IADADEMSTAT COMBINATIONS FOR CANCER THERAPY

Abstract

The present invention relates to a combination comprising iadademstat, or a pharmaceutically acceptable salt or solvate thereof, and a PD(L)1 inhibitor, wherein the PD(L)1 inhibitor is either a PD-1 inhibitor or a PD-L1 inhibitor.

Description

IADADEMSTAT COMBINATIONS FOR CANCER THERAPY FIELD OF INVENTION The present invention relates to iadademstat combinations for cancer therapy, in particular, combinations with immune checkpoint inhibitors as defined herein. BACKGROUND OF THE INVENTION 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 immune checkpoints—key regulators of the immune system that stimulate or inhibit its actions, which tumors can use to protect themselves from immune attacks. Checkpoint therapy can block inhibitory checkpoints, restoring immune system function.In particular, PD(L)1 inhibitors are a group of immune checkpoint inhibitors that act to inhibit the association of programmed cell death protein 1 (PD-1, also called PDCD1 or CD279) with its ligands, programmed death ligand 1 (PD-L1, also known as CD274) and programmed death ligand 2 (PD-L2, also known as CD273). The interaction of these cell surface proteins is involved in immune system suppression and occurs after infection to limit the death of transient host cells and prevent autoimmune disease, but it is also involved in various types of cancer. By recruiting the immune system against cancer cells, PD(L)1 inhibitor therapy shows promise for achieving durable responses in various malignancies, and several PD-1 and PD-L1 inhibitors have already been approved as treatments for various cancers. However, a therapeutic response to immune checkpoint inhibitors such as PD-1 or PD-L1 inhibitors is observed only in a small subset of cancer patients. The low mutational burden of cold tumors allows them to remain undetected by the host's inflammatory response (innate resistance). Furthermore, cancer cells develop a number of adaptive strategies in response to the selective pressure exerted by immune checkpoint inhibitor treatment (recruitment of regulatory cells, defective antigen presentation, immunosuppressive mediators, reduced co-stimulation, and T-cell apoptosis). Therefore, there is a need for improved methods and formulations for cancer treatment that address the problem of resistance and lack of sensitivity to immune checkpoint inhibitors, particularly PD(L)1 inhibitors. BRIEF DESCRIPTION OF THE INVENTION The invention is based on the unexpected finding that the combination of iadademstat with immune checkpoint inhibitors, particularly PD(L)1 inhibitors (as defined herein), exhibits outstanding activity in inhibiting cancer cell growth compared to treatment with the immune checkpoint inhibitor alone. Therefore, iadademstat can be used to sensitize tumors to PD(L)1 inhibitors and enhance tumor sensitivity to PD(L)1 inhibitor therapy. Therefore, the present invention relates to combinations of iadademstat, or a pharmaceutically acceptable salt or solvate thereof, with PD(L)1 inhibitors (as defined herein). Accordingly, the present invention provides a combination comprising iadademstat, 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 for treating cancer in a patient (preferably a human) in need, 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. The present invention further provides a method for treating cancer in a patient (preferably a human) in need, 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 for the use of iadademstat, or a pharmaceutically acceptable salt or solvate thereof, for the manufacture of a cancer treatment drug to be used in combination with a PD(L)1 inhibitor. The present invention further provides for 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 DESCRIPTION OF THE DRAWINGS Figure 1 shows the effect of treatment with a combination of iadademstat (referred to as “ORY1001”) and a PD(L)1 inhibitor (triangles) compared with treatment with the PD(L)1 inhibitor alone (squares) on tumor volume in the B16F10 mouse melanoma model, as will be explained in more detail in Example 1. Data are represented as mean ± standard error of the mean (SEM); p = 0.004. Figure 2 shows the effect of treatment with a combination of iadademstat (“ORY-1001”) and a PD(L)1 inhibitor (triangles) compared with treatment with the PD(L)1 inhibitor alone (squares) on tumor weight in the same B16F10 mouse melanoma model, as will be explained in more detail in Example 1. Data are represented as mean ± standard error of the mean (SEM); p = 0.001. DETAILED DESCRIPTION OF THE INVENTION As previously stated, the present invention is based on the discovery that the combination of iadademstat with PD(L)1 inhibitors exhibits outstanding anticancer activity, with superior anticancer efficacy compared to treatment with the PD(L)1 inhibitor alone. The combination treatment with iadademstat and a PD(L)1 inhibitor results in a significant increase in the antitumor 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 murine melanoma model. Treatment with the combination produces statistically significant reductions 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.Therefore, treatment with iadademstat may enhance the efficacy of, or otherwise act synergistically with, PD(L)1 inhibitors. Therefore, iadademstat can be used in combination with PD(L)1 inhibitors to treat cancer, including to increase the sensitivity of cancers to PD(L)1 inhibitor therapy and / or to sensitize cancers that are refractory, non-responsive, or relapsed 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 PD-L1 and PD-L2, inhibits PD-1 signaling, or reduces PD-1-dependent inhibition of T cell-mediated immune responses against tumor cells. Accordingly, as used herein, a PD(L)1 inhibitor includes a PD-1 inhibitor, a PD-L1 inhibitor, and a PD-L2 inhibitor. Examples thereof are provided later under the heading PD(L)T inhibitors. In detail, the present invention provides a combination comprising iadademstat, 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 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. 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 for use in the treatment of cancer in combination with iadademstat or a pharmaceutically acceptable salt or solvate thereof. The present invention further provides iadademstat, or a pharmaceutically acceptable salt or solvate thereof, for use in the treatment of cancer, wherein the iadademstat or the 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, in which case the PD(L)1 inhibitor is to be administered in combination with iadademstat or a pharmaceutically acceptable salt or solvate thereof. The present invention further provides a method for treating cancer in a patient in need, 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. The present invention further provides a method for treating cancer in a patient in need, 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 for the use of iadademstat, or a pharmaceutically acceptable salt or solvate thereof, for the manufacture of a cancer treatment drug to be used in combination with a PD(L)1 inhibitor. The present invention further provides for the use of a PD(L)1 inhibitor for the manufacture of a cancer treatment drug for use in combination with iadademstat or a pharmaceutically acceptable salt or solvate thereof. The present invention further provides for 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 medicament for the treatment of cancer. The present invention further provides for 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 for 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 for the use of a PD(L)1 inhibitor for the treatment of cancer in combination with iadademstat or a pharmaceutically acceptable salt or solvate thereof. The 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 invention further provides for 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 invention further provides for the use of iadademstat, or a pharmaceutically acceptable salt or solvate thereof, for the manufacture of a medicament for the treatment of cancer by sensitizing the cancer to treatment with a PD(L)1 inhibitor. The present invention further provides a method for treating cancer in a patient in need by sensitizing the cancer to treatment with a PD(L)1 inhibitor, comprising administering to the patient a therapeutically effective amount of iadademstat, or a pharmaceutically acceptable salt or solvate thereof. The 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. nLQ L Ln / Lznz / E / Yli The invention further provides for the use of iadademstat, or a pharmaceutically acceptable salt or solvate thereof, to sensitize cancer to treatment with a PD(L)1 inhibitor. The invention further provides for the use of iadademstat, or a pharmaceutically acceptable salt or solvate thereof, for the manufacture of a medicament for sensitizing cancer to treatment with a PD(L) 1 inhibitor. The present invention further provides a method for sensitizing cancer to treatment with a PD(L)1 inhibitor in a patient in need, comprising administering to the patient a therapeutically effective amount of iadademstat, or a pharmaceutically acceptable salt or solvate thereof. The invention further provides iadademstat, or a pharmaceutically acceptable salt or solvate thereof, for use in increasing the sensitivity of a cancer to PD(L)1 inhibitor therapy. The invention further provides for the use of iadademstat, or a pharmaceutically acceptable salt or solvate thereof, for the manufacture of a medicament for increasing the sensitivity of a cancer to PD(L) 1 inhibitor therapy. The invention further provides a method for increasing the sensitivity of a cancer to PD(L)1 inhibitor therapy in a patient in need, comprising administering to the patient a therapeutically effective amount of iadademstat, or a pharmaceutically acceptable salt or solvate thereof. The invention further provides iadademstat, or a pharmaceutically acceptable salt or solvate thereof, for use in sensitizing a cancer that is refractory, unresponsive, or relapsed to PD(L)1 inhibitor therapy. The invention further provides for the use of iadademstat, or a pharmaceutically acceptable salt or solvate thereof, for the manufacture of a medicament for sensitizing a cancer that is refractory, unresponsive, or relapsed to PD(L)1 inhibitor therapy. The invention further provides a method for sensitizing a refractory, unresponsive, or relapsed cancer to PD(L)1 inhibitor therapy in a patient in need, comprising administering to the patient a therapeutically effective amount of iadademstat, or a pharmaceutically acceptable salt or solvate thereof. The invention further provides iadademstat, or a pharmaceutically acceptable salt or solvate thereof, for use as an adjunct therapy to a PD(L)1 inhibitor. The invention further provides for the use of iadademstat, or a pharmaceutically acceptable salt or solvate thereof, as an adjunct therapy to a PD(L) 1 inhibitor. The invention further provides for the use of iadademstat, or a pharmaceutically acceptable salt or solvate thereof, for the manufacture of a medicament for use as an adjunct therapy to a PD(L)1 inhibitor. The invention further provides a method for treating cancer in a patient in need, the method comprising sensitizing said cancer by administering iadademstat, or a pharmaceutically acceptable salt or solvate thereof, to said patient, followed by administering a therapeutically effective amount of a combination comprising iadademstat or a pharmaceutically acceptable salt or solvate thereof and a PD(L)1 inhibitor. The invention further provides a method for treating cancer in a patient in need, the method comprising a first treatment in which only iadademstat (or a pharmaceutically acceptable salt or solvate thereof) is administered to said patient (i.e., without a PD(L)1 inhibitor), before initiating treatment with a combination comprising iadademstat (or a pharmaceutically acceptable salt or solvate thereof) and a PD(L)1 inhibitor. In some forms, cancer is a solid tumor. In some modalities, the cancer is suitable for treatment with a PD(L)1 inhibitor, where this is particularly a cancer for which PD(L)1 inhibitor therapy is approved, i.e., it has received market approval from regulatory authorities in at least one country. In some modalities, 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 lymphoma, urothelial carcinoma, colorectal cancer, hepatocellular cancer, 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. In some modalities, 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 lymphoma, urothelial carcinoma, colorectal cancer, hepatocellular cancer, cutaneous squamous cell carcinoma, and Merkel cell carcinoma. In some forms, the cancer is melanoma. In some forms, the cancer is small cell lung cancer. In some cases, the cancer is refractory, unresponsive, or recurrent to PD(L)1 inhibitor therapy. Consequently, in some cases, the cancer is refractory, unresponsive, or recurrent to PD(L)1 inhibitor monotherapy. In the methods and uses according to the invention, the patient is a human being or an animal, preferably a human being. In some modalities, the patient who has said cancer has received at least one prior treatment for said cancer comprising a PD(L) 1 inhibitor (alone or in combination with other therapeutic agents). nLQ L Ln / Lznz / E / Yli (Iadademstat): Iadademstat is the International Non-proprietary Yam (INN) name for the compound of formula (I): (YO), [CAS Reg. No. 1431304-21-0], also known as ORY-1001 or (trans)-N1-((1R,2S)-2-phenylcyclopropyl)cyclohexane-1,4-diamine. Ladademstat has been described, e.g., in Example 5 of International Patent Application WO 2013 / 057322. Pharmaceutically acceptable salts thereof are also described therein, including the hydrochloride salt [CAS Reg. No. 1431303-72-8, dihydrochloride]. The most preferred pharmaceutically acceptable salt is a dihydrochloride salt. Ladademstat acts as a selective LSD1 inhibitor. The terms “ladademstat”, “Compound of formula (I)”, “(trans)-N1-((1R,2S)-2-phenylcyclopropyl)cyclohexane1,4-diamine”, and “ORY-1001” are used interchangeably herein (i.e., throughout this description and claims). Unless specifically stated otherwise, any reference to ladademstat throughout this description and claims includes ladademstat and any of its pharmaceutically acceptable salts or solvates. Preferably, ladademstat is used in the form of a pharmaceutically acceptable salt, preferably a hydrochloride salt, more preferably a dihydrochloride salt. Preferably, iadademstat (or a pharmaceutically acceptable salt or solvate thereof) is administered orally. Exemplary formulations that can be administered by peroral ingestion are described in more detail later. PD(L)1 inhibitors: As stated above, as used herein, a “PD(L)1 inhibitor” refers to a compound that inhibits the interaction of PD-1 with either of its ligands, PD-L1 and / or PD-L2, inhibits PD-1 signaling, or reduces PD-1-dependent inhibition of T cell-mediated immune responses against tumor cells. Accordingly, the term “PD(L)T inhibitor” includes PD-1 inhibitors, PD-L1 inhibitors, and PD-L2 inhibitors. Therefore, a PD(L)1 inhibitor may be a PD-1 inhibitor, a PD-L1 inhibitor, or a PD-L2 inhibitor. PD(L)1 inhibitors are well known in the field, and in principle, any molecule that acts as a PD(L)1 inhibitor can be used in the context of the combinations, methods, and uses according to the invention. The PD(L)1 inhibitor can be, for example, a small molecule, a peptide, an antibody, or a vaccine. In some forms, the PD(L)1 inhibitor is an antibody, more preferably a human antibody or humanized antibody. 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 REGN2810) (Regeneren Pharmaceuticals / Sanoficals), known as Cambyl 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), Sintilien (also known as IBI-308) (Eli Lilly / lnnovent), Toripalimab (also known as JS-001) (Shanghai Junshi), Spartalizumab (also known as PDR-001) (Novartis), AGEN-2034 (Agenus), AK-103 (Akeso Βίο), AK-104 (ίο), AK-105 (Akeso Βίο), AK-112 nLQ L Ln / Lznz / E / Yli (Akeso Βίο), AK-123 (Akeso Βίο), AM-0001 (ARMO Bio / Eli Lilly), AMP-224 (Medimmune / GSIMNCI), 1 (KIMNCI), 1 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), KNO-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 (Thesaro) and XmAb-20717 (Xencor)., 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) (Apoll-502), AVActa (Avacta-004), 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), CBAS-327 (Curis / Aurigene), CK-071 (ORrento), (CheckPoint Therapeutics / TG Therapeutics), CS-1001 (CStone Pharmaceuticals), CX-072 (CytomX), FAZ-053 (Novartis), FS-118 (F Star / Merck KGaA), GR1405 (Genrix Biopharmaceutical-XXL), (Henlius Shanghai), 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 (Mer KLAGa-14), 5 (Merus / lncyte), MSB-2311 (Mabspace Biosciences), and SHR-1316 (also known as HTI-1088) (Atridia / Jiangsu Hengrui Therapeutics). The preferred PD-1 inhibitors are Pembrolizumab, Nivolumab, and Cemiplimab. Pembrolizumab (also known as MK-3475 or lambrolizumab, Keytruda®) was first approved by the Food and Drug Administration (FDA) in 2014 for the treatment of melanoma. It was subsequently approved for metastatic non-small cell lung cancer and squamous cell carcinoma of the head and neck. 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. Nivolumab (Opdivo®) was developed by Bristol-Myers Squibb and was first approved by the FDA in 2014 for the treatment of melanoma. It was later approved for non-small cell lung cancer, renal cell carcinoma, Hodgkin lymphoma, squamous cell carcinoma of the head and neck, urothelial carcinoma, metastatic colon cancer, and hepatocellular carcinoma, as well as SCLC. Cemiplimab (Libtayo®) was developed by Regeneran 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. 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 Serano and Pfizer. Avelumab was approved by the FDA for the treatment of metastatic Merkel cell carcinoma, and was subsequently approved for urothelial carcinoma and renal cell carcinoma. Durvalumab (Imfinzi®) was developed by AstraZeneca. Durvalumab received its first FDA approval in 2017 and is currently approved for the treatment of urothelial carcinoma and non-small cell lung cancer. In some forms, the PD(L)1 inhibitor is either a PD-1 inhibitor or 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-12, AK-101, AK-123, AM-0001, AMP-224, AT16201, BCD-100, BH-2950, ​​BH-2996h, BI-754091, BMS-1001, BMS-1166, CS-1003, CX-188, EN-2401, GLS-2018, GLS-2010, h HLX-10, IKT-202, JNJ-63723283, JTX-4014, KNO-46, MEDI-0680, MGA-012, MGD-013, PF-06801591, PRS-332, RO7121661, STI-111, ASR-1042, TSR-0680 XmAb-20717, Atezolizumab, Avelumab, Durvalumab, AK-106, APL-502, AVA-004, BGB-A333, BH-2996h, BMS-936559, CA-170, CA327, CBA-0710, CK-3010, CX-107, CS-107, CBA-0710 FAZ-053, FS-118, GR1405, HLX-20, IKT-201, JS-003, KD033, KN-035, KY1003, LY3300054, M-7824, MCLA-145, MSB-2311, and 16 SHR-16. In some embodiments, the PD(L)1 inhibitor is selected from the group consisting of Pembrolizumab, Nivolumab, Cemiplimab, Atezolizumab, Avelumab, and Durvalumab. In some embodiments, the PD(L)1 inhibitor is 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-12, AK-12, AK-12 AM-0001, AMP-224, AT16201, BCD-100, BH-2950, ​​BH-2996h, BI-754091, BMS-1001, BMS-1166, CS-1003, CX-188, ENUM-244C8, GLAX010, hLAX-210, hLAX-210 IKT-202, JNJ-63723283, JTX-4014, KNO-46, MEDI-0680, MGA-012, MGD-013, PF-06801591, PRS-332, RO7121661, STI-A1110, TSR-20172, and XmAb. In some embodiments, the PD-1 inhibitor is selected from the group consisting of Pembrolizumab, Nivolumab, and Cemiplimab. In some modalities, the PD(L)1 inhibitor is a PD-L1 inhibitor. In some modalities, 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 SHR1316. In some modalities, the PD-L1 inhibitor is selected from the group consisting of Atezolizumab, Avelumab, and Durvalumab. In some modalities, the PD(L)1 inhibitor is a PD-L2 inhibitor. In some embodiments, the 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, AGEN2034, AK-103, AK-104, AK-105, AK-112, AK-123, AM-0001, AMP-224, AT16201, BCD-100, BH-2950, ​​BH-2996h, BI754091, BMS-1001, BMS-1166, CS-1003, CX-188, ENUM-244C8, GLS-010, hAb21, HLX-10, IKT-202, JNJ-63723283, nLQ L Ln / Lznz / E / Yli JTX-4014, KNO-46, MEDI-0680, MGA-012, MGD-013, PF-06801591, PRS-332, RO7121661, STI-A1110, TSR-042, XmAb-20717, Atezolizumab, Durvalumab, Atevalumab, 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, HLX-142, GRX-142 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. In some embodiments, the 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, BMS-1001, BMS-1166, CS-1003, CX-188, ENUM-244C8, GLS-010, hAb21, HLX-10, IKT-202, JNJ-63723283, JTX-4014, KNO-46, MEDI-0680, MGA-012, MGD-013, PF-06801591, PRS-332, RO7121661, STI-A1110, TSR-042, and XmAb-20717. In some preferred modalities, the PD-1 inhibitor is selected from the group consisting of Pembrolizumab, Nivolumab, and Cemiplimab. In some embodiments, the 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, FS118, 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 modalities, the PD-L1 inhibitor is selected from the group consisting of Atezolizumab, Avelumab, and Durvalumab. In some embodiments, the invention provides a combination comprising iadademstat, or a pharmaceutically acceptable salt or solvate thereof, and a PD-L2 inhibitor. Another modality provides pharmaceutical compositions or medicines comprising the combinations as described herein and a pharmaceutically acceptable excipient, as well as methods for using the compound of formula (I) to prepare such combinations, compositions, and medicines. Any reference to iadademstat throughout this specification includes a reference to the compound as such, i.e., the compound in non-saline form (e.g., as a free base) or 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 to a PD(L)1 inhibitor throughout this specification includes a reference to the PD(L)1 inhibitor as such, or in the form of any pharmaceutically acceptable salt or solvate thereof (if applicable), as well as a reference to any pharmaceutical composition comprising said PD(L)1 inhibitor and one or more pharmaceutically acceptable excipients or carriers. nLQ L Ln / Lznz / E / Yli Pharmaceutical formulations of ladademstat and the PD(L)1 inhibitor for use in the combinations as described herein, as well as the pharmaceutical compositions as described herein, may be administered by any suitable means, including oral, topical (including buccal and sublingual), rectal, vaginal, transdermal, parenteral, subcutaneous, intraperitoneal, intrapulmonary, intradermal, intrathecal, epidural, and intranasal, and, if desired for local treatment, intralesional administration. Parenteral infusions include intramuscular, intravenous, intra-arterial, intraperitoneal, or subcutaneous administration. Ladademstat and the other therapeutic agent for use in the combinations as described herein, as well as the pharmaceutical compositions as described herein, may be administered in any convenient pharmaceutical form, e.g., tablets, powders, capsules, solutions, dispersions, suspensions, syrups, sprays, suppositories, gels, emulsions, patches, etc. Such compositions may comprise conventional components in pharmaceutical preparations, e.g., diluents, carriers, pH modifiers, preservatives, solubilizers, stabilizers, wetting agents, emulsifiers, sweeteners, colorants, flavorings, salts for varying osmotic pressure, lamps, masking agents, antioxidants, and additional active agents. They may also comprise other therapeutically valuable substances. A typical formulation is prepared by mixing ladademstat or the other therapeutic agent as described herein, or a combination as described herein, with a pharmaceutically acceptable excipient. Suitable excipients are well known to those experienced in the field and are described in detail in, for example, Ansel's "Pharmaceutical Dosage Forms and Drug Delivery Systems" (2004), Lippincott, Williams & Wilkins, Philadelphia; Remington's "The Science and Practice of Pharmacy" (2000), Lippincott, Williams & Wilkins, Philadelphia; and "Handbook of Pharmaceutical Excipients" (2005), Pharmaceutical Press, Chicago.The formulations may also include one or more lamps, stabilizing agents, surfactants, wetting agents, lubricating agents, emulsifiers, suspending agents, preservatives, antioxidants, opacifying agents, glidants, processing aids, colorants, sweeteners, perfume agents, flavoring agents, diluents, and other known additives to provide an elegant presentation of the drug (i.e., a compound of the present invention or pharmaceutical composition thereof) or to assist in the manufacture of the pharmaceutical product (i.e., medicine). For oral administration, the compound may be incorporated into a formulation that includes pharmaceutically acceptable carriers such as binders (e.g., gelatin, cellulose, tragacanth gum), excipients (e.g., starch, lactose), lubricants (e.g., magnesium stearate, silicon dioxide), disintegrating agents (e.g., alginate, Primogel, and corn starch), and sweetening or flavoring agents (e.g., glucose, sucrose, saccharin, methyl salicylate, and mint). The formulation may be administered orally, for example, in the form of coated gelatin capsules or compressed tablets. The capsules and tablets may be prepared by any conventional technique. The capsules and tablets may also be coated with various coatings known in the field to modify their flavors, tastes, colors, and shapes.Additionally, liquid carriers such as fatty oil can also be included in the capsules. Suitable oral formulations may also be in the form of a suspension, syrup, chewing gum, wafer, elixir, and the like. If desired, conventional agents may also be included to modify flavors, tastes, colors, and shapes of special forms. Additionally, for convenient administration via enteral feeding tube in patients unable to swallow, the active compounds may be dissolved in an acceptable lipophilic vegetable oil vehicle such as olive oil, corn oil, or safflower oil. The compound can also be administered parenterally as a solution or suspension, or in lyophilized form by converting it to a solution or suspension before use. Pharmaceutically acceptable diluents or carriers such as sterile water and physiological saline buffer may be used in such formulations. Other solvents, pH adjusters, stabilizers, antibacterial agents, surfactants, and conventional antioxidants may also be included. Useful components include sodium chloride, acetates, citrate or phosphate binders, glycerin, dextrose, fixed oils, methylparabens, polyethylene glycol, propylene glycol, sodium bisulfate, benzyl alcohol, ascorbic acid, and similar substances. Parenteral formulations can be stored in any conventional container such as bottles and ampoules. For topical administration, the compound can be formulated as lotions, creams, ointments, gels, powders, pastes, sprays, suspensions, drops, and aerosols. Therefore, one or more thickening, wetting, and stabilizing agents may be included in the formulations. Examples of such agents include, but are not limited to, polyethylene glycol, sorbitol, xanthan gum, petrolatum, beeswax or mineral oil, lanolin, squalene, and similar substances. A special form of topical administration is delivery by means of a transdermal patch. Methods for preparing transdermal patches are disclosed, for example, in Brown et al. (1988) Ann. Rev. Med. 39:221-229, which is incorporated herein by reference. Subcutaneous implantation for sustained release of the compound may also be a suitable route of administration. This involves surgical procedures to implant an active compound in any suitable formulation into a subcutaneous space, for example, beneath the anterior abdominal wall. See, for example, Wilson et al. (1984) J. Clin. Psych. 45:242-247. Hydrogels may be used as a carrier for the sustained release of active compounds. Such hydrogels are generally known in the field. They are generally made by crosslinking high molecular weight biocompatible polymers into a network, which swells in water to form a gel-like material. Preferably, the hydrogels are biodegradable or bioabsorbable. For the purposes of this invention, hydrogels made of polyethylene glycols, collagen, or poly(glycolic-co-L-lactic acid) may be useful. See, for example, Phillipsef a / . (1984) J. Pharmaceut. Sel., 73:1718-1720. Pharmaceutical compositions, such as oral and parenteral compositions, may be formulated in unit dosage forms for ease of administration and dosage uniformity. As used herein, “unit dosage forms” refers to physically discrete units suitable as unit dosages for administration to subjects, each unit containing a predetermined amount of active ingredient calculated to produce the desired therapeutic effect, in association with one or more suitable pharmaceutical carriers. In therapeutic applications, pharmaceutical compositions must be administered in a manner appropriate to the disease being treated, as determined by a person skilled in the medical arts. An appropriate dose, duration, and frequency of administration may vary within broad limits and will be determined by considering factors such as the patient's condition, the type and severity of the disease, the specific form of the active ingredient(s), and the method of administration.In general, an appropriate dose and administration regimen provide the pharmaceutical composition in a sufficient quantity to produce a therapeutic benefit, such as an improved clinical outcome, including more frequent complete or partial remissions, longer disease-free and / or overall survival, reduced symptom severity, or any other objectively identifiable improvement as observed by the physician. Effective doses can generally be assessed or extrapolated using experimental models such as dose-response curves derived from in vitro or animal model testing systems, or from clinical trials. Appropriate doses for a PD(L)1 inhibitor are generally those currently used by physicians for the respective immune checkpoint inhibitor, particularly the dose(s) approved by the relevant government authorities. Other doses are also possible; for example, the PD(L)1 inhibitor dose may be reduced due to the combined action of newly identified combinations of such PD(L)1 inhibitors with iadademstat. The combinations as described herein may be administered as a simultaneous or sequential regimen. When administered sequentially, the combination may be administered in two or more doses. Combined administration includes co-administration, using separate formulations, and consecutive administration in any order, where there is preferably a period of time during which both (or all) of the active agents simultaneously exert their biological activities. The combinations of the invention may also be administered as a single pharmaceutical composition comprising the compound of formula (I) and the PD(L)1 inhibitor. The pharmaceutical compositions of the invention can be included in a container, package, or dispenser along with instructions for their administration. In another embodiment of the invention, a manufactured article, or “kit”, is provided containing a combination useful for the treatment of the diseases and disorders described above. In some embodiments, the manufactured article or kit comprises a container and a combination according to the invention as described in this document. In some embodiments, the manufactured article 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. Manufactured items or kits may also include a label or leaflet. The term "leaflet" refers to instructions commonly included in commercial packages of therapeutic products, containing information on indications, use, dosage, administration, contraindications, and / or warnings regarding the use of such therapeutic products. Suitable containers include, for example, bottles, vials, syringes, blister packs, etc. The container may be made from a variety of materials such as glass or plastic. The container may hold a combination, or a formulation thereof, that is effective in treating the condition and may have a sterile access port (for example, the container may be an intravenous solution bag or vial with a stopper that can be pierced with a hypodermic injection needle).The label or leaflet indicates that the composition is used to treat the condition of choice, such as cancer, for example, a cancer as described in this document. In one embodiment, the label or leaflet indicates that the composition comprising the combination can be used to treat cancer. Alternatively, or additionally, the manufactured article may further comprise an additional container comprising 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 commercially and user-desirable materials, including additional lamps, diluents, filters, needles, and syringes. The kit may further include instructions for administering 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 pharmaceutical composition comprising a PD(L)1 inhibitor, the kit may further include instructions for the simultaneous, sequential, or separate administration of the first and second pharmaceutical compositions to a patient in need. In another configuration, kits are suitable for administering solid oral dosage forms of a combination, such as tablets or capsules. The kit preferably includes a number of unit doses. Such kits may include a card with the doses oriented 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 for packaging unit-dose pharmaceutical forms. If desired, a memory aid can be provided, for example, in the form of numbers, letters, or other markings, or with a calendar insert, designating the days in the treatment schedule on which the doses can be administered. According to one embodiment, a kit may comprise (a) a first container with iadademstat, or a pharmaceutically acceptable salt or solvate of the same content; (b) a second container with a PD(L)1 inhibitor. Alternatively, or additionally, the kit may comprise another container comprising 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 commercially and user-desirable materials, including additional lamps, diluents, filters, needles, and syringes. Where 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 a container for holding the separate compositions, such as a split bottle or a split foil packet; however, the separate compositions may also be contained in a single, undivided container. Generally, the kit includes instructions for administering the separate components. The kit form is particularly convenient when the separate components are preferably administered in different dosage forms (e.g., oral and parenteral), at different dosing intervals, or when titration of the individual components of the combination by the prescribing physician is desired. Definitions Unless otherwise defined, all technical and scientific terms used in this document have the same meanings as are commonly understood by someone experienced in the field to which this invention pertains. The following definitions apply throughout this specification and claims, unless specifically stated otherwise. A “patient” or “subject” for the purposes of the present invention includes both humans and other animals, particularly mammals. Therefore, the methods and uses of the invention are applicable to both human therapy 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 a human (e.g., a male or female human). The terms “treatment,” “treat,” and similar terms are used in this document generally in the sense of achieving a desired pharmacological and / or physiological effect. The effect may be prophylactic in terms of completely or partially preventing a disease (in this document, cancer) or a symptom thereof, and / or it may be therapeutic in terms of curing or partially or completely alleviating a disease (i.e., cancer) and / or a symptom or adverse effect attributed to the disease, or partially or completely halting the progression of a disease and / or a symptom or adverse effect attributed to the disease.The term “treatment” as used herein covers any treatment of a disease (i.e., cancer) in a patient and includes, without limitation, any or more of the following: (a) preventing cancer in a patient who may be predisposed to / at risk of developing cancer; (b) delaying the onset of cancer; (c) inhibiting cancer, i.e., stopping, delaying, or slowing its development / progression; or (d) alleviating cancer, i.e., causing the (complete or partial) regression, correction, or relief of the cancer. The present invention relates specifically and distinctly to each of these forms of treatment. As used in this document, the term “therapeutically effective amount” refers to the amount sufficient to produce a desired biological effect (e.g., a therapeutic effect) in a subject. Accordingly, a therapeutically effective amount of a compound may be an amount that is sufficient to treat a disease (i.e., cancer) 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 that disease. As used herein, a “pharmaceutically acceptable salt” is intended to mean a salt that maintains the biological effectiveness of the free acids and / or bases of the specified compound and that is not biologically or otherwise undesirable. A compound may possess a functional group that is sufficiently acidic, sufficiently basic, or both, and consequently react with any of a number of inorganic or organic bases, and inorganic and organic acids, to form a pharmaceutically acceptable salt. Exemplary pharmaceutically acceptable salts include those salts prepared by reacting a compound according to the invention, for example, iadademstat, with a mineral or organic acid, such as hydrochlorides, hydrobroms, sulfates, pyrosulfates, bisulfates, sulfites, bisulfites, phosphates, monohydrophosphates, dihydrophosphates, metaphosphates, pyrophosphates, chlorides, bromides, iodides, nitrates, acetates, propionates, decanoates,caprylates, acrylates, formates, isobutyrates, caproates, heptanoates, propiolates, oxalates, malonates, succinates, suberates, sebacates, fumarates, maleates, butyne-1,4-dioates, hexyne-1,6-dioates, benzoates, chlorobenzoates, methylbenzoates, dinitrobenzoates, hydroxybenzoates, methoxybenzoates, phthalates, sultanates, xylenesulfonates, phenylacetates, phenylpropionates, phenylbutyrates, citrates, lactates, gamma-hydroxybutyrates, glycolates, tartrates, methanesulfonates, ethanesulfonates, propanesulfonates, benzenesulfonates, toluenesulfonates, trifluoromethanesulfonates, naphthalene-1-sulfonates, Naphthalene-2-sulfonates, mandelates, pyruvates, stearates, ascorbates, or salicylates. When a compound carries an acid portion, suitable pharmaceutically acceptable salts of it may include salts of alkali metals, for example, sodium or potassium salts; salts of alkaline earth metals, for example,Calcium or magnesium salts; and salts formed with suitable organic ligands such as ammonia, alkylamines, hydroxyalkylamines, lysine, arginine, N-methylglucamine, procaine, and the like. Pharmaceutically acceptable salts are well known in the field. As used herein, a “pharmaceutically acceptable solvate” refers to a complex of variable stoichiometry formed by a solute and a pharmaceutically acceptable solvent such as water, ethanol, and the like. A complex with water is known as a hydrate. It is understood that the invention encompasses pharmaceutically acceptable solvates of iadademstat in non-saline form and also in the form of a pharmaceutically acceptable salt thereof. As used in this document, a “pharmaceutically acceptable carrier” or “pharmaceutically acceptable excipient” refers to non-API substances (API stands for active pharmaceutical ingredient) such as disintegrants, binders, fillers, and lubricants used in the formulation of pharmaceutical products. These are generally safe for human administration according to established government standards, including 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 experienced in the field. As used in this document, a “small molecule” refers to an organic compound with a molecular weight below 900 Daltons, preferably below 500 Daltons. Molecular weight is the mass of a molecule and is calculated as the sum of the atomic weights of each constituent element multiplied by the number of atoms of that element in the molecular formula. The term “antibody” according to the invention is used in its broadest sense and comprises all antibodies, antibody fragments, and derivatives thereof that are capable of binding to an antigen, in this case the immune checkpoint. This includes whole monoclonal antibodies and also the epitope-binding fragments of these antibodies. In this context, epitope-binding fragments (also referred to herein as antibody fragments or antibody derivatives) comprise all regions of the antibody that are capable of binding to the antigen.Examples of particular antibody fragments according to the invention include, but are not limited to, Fab, Fab', F(ab')2, Fd, single-chain variable fragments (scFv), single-chain antibodies, disulfide-linked variable fragments (sdFv), and fragments containing either a light chain variable region (VL) or a heavy chain variable region (VH). Furthermore, they include recombinantly prepared antibodies such as diabodies and tetrabodies. The antibody fragments contain the variable regions either alone or in combination with additional regions selected from the hinge region and the first, second, and third regions of the constant region (CH1, CH2, CH3).The term antibody also encompasses chimeric antibodies in which different regions of the antibody originate from different species, for example, antibodies with a murine variable region combined with a human constant region. The antibody fragments are optionally linked together by a linker. The linker comprises a short, flexible peptide sequence (particularly 10 to 20 amino acid residues) selected so that the antibody fragment has a three-dimensional VL and VH fold that exhibits the antigenic specificity of the complete antibody. Furthermore, some linkers are composed of a peptide sequence that can enhance the protease resistance of antibody derivatives. The term “inhibitor” as used herein denotes a compound that competes with, diminishes, blocks, inhibits, abrogates, or interferes in any way with the binding of a particular ligand to a particular receptor or enzyme and / or that diminishes, blocks, inhibits, abrogates, or interferes in any way with the activity of a particular protein, e.g., a receptor or enzyme. As used in this document, the term “comprising” (or “comprising,” “includes,” “containing,” “containing,” or “that contains”), unless explicitly stated otherwise or contradicted by the context, has the meaning of “containing, among others,” i.e., “containing, among additional optional elements,....” In addition, this term also includes the narrower meanings of “consisting essentially of” and “consisting of.” For example, the term “A comprising B and C” has the meaning of “A containing, among others, B and C,” where A may contain additional optional elements (e.g., “A containing B, C, and D” would also be encompassed), but this term also includes the meaning of “A consisting essentially of B and C” and the meaning of “A consisting of B and C” (i.e., there are no other components besides B and C included in A). As used in this document, unless explicitly stated otherwise or contradicted by the 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 may be interpreted as referring to a composition comprising “one or more” PD(L)1 inhibitors. Examples The following examples are provided for illustrative purposes. They should not be considered as limiting the scope of the invention, but merely as being representative of it. The results are also presented and described in the figures and figure captions. Example 1: Evaluation of the effect of iadademstat in combination with a PD(L)1 inhibitor in an in vivo mouse model of melanoma Method: B16F10 melanoma cells were maintained in vitro as a monolayer culture in high-glucose DMEM (Sigma, D5796) supplemented with 10% fetal bovine serum (ThermoFisher, 10500064). Cells were harvested on exponential growth for tumor inoculation. Female C57 / BL6 mice were inoculated subcutaneously in the right flank for 6 to 8 weeks with B16F10 melanoma cells (0.5 x 10⁶) in 0.050 mL of DMEM (Dulbecco's modified Eagle medium):matrigel 1:1 (15 mice per group). Mice in groups 1 and 2 received vehicle-treated cells, while the B16F10 cells injected into group 3 were exposed for 96 h to 5 nM iadademstat 2HCl immediately prior to inoculation. Treatment began on the day of inoculation. The animals were injected with ipwith either sterile Dulbecco's Phosphate-Buffered Saline (DPBS) (group #1) or anti-PD1 mAb (100 pg of BioXcell RMP1-14 clone; cat. # BE0146; rat-mouse mAb) on days 4, 7, and 11 (groups #2 and #3). Animals in group #3 also received iadademstat 2HCl 10 pg / kg by oral gavage, starting from day 0 until the end of the experiment (day 22) following a 5 / 2 administration schedule (1111100). The iadademstat concentration for in vitro treatment is expressed as free base, while the administered dose in vivo refers to the iadademstat dihydrochloride salt. Tumor volumes were measured twice weekly in two dimensions using calipers, and the volume was expressed in mm3 using the formula: V = 0.5 ax b2 where “a” and “b” are the long and short diameters of the tumor, respectively. Tumor weight was measured at the end of the study.Statistical analysis was performed using the unpaired t-test. Results: A statistically significant difference (p = 0.004) in tumor volumes (TV) was observed when comparing animals treated with anti-PD1 mAb as a single agent (mean TV = 1099 mm3 on day 22) or with the combination of iadademstat + anti-PD1 mAb (mean TV = 509 mm3 on day 22). The mean tumor volume in vehicle controls was 1677 mm3 on day 19. The measured tumor weights also showed a statistically significant reduction in nLQ L Ln / Lznz / E / Yli tumor weight (p = 0.001) in animals treated with the iadademstat + anti-PD1 mAb combination compared to animals receiving anti-PD1 mAb alone, with an average weight of 0.29 g in tumors treated with the iadademstat + anti-PD1 mAb combination (collected on day 22), compared to an average tumor weight of 1.03 g and 1.39 g in animals receiving anti-PD1 mAb as a single agent (collected on day 22) or vehicle 5 (collected on day 19), respectively. Using methods similar to those described in Example 1, the therapeutic effects of iadademstat combinations with PD(L)1 inhibitors can be verified in other types of cancer. Although the invention has been described in relation to specific embodiments thereof, it shall be understood that it is susceptible of further modifications and this application is intended to cover any variation, use or adaptation 10 of the invention following, in general, the principles of the invention and including such deviations from the present disclosure as being within the known or customary practice within the art to which the invention belongs and that may be applied to the essential features set forth above and as follows in the appended claims. nLQ L Ln / Lznz / E / Yli

Claims

1. A combination comprising iadademstat, or a pharmaceutically acceptable salt or solvate thereof, and a PD(L)1 inhibitor.

2. A combination comprising iadademstat, or a pharmaceutically acceptable salt or solvate thereof, and a PD(L)1 inhibitor for use in therapy.

3. 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.

4. 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.

5. Iadademstat, or a pharmaceutically acceptable salt or solvate thereof, for use in the treatment of cancer in combination with a PD(L)1 inhibitor.

6. A PD(L)1 inhibitor for use in the treatment of cancer in combination with iadademstat or a pharmaceutically acceptable salt or solvate thereof.

7. A method for the treatment of cancer in a patient in need, 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.

8. A method for treating cancer in a patient in need, 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.

9. Use of iadademstat, or a pharmaceutically acceptable salt or solvate thereof, for the manufacture of a drug for the treatment of cancer to be used in combination with a PD(L)1 inhibitor.

10. Use of a PD(L)1 inhibitor for the manufacture of a drug for the treatment of cancer to be used in combination with iadademstat or a pharmaceutically acceptable salt or solvate thereof.

11. 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 drug for the treatment of cancer.

12. 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.

13. Use of iadademstat, or a pharmaceutically acceptable salt or solvate thereof, for the treatment of cancer in combination with a PD(L)1 inhibitor.

14. Use of a PD(L)1 inhibitor for the treatment of cancer in combination with iadademstat or a pharmaceutically acceptable salt or solvate thereof.

15. The combination according to claim 1, the combination for use according to any of claims 2 to 4, the compound for use according to claim 5 or 6, the method according to claim 7 or 8, or the use according to any of claims 9 to 14, wherein the PD(L)1 inhibitor Ln / Lznz / E / Yi is a PD-1 inhibitor or a PD-L1 inhibitor.

16. The combination according to claim 1 or 15, the combination for use according to any one of claims 2 to 4 or 15, the compound for use according to any one of claims 5, 6 or 15, the method according to any one of claims 7, 8 or 15, or the use according to any one of claims 9 to 15, wherein the PD(L)1 inhibitor is selected from the group consisting of Pembrolizumab, Nivolumab, Cemiplimab, Camrelizumab, Tislelizumab, Sintilimab, Toripalimab, Spartalizumab, AGEN2034, AK-103, AK-104, AK-105, AK-112, AK-123, AM-0001, AMP-224, AT16201, BCD-100, BH-2950, ​​BH-2996h, Bl754091, BMS-1001, BMS-1166, CS-1003, CX-188, ENUM-244C8, GLS-010, hAb21, HLX-10, IKT-202, JNJ-63723283, JTX-4014, KNO-46, MEDI-0680, MGA-012, MGD-013, PF-06801591, PRS-332, RO7121661, STI-A1110, TSR-042, 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.

17. The combination according to any one of claims 1, 15 or 16, the combination for use according to any one of claims 2 to 4, 15 or 16, the compound for use according to any one of claims 5, 6, 15 or 16, the method according to any one of claims 7, 8, 15 or 16, or the use according to any one of claims 9 to 16, wherein the PD(L)1 inhibitor is selected from the group consisting of Pembrolizumab, Nivolumab, Cemiplimab, Atezolizumab, Avelumab and Durvalumab.

18. The combination according to claim 1 or 15, the combination for use according to any of claims 2 to 4 or 15, the compound for use according to any of claims 5, 6 or 15, the method according to any of claims 7, 8 or 15, or the use according to any of claims 9 to 15, wherein the PD(L) 1 inhibitor is a PD-1 inhibitor.

19. The combination according to claim 18, the combination for use according to claim 18, the compound for use according to claim 18, the method according to claim 18, or the use according to claim 18, wherein 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, BH2950, ​​BH-2996h, BI-754091, BMS-1001, BMS-1166, CS-1003, CX-188, ENUM-244C8, GLS-010, hAb21, HLX-10, IKT202, JNJ-63723283, JTX-4014, KNO-46, MEDI-0680, MGA-012, MGD-013, PF-06801591, PRS-332, RO7121661, STIA1110, TSR-042, and XmAb-20717.

20. The combination according to claim 18 or 19, the combination for use according to claim 18 or 19, the compound for use according to claim 18 or 19, the method according to claim 18 or 19, or the use according to claim 18 or 19, wherein the PD-1 inhibitor is selected from the group consisting of Pembrolizumab, Nivolumab, and Cemiplimab.

21. The combination according to claim 1 or 15, the combination for use according to any of claims 2 to 4 or 15, the compound for use according to any of claims 5, 6 or 15, the method according to any of claims 7, 8 or 15, or the use according to any of claims 9 to 15, wherein the PD(L) 1 inhibitor is a PD-L1 inhibitor.

22. The combination according to claim 21, the combination for use according to claim 21, the compound for use according to claim 21, the method according to claim 21, or the use according to claim 21, wherein 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.

23. The combination according to claim 21 or 22, the combination for use according to claim 21 or 22, the compound for use according to claim 21 or 22, the method according to claim 21 or 22, or the use according to claim 21 or 22, wherein the PD-L1 inhibitor is selected from the group consisting of Atezolizumab, Avelumab, and Durvalumab.

24. The combination according to claim 1, the combination for use according to any of claims 2 to 4, the compound for use according to claim 5 or 6, the method according to claim 7 or 8, or the use according to any of claims 9 to 14, wherein the PD(L) 1 inhibitor is a PD-L2 inhibitor.

25. The combination for use according to any one of claims 4 or 15 to 24, the compound for use according to any one of claims 5, 6 or 15 to 24, the method according to any one of claims 7, 8 or 15 to 24, or the use according to any one of claims 9 to 24, wherein the cancer is selected from the group consisting of melanoma, small cell lung cancer, non-small cell lung cancer (NSCLC), head and neck cancer, renal cell carcinoma, Hodgkin lymphoma, urothelial carcinoma, colorectal cancer, hepatocellular cancer, cutaneous squamous cell carcinoma, ovarian cancer, gastric cancer, gastroesophageal cancer, Merkel cell carcinoma, nasopharyngeal cancer, breast cancer and esophageal squamous cell carcinoma.

26. The combination for use according to claim 25, the compound for use according to claim 25, the method according to claim 25, or the use according to claim 25, wherein the cancer is melanoma.

27. The combination for use according to claim 25, the compound for use according to claim 25, the method according to claim 25, or the use according to claim 25, wherein the cancer is small cell lung cancer.

28. The combination for use according to any of claims 4 or 15 to 27, the compound for use according to any of claims 5, 6 or 15 to 27, the method according to any of claims 7, 8 or 15 to 27, or the use according to any of claims 9 to 27, wherein the cancer is a cancer that is refractory, unresponsive or relapsed to PD(L)1 inhibitor therapy.

29. The combination according to any one of claims 1 or 15 to 24, the combination for use according to any one of claims 2 to 4 or 15 to 28, the compound for use according to any one of claims 5, 6 or 15 to 28, the method according to any one of claims 7, 8 or 15 to 28, or the use according to any one of claims 9 to 28, wherein iadademstat or a pharmaceutically acceptable salt or solvate thereof is iadademstat dihydrochloride.

30. The combination for use according to any of claims 2 to 4 or 15 to 29, the compound for use according to any of claims 5, 6 or 15 to 29, the method according to any of claims 7, 8 or 15 to 29, or the use according to any of claims 9 to 29, wherein iadademstat or the pharmaceutically acceptable salt or solvate thereof is administered orally.

31. The combination for use according to any of claims 2 to 4 or 15 to 30, the compound for use according to any of claims 5, 6 or 15 to 30, the method according to any of claims 7, 8 or 15 to 30, or the use according to any of claims 9 to 30, wherein iadademstat or the pharmaceutically acceptable salt or solvate thereof and the PD(L)1 inhibitor are administered using separate formulations.

32. The combination for use according to any of claims 2 to 4 or 15 to 31, the compound for use according to any of claims 5, 6 or 15 to 31, the method according to any of claims 7, 8 or 15 to 31, or the use according to any of claims 9 to 31, wherein iadademstat or the pharmaceutically acceptable salt or solvate thereof and the PD(L)1 inhibitor are administered as a concurrent regimen.

33. The combination for use according to any of claims 2 to 4 or 15 to 31, the compound for use according to any of claims 5, 6 or 15 to 31, the method according to any of claims 7, 8 or 15 to 31, or the use according to any of claims 9 to 31, wherein iadademstat or the pharmaceutically acceptable salt or solvate thereof and the PD(L)1 inhibitor are administered as a sequential regimen.

34. The method according to any of claims 7, 8 or 15 to 33, wherein the patient is a human. nLQ L Ln / Lznz / E / Yli