IADADEMSTAT COMBINATIONS FOR CANCER THERAPY

Abstract

The present invention relates to combinations, methods and compositions for the treatment of cancer comprising the administration of iadamstat in combination with a PD(L)1 inhibitor.

Description

[Technical Field]

[0001] Field The present invention relates to iadademstat combinations for cancer therapy, in particular combinations with immune checkpoint inhibitors as defined herein. [Background technology]

[0002] background Cancer immunotherapy, also known as immuno-oncology, is the artificial stimulation of the immune system to treat cancer. Checkpoint inhibitor therapy is a form of cancer immunotherapy that targets key regulators of the immune system, called immune checkpoints, to stimulate or inhibit their action, and can be used to protect tumors from attack by the immune system. Checkpoint therapy blocks inhibitory checkpoints and restores immune system function. In particular, PD(L)1 inhibitors are a group of immune checkpoint inhibitors that act by inhibiting the binding of programmed cell death protein 1 (PD-1, also known as PDCD1 or CD279) to its ligands, programmed cell death ligand 1 (PD-L1, also known as CD274) and programmed cell death ligand 2 (PD-L2, also known as CD273). The interaction of these cell surface proteins is involved in the suppression of the immune system, thereby limiting the killing of nearby host cells following infection and preventing autoimmune diseases, as well as different types of cancer.

[0003] By mobilizing the immune system against cancer cells, PD(L)1 inhibitor therapy holds promise for achieving durable responses in several malignant conditions, and several PD-1 and PD-L1 inhibitors have already been approved for the treatment of several types of cancer. However, therapeutic responses to immune checkpoint inhibitors, such as PD-1 or PD-L1 inhibitors, are observed in only a small proportion of cancer patients. The low mutational burden of "cold" tumors allows them to remain undetected by the host inflammatory response (intrinsic resistance), and cancer cells express multiple replication strategies in response to the selective pressures applied by treatment with immune checkpoint inhibitors (recruitment of regulatory cells, defective antigen presentation, immunosuppressive mediators, reduced costimulation, and T cell apoptosis). Thus, there is a need for improved methods and compositions for treating cancer that address the problem of resistance and lack of responsiveness to immune checkpoint inhibitors, particularly PD(L)1 inhibitors. Summary of the Invention

[0004] The present invention is based on the unexpected finding that immune checkpoint inhibitors, in particular the combination of iadamstat with a PD(L)1 inhibitor (as defined herein), exhibit significantly greater activity in inhibiting cancer cell proliferation when compared to treatment with the immune checkpoint inhibitor alone. This allows iadamstat to be used to sensitize tumors to PD(L)1 inhibitors and improve tumor responsiveness to PD(L)1 inhibitor therapy.

[0005] Thus, the present invention relates to a combination of iadamstat, or a pharmaceutically acceptable salt or solvate thereof, together with a PD(L)1 inhibitor (as defined herein). Thus, the present invention provides a combination comprising iadamstat, or a pharmaceutically acceptable salt or solvate thereof, and a PD(L)1 inhibitor. The present invention further provides a combination comprising iadademstat, or a pharmaceutically acceptable salt or solvate thereof, and a PD(L)1 inhibitor for use in the treatment of cancer. The present invention further provides a method of treating cancer in a patient (preferably a human) in need thereof, comprising administering to the patient a therapeutically effective amount of a combination comprising iadademstat, or a pharmaceutically acceptable salt or solvate thereof, and a PD(L)1 inhibitor.

[0006] The present invention further provides a method of treating cancer in a patient (preferably a human) in need thereof, comprising administering to the patient a therapeutically effective amount of iadademstat, or a pharmaceutically acceptable salt or solvate thereof, and a therapeutically effective amount of a PD(L)1 inhibitor. The present invention further provides the use of iadademstat, or a pharmaceutically acceptable salt or solvate thereof, for the manufacture of a therapeutic agent for the treatment of cancer, to be used in combination with a PD(L)1 inhibitor. The present invention further provides the use of a combination comprising iadademstat, or a pharmaceutically acceptable salt or solvate thereof, and a PD(L)1 inhibitor for the treatment of cancer. [Brief explanation of the drawings]

[0007] [Figure 1] Figure 1 shows the effect of treatment with a combination of iadademstat (also known as "ORY-1001") and a PD(L)1 inhibitor (triangles) compared to treatment with a PD(L)1 inhibitor alone (squares) on tumor volume in a murine B16F10 melanoma model, as described in more detail in Example 1. Data are presented as the mean ± standard error of the mean (SEM); p=0.004. [Figure 2] Figure 2 shows the effect of treatment with a combination of iadademstat ("ORY-1001") and a PD(L)1 inhibitor (triangles) compared to treatment with a PD(L)1 inhibitor alone (squares) on tumor weight in the same murine B16F10 melanoma model, as described in more detail in Example 1. Data are presented as the mean ± standard error of the mean (SEM); p=0.001. DETAILED DESCRIPTION OF THE INVENTION

[0008] Detailed Description of the Invention As described above, the present invention is based on the discovery that the combination of a PD(L)1 inhibitor and iadademstat exhibits excellent anti-cancer activity, with superior anti-cancer efficacy compared to treatment with the PD(L)1 inhibitor alone. Combined treatment with iadademstat and a PD(L)1 inhibitor results in a significantly enhanced anti-tumor effect compared to treatment with the PD(L)1 inhibitor alone, as illustrated in Example 1 and Figures 1 and 2 using an in vivo mouse melanoma model. Treatment with the combination results in a statistically significant reduction in both tumor volume and tumor weight compared to treatment with the PD(L)1 inhibitor alone, as shown in Figures 1 and 2, respectively. Thus, treatment with iadademstat enhances the efficacy of the PD(L)1 inhibitor or otherwise acts synergistically with the PD(L)1 inhibitor.

[0009] Thereby, iadademstat may be used in combination with PD(L)1 inhibitors to treat cancer, including enhancing the responsiveness of cancer to PD(L)1 inhibitor therapy and / or sensitizing refractory, unresponsive or recurrent cancers to PD(L)1 inhibitors. According to the present invention, a "PD(L)1 inhibitor" refers to a compound that inhibits the interaction of PD-1 with any of its ligands, PD-L1, PD-L2, or between PD-L1 and PD-L2, inhibits PD-1 signaling, or relieves PD-1-dependent inhibition of T-cell-mediated immune responses against tumor cells. Thus, as used herein, a PD(L)1 inhibitor includes a PD-1 inhibitor, a PD-L1 inhibitor, and a PD-L2 inhibitor, examples of which are provided below under the heading "PD(L)1 inhibitors." In particular, the present invention provides a combination comprising iadamstat, or a pharmaceutically acceptable salt or solvate thereof, and a PD(L)1 inhibitor.

[0010] The present invention further provides a combination comprising iadademstat, or a pharmaceutically acceptable salt or solvate thereof, and a PD(L)1 inhibitor for use as a therapeutically active substance. The present invention further provides a combination comprising iadademstat, or a pharmaceutically acceptable salt or solvate thereof, and a PD(L)1 inhibitor for use in therapy. The present invention further provides a combination comprising iadademstat, or a pharmaceutically acceptable salt or solvate thereof, and a PD(L)1 inhibitor for use in the treatment of a disease. The present invention further provides a combination comprising iadademstat, or a pharmaceutically acceptable salt or solvate thereof, and a PD(L)1 inhibitor for use in the treatment of cancer.

[0011] The present invention further provides iadademstat, or a pharmaceutically acceptable salt or solvate thereof, for use in the treatment of cancer in combination with a PD(L)1 inhibitor. The present invention further provides a PD(L)1 inhibitor in combination with iadademstat, or a pharmaceutically acceptable salt or solvate thereof, for use in the treatment of cancer. The present invention further provides iadademstat, or a pharmaceutically acceptable salt or solvate thereof, for use in the treatment of cancer, wherein said iadademstat, or a pharmaceutically acceptable salt or solvate thereof, is to be administered in combination with a PD(L)1 inhibitor. The present invention further provides a PD(L)1 inhibitor for use in the treatment of cancer, wherein the PD(L)1 inhibitor is to be administered in combination with iadademstat, or a pharmaceutically acceptable salt or solvate thereof.

[0012] The present invention further provides a method of treating cancer in a patient in need thereof, comprising administering to the patient a combination comprising a therapeutically effective amount of iadademstat, or a pharmaceutically acceptable salt or solvate thereof, and a PD(L)1 inhibitor. The present invention further provides a method of treating cancer in a patient in need thereof, comprising administering to the patient a therapeutically effective amount of iadademstat, or a pharmaceutically acceptable salt or solvate thereof, and a therapeutically effective amount of a PD(L)1 inhibitor. The present invention further provides the use of iadademstat, or a pharmaceutically acceptable salt or solvate thereof, for the manufacture of a therapeutic agent for the treatment of cancer, to be used in combination with a PD(L)1 inhibitor. The present invention further provides the use of a PD(L)1 inhibitor for the manufacture of a therapeutic agent for the treatment of cancer, to be used in combination with iadademstat, or a pharmaceutically acceptable salt or solvate thereof.

[0013] The present invention further provides the use of a combination comprising iadademstat, or a pharmaceutically acceptable salt or solvate thereof, and a PD(L)1 inhibitor for the manufacture of a therapeutic agent for the treatment of cancer. The present invention further provides the use of a combination comprising iadademstat, or a pharmaceutically acceptable salt or solvate thereof, and a PD(L)1 inhibitor for the treatment of cancer. The present invention further provides the use of iadademstat, or a pharmaceutically acceptable salt or solvate thereof, for the treatment of cancer in combination with a PD(L)1 inhibitor. The present invention further provides the use of a PD(L)1 inhibitor in combination with iadamstat, or a pharmaceutically acceptable salt or solvate thereof, for the treatment of cancer.

[0014] The present invention further provides iadademstat, or a pharmaceutically acceptable salt or solvate thereof, for use in the treatment of cancer by sensitizing the cancer to treatment with a PD(L)1 inhibitor. The present invention further provides the use of iadademstat, or a pharmaceutically acceptable salt or solvate thereof, for the treatment of cancer by sensitizing the cancer to treatment with a PD(L)1 inhibitor. The present invention further provides the use of iadademstat, or a pharmaceutically acceptable salt or solvate thereof, for the manufacture of a therapeutic agent for the treatment of cancer by sensitizing the cancer to treatment with a PD(L)1 inhibitor. The present invention further provides a method of treating cancer in a patient in need thereof by sensitizing the cancer to treatment with a PD(L)1 inhibitor, the method comprising administering to the patient a therapeutically effective amount of iadademstat, or a pharmaceutically acceptable salt or solvate thereof.

[0015] The present invention further provides iadademstat, or a pharmaceutically acceptable salt or solvate thereof, for use in sensitizing cancer to treatment with a PD(L)1 inhibitor. The present invention further provides the use of iadamstat, or a pharmaceutically acceptable salt or solvate thereof, for sensitizing cancer to treatment with a PD(L)1 inhibitor. The present invention further provides the use of iadademstat, or a pharmaceutically acceptable salt or solvate thereof, for the manufacture of a therapeutic agent for sensitizing cancer to treatment with a PD(L)1 inhibitor. The present invention further provides a method of sensitizing cancer to treatment with a PD(L)1 inhibitor in a patient in need thereof, comprising administering to the patient a therapeutically effective amount of iadademstat, or a pharmaceutically acceptable salt or solvate thereof.

[0016] The present invention further provides iadademstat, or a pharmaceutically acceptable salt or solvate thereof, for use in enhancing the responsiveness of cancer to PD(L)1 inhibitor therapy. The present invention further provides the use of iadademstat, or a pharmaceutically acceptable salt or solvate thereof, for the manufacture of a therapeutic agent for enhancing the responsiveness of a cancer to PD(L)1 inhibitor therapy. The present invention further provides a method of enhancing the responsiveness of cancer to PD(L)1 inhibitor therapy in a patient in need thereof, comprising administering to the patient a therapeutically effective amount of iadademstat, or a pharmaceutically acceptable salt or solvate thereof.

[0017] The present invention further provides iadademstat, or a pharmaceutically acceptable salt or solvate thereof, for use in sensitizing refractory, unresponsive or recurrent cancer to PD(L)1 inhibitor therapy. The present invention further provides use of iadademstat, or a pharmaceutically acceptable salt or solvate thereof, for the manufacture of a therapeutic agent for sensitizing refractory, unresponsive, or recurrent cancer to PD(L)1 inhibitor therapy. The present invention further provides a method for sensitizing refractory, unresponsive, or recurrent cancer to PD(L)1 inhibitor therapy in a patient in need thereof, comprising administering to the patient a therapeutically effective amount of iadademstat, or a pharmaceutically acceptable salt or solvate thereof.

[0018] The present invention further provides iadademstat, or a pharmaceutically acceptable salt or solvate thereof, for use as adjunctive therapy to a PD(L)1 inhibitor. The present invention further provides the use of iadademstat, or a pharmaceutically acceptable salt or solvate thereof, as adjunctive therapy to a PD(L)1 inhibitor. The present invention further provides the use of iadademstat, or a pharmaceutically acceptable salt or solvate thereof, for the manufacture of a therapeutic agent for use as adjunctive therapy to a PD(L)1 inhibitor. The present invention further provides a method for treating cancer in a patient in need thereof, comprising sensitizing said cancer by administering to said patient iadademstat, or a pharmaceutically acceptable salt or solvate thereof, followed by administering a combination comprising therapeutically effective amounts of iadademstat, or a pharmaceutically acceptable salt or solvate thereof, and a PD(L)1 inhibitor. The present invention further provides a method for treating cancer in a patient in need thereof, comprising a first treatment in which said patient is administered iadademstat (or a pharmaceutically acceptable salt or solvate thereof) alone (i.e., without a PD(L)1 inhibitor), followed by initiation of treatment with a combination comprising iadademstat (or a pharmaceutically acceptable salt or solvate thereof) and a PD(L)1 inhibitor.

[0019] In some embodiments, the cancer is a solid tumor. In some embodiments, the cancer is suitable for treatment with a PD(L)1 inhibitor, particularly a cancer for which PD(L)1 inhibitor therapy has been approved, i.e., for which it has received marketing authorization by a regulatory agency in at least one country. In some embodiments, the cancer is selected from the group consisting of melanoma, small cell lung cancer (SCLC), non-small cell lung cancer (NSCLC), head and neck cancer, renal cell carcinoma, Hodgkin's lymphoma, urothelial carcinoma, colorectal cancer, hepatocellular carcinoma, cutaneous squamous cell carcinoma, ovarian cancer, gastric cancer, gastroesophageal cancer, Merkel cell carcinoma, nasopharyngeal cancer, breast cancer (e.g., triple-negative breast cancer), and esophageal squamous cell carcinoma.

[0020] In some embodiments, the cancer is selected from the group consisting of melanoma, small cell lung cancer (SCLC), non-small cell lung cancer (NSCLC), head and neck cancer, renal cell carcinoma, Hodgkin's lymphoma, urothelial carcinoma, colorectal cancer, hepatocellular carcinoma, cutaneous squamous cell carcinoma, and Merkel cell carcinoma. In some embodiments, the cancer is melanoma. In some embodiments, the cancer is small cell lung cancer.

[0021] In some embodiments, the cancer is a refractory, unresponsive, or recurrent cancer to PD(L)1 inhibitor therapy. Thus, in some embodiments, the cancer is a refractory, unresponsive, or recurrent cancer to monotherapy with a PD(L)1 inhibitor. In the methods and uses according to the present invention, the patient may be a human or an animal, preferably a human. In some embodiments, the patient suffering from said cancer has received at least one prior treatment for said cancer that includes a PD(L)1 inhibitor (alone or in combination with other therapeutic agents).

[0022] Iadademstat: Iadademstat has the following formula (I): [ka]

[0023] [CAS Registry Number 1431304-21-0] is the International Nonproprietary Name (INN) for the compound, which is also known as ORY-1001 or (trans)-N1-((1R,2S)-2-phenylcyclopropyl)cyclohexane-1,4-diamine. Iadademstat is described, for example, in Example 5 of International Patent Application WO2013 / 057322. Pharmaceutically acceptable salts thereof are also described therein, including the hydrochloride salt [CAS Registry Number 1431303-72-8, dihydrochloride salt]. The most preferred pharmaceutically acceptable salt is the dihydrochloride salt. Iadademstat acts as a selective LSD1 inhibitor.

[0024] The terms "iadademstat," "compound of formula (I)," (trans)-N1-((1R,2S)-2-phenylcyclopropyl)cyclohexane-1,4-diamine," and "ORY-1001" are used interchangeably herein (i.e., throughout this specification and claims). Unless specifically stated otherwise, any reference to iadademstat throughout this specification and claims includes any iadademstat, or a pharmaceutically acceptable salt or solvate thereof. Preferably, iadademstat is used in the form of a pharmaceutically acceptable salt, preferably the hydrochloride salt, more preferably the dihydrochloride salt.

[0025] Preferably, iadademstat (or a pharmaceutically acceptable salt or solvate thereof) is administered orally. Exemplary formulations that can be administered via oral ingestion are further described in more detail below.

[0026] PD(L)1 inhibitors: As indicated above, as used herein, a "PD(L)1 inhibitor" refers to a compound that inhibits the interaction of PD-1 with any of its ligands, PD-L1 and / or PD-L2, inhibits PD-1 signaling, or relieves PD-1-dependent inhibition of T-cell-mediated immune responses against tumor cells. Thus, the term "PD(L)1 inhibitor" includes a PD1 inhibitor, a PD-L1 inhibitor, and a PD-L2 inhibitor. Thus, a PD(L)1 inhibitor may be a PD1 inhibitor, a PD-L1 inhibitor, or a PD-L2 inhibitor.

[0027] PD(L)1 inhibitors are well known in the art and in principle any molecule that acts as a PD(L)1 inhibitor may be used in connection with the combinations, methods and uses according to the invention. The PD(L)1 inhibitor may be, for example, a small molecule, a peptide, an antibody or a vaccine. In some embodiments, the PD(L)1 inhibitor is an antibody, more preferably a human or humanized antibody.

[0028] Non-limiting examples of PD-1 inhibitors that may be used in accordance with the present invention include: Pembrolizumab (Merck & Co), Nivolumab (Bristol-Myers Squibb), Cemiplimab (also known as REGN-2810) (Regeneron Pharmaceuticals / Sanofi), Camrelizumab (also known as SHR-1210) (Shanghai Hengrui), Genolimzumab (also known as APL-501, GB226 or CBT-501) (Apollonomics Inc / Genor Biopharma), Tislelizumab (also known as BGB-A317) (Beigene / Celgene), Sintilimab (also known as IBI-308) (Eli Lilly / Innovent), toripalimab (also known as JS-001) (Shanghai Junshi), spartalizumab (also known as PDR-001) (Novartis), AGEN-2034 (Agenus), AK-103 (Akeso Bio), AK-104 (Akeso Bio), AK-105 (Akeso Bio), AK-112 (Akeso Bio), AK-123 (Akeso Bio), AM-0001 (ARMO Bio / Eli Lilly), AMP-224 (Medimmune / GSK / NCI), AT16201 (AIMM), BCD-100 (Biocad), BH-2950 (Beijing Hanmi), BH-2996h (Beijing Hanmi), BI-754091 (Boehringer Ingelheim), BMS-1001 (Bristol-Myers Squibb), BMS-1166 (Bristol-Myers Squibb), CS-1003 (CStone Pharmaceuticals), CX-188 (CytomX), ENUM-244C8 (Enumeral), GLS-010(Harbin / Wuxi / Arcus / Gloria Pharmaceuticals), hAb21 (Suzhou Stainwei), HLX-10 (Shanghai Henlius), IKT-202 (Icell Kealex), JNJ-63723283 (J&J), JTX-4014 (Jounce Therapeutics), KN0-46 (Alphamab), MEDI-0680 (also known as AMP-514) (Medimmune / GSK), MGA-012 (Macrogenics), MGD-013 (Macrogenics), PF-06801591 (Pfizer), PRS-332 (Pieris / Servier), RO7121661 (also known as RG-7769) (Roche), STI-A1110 (Servier / Sorrento), TSR-042 (Tesaro) and XmAb-20717 (Xencor).

[0029] Non-limiting examples of PD-L1 inhibitors that may be used in accordance with the present invention include: atezolizumab, avelumab, durvalumab, AK-106 (Akeso Bio), APL-502 (also known as TQ-B2450) (Apollonomics Inc), AVA-004 (Avacta), BGB-A333 (BeiGene), BH-2996h (Beijing Hanmi), BMS-936559 (also known as MDX-11105) (Bristol-Myers Squibb), CA-170 (Curis / Aurigene), CA-327 (Curis / Aurigene), CBA-0710 (Sorrento), CK-301 (CheckPoint Therapeutics / TG Therapeutics), CS-1001 (CStone Pharmaceuticals), CX-072 (CytomX), FAZ-053 (Novartis), FS-118 (F Star / Merck KGaA), GR1405 (Genrix Biopharmaceutical), HLX-20 (Shanghai Henlius), IKT-201 (Icell Kealex), JS-003 (Shanghai Junshi), KD033 (Kadmon / Jinghua Pharma), KN-035 (3D Medicines Co, Ltd), KY-1003 (Kymab), LY3300054 (Eli Lilly), M-7824 (Merck KGaA), MCLA-145 (Merus / Incyte), MSB-2311 (Mabspace Biosciences), and SHR-1316 (Also known as HTI-1088) (Atridia / Jiangsu Hengrui Therapeutics).

[0030] Preferred PD-1 inhibitors are pembrolizumab, nivolumab, and cemiplimab. Nivolumab (Pembrolizumab) (also known as MK-3475 or lambrolizumab, Keytruda®) was first approved by the Food and Drug Administration in 2014 for the treatment of melanoma. It was subsequently approved for metastatic non-small cell lung cancer and head and neck squamous cell carcinoma. The drug has also been approved for SCLC, Hodgkin lymphoma, primary mediastinal large B-cell lymphoma, urothelial carcinoma, gastric cancer, esophageal cancer, cervical cancer, hepatocellular carcinoma, Merkel cell carcinoma, renal cell carcinoma, and endometrial carcinoma.

[0031] Nivolumab (Opdivo®) was developed by Bristol-Myers Squibb and was first approved by the FDA in 2014 for the treatment of melanoma. It was subsequently approved for non-small cell lung cancer, renal cell carcinoma, Hodgkin lymphoma, head and neck squamous cell carcinoma, urothelial carcinoma, metastatic colorectal cancer and hepatocellular carcinoma, and SCLC. Cemiplimab (Libtayo®) was developed by Regeneron and was first approved by the FDA in 2018 for the treatment of cutaneous squamous cell carcinoma (CSCC). Preferred PD-L1 inhibitors are atezolizumab, avelumab, and durvalumab.

[0032] Atezolizumab (Tecentriq®) was developed by Roche Genentech. In 2016, the FDA approved atezolizumab for urothelial carcinoma and non-small cell lung cancer. It was subsequently approved for SCLC and triple-negative breast cancer. Avelumab (Bavencio®) was developed by Merck Serono and Pfizer. Avelumab was approved by the FDA in 2016 for the treatment of metastatic Merkel cell carcinoma, and was subsequently approved for urothelial carcinoma and renal cell carcinoma.

[0033] Durvalumab (Imfinzi®) was developed by AstraZeneca. Durvalumab first received FDA approval in 2017 and is currently approved for the treatment of urothelial carcinoma and non-small cell lung cancer. In some embodiments, the PD(L)1 inhibitor is a PD-1 inhibitor or a PD-L1 inhibitor.

[0034] In some embodiments, the PD(L)1 inhibitor is selected from the group consisting of pembrolizumab, nivolumab, cemiplimab, camrelizumab, tislelizumab, sintilimab, toripalimab, spartalizumab, AGEN-2034, AK-103, AK-104, AK-105, AK-112, AK-123, AM-0001, AMP-224, AT16201 , BCD-100, BH-2950, ​​BH-2996h, BI-754091, BMS-1001, BMS-1166, CS-1003, CX-188, ENUM-244 C8, GLS-010, hAb21, HLX-10, IKT-202, JNJ-63723283, JTX-4014, KN0-46, MEDI-0680, MGA-012 , MGD-013, PF-06801591, PRS-332, RO7121661, STI-A1110, TSR-042, XmAb-20717, atezolizumab, avelumab, durvalumab, AK-106, APL-502, AVA-004, BGB-A333, BH-2996h, BMS-936559, CA-170, CA-327 , CBA-0710, CK-301, CS-1001, CX-072, FAZ-053, FS-118, GR1405, HLX-20, IKT-201, JS-003, KD033, KN-035, KY-1003, LY3300054, M-7824, MCLA-145, MSB-2311, and SHR-1316. In some embodiments, the PD(L)1 inhibitor is selected from the group consisting of pembrolizumab, nivolumab, cemiplimab, atezolizumab, avelumab, and durvalumab.

[0035] In some embodiments, the PD(L)1 inhibitor is a PD-1 inhibitor, such as pembrolizumab, nivolumab, cemiplimab, camrelizumab, tislelizumab, sintilimab, toripalimab, spartalizumab, AGEN-2034, AK-103, AK-104, AK-105, AK-112, AK-123, AM-0001, AMP-224, AT16201, BCD-100, BH-2950, ​​BH-2996h, BI-754091, BMS-10 01, BMS-1166, CS-1003, CX-188, ENUM-244C8, GLS-010, hAb21, HLX-10, IKT-202, JNJ-63723283, JTX-4014, KN0-46, MEDI-0680, MGA-012, MGD-013, PF-06801591, PRS-332, RO7121661, STI-A1110, TSR-042, and XmAb-20717. In some embodiments, the PD-1 inhibitor is selected from the group consisting of pembrolizumab, nivolumab, and cemiplimab.

[0036] In some embodiments, the PD(L)1 inhibitor is a PD-L1 inhibitor, hi some embodiments, the PD-L1 inhibitor is selected from the group consisting of atezolizumab, avelumab, durvalumab, AK-106, APL-502, AVA-004, BGB-A333, BH-2996h, BMS-936559, CA-170, CA-327, CBA-0710, CK-301, CS-1001, CX-072, FAZ-053, FS-118, GR1405, HLX-20, IKT-201, JS-003, KD033, KN-035, KY-1003, LY3300054, M-7824, MCLA-145, MSB-2311, and SHR-1316. In some embodiments, the PD-L1 inhibitor is selected from the group consisting of atezolizumab, avelumab, and durvalumab.

[0037] In some embodiments, the PD(L)1 inhibitor is a PD-L2 inhibitor. In some embodiments, the present invention provides a combination comprising iadademstat, or a pharmaceutically acceptable salt or solvate thereof, and a PD(L)1 inhibitor selected from a PD-1 inhibitor and a PD-L1 inhibitor. In some embodiments, the PD(L)1 inhibitor is selected from the group consisting of pembrolizumab, nivolumab, cemiplimab, camrelizumab, tislelizumab, sintilimab, toripalimab, spartalizumab, AGEN-2034, AK-103, AK-104, AK-105, AK-112, AK-123, AM-0001, AMP-224, and AT16201. , BCD-100, BH-2950, ​​BH-2996h, BI-754091, BMS-1001, BMS-1166, CS-1003, CX-188, ENUM-244 C8, GLS-010, hAb21, HLX-10, IKT-202, JNJ-63723283, JTX-4014, KN0-46, MEDI-0680, MGA-012 , MGD-013, PF-06801591, PRS-332, RO7121661, STI-A1110, TSR-042, XmAb-20717, atezolizumab, avelumab, durvalumab, AK-106, APL-502, AVA-004, BGB-A333, BH-2996h, BMS-936559, CA-170, CA-327 , CBA-0710, CK-301, CS-1001, CX-072, FAZ-053, FS-118, GR1405, HLX-20, IKT-201, JS-003, KD033, KN-035, KY-1003, LY3300054, M-7824, MCLA-145, MSB-2311, and SHR-1316. In some embodiments, the PD(L)1 inhibitor is selected from the group consisting of pembrolizumab, nivolumab, cemiplimab, atezolizumab, avelumab, and durvalumab.

[0038] In some embodiments, the present invention provides a combination comprising iadademstat, or a pharmaceutically acceptable salt or solvate thereof, and a PD-1 inhibitor. In some embodiments, the PD-1 inhibitor is selected from the group consisting of pembrolizumab, nivolumab, cemiplimab, camrelizumab, tislelizumab, sintilimab, toripalimab, spartalizumab, AGEN-2034, AK-103, AK-104, AK-105, AK-112, AK-123, AM-0001, AMP-224, AT16201, BCD-100, BH-2950, ​​BH-2996h, BI-754091, and BMS-10 01, BMS-1166, CS-1003, CX-188, ENUM-244C8, GLS-010, hAb21, HLX-10, IKT-202, JNJ-63723283, JTX-4014, KN0-46, MEDI-0680, MGA-012, MGD-013, PF-06801591, PRS-332, RO7121661, STI-A1110, TSR-042, and XmAb-20717. In some preferred embodiments, the PD-1 inhibitor is selected from the group consisting of pembrolizumab, nivolumab, and cemiplimab.

[0039] In some embodiments, the present invention provides a combination comprising iadademstat, or a pharmaceutically acceptable salt or solvate thereof, and a PD-L1 inhibitor. In some preferred embodiments, the PD-L1 inhibitor is selected from the group consisting of atezolizumab, avelumab, durvalumab, AK-106, APL-502, AVA-004, BGB-A333, BH-2996h, BMS-936559, CA-170, CA-327, CBA-0710, CK-301, CS-1001, CX-072, FAZ-053, FS-118, GR1405, HLX-20, IKT-201, JS-003, KD033, KN-035, KY-1003, LY3300054, M-7824, MCLA-145, MSB-2311, and SHR-1316. In some preferred embodiments, the PD-L1 inhibitor is selected from the group consisting of atezolizumab, avelumab, and durvalumab.

[0040] In some embodiments, the present invention provides a combination comprising iadademstat, or a pharmaceutically acceptable salt or solvate thereof, and a PD-L2 inhibitor. Another embodiment provides pharmaceutical compositions or therapeutic agents comprising the combinations described herein and pharmaceutically acceptable excipients, and methods of using compounds of formula (I) to prepare such combinations, compositions and therapeutic agents.

[0041] Any reference to iadamstat throughout this specification includes a reference to the compound itself, i.e., in non-salt form (e.g., as the free base), or to the corresponding compound in the form of any pharmaceutically acceptable salt or solvate thereof, as well as a reference to any pharmaceutical composition comprising said compound and one or more pharmaceutically acceptable excipients or carriers. Any reference throughout this specification to a PD(L)1 inhibitor includes a reference to the PD(L)1 inhibitor per se or (where appropriate) the corresponding compound in the form of any pharmaceutically acceptable salt or solvate thereof, as well as a reference to any pharmaceutical composition comprising said PD(L)1 inhibitor and one or more pharmaceutically acceptable excipients or carriers.

[0042] Pharmaceutical preparations The combinations described herein, and iadademstat and PD(L)1 inhibitors for use in the pharmaceutical compositions described herein, may be administered by any suitable method, including oral, topical (including buccal and sublingual), rectal, vaginal, transdermal, parenteral, subcutaneous, intraperitoneal, intrapulmonary, intradermal, intrathecal, epidural and intranasal, as well as local treatment, intralesional administration, as appropriate. Parenteral administration includes intramuscular, intravenous, intraarterial, intraperitoneal, or subcutaneous administration.

[0043] Like iadademstat and other therapeutic agents for use in the combinations described herein, the pharmaceutical compositions described herein can also be administered in the form of pharmaceutical products, such as tablets, powders, capsules, liquids, dispersions, suspensions, syrups, sprays, suppositories, gels, emulsions, patches, etc. Such compositions may contain conventional ingredients in pharmaceutical formulations, such as diluents, carriers, pH adjusters, preservatives, solubilizers, stabilizers, wetting agents, sweeteners, colorants, flavorings, salts for changing osmotic pressure, buffers, masking agents, antioxidants, and additional active agents. They may also further contain other therapeutically valuable substances.

[0044] A typical formulation is prepared by mixing iadademstat or another therapeutic agent described herein or a combination described herein with a pharmaceutically acceptable excipient. Suitable excipients are well known to those skilled in the art and are described in detail, for example, in Ansel's Pharmaceutical Dosage Forms and Drug Delivery Systems (2004) Lippincott, Williams & Wilkins, Philadelphia; Remington: The Science and Practice of Pharmacy (2000) Lippincott, Williams & Wilkins, Philadelphia; and Handbook of Pharmaceutical Excipients (2005) Pharmaceutical Press, Chicago. The formulation may also include one or more buffers, stabilizers, surfactants, wetting agents, lubricants, emulsifiers, suspending agents, preservatives, antioxidants, opacifiers, flow agents, processing aids, colorants, sweeteners, flavors, flavorings, diluents, and other known excipients to provide aesthetic appeal for the drug (i.e., the compound of the present invention or a pharmaceutical composition thereof) or to aid in the manufacture of the pharmaceutical product (i.e., the therapeutic agent).

[0045] For oral delivery, the compounds can be formulated into formulations containing pharmaceutically acceptable carriers, such as binders (e.g., gelatin, cellulose, gum tragacanth), excipients (e.g., starch, lactose), lubricants (e.g., magnesium stearate, silicon dioxide), disintegrants (e.g., alginate, Primogel, and corn starch), and sweeteners or flavoring agents (e.g., glucose, sucrose, saccharin, methyl salicylate, and peppermint). The formulations can be orally delivered, for example, in the form of encapsulated gelatin capsules or compressed tablets. Capsules and tablets can be prepared by any conventional technique. Capsules and tablets can also be coated with various coatings known in the art to modify the flavor, taste, color, and shape of the capsules and tablets. A liquid carrier, such as a fatty oil, can also be contained in the capsule. Suitable oral formulations can also be in the form of suspensions, syrups, chewing gums, wafers, elixirs, and the like. If necessary, conventional agents for modifying flavor, taste, color, and shape of the special form may also be included.Furthermore, for convenient administration by enteral feeding tube in patients who cannot swallow, the active compound can be dissolved in an acceptable lipophilic vegetable oil vehicle such as olive oil, corn oil, and safflower oil.

[0046] The compounds can also be administered parenterally in the form of a solution or suspension, or in a lyophilized form that can be converted into a solution or suspension before use. In such formulations, diluents or pharmaceutically acceptable carriers, such as sterile water and physiological saline buffer, can be used. Other conventional solvents, pH buffers, stabilizers, antibacterial agents, surfactants, and antioxidants can all be included. For example, useful ingredients include sodium chloride, acetate, citrate, or phosphate buffers, glycerin, dextrose, fixed oils, methylparaben, polyethylene glycol, propylene glycol, sodium bisulfate, benzyl alcohol, ascorbic acid, etc. Parenteral formulations can be stored in conventional containers such as vials and ampoules.

[0047] For topical administration, compound can be formulated into lotion, cream, ointment, gel, powder, paste, spray, suspension, drop and aerosol.Therefore, one or more thickeners, moisturizers and stabilizers can be included in the formulation.Examples of such agents include but are not limited to polyethylene glycol, sorbitol, xanthan gum, petrolatum, beeswax, or mineral oil, lanolin, squalene, etc.A special form of topical administration is delivery by transdermal patch.The method of producing transdermal patch is disclosed, for example, in Brown, et al. (1988) Ann. Rev. Med. 39:221-229, etc., which is incorporated herein by reference.

[0048] Subcutaneous implantation for sustained release of a compound may also be a suitable route of administration. This requires a surgical procedure to implant the active compound in any suitable formulation into the subcutaneous space, e.g., under the anterior abdominal wall. See, e.g., Wilson et al. (1984) J. Clin. Psych. 45:242-247. Hydrogels can be used as carriers for sustained release of active compounds. Hydrogels are generally known in the art. They are typically made by crosslinking high molecular weight biocompatible polymers into a network that swells in water to form a gel-like material. Preferably, the hydrogel is biodegradable or bioabsorbable. For purposes of the present invention, hydrogels made of polyethylene glycol, collagen, or poly(glycolic acid-co-L-lactic acid) may be useful. See, e.g., Phillips et al. (1984) J. Pharmaceut. Sci., 73:1718-1720.

[0049] Pharmaceutical compositions, such as oral and parenteral compositions, can be formulated in unit dosage form for ease of administration and uniformity of dosage. As used herein, "unit dosage form" refers to a physically discrete unit suitable for administration to a subject as a unitary dose, each unit containing a predetermined amount of active ingredient calculated to produce a desired therapeutic effect, together with one or more suitable pharmaceutical carriers.

[0050] For therapeutic use, the pharmaceutical composition should be administered in a manner appropriate to the disease being treated, as determined by one skilled in the medical field. The appropriate dose and the appropriate duration and frequency of administration can vary within wide limits and are determined by factors such as the patient's condition, the type and severity of the disease, the specific form of the active ingredient, and the method of administration. In general, an appropriate dose and regimen provides a sufficient amount of the pharmaceutical composition to provide a therapeutic benefit, e.g., an improved clinical outcome, such as more frequent complete or partial remissions, or longer disease-free and / or overall survival, or a reduction in the severity of symptoms, or other improvement that can identify the objectives indicated by the clinician. Effective doses can generally be assessed or estimated using experimental models, such as in vitro or animal model test systems, or dose-response curves obtained from clinical trials.

[0051] Suitable doses of the PD(L)-1 inhibitor are typically those currently used by physicians for the respective immune checkpoint inhibitor, particularly the dose(s) approved by the respective governmental authorities. Other doses may also be possible, for example, the dose of the PD(L)-1 inhibitor may be lower due to the combined effect of the newly identified combination of said PD(L)-1 inhibitor with iadademstat.

[0052] The combinations described herein can be administered as a simultaneous or sequential regimen. When administered sequentially, the combination can be administered in two or more doses. Co-administration includes simultaneous administration using separate formulations and sequential administration in either order, preferably with a period during which both (or all) active agents simultaneously exert their biological activity. The combinations of the present invention can also be administered as a single pharmaceutical composition comprising a compound of Formula (I) and a PD(L)1 inhibitor.

[0053] The pharmaceutical compositions of the present invention can be included in a container, pack, or dispenser together with instructions for administration. In another embodiment of the present invention, articles of manufacture, or "kits," are provided containing combinations useful for treating the diseases and disorders described above. In some embodiments, the article of manufacture or kit comprises a container and a combination according to the invention described herein. In some embodiments, the article of manufacture or kit comprises: a) a container comprising iadademstat (or a pharmaceutically acceptable salt or solvate thereof) and b) a container comprising a PD(L)1 inhibitor.

[0054] The article of manufacture or kit may further include a label or package insert. The term "package insert" is used to refer to instructions typically included in retail packaging of a therapeutic product, which contain information about the therapeutic product's efficacy, usage, dosage, administration, contraindications, and / or warnings regarding use. Suitable containers include, for example, bottles, vials, syringes, blister packs, etc. The container may be formed from a variety of materials, such as glass or plastic. The container may hold a combination or a formulation thereof effective for treating a condition and may have a sterile access port (e.g., the container may be an intravenous solution bag or vial having a stopper pierceable by a hypodermic injection needle). The label or package insert indicates that the composition is used to treat a selected condition, such as cancer, e.g., a cancer described herein. In one embodiment, the label or package insert indicates that the composition including the combination can be used to treat cancer. Alternatively, or additionally, the article of manufacture may further comprise additional containers containing pharmaceutically acceptable buffers, such as bacteriostatic water for injection (BWFI), phosphate-buffered saline, Ringer's solution, dextrose solution, etc. It may further include other materials desirable from a commercial and user standpoint, including other buffers, diluents, filters, needles, and syringes.

[0055] The kit may further comprise instructions for the administration of the combination and, if present, the second pharmaceutical formulation. For example, if the kit comprises a first composition comprising iadademstat, or a pharmaceutically acceptable salt thereof, and a second composition comprising a PD(L)1 inhibitor, the kit may further comprise instructions for the simultaneous, sequential, or separate administration of the first and second pharmaceutical compositions to a patient in need thereof.

[0056] In another embodiment, the kit is suitable for delivery of a solid oral form of the combination, such as a tablet or capsule. Such a kit preferably contains a number of unit doses. Such a kit may include a card with the dosage amounts in the order of their intended use. An example of such a kit is a "blister pack." Blister packs are well known in the packaging industry and are widely used to package pharmaceutical unit dosage forms. Optionally, a memory aid may be provided, for example, in the form of numbers, letters, or other markings, or with a calendar insert, indicating the days in the treatment schedule on which the doses can be administered.

[0057] According to one embodiment, the kit may comprise: (a) a first container having iadademstat, or a pharmaceutically acceptable salt or solvate thereof, contained therein; and (b) a second container having a PD(L)1 inhibitor. Alternatively, or additionally, the kit may comprise another container containing a pharmaceutically acceptable buffer, such as bacteriostatic water for injection (BWFI), phosphate-buffered saline, Ringer's solution, and dextrose solution. It may further include other materials desirable from a commercial and user standpoint, including other buffers, diluents, filters, needles, and syringes.

[0058] When the kit comprises a composition of iadademstat, or a pharmaceutically acceptable salt or solvate thereof, and a PD(L)1 inhibitor, the kit may include containers for housing the separate compositions, such as divided bottles or divided foil pockets, although the separate compositions may also be housed in a single, undivided container. Typically, the kit includes instructions for the administration of the separate components. The kit form is particularly advantageous when the separate components are preferably administered in different dosage forms (e.g., oral and parenteral), administered at different dosage intervals, or when dosage adjustment of the individual components of the combination is desired by the prescribing physician.

[0059] definition Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention pertains. The following definitions apply throughout the present specification and claims, unless otherwise stated. For purposes of the present invention, a "patient" or "subject" includes both humans and other animals, particularly mammals. Thus, the methods and uses of the present invention are applicable to both human treatment and veterinary applications. In a preferred embodiment, the subject or patient is a mammal, and in a most preferred embodiment, the subject or patient is human (e.g., male or female).

[0060] As used herein, the terms "treatment," "treating," and the like are generally used to mean obtaining a desired pharmacological and / or physiological effect. The effect may be preventative, in that it completely or partially prevents a disease (herein, cancer) or its symptoms, and / or therapeutic, in that it partially or completely cures or ameliorates the disease (i.e., cancer) and / or symptoms or side effects caused by the disease, or partially or completely halts the progression of the disease and / or symptoms or side effects caused by the disease. The term "treatment," as used herein, extends to any treatment of a disease (i.e., cancer) in a patient and includes, but is not limited to, any one or more of the following: (a) preventing cancer in patients predisposed to / at risk of developing cancer; (b) delaying the onset of cancer; (c) inhibiting cancer, i.e., preventing, delaying, or slowing its onset / progression; or palliating cancer, i.e., causing regression, correction, or remission of cancer. The present invention specifically and explicitly relates to each of these forms of treatment.

[0061] As used herein, the term "therapeutically effective amount" refers to an amount sufficient to produce a desired biological effect (e.g., a therapeutic effect) in a subject. Thus, a therapeutically effective amount of a compound can be an amount sufficient to treat the disease and / or delay the onset or progression of the disease and / or alleviate one or more symptoms of the disease when administered to a subject suffering from or susceptible to the disease.

[0062] As used herein, "pharmaceutically acceptable salts" shall mean salts that retain the biological effectiveness of the free acid and / or base of the particular compound and that are not biologically or otherwise undesirable. Compounds may have sufficiently acidic, sufficiently basic, or both functional groups and thus may react with any of a number of inorganic or organic bases, and inorganic and organic acids, to form pharmaceutically acceptable salts. Exemplary pharmaceutically acceptable salts include those of the compounds according to the invention, such as hydrochloride, hydrobromide, sulfate, pyrosulfate, bisulfate, sulfite, bisulfite, phosphate, monohydrophosphate, dihydrophosphate, metaphosphate, pyrophosphate, chloride, bromide, iodide, nitrate, acetate, propionate, decanoate, caprylate, acrylate, formate, isobutyrate, caproate, heptanoate, propionate, oxalate, malonate, succinate, suberate, sebacate, fumarate, maleate, butyne-1,4-dioate, hexyne-1,6-dioate, benzoate, chlorobenzoate, methylbenzoate, dinitrobenzoate. Examples of suitable pharmaceutically acceptable salts include salts prepared by the reaction of iadamstat with a mineral or organic acid, such as salts of hydroxybenzoate, methoxybenzoate, phthalate, sulfonate, xylenesulfonate, phenylacetate, phenylpropionate, phenylbutyrate, citrate, lactate, gamma-hydroxybutyrate, glycolate, tartrate, methanesulfonate, ethanesulfonate, propanesulfonate, benzenesulfonate, toluenesulfonate, trifluoromethanesulfonate, naphthalene-1-sulfonate, naphthalene-2-sulfonate, mandelate, pyruvate, stearate, ascorbate, or salicylate. When the compound contains an acidic moiety, suitable pharmaceutically acceptable salts include alkali metal salts, such as sodium or potassium salts; alkaline earth metal salts, such as calcium or magnesium salts; and salts formed with suitable organic ligands, such as ammonia, alkylamines, hydroxyalkylamines, lysine, arginine, N-methylglucamine, procaine, etc. Pharmaceutically acceptable salts are well known in the art.

[0063] As used herein, "pharmaceutically acceptable solvate" refers to a complex of variable stoichiometry formed by a solute and a pharmaceutically acceptable solvent, such as water, ethanol, etc. A complex with water is known as a hydrate. It is to be understood that the present invention encompasses any pharmaceutically acceptable solvate of iadamstat in its non-salt form and in the form of a pharmaceutically acceptable salt.

[0064] As used herein, "pharmaceutically acceptable carrier" or "pharmaceutically acceptable excipient" refers to non-API (API means active pharmaceutical ingredient) materials such as disintegrants, binders, fillers, and lubricants used in the formulation of pharmaceuticals that are generally safe for human administration according to established government standards, such as those promulgated by the U.S. Food and Drug Administration and / or the European Medicines Agency. Pharmaceutically acceptable carriers or excipients are well known to those skilled in the art.

[0065] As used herein, "small molecule" refers to an organic compound having a molecular weight of less than 900 daltons, preferably less than 500 daltons. Molecular weight is the mass of a molecule, calculated as the sum of the atomic weights of each component multiplied by the number of atoms of that element in the molecular formula.

[0066] The term "antibody" according to the present invention is used in its broadest sense and includes all antibodies, antibody fragments, and derivatives thereof that are capable of binding to an antigen, in this case an immune checkpoint. This encompasses complete monoclonal antibodies and also epitope-binding fragments of such antibodies. In this context, epitope-binding fragments (also referred to herein as antibody fragments or antibody derivatives) include any region of an antibody that is capable of binding to an antigen. Particular examples of antibody fragments according to the present invention include, but are not limited to, Fab, Fab', F(ab'), Fd, individual chain (single-chain) variable fragments (scFv), single-chain antibodies, disulfide-linked variable fragments (sdFv), and light chain variable regions (V L ) or the variable region of the heavy chain (V H) are included. Furthermore, this includes recombinantly prepared antibodies, such as diabodies and tetrabodies. Antibody fragments contain the variable region either alone or in combination with additional regions selected from the hinge region and the first, second, and third constant region (CH1, CH2, CH3). The term antibody also includes chimeric antibodies in which different regions of the antibody are derived from different species, for example, antibodies in which a murine variable region is combined with a human constant region. Antibody fragments are optionally connected to each other by a linker. The linker comprises a short (particularly 10-20 amino acid residues) flexible peptide sequence selected to allow the antibody fragment to 3-dimensionally fold between VL and VH so as to exhibit the antigen specificity of the intact antibody. Furthermore, specific linkers comprise peptide sequences that can increase the protease resistance of the antibody derivative.

[0067] The term "inhibitor," as used herein, means a compound that competes with, in any way reduces, blocks, inhibits, abolishes, or interferes with, the binding of a particular ligand to a particular receptor or enzyme, and / or that reduces, blocks, inhibits, abolishes, or interferes in any way with the activity of a particular protein, e.g., a receptor or enzyme.

[0068] As used herein, the term "comprising" (or "comprise," "comprises," "contain," "contains," or "containing") means "in particular," i.e., "including, among other optional elements," unless otherwise indicated or contradicted by context. In addition, the term also encompasses the narrower meanings of "consisting essentially of" and "consisting of." For example, the term "A comprising B and C" means "A comprising, in particular, B and C," where A can include additional optional elements (e.g., "A comprising B, C, and D" is also encompassed), but the term also encompasses the meaning of "A consisting essentially of B and C" (i.e., A does not include elements other than B and C).

[0069] As used herein, unless otherwise indicated or contradicted by context, the terms "a," "an," and "the" are used interchangeably with "one or more" and "at least one." Thus, for example, a composition comprising "a" PD(L)1 inhibitor can be interpreted as meaning a composition comprising "one or more" PD(L)1 inhibitors. [Example]

[0070] The following examples are given to illustrate the invention. They should not be considered as limiting the scope of the invention, but merely as representative thereof. Results are also shown and described in the figures and figure legends.

[0071] Example 1: Evaluation of the effects of iademstat in combination with a PD(L)1 inhibitor in an in vivo model of melanoma in mice method: B16F10 melanoma cells were maintained in vitro as monolayer cultures in DMEM-high glucose (Sigma, D5796) supplemented with 10% fetal bovine serum (ThermoFisher, 10500064). Exponentially growing cells were harvested for tumor inoculation. Six to eight-week-old C57 / BL6 female mice were inoculated with B16F10 melanoma cells (0.5 × 10) in 0.050 mL of DMEM (Dulbecco's modified Eagle's medium):Matrigel 1:1. 6) were inoculated subcutaneously into the right flank (15 mice per group). Mice from groups 1 and 2 received vehicle-treated cells, while B16F10 cells injected into group 3 were exposed to 5 nM iadademstat 2HCl for 96 hours immediately prior to inoculation. Treatment began on the day of inoculation. Animals were injected i.p. with either sterile Dulbecco's phosphate-buffered saline (DPBS) (group 1) or anti-PD1 mAb (100 μg of BioXcell clone RMP1-14; cat. #BE0146; rat anti-mouse mAb) on days 4, 7, and 11 (groups 2 and 3). In addition, animals from group 3 received 10 μg / kg iadademstat 2HCl by oral gavage according to a 5 / 2 dosing schedule (1111100) starting on day 0 until the end of the experiment (day 22). Iadademstat concentrations for in vitro treatments are expressed as the free base, while doses administered in vivo refer to Iadademstat dihydrochloride. Tumor volumes were measured twice weekly in two dimensions using calipers, and volumes were calculated using the formula: V = 0.5a × b 2 where "a" and "b" are the long and short diameters of the tumor, respectively. 3 The tumor weight was measured at the end of the study. Statistical analysis was performed using an unpaired t-test.

[0072] result: There was a statistically significant (p=0.004) difference in tumor volume (TV) in animals treated with anti-PD1 mAb as a single agent (mean TV at day 22 = 1099 mm 3 ) or the combination iadamstat + anti-PD1 mAb (mean TV on day 22 = 509 mm 3 The mean tumor volume in the vehicle control group was 1677 mm at day 19. 3 It was. Measured tumor weights also showed a statistically significant reduction in tumor weight (p=0.001) in animals treated with the combination iadamstat + anti-PD1 mAb compared to animals receiving anti-PD1 mAb alone, with a mean tumor weight of 0.29 g in tumors treated with the combination iadamstat + anti-PD1 mAb (collected on day 22) compared to mean tumor weights of 1.03 g and 1.39 g in animals treated with anti-PD1 mAb as a single agent (collected on day 22) or vehicle (collected on day 19), respectively. Methods similar to those described in Example 1 can be used to confirm the therapeutic efficacy of the combination of iadamstat with a PD(L)1 inhibitor in other cancer types.

[0073] While the invention has been described in relation to particular embodiments thereof, it is to be understood that further modifications are possible, and this application is generally intended to cover any variations, uses, or adaptations of the invention which follow the principles of the invention and which are within known or customary limits within the art to which this invention pertains, including departures from the present disclosure applicable to the essential features set forth above and in the following claims.

Claims

1. A pharmaceutical composition comprising iadademstat, or a pharmaceutically acceptable salt or solvate thereof, and a PD(L)1 inhibitor for use in treating cancer, wherein the PD(L)1 inhibitor is an antibody, and the cancer is melanoma or small cell lung cancer.

2. A pharmaceutical composition comprising iadademstat, or a pharmaceutically acceptable salt or solvate thereof, for use in the treatment of cancer in combination with a PD(L)1 inhibitor, wherein the PD(L)1 inhibitor is an antibody and the cancer is melanoma or small cell lung cancer.

3. A pharmaceutical composition comprising a PD(L)1 inhibitor in combination with iadademstat, or a pharmaceutically acceptable salt or solvate thereof, for use in the treatment of cancer, wherein the PD(L)1 inhibitor is an antibody, and the cancer is melanoma or small cell lung cancer.

4. Use of iadademstat, or a pharmaceutically acceptable salt or solvate thereof, for the manufacture of a therapeutic agent for the treatment of cancer, to be used in combination with a PD(L)1 inhibitor, wherein the PD(L)1 inhibitor is an antibody and the cancer is melanoma or small cell lung cancer.

5. Use of a PD(L)1 inhibitor for the manufacture of a therapeutic agent for the treatment of cancer, to be used in combination with iadademstat, or a pharmaceutically acceptable salt or solvate thereof, wherein the PD(L)1 inhibitor is an antibody and the cancer is melanoma or small cell lung cancer.

6. Use of a combination comprising iadademstat, or a pharmaceutically acceptable salt or solvate thereof, and a PD(L)1 inhibitor for the manufacture of a therapeutic agent for the treatment of cancer, wherein the PD(L)1 inhibitor is an antibody, and the cancer is melanoma or small cell lung cancer.

7. The pharmaceutical composition according to any one of claims 1 to 3, wherein the PD(L)1 inhibitor is a PD-1 inhibitor or a PD-L1 inhibitor.

8. The PD(L)1 inhibitor is selected from the group consisting of pembrolizumab, nivolumab, cemiplimab, camrelizumab, tislelizumab, sintilimab, toripalimab, and spartalizumab. mab), AGEN-2034, AK-103, AK-104, AK-105, AK-112, AK-123, AMP-224, BCD-100, BH-2950, ​​BH-2996h, BI-7 54091, CS-1003, CX-188, GLS-010, hAb21, HLX-10, JNJ-63723283, JTX-4014, KN0-46, MEDI-0680, MGA-012 , MGD-013, PF-06801591, PRS-332, RO7121661, STI-A1110, TSR-042, XmAb-20717, Atezolizumab, Avelumab, Durvalumab, AK-106, APL-502, AVA-004, BGB-A333, BH-2996h, BMS-9365 59, CBA-0710, CK-301, CS-1001, CX-072, FAZ-053, FS-118, GR1405, HLX-20, JS-003, KD033, KN-035, KY-1003, LY3300054, M-7824, MCLA-145, MSB-2311, and SHR-1316.

9. 9. The pharmaceutical composition of any one of claims 1 to 3, 7 or 8, wherein the PD(L)1 inhibitor is selected from the group consisting of pembrolizumab, nivolumab, cemiplimab, atezolizumab, avelumab, and durvalumab.

10. The pharmaceutical composition of any one of claims 1 to 3 or 7, wherein the PD(L)1 inhibitor is a PD-1 inhibitor.

11. The pharmaceutical composition of any one of claims 1 to 3 or 7, wherein the PD(L)1 inhibitor is a PD-L1 inhibitor.

12. The pharmaceutical composition according to any one of claims 1 to 3 or 7 to 11, wherein the cancer is melanoma.

13. The pharmaceutical composition according to any one of claims 1 to 3 or 7 to 11, wherein the cancer is small cell lung cancer.

14. The pharmaceutical composition according to any one of claims 1 to 3 or 7 to 13, wherein the cancer is refractory, unresponsive or recurrent cancer to PD(L)1 inhibitor therapy.

15. 15. The pharmaceutical composition of any one of claims 1 to 3 or 7 to 14, wherein said iadademstat, or a pharmaceutically acceptable salt or solvate thereof, is iadademstat dihydrochloride.

16. 16. The pharmaceutical composition of any one of claims 1 to 3 or 7 to 15, wherein the iadamstat, or a pharmaceutically acceptable salt or solvate thereof, is administered orally.

17. 17. The pharmaceutical composition of any one of claims 2, 3, or 7 to 16, wherein the iadademstat, or a pharmaceutically acceptable salt or solvate thereof, and the PD(L)1 inhibitor are administered using separate formulations.

18. 18. The pharmaceutical composition of any one of claims 2, 3, or 7-17, wherein the iadademstat, or a pharmaceutically acceptable salt or solvate thereof, and the PD(L)1 inhibitor are administered as a simultaneous regimen or as a sequential regimen.

19. The pharmaceutical composition of any one of claims 1 to 3 or 7 to 18, wherein the patient to be treated is a human.

20. The use according to any one of claims 4 to 6, wherein the PD(L)1 inhibitor is a PD-1 inhibitor or a PD-L1 inhibitor.

21. The PD(L)1 inhibitor is selected from the group consisting of pembrolizumab, nivolumab, cemiplimab, camrelizumab, tislelizumab, sintilimab, toripalimab, and spartalizumab. umab), AGEN-2034, AK-103, AK-104, AK-105, AK-112, AK-123, AMP-224, BCD-100, BH-2950, ​​BH-2996h, BI- 754091, CS-1003, CX-188, GLS-010, hAb21, HLX-10, JNJ-63723283, JTX-4014, KN0-46, MEDI-0680, MGA-01 2, MGD-013, PF-06801591, PRS-332, RO7121661, STI-A1110, TSR-042, XmAb-20717, Atezolizumab, Avelumab, Durvalumab, AK-106, APL-502, AVA-004, BGB-A333, BH-2996h, BMS-93 6559, CBA-0710, CK-301, CS-1001, CX-072, FAZ-053, FS-118, GR1405, HLX-20, JS-003, KD033, KN-035, KY-1003, LY3300054, M-7824, MCLA-145, MSB-2311, and SHR-1316.

22. 22. The use of any one of claims 4 to 6, 20 or 21, wherein the PD(L)1 inhibitor is selected from the group consisting of pembrolizumab, nivolumab, cemiplimab, atezolizumab, avelumab, and durvalumab.

23. 21. The use of any one of claims 4 to 6 or 20, wherein the PD(L)1 inhibitor is a PD-1 inhibitor.

24. 21. The use of any one of claims 4 to 6 or 20, wherein the PD(L)1 inhibitor is a PD-L1 inhibitor.

25. 25. The use of any one of claims 4 to 6 or 20 to 24, wherein the cancer is melanoma.

26. 25. The use of any one of claims 4 to 6 or 20 to 24, wherein the cancer is small cell lung cancer.

27. 27. The use of any one of claims 4 to 6 or 20 to 26, wherein the cancer is refractory, unresponsive or recurrent cancer to PD(L)1 inhibitor therapy.

28. 28. The use according to any one of claims 4 to 6 or 20 to 27, wherein said iadamstat, or a pharmaceutically acceptable salt or solvate thereof, is iadamstat dihydrochloride.

29. 29. The use according to any one of claims 4 to 6 or 20 to 28, wherein the iadamstat, or a pharmaceutically acceptable salt or solvate thereof, is administered orally.

30. 30. The use according to any one of claims 4 to 6 or 20 to 29, wherein the iadademstat, or a pharmaceutically acceptable salt or solvate thereof, and the PD(L)1 inhibitor are administered using separate formulations.

31. 31. The use of any one of claims 4 to 6 or 20 to 30, wherein the iadademstat, or a pharmaceutically acceptable salt or solvate thereof, and the PD(L)1 inhibitor are administered as a simultaneous regimen or as a sequential regimen.

32. The use according to any one of claims 4 to 6 or 20 to 31, wherein the patient to be treated is a human.

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