplatin. Carboplatin is also marketed under the brand name Paraplatin, among others. It is used to treat numerous forms of cancer, including ovarian cancer, lung cancer, head and neck cancer, brain cancer, and neuroblastoma. It can be used for several types of testicular cancer. It is also used to treat triple-negative breast cancer. Carboplatin is particularly used to treat several types of lung and ovarian cancer. Carboplatin can be used in combination with other anticancer drugs and radiotherapy. Carboplatin belongs to the alkylating agent class of cytotoxic drugs. Carboplatin has the following structure: [ka]

[0072] In some embodiments, the chemotherapeutic agent is gemcitabine. Gemcitabine is marketed, among other names, Gemzar. It is used to treat cancers including testicular cancer, breast cancer, ovarian cancer, non-small cell lung cancer, pancreatic cancer, and bladder cancer. It is administered by intravenous infusion. It acts against neoplastic growth and inhibits the replication of orthohepey virus A, the causative agent of hepatitis E, through upregulation of interferon signaling. Gemcitabine has the following structure: [ka]

[0073] Gemcitabine can be used in combination with other anticancer drugs and radiotherapy. Gemcitabine can be used as monotherapy or in combination with cisplatin to treat a variety of cancers, including bladder cancer and non-small cell lung cancer. Gemcitabine can be used as monotherapy or in combination with carboplatin to treat ovarian cancer. Gemcitabine can be used as monotherapy or in combination with paclitaxel to treat breast cancer. Gemcitabine is also approved as monotherapy for the treatment of pancreatic adenocarcinoma. Gemcitabine is an antimetabolite.

[0074] In some embodiments, the chemotherapeutic agent is cisplatin. Cisplatin is used to treat a number of cancers, including testicular cancer, ovarian cancer, cervical cancer, bladder cancer, head and neck cancer, lung cancer, and brain tumors. Cisplatin is indicated for the treatment of cervical cancer in combination with other chemotherapeutic agents or radiotherapy. Cisplatin can be used in combination with other anticancer drugs and radiotherapy. Cisplatin is administered by intravenous infusion. Cisplatin belongs to the alkylating agent class of cytotoxic drugs. Cisplatin has the following structure: [ka]

[0075] In some embodiments, the chemotherapeutic agent is pemetrexed. Pemetrexed is marketed, in particular, under the name Alimta. Pemetrexed is used to treat a number of cancers, including mesothelioma and lung cancer. Pemetrexed is indicated for the treatment of mesothelioma and non-small cell lung cancer in combination with cisplatin. Pemetrexed is also recommended as a first-line treatment for advanced non-small cell lung cancer in combination with carboplatin and pembrolizumab. Pemetrexed is administered by intravenous infusion. Pemetrexed is a folate antagonist. Pemetrexed has the following structure: [ka]

[0076] In some embodiments, the chemotherapeutic agent is docetaxel. Docetaxel is marketed under the name Taxotere, among others. Docetaxel is used to treat a number of cancers, including breast cancer, head and neck cancer, gastric cancer, prostate cancer, and lung cancer. Docetaxel is indicated for the treatment of breast cancer in combination with doxorubicin, trastuzumab, or capecitabine. Docetaxel is also recommended in combination with cisplatin as a first-line treatment for advanced non-small cell lung cancer. Docetaxel is also recommended in combination with cisplatin and 5-fluorouracil (5-FU) for the treatment of gastric cancer. Docetaxel is administered by intravenous infusion. Docetaxel is a taxane. Docetaxel has the following structure: [ka]

[0077] In some embodiments, the chemotherapeutic agent is selected from carboplatin, gemcitabine, doxorubicin, docetaxel, mitoxantrone, 5-fluorouracil (5-FU), capecitabine, irinotecan, oxaliplatin, trifluridine, and tipiracil.

[0078] In some embodiments, the chemotherapeutic agent is selected from carboplatin, gemcitabine, doxorubicin, mitoxantrone, 5-fluorouracil (5-FU), capecitabine, irinotecan, oxaliplatin, trifluridine, and tipiracil.

[0079] In some embodiments, compound 1 is administered in combination with a PD-1 or PD-L1 inhibitor selected from nivolumab, pembrolizumab, atezolizumab, durvalumab, and semiprimab, as well as a chemotherapeutic agent selected from carboplatin, gemcitabine, doxorubicin, docetaxel, mitoxantrone, 5-fluorouracil (5-FU), capecitabine, irinotecan, oxaliplatin, trifluridine, and tipiracil.

[0080] In some embodiments, compound 1 is administered in combination with a PD-1 or PD-L1 inhibitor selected from nivolumab, pembrolizumab, atezolizumab, durvalumab, and semiprimab, as well as a chemotherapeutic agent selected from carboplatin, gemcitabine, doxorubicin, mitoxantrone, 5-fluorouracil (5-FU), capecitabine, irinotecan, oxaliplatin, trifluridine, and tipiracil.

[0081] In some embodiments, the present invention relates to a method for treating cancer, comprising administering to a subject a first amount of a compound of Formula 1, a second amount of a PD-1 or PD-L1 inhibitor selected from nivolumab, pembrolizumab, atezolizumab, durvalumab, and semiprimab, and a third amount of a chemotherapeutic agent selected from carboplatin, gemcitabine, doxorubicin, docetaxel, mitoxantrone, 5-fluorouracil (5-FU), capecitabine, irinotecan, oxaliplatin, trifluridine, and tipiracil.

[0082] In some embodiments, the present invention relates to a method for treating cancer, comprising administering to a subject a first amount of a compound of Formula 1, a second amount of a PD-1 or PD-L1 inhibitor selected from nivolumab, pembrolizumab, atezolizumab, durvalumab, and semiprimab, and a third amount of a chemotherapeutic agent selected from carboplatin, gemcitabine, doxorubicin, mitoxantrone, 5-fluorouracil (5-FU), capecitabine, irinotecan, oxaliplatin, trifluridine, and tipiracil.

[0083] In some embodiments, the present invention relates to a method for treating cancer, comprising administering to a subject a first amount of a compound of formula 1, a second amount of a PD-1 inhibitor, and a third amount of a chemotherapeutic agent selected from carboplatin, gemcitabine, doxorubicin, docetaxel, mitoxantrone, 5-fluorouracil (5-FU), capecitabine, irinotecan, oxaliplatin, trifluridine, and tipiracil.

[0084] In some embodiments, the present invention relates to a method for treating cancer, comprising administering to a subject a first amount of a compound of formula 1, a second amount of a PD-1 inhibitor, and a third amount of a chemotherapeutic agent selected from carboplatin, gemcitabine, doxorubicin, mitoxantrone, 5-fluorouracil (5-FU), capecitabine, irinotecan, oxaliplatin, trifluridine, and tipiracil.

[0085] In some embodiments, compound 1 is administered in combination with nivolumab and carboplatin. In some embodiments, compound 1 is administered in combination with nivolumab and cisplatin. In some embodiments, compound 1 is administered in combination with nivolumab and gemcitabine. In some embodiments, compound 1 is administered in combination with atezolizumab and docetaxel. In some embodiments, compound 1 is administered in combination with pembrolizumab and docetaxel.

[0086] In some embodiments, the present invention relates to a method for treating cancer, comprising administering to a subject a first amount of a compound of formula 1, a second amount of nivolumab, and a third amount of carboplatin.

[0087] In some embodiments, the present invention relates to a method for treating cancer, comprising administering to a subject a first amount of the compound of formula 1, a second amount of nivolumab, and a third amount of cisplatin.

[0088] In some embodiments, the present invention relates to a method for treating cancer, comprising administering to a subject a first amount of a compound of formula 1, a second amount of nivolumab, and a third amount of gemcitabine.

[0089] In some embodiments, the present invention relates to a method for treating cancer, comprising administering to a subject a first amount of a compound of formula 1, a second amount of atezolizumab, and a third amount of docetaxel.

[0090] In some embodiments, the present invention relates to a method for treating cancer, comprising administering to a subject a first amount of a compound of formula 1, a second amount of pembrolizumab, and a third amount of docetaxel.

[0091] definition The term "pharmaceutical composition" includes a composition comprising an active ingredient and a pharmaceutically acceptable excipient, carrier, or diluent, wherein the active ingredient is compound 1 or a pharmaceutically acceptable salt thereof, or a PD-1 or PD-L1 inhibitor or a pharmaceutically acceptable salt thereof, or a further chemotherapeutic agent. The term "pharmaceutically acceptable excipient, carrier, or diluent" includes compounds, materials, compositions, and / or dosage forms that, within the bounds of sound medical judgment and as can be confirmed by those skilled in the art, are suitable for use in contact with human and animal tissues without excessive toxicity, irritation, allergic reactions, or other problems or complications. In some embodiments, the pharmaceutical composition is a solid dosage form such as a capsule, tablet, granule, powder, or sachet. In some embodiments, the pharmaceutical composition is in the form of a sterile, injectable solution in one or more aqueous or non-aqueous, non-toxic, parenterally acceptable buffer systems, diluents, solubilizers, co-solvents, or carriers. Sterile injectable preparations may also be sterile injectable aqueous or oily suspensions or suspends in a non-aqueous diluent, carrier, or co-solvent, and may be formulated according to known procedures using one or more suitable dispersants or wetting agents and suspending agents. Pharmaceutical compositions may be solutions for IV bolus / injection, or lyophilized systems (alone or with excipients) for reconstitution in buffer systems with or without other excipients. Lyophilized freeze-dried materials may be prepared from non-aqueous or aqueous solvents. Dosage forms may also be concentrates for further dilution for subsequent injections.

[0092] The terms “to treat,” “to treat,” and “treatment” include reducing or suppressing tumor cells of hematological malignancies in the subject, improving one or more symptoms of hematological malignancies in the subject, or slowing or delaying the progression of hematological malignancies in the subject. The terms “to treat,” “to treat,” and “treatment” also include reducing or inhibiting tumor growth or proliferation of cancer cells in the subject.

[0093] The terms "inhibit," "inhibit," or "the act of inhibiting" include a reduction in the baseline activity of a biological activity or process.

[0094] The term "subject" includes warm-blooded mammals, such as primates, dogs, cats, rabbits, rats, and mice. In some embodiments, the subject is a primate, such as a human.

[0095] The term "therapeutic dose" includes the amount of compound 1 and the amount of a PD-1 or PD-L1 inhibitor and the amount of a chemotherapeutic agent that together produce a biological or medical response in the subject, such as a reduction or inhibition of cancer cells or tumor cells, improvement of cancer symptoms, or slowing or delaying the progression of cancer. In some embodiments, the term "therapeutic dose" includes the combined amount of compound 1 and the PD-1 or PD-L1 inhibitor and the chemotherapeutic agent that is effective in at least partially mitigating, inhibiting and / or improving cancer, or inhibiting tumor cells, and / or reducing or inhibiting the proliferation of cancer cells in the subject.

[0096] In some embodiments, a method is disclosed for treating cancer in a subject requiring treatment for cancer, comprising administering to the subject a first amount of compound 1 or a pharmaceutically acceptable salt thereof, a second amount of a PD-1 or PD-L1 inhibitor or a pharmaceutically acceptable salt thereof, and a third amount of a chemotherapeutic agent or a pharmaceutically acceptable salt thereof. In the method, the first amount, the second amount, and the third amount together constitute a therapeutically effective dose.

[0097] In some embodiments, a pharmaceutically acceptable salt of compound 1 or a pharmaceutically acceptable salt thereof is provided for use in the treatment of cancer in a subject, wherein the treatment comprises administering to the subject separately, sequentially, or simultaneously, i) compound 1 or a pharmaceutically acceptable salt thereof, ii) a PD-1 or PD-L1 inhibitor or a pharmaceutically acceptable salt thereof, and iii) a chemotherapeutic agent or a pharmaceutically acceptable salt thereof.

[0098] In some embodiments, a PD-1 or PD-L1 inhibitor or a pharmaceutically acceptable salt thereof is provided for use in the treatment of cancer in a subject, wherein the treatment comprises administering to the subject separately, sequentially, or simultaneously, i) the PD-1 or PD-L1 inhibitor or a pharmaceutically acceptable salt thereof, ii) compound 1 or a pharmaceutically acceptable salt thereof, and iii) a chemotherapeutic agent.

[0099] In some embodiments, the use of compound 1 or a pharmaceutically acceptable salt thereof in the manufacture of a drug for use in the treatment of cancer in a subject is provided, wherein the treatment comprises administering to the subject separately, sequentially, or simultaneously: i) the drug comprising compound 1 or a pharmaceutically acceptable salt thereof, ii) a PD-1 or PD-L1 inhibitor or a pharmaceutically acceptable salt thereof, and iii) a chemotherapeutic agent.

[0100] In some embodiments, compound 1 or a pharmaceutically acceptable salt thereof, a PD-1 or PD-L1 inhibitor or a pharmaceutically acceptable salt thereof, and further chemotherapeutic agents are administered separately, sequentially, or simultaneously in a treatment cycle. In some embodiments, compound 1 or a pharmaceutically acceptable salt thereof is administered sequentially in a treatment cycle, a PD-1 or PD-L1 inhibitor or a pharmaceutically acceptable salt thereof is also administered sequentially in a treatment cycle, and the chemotherapeutic agents are administered sequentially in a treatment cycle. In some embodiments, compound 1 or a pharmaceutically acceptable salt thereof, a PD-1 or PD-L1 inhibitor or a pharmaceutically acceptable salt thereof, and further chemotherapeutic agents are administered sequentially.

[0101] In some embodiments, the PD-1 or PD-L1 inhibitor is nivolumab or pembrolizumab. In further embodiments, the PD-1 or PD-L1 inhibitor is nivolumab.

[0102] The terms "continuous" or "sequentially" refer to administering a therapeutic agent, such as compound 1, regularly and without interruption or cessation, i.e., without any ineffective days. An "ineffective day" means a day on which the therapeutic agent is not administered.

[0103] As used herein, “cycle,” “treatment cycle,” or “medication schedule” refers to a period of combination therapy repeated on a regular schedule. For example, treatment may last for one week, two weeks, or three weeks, with compound 1 and PD-1 or PD-L1 inhibitors and chemotherapeutic agents administered in a coordinated manner. In some embodiments, the treatment cycle is approximately one week to three months. In some embodiments, the treatment cycle is approximately five days to one month. In some embodiments, the treatment cycle is approximately one week to three weeks. In some embodiments, the treatment cycle is approximately one week, ten days, two weeks, three weeks, four weeks, two months, or three months.

[0104] In some embodiments, compound 1 or a pharmaceutically acceptable salt thereof, a PD-1 or PD-L1 inhibitor or a pharmaceutically acceptable salt thereof, and a further chemotherapeutic agent or a pharmaceutically acceptable salt thereof are administered to a human subject in one or more treatment cycles, e.g., a treatment course. A “treatment course” comprises multiple treatment cycles and can be repeated on a normal schedule or adjusted as a schedule that is gradually adjusted while monitoring the progression of the patient’s disease. For example, a patient’s treatment cycles may have longer treatment periods and / or shorter rest periods at the start of a treatment course (e.g., when the patient is first diagnosed), and as the cancer enters remission, the rest periods may lengthen, thereby increasing the length of a single treatment cycle. The duration of treatment and rest in a treatment cycle, the number of treatment cycles, and the length of a treatment course may be determined and adjusted throughout the treatment course by those skilled in the art based on the progression of the patient’s disease, treatment resistance, and prognosis. In some embodiments, the method comprises 1 to 10 treatment cycles. In some embodiments, the method comprises 2 to 8 treatment cycles.

[0105] In some embodiments, compound 1 or a pharmaceutically acceptable salt thereof is administered for 28 days in a 28-day treatment cycle.

[0106] Dosage compound 1 In some embodiments, compound 1 or a pharmaceutically acceptable salt thereof is administered orally. In some embodiments, compound 1 or a pharmaceutically acceptable salt thereof is in tablet form. In some embodiments, compound 1 as hemi-fumarate is administered at a dose of 40 mg per day. In some embodiments, compound 1 as hemi-fumarate is administered at a dose of 80 mg per day.

[0107] PD-1 or PD-L1 inhibitors In some embodiments, the PD-1 or PD-L1 inhibitor is administered orally. In some embodiments, the PD-1 or PD-L1 inhibitor is in tablet form. In some embodiments, the PD-1 or PD-L1 inhibitor is in capsule form. In some embodiments, the PD-1 or PD-L1 inhibitor is administered by injection. In some embodiments, the PD-1 or PD-L1 inhibitor is administered by intravenous (IV) infusion. In some embodiments, the PD-1 or PD-L1 inhibitor is administered in doses of 10 mg to 1 g.

[0108] In some embodiments, a PD-1 or PD-L1 inhibitor or a pharmaceutically acceptable salt thereof is administered as an intravenous (IV) infusion. In some embodiments, the PD-1 or PD-L1 inhibitor or a pharmaceutically acceptable salt thereof is nivolumab, which is administered as an intravenous (IV) infusion.

[0109] In some embodiments, the PD-1 or PD-L1 inhibitor is nivolumab or a pharmaceutically acceptable salt thereof, administered as an intravenous (IV) infusion, containing approximately 10 mg of nivolumab per 1 mL of concentrate for solution. In some embodiments, nivolumab is administered as an intravenous (IV) infusion in doses of 40 mg, 100 mg, 120 mg, or 240 mg. In some embodiments, nivolumab is administered at a dose of 240 mg over 30 minutes every two weeks, or at a dose of 480 mg over 60 minutes every four weeks.

[0110] In some embodiments, the PD-1 or PD-L1 inhibitor is pembrolizumab or a pharmaceutically acceptable salt thereof, and is administered as an intravenous (IV) infusion. In further embodiments, pembrolizumab is administered at a dose of 200 mg every three weeks, or at a dose of 400 mg every six weeks. In some embodiments, pembrolizumab is administered via intravenous infusion over 15 to 60 minutes. In further embodiments, pembrolizumab is administered via intravenous infusion over approximately 30 minutes. In some embodiments, pembrolizumab is administered at a dose of 200 mg via intravenous infusion over approximately 30 minutes every three weeks. In some embodiments, pembrolizumab is administered at a dose of 400 mg via intravenous infusion over approximately 30 minutes every six weeks.

[0111] In some embodiments, the PD-L1 inhibitor is atezolizumab (Tecentriq) or a pharmaceutically acceptable salt thereof, and is administered by intravenous infusion. In some embodiments, atezolizumab is administered via intravenous infusion at a dose of 840 mg every two weeks. In some embodiments, atezolizumab is administered via intravenous infusion at a dose of 1200 mg every three weeks. In some embodiments, atezolizumab is administered via intravenous infusion at a dose of 1680 mg every four weeks.

[0112] In some embodiments, the PD-L1 inhibitor is avelumab or a pharmaceutically acceptable salt thereof, and is administered as an intravenous infusion. In some embodiments, avelumab is administered via intravenous infusion at a dose of 600–1000 mg every two weeks. In some embodiments, avelumab is administered via intravenous infusion at a dose of 800 mg over 60 minutes every two weeks.

[0113] In some embodiments, the PD-L1 inhibitor is durvalumab or a pharmaceutically acceptable salt thereof, and is administered as an intravenous infusion. In some embodiments, durvalumab is administered via intravenous infusion at a dose of 10 mg / kg every two weeks, or at a dose of 1500 mg every four weeks. In some embodiments, durvalumab is administered via intravenous infusion at a dose of 1500 mg in combination with chemotherapy for up to eight cycles, followed by a dose of 1500 mg every four weeks as monotherapy.

[0114] In some embodiments, the PD-1 inhibitor is cemiplimab or a pharmaceutically acceptable salt thereof, and is administered by intravenous infusion. In some embodiments, cemiplimab is administered via intravenous infusion at doses of 150–500 mg every 1–3 weeks. In some embodiments, cemiplimab is administered via intravenous infusion at doses of 350 mg every 3 weeks.

[0115] Chemotherapy agents In some embodiments, the further chemotherapeutic agent is administered orally. In some embodiments, the further chemotherapeutic agent is in tablet form. In some embodiments, the further chemotherapeutic agent is in capsule form. In some embodiments, the further chemotherapeutic agent is administered by injection. In some embodiments, the further chemotherapeutic agent is administered by intravenous (IV) injection. In some embodiments, the further chemotherapeutic agent is administered in doses of 10 mg to 2 g per day.

[0116] In some embodiments, only a single chemotherapeutic agent is present, i.e., one or fewer chemotherapeutic agents are administered.

[0117] In some embodiments, the chemotherapeutic agent is carboplatin. In some embodiments, carboplatin is administered by intravenous (IV) infusion. The recommended dose varies depending on the patient's medical condition, size, and kidney function. The physician will examine the patient's kidney function using blood or urine samples. There is likely to be an interval of approximately four weeks between each dose of carboplatin. The dose of carboplatin is calculated using Calvert's formula (dose (mg) = AUC·(GFR+25)). This takes into account creatinine clearance and the desired area under the curve. After 24 hours, nearly 70% of carboplatin is excreted unchanged in the urine. This means that the dose of carboplatin must be adjusted for impaired renal function.

[0118] In some embodiments, the chemotherapeutic agent is gemcitabine. In some embodiments, gemcitabine is administered by intravenous (IV) infusion. In some embodiments, gemcitabine is administered at a dose of 10 mg per 1 ml of infusion solution, enabling delivery of 120 ml / 130 ml / 140 ml / 150 ml / 160 ml / 170 ml / 180 ml / 200 ml / 220 ml of solution (corresponding to 1200 mg / 1400 mg / 1600 mg / 1700 mg / 1800 mg / 2000 mg / 2200 mg, respectively). Gemcitabine may be provided as a concentrate or as a powder in the infusion solution.

[0119] In some embodiments, the chemotherapeutic agent is cisplatin. In some embodiments, cisplatin is administered by intravenous (IV) infusion. In some embodiments, cisplatin is administered at a concentration of 1 mg / ml. In some embodiments, cisplatin is administered intravenously at doses of 10 mg / 10 ml, 50 mg / 50 ml, or 100 mg / 100 ml. In some embodiments, cisplatin is administered to the body surface at a dose of 1 m 2 It is administered as a single dose of 50-120 mg every 3-4 weeks. In some embodiments, cisplatin is 15-20 mg / m² per day. 2It is administered every 3 to 4 weeks for 5 days at a dose of 2 or more, once every 3 to 4 weeks. In some embodiments, cisplatin is 2 administered at a dose of 40 mg / m

[0120] In some embodiments, the chemotherapeutic agent is docetaxel. In some embodiments, docetaxel is administered by intravenous (IV) infusion. In some embodiments, docetaxel is administered at a concentration of <0.74 mg / ml. In some embodiments, docetaxel is 2 administered at a single dose of 65 - 100 mg per square meter of body surface area every 3 to 4 weeks. In some embodiments, docetaxel is 2 administered at a dose of 75 mg / m 2 once every 3 weeks. In some embodiments, cisplatin is

[0121] administered at a dose of 100 mg / m 2 once every 3 weeks. In some embodiments, pemetrexed or a pharmaceutically acceptable salt thereof is the chemotherapeutic agent and is administered by intravenous infusion. In some embodiments, pemetrexed is 2 administered at a dose of 500 mg per square meter of body surface area (BSA) via intravenous infusion. In some embodiments, pemetrexed is

[0122] The method of the present invention As described in more detail below, the inventors have surprisingly found that the combination of Compound 1 with a checkpoint inhibitor and chemotherapy has a synergistic effect in enhancing the anti - tumor immune response and cytotoxicity against tumor cells. Thus, a combination therapy with improved anti - tumor activity can be provided.

[0123] Secondly, the inventors have surprisingly found that the synergistic antitumor activity of compound 1 in combination with checkpoint inhibitors and chemotherapy is not limited to specific malignancies. Therefore, it is possible to provide combination therapies with improved cross-reactivity against multiple malignancies.

[0124] Furthermore, the inventors have surprisingly discovered that the combination of compound 1 with a checkpoint inhibitor and chemotherapy leads to the killing of tumor cells, which is not observed with any of the inhibitors alone. Therefore, a tripartite combination therapy that can reduce tumor burden can be provided.

[0125] Furthermore, the inventors have surprisingly found that the combination of compound 1 with a checkpoint inhibitor and a chemotherapeutic agent already exhibits a synergistic effect at sub-thermal doses. Therefore, improved tolerability of the combination therapy may be achieved.

[0126] The inventors have surprisingly found that the combination of compound 1 with a checkpoint inhibitor and chemotherapy treats patients with malignant tumors that are refractory to checkpoint inhibitor plus chemotherapy or that recur after checkpoint inhibitor plus chemotherapy.

[0127] This combination can therefore be used to treat a wide variety of cancers, including breast cancer, bladder cancer, cervical cancer, colon cancer, head and neck cancer, hematological cancer, liver cancer, lung cancer, kidney cancer, skin cancer including melanoma, uveal melanoma, gastric cancer, rectal cancer, mesothelioma, endometrial cancer, small intestine cancer, biliary tract cancer, ovarian cancer, brain cancer, testicular cancer, pancreatic cancer, bone cancer, and any solid tumors that cannot repair the DNA errors that occur when DNA is copied.

[0128] In some embodiments, cancer is breast cancer, bladder cancer, cervical cancer, colon cancer, head and neck cancer, hematological cancer, liver cancer, lung cancer, kidney cancer, skin cancer including melanoma, uveal melanoma, gastric cancer, rectal cancer, mesothelioma, endometrial cancer, small intestine cancer, biliary tract cancer, ovarian cancer, brain cancer, testicular cancer, pancreatic cancer, or bone cancer.

[0129] In some embodiments, the cancer is lung cancer. In further embodiments, the cancer is non-small cell lung cancer or small cell lung cancer.

[0130] In some embodiments, the cancer is mesothelioma.

[0131] In some embodiments, the cancer is bladder cancer.

[0132] In some embodiments, the cancer is melanoma. In further embodiments, the cancer is cutaneous melanoma or uveal melanoma.

[0133] In some embodiments, the cancer is refractory to checkpoint inhibitors plus chemotherapy, or recurs after checkpoint inhibitors plus chemotherapy.

[0134] In some embodiments, the present invention relates to a method for treating cancer in a subject requiring treatment for cancer, comprising administering to the subject a first amount of compound 1 or a pharmaceutically acceptable salt thereof, a second amount of a PD-1 or PD-L1 inhibitor or a pharmaceutically acceptable salt thereof, and a third amount of a chemotherapeutic agent, wherein the first, second, and third amounts together constitute a therapeutically effective dose, and the subject has been previously treated with chemotherapy and / or a PD-1 or PD-L1 inhibitor, and the cancer is refractory or resistant.

[0135] In further embodiments, the subject has been previously treated with chemotherapy and / or a PD-1 or PD-L1 inhibitor and has not responded to treatment or is resistant to treatment. In further embodiments, the subject has been previously treated with chemotherapy selected from carboplatin, cisplatin, or gemcitabine, either alone or in combination with nivolumab, and the cancer is refractory or resistant.

[0136] In further embodiments, the subject has previously been treated for 1 to 12 months with chemotherapy selected from carboplatin, cisplatin, or gemcitabine, either alone or in combination with nivolumab, and the subject is unresponsive to treatment, and / or the cancer is refractory or resistant.

[0137] In some embodiments, the subjects have previously been treated with carboplatin alone or in combination with nivolumab over a period of 1 to 12 months, and the subjects are unresponsive to treatment, and / or the cancer is refractory or resistant.

[0138] In some embodiments, the subjects have previously been treated with gemcitabine alone or in combination with nivolumab over a period of 1 to 12 months, the subjects have not responded well to treatment, and / or the cancer is refractory or resistant.

[0139] In some embodiments, the subjects have previously been treated with nivolumab alone or in combination with carboplatin over a period of 1 to 12 months, and the subjects are unresponsive to treatment and / or the cancer is refractory or resistant.

[0140] In some embodiments, the subjects have previously been treated with nivolumab alone or in combination with gemcitabine over a period of 1 to 12 months, the subjects have not responded well to treatment, and / or the cancer is refractory or resistant.

[0141] In some embodiments, the subjects have not been previously treated with chemotherapy and / or PD-1 or PD-L1 inhibitors. **

[0142] The features disclosed in the foregoing description, or in the following claims, or in the accompanying drawings, are expressed in their specific forms, or in terms of means for performing the disclosed functions, or methods or processes for obtaining the disclosed results, and such features can be used individually or in any combination as needed to realize the present invention in a variety of forms.

[0143] While the present invention has been described in conjunction with the exemplary embodiments described above, many equivalent modifications and variations will be apparent to those skilled in the art if this disclosure is provided. Therefore, the exemplary embodiments of the present invention described above are illustrative and not limiting. Various modifications can be made to the embodiments described without departing from the spirit and scope of the invention.

[0144] To avoid misunderstanding, the theoretical explanations provided herein are intended to enhance the reader's understanding. The inventors do not intend to be bound by any of these theoretical explanations.

[0145] Any section headings used herein are for structural purposes only and should not be construed as limiting the subject matter described herein.

[0146] Throughout this Specification, including the following claims, unless otherwise specified in the context, the words “comprise” and “include,” and their variations (such as “comprises,” “comprising,” and “including”), are understood to mean that they encompass the integers or steps, or groups of integers or steps, described, but do not exclude other integers or steps, or groups of integers or steps.

[0147] It should be noted that, as used herein and in the appended claims, the singular forms “a,” “an,” and “the” refer to multiple subjects unless the context clearly indicates otherwise. Ranges may be expressed herein as “approximately” from one particular value and / or “approximately” to another particular value. Where such ranges are expressed, another embodiment includes one particular value and / or other particular values. Similarly, where a value is expressed as an approximation by the use of the antecedent “approximately,” it will be understood that the particular value forms another embodiment. The term “approximately” with respect to numbers is arbitrary and means, for example, + / - 10%.

[0148] The compounds of this application will be further described by reference to the following non-limiting examples. [Examples]

[0149] Example 1 - In vitro assay using patient-derived co-culture systems including tumor cells, fibroblasts (MRC-5), and PBMCs in NSCLC (non-small cell lung cancer) and mesothelioma models. We obtained our own patient-derived mesothelioma (MPM) cell lines 420 and 353 from the Biological Bank of Mesothelioma, Azienda Ospedaliera (AO) Nazionale Ss Antonio e Biagio, Alessandria, Italy. For NSCLC cells, we obtained patient-derived cell lines #1, #3, #4, #5, #15, #16, #18, #21, #26, and #34 from AOU San Luigi Gonzaga, Orbassano, Italy.

[0150] 1.1 Organizational Processing 0.5 g of tissue was washed twice with 5 ml of sterile phosphate-buffered saline containing a sterile aqueous solution of 2 g / l ciprofloxacin. The tissue was manually dissected and digested in 2 ml of RPMI-1640 medium containing freshly prepared 1 mg / ml collagenase and 0.2 mg / ml hyaluronidase, supplemented with GlutaMAX®, at 37°C, 5% CO2, and 20% O2 for 1 hour. The digested sample was centrifuged at 12,000 × g for 5 minutes at room temperature and resuspended in 1 ml of HAM's F12 medium containing 1 ml (v / v) penicillin-streptomycin (#P4333, Sigma-Aldrich) and 10% (v / v)% fetal bovine serum. Live cells were counted and measured in 60 mm diameter cells. 3 1 x 10 in a Petri dish 6 Cells were plated at a cell / dish density. Every three days, cells were washed twice with sterile PBS and fresh complete medium was added. When the cells reached 80% confluence, they were subcultured. The experimental procedure described uses cells between subculturing 3 and 6.

[0151] 1.2 Lung fibroblast culture The MRC-5 lung fibroblast cell line was purchased from the American Type Culture Collection (ATCC) (#CCL-171). The cells were cultured in OptiMEM (#11058021, Gibco ThermoFisher Scientific) containing 1% (v / v) penicillin-streptomycin and 10% (v / v) FBS, and were grown to a diameter of 100 mm. 3 Petri dish (#P5606, Sigma-Aldrich) medium, 2.5 x 10 6 Cells were maintained at a cell / dish density. Every 3 days, cells were washed twice with sterile PBS and added complete culture medium. When the cells reached 80% confluence, they were subcultured in 100 mm diameter containers. 3 2.5 x 10 in a Petri dish 6 Cells were plated at a cell / dish density. The experimental procedure described uses cells up to passage 12-15.

[0152] 1.3 Co-culture of MPM fibroblasts or NSCLC fibroblasts For culturing MPM or NSCLC cells alone, resuspend 5 × 10⁶ cells in 0.5 ml of complete HAM's F12 medium. 5 Patient-derived MPM or NSCLC cells were seeded on top of 0.25 ml coated MaxGel® ECM (#E0282, Sigma-Aldrich) added 18 hours prior to cell development, in 24-well plates (#CLS3526, Sigma-Aldrich), and maintained in an incubator at 37°C, 5% CO2, and 20% O2.

[0153] In co-culture, 1 × 10 5 5 × 10⁴ MRC-5 cells were mixed with 0.25 ml of coated MaxGel® ECM / well and placed in a 24-well plate, incubating at 37°C for 18 hours. After this incubation period, 5 × 10⁴ cells were resuspended in 0.5 ml of complete HAM's F12 medium. 5 Patient-derived MPM or NSCLC cells were seeded on top of MaxGel® ECM. Cultures of MPM or NSCLC cells, or co-cultures of MPM / MRC-5 cells or NSCLC / MRC-5 cells, were maintained for 48 hours in an incubator at 37°C, 5% CO2, and 20% O2, after which survival assays or co-cultures with peripheral blood mononuclear cells (PBMCs) were performed.

[0154] 1.4 Peripheral blood monocytic cell (PBMC) co-culture Four heparinized tubes, each containing 5 ml of whole blood, were collected from the patient's peripheral veins and kept at room temperature for less than 1 hour with gentle agitation using a mechanical shaker (50 rpm) before further processing. The tubes were wiped with 70% (v / v) ethanol under a biosafety level 2 membrane hood. Blood was collected in a 50 ml conical sterile plastic tube (Falcon®, #734-0448, Avantor) and diluted 1:2 (v / v) with sterile 0.9% (w / v) NaCl solution (No. S8776, Sigma-Aldrich), and gently mixed up to 10 times with a 10 ml sterile pipette. 15 ml of Ficoll®-Paque Premium (#GE17-5442-03, Sigma-Aldrich) was added to the bottom of a new 50 ml conical sterile plastic tube using a 25 ml sterile pipette. Diluted blood was poured into the side of the tube and pooled at the top of the Ficoll density gradient without disturbing the surface. The tube was centrifuged at 760 × g for 25 minutes at room temperature with the "brake off" function selected. The supernatant (plasma fraction) was removed by gentle pipetting, while peripheral blood mononuclear cells (PBMCs) at the plasma / Ficoll interface were transferred to a new series of 15 ml conical tubes (Falcon®, #734-045, Avantor) using a disposable sterile 1 mL pipette. Each tube was filled with sterile PBS and centrifuged at 350 × g for 8 minutes, then the supernatant was carefully removed. The pellet was resuspended in sterile PBS by gentle pipetting to fill the tubes. This wash-centrifugation step was repeated twice. After a second wash, the pellet was resuspended in 3 ml of erythrocyte solution (eBioscience® 1X RBC lysis buffer, #00-4333-57, ThermoFisher Scientific) and incubated at room temperature for 15 minutes in a tube filled with RPMI-1640 medium. The tube was then centrifuged at 350 × g for 8 minutes. The supernatant was carefully removed, and the PBMCs contained in the pellet were resuspended in 1 ml of RPMI-1640 medium containing 1% (v / v) penicillin-streptomycin and 10% (v / v) FBS.PBMCs were counted using an automated cell counter, Acella 50, with 10 μL aliquots diluted 1:10 in RPMI-1640 medium. For MPM / MRC-5 or NSCLC / MRC-5 co-cultures, PBMCs were added to the co-culture in a 1:10 ratio (PBMC:MPM or PBMC:NSCLC) 48 hours after seeding of MPM or NSCLC cells (i.e., 5 × 10⁻¹⁰). 5 Each 24-well plate contains 5 × 10⁶ MPM or NSCLC cells. 4 (A number of PBMCs were added.) The PBMCs were co-cultured with MPM / MRC-5 or NSCLC / MRC-5 for 5 days, after which an immunophenotypic assay was performed.

[0155] 1.5 IC 50 Pharmacological treatment for evaluation: I C 50 In the evaluation, MPM or NSCLC cultures seeded 48 hours prior, or MPM / MRC-5 or NSCLC / MRC-5 co-cultures, were incubated for 72 hours with the following drugs or combinations: 1) Final concentration 10 -9 M, 10 -8 M, 10 -7 M, 10 -6 M, 10 -5 M, 10 -4 M, 10 -3 Compound 1 dissolved in DMSO (#D2438, Sigma-Aldrich) in M; 2) Final concentration 10 -9 M, 10 -8 M, 10 -7 M, 10 -6 M, 10 -5 M, 10 -4 M, 10 -3 Carboplatin (#C2538, Sigma-Aldrich) dissolved in a sterile aqueous solution at M; 3) Final concentration 10 -9 M, 10 -8 M, 10 -7 M, 10 -6 M, 10 -5 M, 10 -4 M, 10 -3Gemcitabine (#G6423, Sigma-Aldrich) dissolved in a sterile aqueous solution at M; 3) Final concentration 10 -9 M, 10 -8 M, 10 -7 M, 10 -6 M, 10 -5 M, 10 -4 M, 10 -3 Nivolumab dissolved in sterile aqueous solution at M; 4) Final concentration of each 10 -9 M, 10 -8 M, 10 -7 M, 10 -6 M, 10 -5 M, 10 -4 M, 10 -3 Carboplatin + nivolumab for M; 5) Final concentration of each 10 -9 M, 10 -8 M, 10 -7 M, 10 -6 M, 10 -5 M, 10 -4 M, 10 -3 Gemcitabine + nivolumab (M) 6) Final concentration of each 10 -9 M, 10 -8 M, 10 -7 M, 10 -6 M, 10 -5 M, 10 -4 M, 10 -3 Compound M 1 + carboplatin + nivolumab, 72 hours (simultaneous treatment a); 7) Final concentration of each 10 -9 M, 10 -8 M, 10 -7 M, 10 -6 M, 10 -5 M, 10 -4 M, 10 -3 Compound M 1 + gemcitabine + nivolumab, 72 hours (simultaneous treatment b); 8) Final concentration of each 10 -9 M, 10 -8 M, 10 -7 M, 10 -6 M, 10 -5 M, 10 -4 M, 10 -3Carboplatin + nivolumab of M, 72 hours, plus final concentration 10 -9 M, 10 -8 M, 10 -7 M, 10 -6 M, 10 -5 M, 10 -4 M, 10 -3 Compound 1 added in the last 24 hours with M (continuous treatment a); 9) Each with final concentration 10 -9 M, 10 -8 M, 10 -7 M, 10 -6 M, 10 -5 M, 10 -4 M, 10 -3 Gemcitabine + nivolumab of M, 72 hours, plus final concentration 10 -9 M, 10 -8 M, 10 -7 M, 10 -6 M, 10 -5 M, 10 -4 M, 10 -3 Compound 1 added in the last 24 hours with M (continuous treatment b); 10) Each with final concentration 10 -9 M, 10 -8 M, 10 -7 M, 10 -6 M, 10 -5 M, 10 -4 M, 10 -3 Compound 1 + docetaxel + pembrolizumab of M, 72 hours (simultaneous treatment a); 11) Each with final concentration 10 -9 M, 10 -8 M, 10 -7 M, 10 -6 M, 10 -5 M, 10 -4 M, 10 -3 Compound 1 + docetaxel + atezolizumab of M, 72 hours (simultaneous treatment b); 12) Each with final concentration 10 -9 M, 10 -8 M, 10 -7 M, 10 -6 M, 10 -5 M, 10 -4 M, 10 -3M's docetaxel + pembrolizumab, 72 hours, plus final concentration 10 -9 M, 10 -8 M, 10 -7 M, 10 -6 M, 10 -5 M, 10 -4 M, 10 -3 Compound 1 (continuous treatment a) is added to M during the last 24 hours; 13) Final concentration of 10 each -9 M, 10 -8 M, 10 -7 M, 10 -6 M, 10 -5 M, 10 -4 M, 10 -3 M's docetaxel + atezolizumab, 72 hours, plus final concentration 10 -9 M, 10 -8 M, 10 -7 M, 10 -6 M, 10 -5 M, 10 -4 M, 10 -3 Compound 1 (continuous treatment b) is added during the last 24 hours in M.

[0156] Cells grown in complete culture medium were considered the control group.

[0157] 1.6 IC 50 evaluation At the end of the pharmacological treatment, MPM and NSCLC cells grown on the top of MaxGel® ECM coatings containing or not containing MRC-5 cells were collected by carefully removing the cell culture medium and adding 0.5 ml of cell dissociation solution (#C5914, Sigma-Aldrich) to the top of the MaxGel ECM surface. The samples were maintained in an incubator at 37°C, 5% CO2, and 20% O2 for 10 minutes, then 0.5 ml of sterile PBS was added, and the soluble phase containing MPM or NSCLC cells was transferred to a 1.5 ml sterile plastic tube. The cells were centrifuged at 1,200 × g for 2 minutes at room temperature, the supernatant was removed, and the pellet was resuspended in 0.45 ml of OptiMEM without phenol red. 100 μl of the cell suspension was seeded into 96-well plates using technical quadruplicates for each sample. The plates were maintained in an incubator at 37°C, 5% CO2, and 20% O2 for 2 hours to allow the cells to adhere. Afterward, 10 μl / well of cell proliferation reagent WST-1 (CELLPRO-RO, Sigma-Aldrich) was added for a further 2 hours. The samples were maintained in the incubator, and then the plates were transferred to a Synergy® HTX multimode microplate reader (Cytation 3, Bio-Tek Agilent) and shaken at room temperature for 1 minute. The absorbance at 450 nm was read using Gene-5 software (Bio-Tek). The absorbance at 650 nm was also read and used as a reference length. The absorbance at 650 nm was subtracted from the absorbance at 450 nm from each well. The technical quadruplicates were averaged for each sample. The percentage of cell viability was calculated using the following formula: Live cells % = (100 × (absorbance of untreated cells - absorbance of sample X)) / absorbance of untreated cells Survival rates were plotted against drug concentration using GraphPad PRISM software (v.9.5.1). IC50 was calculated using the "log (inhibitor) vs. response (3 parameters)" function of the same software.

[0158] 1.7 Pharmacological preparations for immunophenotypic assays: To evaluate the effect of pharmacological treatment on PBMC immunophenotypes, 5-day co-cultures of MPM / MRC-5+PBMC or NSCLC / MRC-5+PBMC were prepared, as determined above, for their ICs. 50 The following drugs used were incubated for the last 72 hours. 1) Compound 1 2) Carboplatin + Nivolumab 3) Gemcitabine + Nivolumab 4) Compound 1 + Carboplatin + Nivolumab (simultaneous treatment a); 5) Compound 1 + gemcitabine + nivolumab (simultaneous treatment b); 6) Carboplatin + nivolumab, plus compound 1 added during the last 24 hours (continuous treatment a); 7) Gemcitabine + nivolumab, plus compound 1 added during the last 24 hours (continuous treatment b).

[0159] Cells grown in complete culture medium were considered the control group.

[0160] 1.8 Results In co-cultures with fibroblasts, immune cells, and patient-derived tumor cells, treatment with compound 1 as monotherapy for 72 hours impaired tumor cell viability and informed consent in NSCLC patients. 50 The values ​​ranged from 0.12 to 11.7 micromoles, but the effectiveness of monotherapy in mesothelioma is limited. 50 These were 46.31 and 49.77 micromoles (Tables 1 and 2).

[0161] However, when added to combination therapy with chemotherapy and immunotherapy, compound 1 is the IC of the three drugs when used in combination. 50 This significantly reduces cytotoxicity. This increased cytotoxicity is particularly relevant in NSCLC patients who are resistant to immunotherapy (NR) (Tables 1 and 2). [Table 1] [Table 2]

[0162] 1.9 Evaluation of the Composite Indicator (CI) Using CompuSyn (a computer program for quantifying synergistic and antagonistic effects in drug combinations), combination coefficients were calculated for NSCLC patient samples co-cultured with fibroblasts and PBMCs in the presence of the drugs listed in Table 1. Cell viability data was entered as the average for all patients and further stratified as responders or non-responders based on their response to CPI as listed in Table 1. Confidence Index (CI) was calculated for i) simultaneous administration of drugs or ii) sequential application of drugs. CI was classified as follows: <0.1 Very strong synergy, 0.1-0.3 Strong synergy, 0.3-0.7 Synergistic, 0.7-0.85 Moderate synergy, 0.85-0.90 Slight synergy, 0.90-1.10 Nearly additive, 1.10-1.20 Slight antagonistic, 1.20-1.45 Moderate antagonistic, 1.45-3.3 Antagonistic, 3.3-10 Strong antagonistic, >10 Very strong antagonistic.

[0163] 1.10 Results In a combination assay with nivolumab, in which all three drugs were used simultaneously, the average across all patient samples showed that ED 50 An additive effect was observed with increasing concentration, and a higher synergistic effect was observed at higher concentrations. When patients were stratified into responders and non-responders to CPI, this combination was effective in responders. 50 In the case of non-responders, the effects are additive and antagonistic at higher concentrations, whereas in non-responders, this combination is ED 50 The effects are additive at low concentrations and shift synergistically at higher concentrations (Table 3). When the drug was administered sequentially, a synergistic effect was observed in all patients and at all concentrations, with the strongest synergistic effect observed in CPI non-responders, and this synergistic effect shifted to a stronger synergistic effect as the concentration increased (Table 3). [Table 3]

[0164] In combination assays with atezolizumab, in which all three drugs were administered simultaneously, a synergistic effect was observed at all concentrations in both responder and non-responder patients, and this tended to increase with increasing concentration (Table 4). When the drugs were administered sequentially, a synergistic effect was again observed in all patients and at all concentrations, but it did not shift to a strong synergistic effect with increasing concentration (Table 4). [Table 4]

[0165] In combination assays with pembrolizumab, in which all three drugs were administered concurrently or sequentially, a synergistic effect was observed at almost all concentrations, and the synergistic effect clearly shifted to a stronger effect as the concentration increased. In patients who were non-responsive to concurrent administration only, ED 50 No synergistic effect was observed (Table 5). [Table 5]

[0166] Example 2. Immunophenotypic assay 2.1 Cell collection and counting: 0.4 ml of cell culture medium containing suspended PBMCs was gently pipettered from MPM / MRC-5+PBMC or NSCLC / MRC-5+PBMC that had been co-cultured for 5 days, left untreated, or treated for the last 72 hours as described in Section 1.7 above, and transferred to a 1.5 ml Eppendorf sterile plastic tube. A further 0.1 ml of medium on the MaxGel ECM surface was gently removed and drained, avoiding contact with the MaxGel ECM. The exposed MaxGel ECM surface was rinsed with 0.5 ml of cell dissociation solution (#C5914, Sigma-Aldrich) and covered with the MaxGel ECM surface. The sample was maintained in an incubator at 37°C, 5% CO2, 20% O2 for 10 minutes, then 0.5 ml of sterile PBS was added, and the soluble phase containing MPM or NSCLC cells was transferred to another 1.5 ml Eppendorf sterile plastic tube series. Samples containing PBMC, MPM, or NSCLC cells were centrifuged at 1,200 × g at room temperature for 5 minutes, washed in 1 ml of sterile PBS, and resuspended. The centrifugation, washing, and resuspendion steps were repeated once, and then the cells were resuspended in 1 ml of sterile PBS containing 5% (v / v) FBS. 10 μl aliquots were transferred to new 1.5 ml Eppendorf sterile plastic tubes, the volume was reduced to 0.3 ml with PBS, and the cells were counted using a Guava EasyCyte flow cytometer (Millipore) with InCyte software. For PBMCs, each sample was divided into 12 aliquots, each containing more than 3,000 cells. The volume was reduced to 0.3 ml with sterile PBS containing 1% (v / v) FBS. For MPM or NSCLC cells, each sample was divided into 2 aliquots, each containing more than 3,000 cells. The volume was reduced to 0.3 ml with sterile PBS containing 1% (v / v) FBS.

[0167] 2.2. PBMC Immunophenotyping Tests: Each PBMC aliquot was incubated for 1 hour at room temperature with the antibody combinations detailed below. All acquisitions and analyses were performed on a Guava EasyCyte flow cytometer (Millipore) equipped with InCyte software. A minimum of 3,000 events were counted. CD3 + CD8 + cells Antibodies used: anti-CD3 APC (REA613, #130-113-135, Miltenyi, diluted 1:50), anti-CD8 FITC (clone BW135 / 80, #130-113-157, Miltenyi, diluted 1:50). Acquisition strategy: CD3 + (T lymphocytes) and CD3 + CD8 + cells (T cell cytotoxic lymphocytes) were acquired. Results were expressed as % of CD3 + cells to CD3 + CD8 + cells. CD8 + CD107a + IFNγ cells Sample processing: Cells were processed using an intracellular staining kit (#130-090-477, Miltenyi) according to the manufacturer's protocol. Antibodies used: anti-CD8 FITC (clone BW135 / 80, #130-113-157, Miltenyi, diluted 1:50), anti-CD107a APC (REA792, #130-111-847, Miltenyi, diluted 1:50), anti-IFN-γ PE (REA600, #130-113-498, Miltenyi, diluted 1:50). Acquisition strategy: CD8 + (T cell cytotoxic lymphocytes) and CD8 + CD107a + IFNγ + (activated T cell cytotoxic lymphocytes) were acquired. Results were expressed as % of CD8 + cells to CD107a + IFNγ + cells. CD8 + PD-1 and CD8+ TIM-3 cells Antibodies used: anti-CD8 FITC (clone BW135 / 80, #130-113-157, Miltenyi, diluted 1:50), anti-CD279 / PD-1 APC (clone PD1.3.1.3, #130-117-806, Miltenyi, diluted 1:50), anti-CD366 / TIM-3 PE (REA635, #130-119-785, Miltenyi, diluted 1:50). Harvesting strategy: Strategy: CD8 + , CD8 + PD-1 + , and CD8 + TIM-3 + cells were harvested. The results were expressed as the percentage of CD8 + cells against CD8 + PD-1 + cells or CD8 + TIM-3 + cells. CD8 + LAG-3 + cells and CD8 + CTLA-4 + cells Antibodies used: anti-CD8 FITC (clone BW135 / 80, #130-113-157, Miltenyi, diluted 1:50), anti-CD233 / LAG-3 APC (REA351, #130-119-567, Miltenyi, diluted 1:50), anti-CD152 / CTLA-4 PE (REA1003, #130-116-810, Miltenyi, diluted 1:50). Harvesting strategy: CD8 + , CD8 + LAG-3 + , and CD8 + CTLA-4 + cells were harvested. The results were expressed as the percentage of CD8 + cells against CD8 + LAG-3 + cells or CD8 + CTLA-4 + cells. CD3 + CD4 + and CD4 + FoxP3+ cell Antibodies used: Anti-CD3 APC (REA613, #130-113-135, Miltenyi, diluted 1:50), Anti-CD4 FITC (clone M-T466, #130-113-253, Miltenyi, diluted 1:50), Anti-FoxP3 PE (REA1253, #130-125-579, Miltenyi, diluted 1:50). Acquisition strategy: CD3 + CD4 + Cells (T helper lymphocytes) and CD3 + CD4 + FoxP3 + (T-regulatory Treg cells) were obtained. The result was CD3 + CD4 + Cell percentage or CD4 + FoxP3 against cells + Expressed as a percentage of cells. CD68 + CD86 + Inos + cell Antibodies used: Anti-CD68 APC (clone Y1 / 82A, #130-125-857, Miltenyi, diluted 1:50), anti-CD86 PE (REA968, #130-116-160, Miltenyi, diluted 1:50), anti-inducible nitric oxide synthase (Inos) Alexa Fluor 488 (#NBP2-99091AF488, Novus Biological, diluted 1 / 10). Acquisition strategy: CD68 + (Macrophage) and CD68 + CD86 + Inos + Cells (M1 polarized macrophages) were obtained. The result was CD68 + CD68 in cells + CD86 + Inos + Expressed as a percentage of cells. CD68 + CD206 + Arg + cell Antibodies used: Anti-CD68 APC (clone Y1 / 82A, #130-125-857, Miltenyi, diluted 1:50), Anti-CD206 FITC (clone DCN228, #130-123-671, Miltenyi, diluted 1:50), Anti-arginase PE (clone 14D2C43, #369704, BioLegend, diluted 1 / 100) Acquisition strategy: CD68 + (Macrophage) and CD68 + CD206 + Arginase + Cells (M2 polarized macrophages) were obtained. The result was CD68 + CD68 in cells + CD206 + Arginase + Expressed as a percentage of cells.

[0168] 2.3 Results In ex vivo co-culture models of patient-derived mesothelioma cells (n=2) or NSCLCs (n=10) with compatible PBMCs and fibroblasts, the addition of compound 1 to chemotherapy plus nivolumab specifically increased activated Ki67+ / IFNg+CD8 T cells and M1-like macrophages, while simultaneously decreasing Tregs, exhausting TIM3+CD8 T cells and MDSCs, resulting in an overall effect of increased antitumor immune response. These data demonstrate that compound 1 increases the cytotoxicity of chemotherapy / immunotherapy by increasing antitumor immune cells and decreasing pretumor immune cells (Figures 1 and 2). The data shown in Figures 1 and 2 are representative of the immune cell changes observed in mesothelioma and lung cancer, respectively. They were replicated in a total of 2 mesothelioma patients and 10 lung cancer patients.

[0169] Figure 1 shows BAP1 wild-type (BAP+) MPM cells co-cultured with peripheral mononuclear cells (PBMCs), treated with compound 1 alone in the presence of fibroblasts (+MRC5), and co-incubated with cisplatin / nivolumab. Immunophenotyping of immune cells was analyzed by flow cytometry (n=2, two independent experiments). *p<0.05, **p<0.01, ***p<0.001.

[0170] Figure 2 shows that NSCLC cells from CPI-refractory patient #4 were co-cultured with peripheral mononuclear cells (PBMCs), treated with compound 1 alone in the presence of fibroblasts (+MRC5), and co-incubated with cisplatin / nivolumab. The immunophenotype of immune cells was analyzed by flow cytometry (n=2, two independent experiments). *p<0.05, **p<0.01, ***p<0.001.

[0171] References Numerous publications are cited above in order to describe and disclose the present invention and the state of the art to which it pertains in a more complete manner. A complete citation of these references is provided below. Each of these references in its entirety is incorporated herein. [Table 6]

[0172] For standard molecular biology techniques, please refer to Sambrook, J., and Russel, DWMolecular Cloning, A Laboratory Manual, 3rd ed. 2001, Cold Spring Harbor, New York: Cold Spring Harbor Laboratory Press.

[0173] statement 1. A method for treating cancer in a subject requiring cancer treatment, wherein the subject is given a first amount of formula I: [ka] administering a first amount of a compound or a pharmaceutically acceptable salt thereof, and a second amount of a PD-1 or PD-L1 inhibitor or a pharmaceutically acceptable salt thereof, and a third amount of a chemotherapeutic agent, wherein the first amount, the second amount, and the third amount together constitute a therapeutically effective amount, said method.

[0174] 2. The method according to statement 1, wherein the PD-1 or PD-L1 inhibitor is a PD-1 inhibitor.

[0175] 3. The method according to statement 1 or 2, wherein the cancer is breast cancer, bladder cancer, cervical cancer, colon cancer, head and neck cancer, blood cancer, liver cancer, lung cancer, kidney cancer, skin cancer including melanoma, uveal melanoma, gastric cancer, rectal cancer, mesothelioma, endometrial cancer, small intestine cancer, biliary tract cancer, ovarian cancer, brain cancer, testicular cancer, pancreatic cancer, bone cancer, and any solid tumor that cannot repair errors in its DNA that occur when the DNA is copied.

[0176] 4. The method according to any one of statements 1 to 3, wherein the cancer is lung cancer, mesothelioma, bladder cancer, melanoma, or uveal melanoma.

[0177] 5. The method according to any one of statements 1 to 3, wherein the cancer is refractory to checkpoint inhibitor plus chemotherapy or recurs after checkpoint inhibitor plus chemotherapy.

[0178] 6. The method according to any one of statements 1 to 5, wherein the PD-1 or PD-L1 inhibitor is a PD-1 inhibitor selected from atezolizumab, nivolumab, pembrolizumab, semiprimab, dostarlimab, retifanlimab, and toripalimab.

[0179] 7. The method according to statement 6, wherein the PD-1 inhibitor is nivolumab.

[0180] 8. The method according to statement 6, wherein the PD-1 inhibitor is pembrolizumab.

[0181] 9. The method according to Statement 6, wherein the PD-1 inhibitor is dostallimab.

[0182] 10. The method according to Statement 6, wherein the PD-L1 inhibitor is atezolizumab.

[0183] 11. The method according to any one of statements 1 to 10, wherein the chemotherapeutic agent is selected from carboplatin, gemcitabine, cisplatin, docetaxel, doxorubicin, mitoxantrone, 5-fluorouracil (5-FU), capecitabine, irinotecan, oxaliplatin, pemetrexed, trifluridine, and tipiracil.

[0184] 12. The method according to any one of statements 1 to 11, wherein the chemotherapeutic agent is selected from carboplatin, gemcitabine, cisplatin, and docetaxel.

[0185] 13. The method according to any one of statements 1 to 11, wherein the chemotherapeutic agent is carboplatin.

[0186] 14. The method according to any one of statements 1 to 11, wherein the chemotherapeutic agent is cisplatin.

[0187] 15. The method according to any one of statements 1 to 11, wherein the chemotherapeutic agent is gemcitabine.

[0188] 16. The method according to any one of statements 1 to 11, wherein the chemotherapeutic agent is docetaxel.

[0189] 17. The method according to any one of statements 1 to 7, comprising administering to the subject a first amount of compound 1, a second amount of nivolumab, and a third amount of carboplatin.

[0190] 18. The method according to any one of statements 1 to 7, comprising administering to the subject a first amount of compound 1, a second amount of nivolumab, and a third amount of cisplatin.

[0191] 19. The method according to any one of statements 1 to 7, comprising administering to the subject a first amount of compound 1, a second amount of nivolumab, and a third amount of gemcitabine.

[0192] 20. The method according to any one of statements 1 to 6, comprising administering to the subject a first amount of compound 1, a second amount of pembrolizumab, and a third amount of docetaxel.

[0193] 21. The method according to any one of statements 1 to 6, comprising administering to the subject a first amount of compound 1, a second amount of atezolizumab, and a third amount of docetaxel.

[0194] 22. The method according to any one of statements 1 to 21, wherein compound 1 is administered as hemi-fumarate in doses of 40 mg or 80 mg per day.

[0195] 23. The method according to any one of Statements 1 to 22, wherein the subject has been previously treated with chemotherapy and / or a PD-1 or PD-L1 inhibitor, and the cancer is refractory or resistant.

[0196] 24. The method according to any one of Statements 1 to 22, wherein the subject has been previously treated with chemotherapy and / or a PD-1 or PD-L1 inhibitor and has not responded to said treatment or is resistant to said treatment.

[0197] 25. The method according to any one of Statements 1 to 22, wherein the subject has previously been treated with chemotherapy consisting of carboplatin, cisplatin, or gemcitabine, either alone or in combination with nivolumab, and the cancer is refractory or resistant.

[0198] 26. The method according to any one of Statements 1 to 22, wherein the subject has been previously treated with nivolumab alone or in combination with chemotherapy selected from carboplatin, cisplatin, or gemcitabine, and the cancer is refractory or resistant.

[0199] 27. Formula I for use in the treatment of cancer in the subject: [ka] A compound or a pharmaceutically acceptable salt thereof, wherein the treatment comprises administering to the subject separately, sequentially, or simultaneously, i) a pharmaceutically acceptable salt thereof, ii) a PD-1 or PD-L1 inhibitor or a pharmaceutically acceptable salt thereof, and iii) a chemotherapeutic agent or a pharmaceutically acceptable salt thereof.

[0200] 28. Compound 1 or a pharmaceutically acceptable salt thereof for use as described in Statement 27, wherein the PD-1 or PD-L1 inhibitor is a PD-1 inhibitor.

[0201] 29. Compound 1 or any pharmaceutically acceptable salt thereof for use as described in Statement 27 or 28, wherein the cancer is breast cancer, bladder cancer, cervical cancer, colon cancer, head and neck cancer, hematological cancer, liver cancer, lung cancer, kidney cancer, skin cancer including melanoma, uveal melanoma, gastric cancer, rectal cancer, mesothelioma, endometrial cancer, small intestine cancer, biliary tract cancer, ovarian cancer, brain cancer, testicular cancer, pancreatic cancer, bone cancer, and any solid tumor that cannot repair the DNA errors that occur when DNA is copied.

[0202] 30. Compound 1 or a pharmaceutically acceptable salt thereof for use as described in Statement 29, wherein the cancer is lung cancer, mesothelioma, bladder cancer, melanoma, or uveal melanoma.

[0203] 31. Compound 1 or a pharmaceutically acceptable salt thereof for use as described in any one of Statements 27-30, for cancers that are refractory to checkpoint inhibitor plus chemotherapy or that recur after checkpoint inhibitor plus chemotherapy.

[0204] 32. Compound 1 or a pharmaceutically acceptable salt thereof for use as described in any one of Statements 23 to 27, wherein the PD-1 or PD-L1 inhibitor is a PD-1 inhibitor selected from atezolizumab, nivolumab, pembrolizumab, semiprimab, dostallimab, retifanlimab, and tripalimab.

[0205] 33. Compound 1 or a pharmaceutically acceptable salt thereof for use as described in Statement 32, wherein the PD-1 inhibitor is nivolumab.

[0206] 34. Compound 1 or a pharmaceutically acceptable salt thereof for use as described in Statement 32, wherein the PD-1 inhibitor is pembrolizumab.

[0207] 35. Compound 1 or a pharmaceutically acceptable salt thereof for use as described in Statement 32, wherein the PD-1 inhibitor is dostallimab.

[0208] 36. Compound 1 or a pharmaceutically acceptable salt thereof for use as described in Statement 32, wherein the PD-1 inhibitor is atezolizumab.

[0209] 37. Compound 1 or a pharmaceutically acceptable salt thereof for use as described in any one of Statements 27 to 36, wherein the chemotherapeutic agent is selected from carboplatin, gemcitabine, cisplatin, docetaxel, doxorubicin, mitoxantrone, 5-fluorouracil (5-FU), capecitabine, irinotecan, oxaliplatin, pemetrexed, trifluridine, and tipiracil.

[0210] 38. Compound 1 or a pharmaceutically acceptable salt thereof for use as described in any one of Statements 27 to 37, wherein the chemotherapeutic agent is selected from carboplatin, gemcitabine, cisplatin, and docetaxel.

[0211] 39. Compound 1 or a pharmaceutically acceptable salt thereof for use as described in any one of Statements 27 to 38, wherein the chemotherapeutic agent is carboplatin.

[0212] 40. Compound 1 or a pharmaceutically acceptable salt thereof for use as described in any one of Statements 27 to 38, wherein the chemotherapeutic agent is cisplatin.

[0213] 41. Compound 1 or a pharmaceutically acceptable salt thereof for use as described in any one of Statements 27 to 38, wherein the chemotherapeutic agent is gemcitabine.

[0214] 42. Compound 1 or a pharmaceutically acceptable salt thereof for use as described in any one of Statements 27 to 38, wherein the chemotherapeutic agent is docetaxel.

[0215] 43. For use according to any one of statements 27-33, comprising administering to the subject a first amount of compound 1, a second amount of nivolumab, and a third amount of carboplatin.

[0216] 44. For use according to any one of statements 27 to 33, comprising administering to the subject a first amount of compound 1, a second amount of nivolumab, and a third amount of cisplatin.

[0217] 45. For use according to any one of statements 27 to 33, comprising administering to the subject a first amount of compound 1, a second amount of nivolumab, and a third amount of gemcitabine, compound 1 or a pharmaceutically acceptable salt thereof.

[0218] 46. ​​For use according to any one of Statements 27-32, comprising administering to the subject a first amount of compound 1, a second amount of pembrolizumab, and a third amount of docetaxel, compound 1 or a pharmaceutically acceptable salt thereof.

[0219] 47. For use according to any one of statements 27 to 32, comprising administering to the subject a first amount of compound 1, a second amount of atezolizumab, and a third amount of docetaxel, compound 1 or a pharmaceutically acceptable salt thereof.

[0220] 48. Compound 1 or a pharmaceutically acceptable salt thereof, for use as described in any one of Statements 27-47, administered in doses of 40 mg or 80 mg per day as hemi-fumarate.

[0221] 49. Compound 1 or a pharmaceutically acceptable salt thereof for use as described in any one of Statements 27-48, for subjects who have been previously treated with chemotherapy and / or PD-1 or PD-L1 inhibitors, and whose cancer is refractory or resistant.

[0222] 50. Compound 1 or a pharmaceutically acceptable salt thereof for use as described in any one of Statements 27-48, for subjects who have been previously treated with chemotherapy and / or PD-1 or PD-L1 inhibitors and have not responded to or are resistant to said treatment.

[0223] 51. Compound 1 or a pharmaceutically acceptable salt thereof for use as described in any one of Statements 27-48, for subjects who have previously been treated with chemotherapy selected from carboplatin, cisplatin, or gemcitabine, either alone or in combination with nivolumab, and whose cancer is refractory or resistant.

[0224] 52. Compound 1 or a pharmaceutically acceptable salt thereof for use as described in any one of Statements 27-48, for subjects who have been previously treated with nivolumab alone or in combination with chemotherapy selected from carboplatin, cisplatin, or gemcitabine, and whose cancer is refractory or resistant.

[0225] 53. Compound 1 or a pharmaceutically acceptable salt thereof for use according to any one of statements 27 to 52, wherein the treatment comprises the sequential administration of i) Compound 1 or a pharmaceutically acceptable salt thereof, ii) a PD-1 or PD-L1 inhibitor or a pharmaceutically acceptable salt thereof, and iii) a chemotherapeutic agent or a pharmaceutically acceptable salt thereof to the subject.

[0226] 54. A PD-1 or PD-L1 inhibitor or a pharmaceutically acceptable salt thereof for use in the treatment of cancer in the subject, wherein the treatment is i) the PD-1 or PD-L1 inhibitor or a pharmaceutically acceptable salt thereof, ii) formula I: [ka] iii) a compound or a pharmaceutically acceptable salt thereof, and iii) a chemotherapeutic agent or a pharmaceutically acceptable salt thereof, comprising administering the PD-1 or PD-L1 inhibitor or a pharmaceutically acceptable salt thereof separately, sequentially, or simultaneously to the subject.

[0227] 55. The cancer is breast cancer, bladder cancer, cervical cancer, colon cancer, head and neck cancer, hematological cancer, liver cancer, lung cancer, kidney cancer, skin cancer including melanoma, uveal melanoma, gastric cancer, rectal cancer, mesothelioma, endometrial cancer, small intestine cancer, biliary tract cancer, ovarian cancer, brain cancer, testicular cancer, pancreatic cancer, bone cancer, and any solid tumor that cannot repair the DNA errors that occur when DNA is copied, for use as described in Statement 54. PD-1 or PD-L1 inhibitors or pharmaceutically acceptable salts thereof.

[0228] 56. PD-1 or PD-L1 inhibitors or pharmaceutically acceptable salts thereof, for use as described in Statement 55, wherein the cancer is lung cancer, mesothelioma, bladder cancer, melanoma, or uveal melanoma.

[0229] 57. A PD-1 or PD-L1 inhibitor or a pharmaceutically acceptable salt thereof for use as described in any of statements 54-56, for cancers that are refractory to checkpoint inhibitor plus chemotherapy or recur after checkpoint inhibitor plus chemotherapy.

[0230] 58. A PD-1 or PD-L1 inhibitor or a pharmaceutically acceptable salt thereof for use as described in any one of Statements 54 to 57, wherein the PD-1 or PD-L1 inhibitor is a PD-1 inhibitor selected from atezolizumab, nivolumab, pembrolizumab, semiprimab, dostallimab, retifanlimab, and tripalimab.

[0231] 59. A PD-1 or PD-L1 inhibitor or a pharmaceutically acceptable salt thereof for use as described in Statement 58, wherein the PD-1 inhibitor is nivolumab.

[0232] 60. A PD-1 or PD-L1 inhibitor or a pharmaceutically acceptable salt thereof for use as described in Statement 58, wherein the PD-1 inhibitor is pembrolizumab.

[0233] 61. A PD-1 or PD-L1 inhibitor or a pharmaceutically acceptable salt thereof for use as described in Statement 58, wherein the PD-1 inhibitor is dostallimab.

[0234] 62. A PD-1 or PD-L1 inhibitor or a pharmaceutically acceptable salt thereof for use as described in Statement 58, wherein the PD-1 inhibitor is atezolizumab.

[0235] 63. A PD-1 or PD-L1 inhibitor or a pharmaceutically acceptable salt thereof for use as described in any one of Statements 54 to 62, wherein the chemotherapeutic agent is selected from carboplatin, gemcitabine, cisplatin, docetaxel, doxorubicin, mitoxantrone, 5-fluorouracil (5-FU), capecitabine, irinotecan, oxaliplatin, pemetrexed, trifluridine, and tipiracil.

[0236] 64. A PD-1 or PD-L1 inhibitor or a pharmaceutically acceptable salt thereof for use as described in any one of statements 54 to 63, wherein the chemotherapeutic agent is selected from carboplatin, gemcitabine, cisplatin, and docetaxel.

[0237] 65. A PD-1 or PD-L1 inhibitor or a pharmaceutically acceptable salt thereof, for use as described in any one of Statements 54 to 64, wherein the chemotherapeutic agent is carboplatin.

[0238] 66. A PD-1 or PD-L1 inhibitor or a pharmaceutically acceptable salt thereof, for use as described in any one of Statements 54 to 64, wherein the chemotherapeutic agent is cisplatin.

[0239] 67. A PD-1 or PD-L1 inhibitor or a pharmaceutically acceptable salt thereof, for use as described in any one of Statements 54 to 64, wherein the chemotherapeutic agent is gemcitabine.

[0240] 68. A PD-1 or PD-L1 inhibitor or a pharmaceutically acceptable salt thereof, for use as described in any one of Statements 54 to 64, wherein the chemotherapeutic agent is docetaxel.

[0241] 69. A PD-1 or PD-L1 inhibitor or a pharmaceutically acceptable salt thereof for use according to any one of statements 54 to 59, comprising administering to the subject a first amount of compound 1, a second amount of nivolumab, and a third amount of carboplatin.

[0242] 70. A PD-1 or PD-L1 inhibitor or a pharmaceutically acceptable salt thereof for use according to any one of statements 54 to 59, comprising administering to the subject a first amount of compound 1, a second amount of nivolumab, and a third amount of cisplatin.

[0243] 71. A PD-1 or PD-L1 inhibitor or a pharmaceutically acceptable salt thereof for use according to any one of statements 54 to 59, comprising administering to the subject a first amount of compound 1, a second amount of nivolumab, and a third amount of gemcitabine.

[0244] 72. A PD-1 or PD-L1 inhibitor or a pharmaceutically acceptable salt thereof for use according to any one of statements 54 to 58, comprising administering to the subject a first amount of compound 1, a second amount of pembrolizumab, and a third amount of docetaxel.

[0245] 73. A PD-1 or PD-L1 inhibitor or a pharmaceutically acceptable salt thereof for use according to any one of statements 54 to 58, comprising administering to the subject a first amount of compound 1, a second amount of atezolizumab, and a third amount of docetaxel.

[0246] 74. Compound 1 is administered as hemi-fumarate in doses of 40 mg or 80 mg per day, for use as described in any one of Statements 54-73, as a PD-1 or PD-L1 inhibitor or a pharmaceutically acceptable salt thereof.

[0247] 75. The subject has been previously treated with chemotherapy and / or a PD-1 or PD-L1 inhibitor, and the cancer is refractory or resistant, for use as described in any one of Statements 54 to 74, a PD-1 or PD-L1 inhibitor or a pharmaceutically acceptable salt thereof.

[0248] 76. A PD-1 or PD-L1 inhibitor or a pharmaceutically acceptable salt thereof for use as described in any one of Statements 54 to 74, wherein the subject has been previously treated with chemotherapy and / or a PD-1 or PD-L1 inhibitor and has not responded to or is resistant to said treatment.

[0249] 77. The subject has been previously treated with chemotherapy consisting of carboplatin, cisplatin, or gemcitabine, either alone or in combination with nivolumab, and the cancer is refractory or resistant, for use as described in any one of Statements 54-74, wherein the subject has been previously treated with chemotherapy consisting of carboplatin, cisplatin, or gemcitabine, and the cancer is refractory or resistant.

[0250] 78. The subject has been previously treated with nivolumab alone or in combination with chemotherapy selected from carboplatin, cisplatin, or gemcitabine, and the cancer is refractory or resistant, for use as described in any one of Statements 54-74, a PD-1 or PD-L1 inhibitor or a pharmaceutically acceptable salt thereof.

[0251] 79. A PD-1 or PD-L1 inhibitor or a pharmaceutically acceptable salt thereof for use according to any one of statements 54 to 78, wherein the treatment comprises administering to the subject in sequence: i) compound 1 or a pharmaceutically acceptable salt thereof, ii) a PD-1 or PD-L1 inhibitor or a pharmaceutically acceptable salt thereof, and iii) a chemotherapeutic agent or a pharmaceutically acceptable salt thereof.

[0252] 80. Formula I in the manufacture of drugs used for the treatment of cancer: [ka] The use of a compound or a pharmaceutically acceptable salt thereof, wherein the treatment comprises administering to the subject separately, sequentially, or simultaneously: i) the agent comprising compound 1 or a pharmaceutically acceptable salt thereof; ii) a PD-1 or PD-L1 inhibitor or a pharmaceutically acceptable salt thereof; and iii) a chemotherapeutic agent or a pharmaceutically acceptable salt thereof.

[0253] 81. Use of Compound 1 or a pharmaceutically acceptable salt thereof described in Statement 80, wherein the PD-1 or PD-L1 inhibitor is a PD-1 inhibitor.

[0254] 82. Use of Compound 1 or any pharmaceutically acceptable salt thereof as described in Statement 80 or 81, wherein the cancer is breast cancer, bladder cancer, cervical cancer, colon cancer, head and neck cancer, hematological cancer, liver cancer, lung cancer, kidney cancer, skin cancer including melanoma, uveal melanoma, gastric cancer, rectal cancer, mesothelioma, endometrial cancer, small intestine cancer, biliary tract cancer, ovarian cancer, brain cancer, testicular cancer, pancreatic cancer, bone cancer, and any solid tumor that cannot repair the DNA errors that occur when DNA is copied.

[0255] 83. Use of Compound 1 or a pharmaceutically acceptable salt thereof as described in any one of Statements 80-82, wherein the cancer is lung cancer, mesothelioma, bladder cancer, melanoma, or uveal melanoma.

[0256] 84. Use of compound 1 or a pharmaceutically acceptable salt thereof described in any one of statements 80-82, where the cancer is refractory to checkpoint inhibitor plus chemotherapy or recurs after checkpoint inhibitor plus chemotherapy.

[0257] 85. Use of compound 1 or a pharmaceutically acceptable salt thereof as described in any one of statements 80-84, wherein the PD-1 or PD-L1 inhibitor is selected from atezolizumab, nivolumab, pembrolizumab, semiprimab, dostallimab, retifanlimab, and tripalimab.

[0258] 86. Use of Compound 1 or a pharmaceutically acceptable salt thereof as described in Statement 85, wherein the PD-1 or PD-L1 inhibitor is nivolumab.

[0259] 87. Use of Compound 1 or a pharmaceutically acceptable salt thereof as described in Statement 85, wherein the PD-1 or PD-L1 inhibitor is pembrolizumab.

[0260] 88. Use of Compound 1 or a pharmaceutically acceptable salt thereof as described in Statement 85, wherein the PD-1 or PD-L1 inhibitor is dostallimab.

[0261] 89. Use of Compound 1 or a pharmaceutically acceptable salt thereof as described in Statement 85, wherein the PD-1 or PD-L1 inhibitor is atezolizumab.

[0262] 90. Use of compound 1 or a pharmaceutically acceptable salt thereof as described in any one of statements 80-89, wherein the chemotherapeutic agent is selected from carboplatin, gemcitabine, cisplatin, docetaxel, doxorubicin, mitoxantrone, 5-fluorouracil (5-FU), capecitabine, irinotecan, oxaliplatin, pemetrexed, trifluridine, and tipiracil.

[0263] 91. Use of compound 1 or a pharmaceutically acceptable salt thereof described in any one of statements 80-90, wherein the chemotherapeutic agent is selected from carboplatin, gemcitabine, cisplatin, and docetaxel.

[0264] 92. Use of compound 1 or a pharmaceutically acceptable salt thereof as described in any one of statements 80 to 91, wherein the chemotherapeutic agent is carboplatin.

[0265] 93. Use of compound 1 or a pharmaceutically acceptable salt thereof as described in any one of statements 80 to 91, wherein the chemotherapeutic agent is cisplatin.

[0266] 94. Use of compound 1 or a pharmaceutically acceptable salt thereof as described in any one of statements 80 to 91, wherein the chemotherapeutic agent is gemcitabine.

[0267] 95. Use of compound 1 or a pharmaceutically acceptable salt thereof as described in any one of statements 80 to 91, wherein the chemotherapeutic agent is docetaxel.

[0268] 96. Use of compound 1 or a pharmaceutically acceptable salt thereof as described in any one of statements 80 to 86, comprising administering to the subject a first amount of compound 1, a second amount of nivolumab, and a third amount of carboplatin.

[0269] 97. Use of compound 1 or a pharmaceutically acceptable salt thereof as described in any one of statements 80 to 86, comprising administering to the subject a first amount of compound 1, a second amount of nivolumab, and a third amount of cisplatin.

[0270] 98. Use of compound 1 or a pharmaceutically acceptable salt thereof as described in any one of statements 80 to 86, comprising administering to the subject a first amount of compound 1, a second amount of nivolumab, and a third amount of gemcitabine.

[0271] 99. Use of compound 1 or a pharmaceutically acceptable salt thereof as described in any one of statements 80 to 85, comprising administering to the subject a first amount of compound 1, a second amount of pembrolizumab, and a third amount of docetaxel.

[0272] 100. Use of compound 1 or a pharmaceutically acceptable salt thereof as described in any one of statements 80 to 85, comprising administering to the subject a first amount of compound 1, a second amount of atezolizumab, and a third amount of docetaxel.

[0273] 101. Use of Compound 1 or a pharmaceutically acceptable salt thereof as described in any one of Statements 80-100, administered in doses of 40 mg or 80 mg per day as hemi-fumarate.

[0274] 102. Use of compound 1 or a pharmaceutically acceptable salt thereof described in any one of statements 80-101, where the subject has been previously treated with chemotherapy and / or a PD-1 or PD-L1 inhibitor, and the cancer is refractory or resistant.

[0275] 103. Use of compound 1 or a pharmaceutically acceptable salt thereof as described in any one of statements 80-101, where the subject has been previously treated with chemotherapy and / or a PD-1 or PD-L1 inhibitor and has not responded to or is resistant to said treatment.

[0276] 104. Use of compound 1 or a pharmaceutically acceptable salt thereof described in any one of statements 80-101, where the subject has been previously treated with chemotherapy selected from carboplatin, cisplatin, or gemcitabine, either alone or in combination with nivolumab, and the cancer is refractory or resistant.

[0277] 105. Use of compound 1 or a pharmaceutically acceptable salt thereof described in any one of statements 80-101, where the subject has been previously treated with nivolumab alone or in combination with chemotherapy selected from carboplatin, cisplatin, or gemcitabine, and the cancer is refractory or resistant.

[0278] 106. The use of compound 1 or a pharmaceutically acceptable salt thereof as described in any one of statements 80 to 105, wherein the treatment comprises the sequential administration of i) the agent comprising compound 1 or a pharmaceutically acceptable salt thereof, ii) a PD-1 or PD-L1 inhibitor or a pharmaceutically acceptable salt thereof, and iii) a chemotherapeutic agent or a pharmaceutically acceptable salt thereof to the subject.

[0279] 107.i) Equation I: [ka] ii) a compound or a pharmaceutically acceptable salt thereof, ii) a PD-1 or PD-L1 inhibitor or a pharmaceutically acceptable salt thereof, and iii) a chemotherapeutic agent or a pharmaceutically acceptable salt thereof, comprising a pharmaceutical product.

[0280] 108. Equation I: [ka] A kit comprising: a first pharmaceutical composition containing a compound or a pharmaceutically acceptable salt thereof; a second pharmaceutical composition containing a PD-1 or PD-L1 inhibitor or a pharmaceutically acceptable salt thereof; a third pharmaceutical composition containing a chemotherapeutic agent or a pharmaceutically acceptable salt thereof; and instructions for using the first and second pharmaceutical compositions in combination.

Claims

1. Formula I for use in the treatment of cancer in the target population: 【Chemistry 1】 A compound or a pharmaceutically acceptable salt thereof, wherein the treatment comprises administering to the subject separately, sequentially, or simultaneously: i) a pharmaceutically acceptable salt thereof, ii) a PD-1 or PD-L1 inhibitor or a pharmaceutically acceptable salt thereof, and iii) a chemotherapeutic agent or a pharmaceutically acceptable salt thereof.

2. Compound 1 or a pharmaceutically acceptable salt thereof for use according to claim 1, wherein the PD-1 or PD-L1 inhibitor is a PD-1 inhibitor.

3. Compound 1 or a pharmaceutically acceptable salt thereof for use according to claim 1 or 2, wherein the cancer is breast cancer, bladder cancer, cervical cancer, colon cancer, head and neck cancer, hematological cancer, liver cancer, lung cancer, kidney cancer, skin cancer including melanoma, uveal melanoma, gastric cancer, rectal cancer, mesothelioma, endometrial cancer, small intestine cancer, biliary tract cancer, ovarian cancer, brain cancer, testicular cancer, pancreatic cancer, bone cancer, and any solid tumor that cannot repair the DNA errors that occur when DNA is copied.

4. Compound 1 or a pharmaceutically acceptable salt thereof for use according to claim 3, wherein the cancer is lung cancer, mesothelioma, bladder cancer, melanoma, or uveal melanoma.

5. Compound 1 or a pharmaceutically acceptable salt thereof for use according to any one of claims 1 to 3, wherein the cancer is refractory to checkpoint inhibitor plus chemotherapy or recurs after checkpoint inhibitor plus chemotherapy.

6. Compound 1 or a pharmaceutically acceptable salt thereof for use according to any one of claims 1 to 5, wherein the PD-1 or PD-L1 inhibitor is a PD-1 inhibitor selected from atezolizumab, nivolumab, pembrolizumab, semiprimab, dostallimab, retifanlimab, and tripalimab.

7. Compound 1 or a pharmaceutically acceptable salt thereof for use according to claim 6, wherein the PD-1 inhibitor is atezolizumab, nivolumab, pembrolizumab, or dostallimab.

8. Compound 1 or a pharmaceutically acceptable salt thereof for use according to any one of claims 1 to 7, wherein the chemotherapeutic agent is selected from carboplatin, gemcitabine, cisplatin, docetaxel, doxorubicin, mitoxantrone, 5-fluorouracil (5-FU), capecitabine, irinotecan, oxaliplatin, pemetrexed, trifluridine, and tipiracil.

9. Compound 1 or a pharmaceutically acceptable salt thereof for use according to any one of claims 1 to 8, wherein the chemotherapeutic agent is selected from carboplatin, gemcitabine, cisplatin, and docetaxel.

10. Compound 1 or a pharmaceutically acceptable salt thereof for use according to any one of claims 1 to 9, wherein the chemotherapeutic agent is carboplatin.

11. Compound 1 or a pharmaceutically acceptable salt thereof for use according to any one of claims 1 to 9, wherein the chemotherapeutic agent is cisplatin.

12. Compound 1 or a pharmaceutically acceptable salt thereof for use according to any one of claims 1 to 9, wherein the chemotherapeutic agent is gemcitabine.

13. Compound 1 or a pharmaceutically acceptable salt thereof for use according to any one of claims 1 to 9, wherein the chemotherapeutic agent is docetaxel.

14. A pharmaceutically acceptable salt of compound 1 or the same for use according to any one of claims 1 to 9, comprising administering to the subject a first amount of compound 1, a second amount of nivolumab, and a third amount of carboplatin.

15. A pharmaceutically acceptable salt of compound 1 or the same for use according to any one of claims 1 to 9, comprising administering to the subject a first amount of compound 1, a second amount of nivolumab, and a third amount of cisplatin.

16. A pharmaceutically acceptable salt of compound 1 or the same for use according to any one of claims 1 to 9, comprising administering to the subject a first amount of compound 1, a second amount of nivolumab, and a third amount of gemcitabine.

17. A pharmaceutically acceptable salt of compound 1 or the same for use according to any one of claims 1 to 9, comprising administering to the subject a first amount of compound 1, a second amount of pembrolizumab, and a third amount of docetaxel.

18. A pharmaceutically acceptable salt of compound 1 or the same for use according to any one of claims 1 to 9, comprising administering to the subject a first amount of compound 1, a second amount of atezolizumab, and a third amount of docetaxel.

19. Compound 1 or a pharmaceutically acceptable salt thereof for use according to any one of claims 1 to 18, wherein Compound 1 is administered in a dose of 40 mg or 80 mg per day as hemifumarate.

20. The aforementioned subject is, (a) The patient has previously been treated with chemotherapy and / or PD-1 or PD-L1 inhibitors, and the cancer is refractory or resistant, (b) The patient has previously been treated with chemotherapy and / or PD-1 or PD-L1 inhibitors and has not responded to or is resistant to such treatment. (c) The patient has previously been treated with chemotherapy consisting of carboplatin, cisplatin, or gemcitabine, either alone or in combination with nivolumab, and the cancer is refractory or resistant, or (d) Compound 1 or a pharmaceutically acceptable salt thereof for use according to any one of claims 1 to 19, wherein the cancer has been previously treated with nivolumab alone or in combination with chemotherapy selected from carboplatin, cisplatin, or gemcitabine, and the cancer is refractory or resistant.

21. Compound 1 or a pharmaceutically acceptable salt thereof for use according to any one of claims 1 to 20, wherein the treatment comprises administering to the subject, in sequence, i) compound 1 or a pharmaceutically acceptable salt thereof, ii) a PD-1 or PD-L1 inhibitor or a pharmaceutically acceptable salt thereof, and iii) a chemotherapeutic agent or a pharmaceutically acceptable salt thereof.

22. Compound 1 or a pharmaceutically acceptable salt thereof for use according to any one of claims 1 to 21, in which only a single chemotherapeutic agent is administered.

23. i) Equation I: 【Chemistry 2】 A pharmaceutical product comprising: ii) a compound or a pharmaceutically acceptable salt thereof; ii) a PD-1 or PD-L1 inhibitor or a pharmaceutically acceptable salt thereof; and iii) a chemotherapeutic agent or a pharmaceutically acceptable salt thereof.

24. Formula I: 【Transformation 3】 A kit comprising: a first pharmaceutical composition comprising a compound or a pharmaceutically acceptable salt thereof; a second pharmaceutical composition comprising a PD-1 or PD-L1 inhibitor or a pharmaceutically acceptable salt thereof; a third pharmaceutical composition comprising a chemotherapeutic agent or a pharmaceutically acceptable salt thereof; and instructions for using the first and second pharmaceutical compositions in combination.

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