Combining LSD1 and menin inhibitors for cancer treatment

Abstract

The present invention relates to a combination of an LSD1 inhibitor (or a pharmaceutically acceptable salt thereof) and a menin inhibitor (or a pharmaceutically acceptable salt thereof), which is particularly useful in the treatment of cancer, including hematological cancers such as acute myeloid leukemia or myelodysplastic syndrome.

Description

[Technical Field]

[0001] The present invention relates to the combination of an LSD1 inhibitor and a menin inhibitor, which is particularly useful in the treatment of cancer, including hematological cancers such as acute myeloid leukemia or myelodysplastic syndrome. [Background technology]

[0002] Cancer is a significant burden on human health and one of the leading causes of death worldwide. Despite significant efforts in the development and improvement of cancer treatments, there were 23.6 million new cancer cases and 10 million cancer deaths worldwide in 2019, representing an increase of 26.3% and 20.9%, respectively, since 2010 (Kocarnik JM et al., JAMA Oncol, 2022, 8(3):420-44, doi:10.1001 / jamaoncol.2021.6987).

[0003] As a result, there is an urgent unmet need for new and improved therapeutic approaches to cancer treatment. The present invention addresses this and other needs. Thus, in the context of the present invention, it has been discovered that the combination of an LSD1 inhibitor and a menin inhibitor provides an unexpected and powerful therapeutic enhancement in the treatment of cancer, including hematological cancers. In particular, it has been discovered that the corresponding combination, as described herein, surprisingly provides highly beneficial synergistic anti-cancer effects, as also demonstrated in the Examples below. LSD1 inhibitors and menin inhibitors constitute a promising class of anti-cancer agents. Literature regarding such compounds is provided below in the sections entitled "LSD1 inhibitors" and "menin inhibitors." [Prior art documents] [Non-patent literature]

[0004] [Non-Patent Document 1] Kocarnik JM et al.,JAMA Oncol,2022,8(3):420-44,doi:10.1001 / jamaoncol.2021.6987 Summary of the Invention

[0005] The present invention is based on the unexpected discovery that a combination of an LSD1 inhibitor and a menin inhibitor, as described herein, exhibits superior activity in inhibiting the proliferation of cancer cells, particularly hematological cancer cells, compared to treatment with either an LSD1 inhibitor alone or a menin inhibitor alone. Thus, the present invention relates to a novel combination for treating cancer, preferably hematological cancers such as acute myeloid leukemia (AML) or myelodysplastic syndromes (MDS), by combining an LSD1 inhibitor with a menin inhibitor.

[0006] Accordingly, the present invention provides a combination product comprising an LSD1 inhibitor, or a pharmaceutically acceptable salt thereof, and a menin inhibitor, or a pharmaceutically acceptable salt thereof, in the same pharmaceutical formulation or in separate pharmaceutical formulations.

[0007] The present invention further provides a pharmaceutical composition comprising an LSD1 inhibitor or a pharmaceutically acceptable salt thereof and a menin inhibitor or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable excipients.

[0008] The present invention further provides an article of manufacture (or "kit") comprising an LSD1 inhibitor, or a pharmaceutically acceptable salt thereof, and a menin inhibitor, or a pharmaceutically acceptable salt thereof, either in the same pharmaceutical formulation or in separate pharmaceutical formulations.

[0009] The present invention further relates to a combination product, pharmaceutical composition or article of manufacture as described above for use in therapy (or for use as a medicine / drug), in particular for use in the treatment of cancer, such as haematological cancer.

[0010] The present invention further provides an LSD1 inhibitor or a pharmaceutically acceptable salt thereof for use in the treatment of cancer (e.g., blood cancer), wherein the LSD1 inhibitor or a pharmaceutically acceptable salt thereof is used in combination with a menin inhibitor or a pharmaceutically acceptable salt thereof.

[0011] The present invention further provides a menin inhibitor, or a pharmaceutically acceptable salt thereof, for use in the treatment of cancer (e.g., blood cancer), wherein the menin inhibitor, or a pharmaceutically acceptable salt thereof, is used in combination with an LSD1 inhibitor, or a pharmaceutically acceptable salt thereof.

[0012] The present invention further provides a method for treating cancer (e.g., a hematological cancer) in a patient in need of such treatment, the method comprising administering to the patient a therapeutically effective amount of the above-described combination product, pharmaceutical composition or article of manufacture.

[0013] The present invention further provides a method for treating cancer (e.g., a hematological cancer) in a patient in need of cancer treatment, the method comprising administering to the patient a therapeutically effective amount of an LSD1 inhibitor, or a pharmaceutically acceptable salt thereof, and a therapeutically effective amount of a menin inhibitor, or a pharmaceutically acceptable salt thereof.

[0014] The present invention further provides the use of a combination comprising an LSD1 inhibitor, or a pharmaceutically acceptable salt thereof, and a menin inhibitor, or a pharmaceutically acceptable salt thereof, for the manufacture of a medicament for the treatment of cancer (e.g., a blood cancer).

[0015] The present invention further provides the use of a combination comprising an LSD1 inhibitor, or a pharmaceutically acceptable salt thereof, and a menin inhibitor, or a pharmaceutically acceptable salt thereof, for the treatment of cancer (e.g., a hematological cancer).

[0016] In a preferred embodiment, the LSD1 inhibitor is iadademstat or a pharmaceutically acceptable salt thereof (e.g., iadademstat dihydrochloride). Further, in a preferred embodiment, the menin inhibitor is revumenib (SNDX-5613) or diftomenib (KO-539) or a pharmaceutically acceptable salt thereof. [Brief explanation of the drawings]

[0017] [Figure 1] FIG. 1 shows the plate configuration of the matrix assay used to determine the synergistic effects of the combination of the present invention, as described in Example 1. DETAILED DESCRIPTION OF THE INVENTION

[0018] As noted above, the present invention is based on the surprising discovery that an LSD1 inhibitor and a menin inhibitor, as described herein, can be used in combination to treat cancer, particularly hematological cancers, and as explained in more detail below and in the Examples, exerts superior anti-cancer effects than those achieved by treatment with either an LSD1 inhibitor alone or a menin inhibitor alone.

[0019] According to the present invention, an "LSD1 inhibitor" refers to a compound that reduces, decreases, blocks or inhibits the gene expression, activity or function of LSD1. Examples thereof are provided below under the heading "LSD1 inhibitors." A suitable LSD1 inhibitor is iadamstat or a pharmaceutically acceptable salt thereof (e.g., iadamstat dihydrochloride).

[0020] Similarly, according to the present invention, a "menin inhibitor" refers to a compound that reduces, decreases, blocks, antagonizes or inhibits the gene expression, activity or function of menin, examples of which are provided below under the heading "Menin Inhibitors". Suitable menin inhibitors are inhibitors that interfere with (the binding of) the menin-MLL1 complex, such as, for example, revumenib (SNDX-5613) or diftomenib (KO-539) or pharmaceutically acceptable salts thereof.

[0021] In particular, the present invention provides a combination product comprising an LSD1 inhibitor or a pharmaceutically acceptable salt thereof and a menin inhibitor or a pharmaceutically acceptable salt thereof in the same or separate pharmaceutical formulations. The LSD1 inhibitor (or a pharmaceutically acceptable salt thereof) and the menin inhibitor (or a pharmaceutically acceptable salt thereof) may thus be present in a single pharmaceutical formulation (e.g., in the same pharmaceutical formulation) or may each be provided in a different (separate) pharmaceutical formulation.

[0022] The present invention further provides a pharmaceutical composition comprising an LSD1 inhibitor or a pharmaceutically acceptable salt thereof and a menin inhibitor or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable excipients.

[0023] The present invention further provides articles of manufacture (or "kits") comprising an LSD1 inhibitor, or a pharmaceutically acceptable salt thereof, and a menin inhibitor, or a pharmaceutically acceptable salt thereof, in the same pharmaceutical formulation or in separate pharmaceutical formulations.

[0024] The present invention further provides a combination product comprising an LSD1 inhibitor, or a pharmaceutically acceptable salt thereof, and a menin inhibitor, or a pharmaceutically acceptable salt thereof, in the same or separate pharmaceutical formulations for use in therapy (or for use as a medicament / drug). The present invention also relates to the above pharmaceutical compositions or articles of manufacture for use in therapy (or for use as a medicament / drug).

[0025] The present invention still further provides a combination product, pharmaceutical composition or article of manufacture as described above for use in the treatment of cancer, preferably for use in the treatment of haematological cancer. The present invention therefore provides in particular a combination product comprising an LSD1 inhibitor, or a pharmaceutically acceptable salt thereof, and a menin inhibitor, or a pharmaceutically acceptable salt thereof, in the same or in separate pharmaceutical formulations for use in the treatment of cancer, preferably haematological cancer.

[0026] The present invention further provides an LSD1 inhibitor or a pharmaceutically acceptable salt thereof for use in the treatment of cancer (preferably blood cancer), wherein the LSD1 inhibitor or a pharmaceutically acceptable salt thereof is used in combination with a menin inhibitor or a pharmaceutically acceptable salt thereof. Accordingly, the present invention provides an LSD1 inhibitor or a pharmaceutically acceptable salt thereof for use in the treatment of cancer (preferably blood cancer), wherein the LSD1 inhibitor or a pharmaceutically acceptable salt thereof is administered in combination with a menin inhibitor or a pharmaceutically acceptable salt thereof. The LSD1 inhibitor (or a pharmaceutically acceptable salt thereof) and the menin inhibitor (or a pharmaceutically acceptable salt thereof) may be provided in the same pharmaceutical formulation or in separate pharmaceutical formulations.

[0027] The present invention further provides a menin inhibitor or a pharmaceutically acceptable salt thereof for use in the treatment of cancer (preferably blood cancer), wherein the menin inhibitor or a pharmaceutically acceptable salt thereof is used in combination with an LSD1 inhibitor or a pharmaceutically acceptable salt thereof. Accordingly, the present invention provides a menin inhibitor or a pharmaceutically acceptable salt thereof for use in the treatment of cancer (preferably blood cancer), wherein the menin inhibitor or a pharmaceutically acceptable salt thereof is administered in combination with an LSD1 inhibitor or a pharmaceutically acceptable salt thereof. The menin inhibitor (or a pharmaceutically acceptable salt thereof) and the LSD1 inhibitor (or a pharmaceutically acceptable salt thereof) may be provided in the same pharmaceutical formulation or in separate pharmaceutical formulations.

[0028] The present invention further provides a method for treating cancer (preferably a hematological cancer) in a patient in need of such treatment, the method comprising administering to the patient a therapeutically effective amount of the above-described combination product, pharmaceutical composition or article of manufacture.

[0029] In particular, the present invention provides a method for treating cancer (preferably a hematological cancer) in a patient in need of cancer treatment, the method comprising administering to the patient therapeutically effective amounts of a combination product comprising an LSD1 inhibitor, or a pharmaceutically acceptable salt thereof, and a menin inhibitor, or a pharmaceutically acceptable salt thereof, in the same pharmaceutical formulation or in separate pharmaceutical formulations.

[0030] The present invention further provides a method for treating cancer (preferably a hematological cancer) in a patient in need thereof, the method comprising administering to the patient a therapeutically effective amount of an LSD1 inhibitor, or a pharmaceutically acceptable salt thereof, and a therapeutically effective amount of a menin inhibitor, or a pharmaceutically acceptable salt thereof. The LSD1 inhibitor (or a pharmaceutically acceptable salt thereof) and the menin inhibitor (or a pharmaceutically acceptable salt thereof) may be provided / administered in the same pharmaceutical formulation or in separate pharmaceutical formulations.

[0031] The present invention further provides the use of a combination comprising an LSD1 inhibitor or a pharmaceutically acceptable salt thereof and a menin inhibitor or a pharmaceutically acceptable salt thereof for the manufacture of a medicament for the treatment of cancer (preferably a blood cancer).

[0032] The present invention further provides the use of an LSD1 inhibitor, or a pharmaceutically acceptable salt thereof, in combination with a menin inhibitor, or a pharmaceutically acceptable salt thereof, for the manufacture of a medicament comprising the LSD1 inhibitor, or a pharmaceutically acceptable salt thereof, and the menin inhibitor, or a pharmaceutically acceptable salt thereof, in the same pharmaceutical formulation or in separate pharmaceutical formulations, for the treatment of cancer, preferably a hematological cancer.

[0033] The present invention further provides the use of an LSD1 inhibitor or a pharmaceutically acceptable salt thereof in combination with a menin inhibitor or a pharmaceutically acceptable salt thereof for the manufacture of a medicament for the treatment of cancer (preferably a hematological cancer), said medicament comprising the LSD1 inhibitor or a pharmaceutically acceptable salt thereof and the menin inhibitor or a pharmaceutically acceptable salt thereof in the same pharmaceutical formulation or in separate pharmaceutical formulations.

[0034] The present invention further provides use of an LSD1 inhibitor or a pharmaceutically acceptable salt thereof in combination with a menin inhibitor or a pharmaceutically acceptable salt thereof for the manufacture of a medicament for treating cancer (preferably blood cancer).

[0035] The present invention further provides the use of an LSD1 inhibitor, or a pharmaceutically acceptable salt thereof, in combination with a menin inhibitor, or a pharmaceutically acceptable salt thereof, for the manufacture of a medicament for the treatment of cancer (preferably a hematological cancer).

[0036] The present invention further provides use of an LSD1 inhibitor or a pharmaceutically acceptable salt thereof for the manufacture of a medicament for treating cancer (preferably blood cancer), wherein the medicament is formulated to be used in combination with (or in combination with) a menin inhibitor or a pharmaceutically acceptable salt thereof.

[0037] The present invention further provides use of a menin inhibitor or a pharmaceutically acceptable salt thereof in combination with an LSD1 inhibitor or a pharmaceutically acceptable salt thereof for the manufacture of a medicament for treating cancer (preferably blood cancer).

[0038] The present invention further provides the use of a menin inhibitor, or a pharmaceutically acceptable salt thereof, in combination with an LSD1 inhibitor, or a pharmaceutically acceptable salt thereof, for the manufacture of a medicament for the treatment of cancer (preferably a hematological cancer).

[0039] The present invention further provides use of a menin inhibitor or a pharmaceutically acceptable salt thereof for the manufacture of a medicament for treating cancer (preferably a blood cancer), wherein the medicament is formulated to be used in combination with (or in combination with) an LSD1 inhibitor or a pharmaceutically acceptable salt thereof.

[0040] The present invention further provides the use of a combination comprising an LSD1 inhibitor, or a pharmaceutically acceptable salt thereof, and a menin inhibitor, or a pharmaceutically acceptable salt thereof, for treating cancer (preferably a hematological cancer).

[0041] The present invention further provides the use of an LSD1 inhibitor or a pharmaceutically acceptable salt thereof in combination with a menin inhibitor or a pharmaceutically acceptable salt thereof for treating cancer (preferably a hematological cancer), wherein said LSD1 inhibitor or a pharmaceutically acceptable salt thereof and said menin inhibitor or a pharmaceutically acceptable salt thereof are provided in the same pharmaceutical formulation or in separate pharmaceutical formulations.

[0042] The present invention further provides the use of an LSD1 inhibitor or a pharmaceutically acceptable salt thereof in combination with a menin inhibitor or a pharmaceutically acceptable salt thereof for the treatment of cancer (preferably a hematological cancer).

[0043] The present invention further provides the use of an LSD1 inhibitor, or a pharmaceutically acceptable salt thereof, in combination with a menin inhibitor, or a pharmaceutically acceptable salt thereof, for treating cancer (preferably a hematological cancer).

[0044] The present invention further provides use of an LSD1 inhibitor or a pharmaceutically acceptable salt thereof for treating cancer (preferably blood cancer), wherein the LSD1 inhibitor or a pharmaceutically acceptable salt thereof is administered in combination with a menin inhibitor or a pharmaceutically acceptable salt thereof.

[0045] The present invention further provides the use of a menin inhibitor or a pharmaceutically acceptable salt thereof in combination with an LSD1 inhibitor or a pharmaceutically acceptable salt thereof for the treatment of cancer (preferably a blood cancer).

[0046] The present invention further provides the use of a menin inhibitor, or a pharmaceutically acceptable salt thereof, in combination with an LSD1 inhibitor, or a pharmaceutically acceptable salt thereof, for treating cancer, preferably a hematological cancer.

[0047] The present invention further provides use of a menin inhibitor or a pharmaceutically acceptable salt thereof for treating cancer (preferably a hematological cancer), wherein the menin inhibitor or a pharmaceutically acceptable salt thereof is administered in combination with an LSD1 inhibitor or a pharmaceutically acceptable salt thereof.

[0048] In the methods and uses (including products for use) according to the present invention, the patient treated is a human or animal (eg a non-human mammal), preferably a human. In some embodiments, the LSD1 inhibitor is a small molecule.

[0049] In some embodiments, the LSD1 inhibitor is selected from the group consisting of iadamstat, pleurodemstat, vomedemstat, seclidemstat, 1-((4-(methoxymethyl)-4-(((1R,2S)-2-phenylcyclopropylamino)methyl)piperidin-1-yl)methyl)cyclobutanecarboxylic acid, 3-(cyanomethyl)-3-(4-{[(1R,2S)-2-phenylcyclopropyl]amino}piperidin-1-yl)azetidine-1-sulfonamide, and pharmaceutically acceptable salts thereof (i.e., a pharmaceutically acceptable salt of any one of the above agents).

[0050] In some embodiments, the LSD1 inhibitor is selected from the group consisting of iadamstat, pleurodemstat, vomedemstat, and pharmaceutically acceptable salts thereof. In some embodiments, the LSD1 inhibitor is plerodemstat or a pharmaceutically acceptable salt thereof.

[0051] In some embodiments, the LSD1 inhibitor is vomedemstat or a pharmaceutically acceptable salt thereof. Preferably, the LSD1 inhibitor is iademstat or a pharmaceutically acceptable salt thereof. In some embodiments, the LSD1 inhibitor is iademstat dihydrochloride.

[0052] In some embodiments, the menin inhibitor is selected from revumenib, VTP50469, diftomenib, JNJ-75276617, DS-1594, DSP-5336, MI-136, menin-MLL inhibitor 20, BMF-219, MI-3454, BAY-155, MI-503, BN104, and pharmaceutically acceptable salts thereof.

[0053] In some embodiments, the menin inhibitor is selected from revumenib, diftomenib, JNJ-75276617, DS-1594, DSP-5336, MI-136, menin-MLL inhibitor 20, BMF-219, BN104, and pharmaceutically acceptable salts thereof.

[0054] In some embodiments, the menin inhibitor is selected from revumenib, diftomenib, DS-1594, DSP-5336, MI-136, menin-MLL inhibitor 20, BMF-219, BN104, and pharmaceutically acceptable salts thereof.

[0055] In some embodiments, the menin inhibitor is selected from revumenib, diftomenib, DS-1594, DSP-5336, BMF-219, BN104, and pharmaceutically acceptable salts thereof.

[0056] In some embodiments, the menin inhibitor is revumenib or a pharmaceutically acceptable salt thereof. In some embodiments, the menin inhibitor is diftomenib or a pharmaceutically acceptable salt thereof.

[0057] In some embodiments, the menin inhibitor is JNJ-75276617 or a pharmaceutically acceptable salt thereof. In some embodiments, the menin inhibitor is DS-1594 or a pharmaceutically acceptable salt thereof.

[0058] In some embodiments, the menin inhibitor is DSP-5336 or a pharmaceutically acceptable salt thereof. In some embodiments, the menin inhibitor is BMF-219 or a pharmaceutically acceptable salt thereof.

[0059] In some embodiments, the menin inhibitor is BN104 or a pharmaceutically acceptable salt thereof. Preferably, the menin inhibitor is revumenib (or a pharmaceutically acceptable salt thereof) or diftomenib (or a pharmaceutically acceptable salt thereof).

[0060] The cancer treated according to the present invention can be, for example, a blood cancer or a solid cancer. In a preferred embodiment, the cancer is a hematological cancer (e.g., leukemia, lymphoma, myelodysplastic syndrome, or multiple myeloma). Corresponding examples are, in particular, myeloid leukemias, such as acute myeloid leukemia (acute myeloid leukemia or acute myelogenous leukemia); for example, acute monocytic leukemia, acute myelomonocytic leukemia, acute monoblastic leukemia, acute megakaryoblastic leukemia, acute erythrocyte leukemia (or Di Guglielmo syndrome; e.g., erythroleukemia, pure erythroid leukemia, or erythroleukemia and anaplastic erythroleukemia), or acute promyelocytic leukemia), chronic myeloid leukemia (chronic myeloid leukemia or chronic myelogenous leukemia). leukemia, subacute myeloid leukemia, monocytic leukemia (including, for example, acute monocytic leukemia or chronic myelomonocytic leukemia), or myeloid sarcoma (including, for example, chloroma or granulocytic sarcoma); erythroleukemia, including, for example, acute erythrocytes or chronic erythrocytes (including, for example, Heilmeyer-Schoner disease); mixed lineage leukemia (including, for example, acute mixed phenotype leukemia), mixed phenotype leukemia (including, for example, acute mixed phenotype leukemia); acute leukemia of ambiguous lineage myeloproliferative neoplastic disorders, including, for example, polycythemia vera, essential thrombocythemia, or idiopathic myelofibrosis; mast cell leukemia; acute panmyelosis (e.g., acute panmyelosis with myelofibrosis); acute myelofibrosis; plasma cell leukemia; lymphocytic leukemia, for example, acute lymphoblastic leukemia (or acute lymphocytic leukemia), chronic lymphocytic leukemia, subacute lymphocytic leukemia, prolymphocytic leukemia, hairy cell leukemia (e.g., leukemic reticuloendotheliosis), or adult T-cell leukemia; Hodgkin's lymphoma, e.g., nodular sclerosing Hodgkin's lymphoma, mixed cellularity Hodgkin's lymphoma, lymphocyte-rich Hodgkin's lymphoma, or lymphocyte-depleted Hodgkin's lymphoma; non-Hodgkin's lymphoma, e.g., follicular non-Hodgkin's lymphoma, mantle cell lymphoma, or diffuse non-Hodgkin's lymphoma (e.g., diffuse large B-cell lymphoma or Burkitt's lymphoma);nodular lymphocyte-predominant Hodgkin's lymphoma; peripheral or cutaneous T-cell lymphoma, including, for example, mycosis fungoides, Sézary syndrome, T-zone lymphoma, lymphoepithelioid lymphoma (e.g., Lennert's lymphoma), or peripheral T-cell lymphoma; lymphosarcoma; malignant immunoproliferative disorders, including, for example, Waldenstrom's macroglobulinemia, alpha heavy chain disease, gamma heavy chain disease (e.g., Franklin's disease), or Mediterranean lymphoma; myelodysplastic syndrome; or multiple myeloma, including, for example, Kahler's disease or myelomatosis;

[0061] Suitable examples of hematological cancers include acute myeloid leukemia (e.g., acute monocytic leukemia, acute myelomonocytic leukemia, acute monoblastic leukemia, acute megakaryoblastic leukemia, acute erythroid leukemia (or Di Guglielmo syndrome; e.g., erythroleukemia, undifferentiated erythroleukemia, or erythroleukemia and undifferentiated erythroleukemia), or acute promyelocytic leukemia), acute lymphoblastic leukemia, chronic myeloid leukemia, chronic lymphocytic leukemia, mixed plasmatic leukemia (e.g., mixed plasmatic acute leukemia), mixed phenotype leukemia (e.g., mixed phenotype acute leukemia), non-Hodgkin's lymphoma (e.g., follicular non-Hodgkin's lymphoma, mantle cell lymphoma, diffuse large B-cell lymphoma, or Burkitt's lymphoma), myelodysplastic syndrome, or multiple myeloma, among others.

[0062] The cancer to be treated may be a solid tumor (or solid malignant tumor, particularly a carcinoma or sarcoma). Corresponding examples are, inter alia, lung cancer (e.g. small cell lung cancer or non-small cell lung cancer), kidney cancer (e.g. renal carcinoma), gastrointestinal cancer, stomach cancer (e.g. gastric adenocarcinoma), colorectal cancer (e.g. colorectal carcinoma), colon cancer, anal cancer, genitourinary cancer, bladder cancer, urothelial cancer (e.g. urothelial carcinoma), liver cancer (e.g. hepatocellular carcinoma), pancreatic cancer (e.g. pancreatic adenocarcinoma or pancreatic duct adenocarcinoma), ovarian cancer, cervical cancer, endometrial cancer, vaginal cancer, vulvar cancer, ovarian cancer (e.g. ovarian carcinoma), uterine cancer (e.g. endometrial cancer or uterine sarcoma), prostate cancer (e.g. hormone-refractory prostate cancer), testicular cancer, biliary tract cancer (or bile duct cancer). cancer);Cancers that may be present include, but are not limited to, cholangiocarcinoma, hepatobiliary cancer, gallbladder cancer (e.g., gallbladder carcinoma), thyroid cancer (e.g., papillary thyroid cancer, follicular thyroid cancer, medullary thyroid cancer, or anaplastic thyroid cancer), neuroblastoma, brain tumors (e.g., glioblastoma), breast cancer (including, for example, triple-negative breast cancer, particularly COX-2-expressing triple-negative breast cancer, or breast cancer with BRCA1 and / or BRCA2 gene mutations), head and neck cancer (e.g., head and neck squamous cell carcinoma), skin cancer, melanoma, Merkel-cell cancer (e.g., Merkel-cell carcinoma), epidermoid carcinoma, squamous cell cancer (e.g., oral squamous cell carcinoma / squamous-cell mouth cancer), and thyroid cancer (e.g., thyroid cancer). carcinoma, squamous-cell skin cancer, squamous-cell epithelial cancer (e.g., NUT carcinoma), squamous cell lung cancer, squamous cell thyroid cancer, squamous cell esophageal cancer, or squamous cell vaginal cancer), bone cancer (e.g., osteosarcoma or osteogenic sarcoma), soft tissue sarcoma, fibrosarcoma, Ewing's sarcoma, Kaposi's sarcoma, rhabdomyosarcoma, malignant mesothelioma, esophageal cancer, laryngeal cancer, oral cancer, thymic cancer (e.g., thymoma), neuroendocrine cancer (e.g., neuroendocrine carcinoma), goblet cell cancer (e.g., goblet cell carcinoid), or splenic cancer;

[0063] Suitable examples of solid cancers include breast cancer, colon cancer, gastric cancer, neuroblastoma, head and neck cancer, liver cancer, lung cancer, neuroblastoma, cervical cancer, ovarian cancer, pancreatic cancer, prostate cancer, kidney cancer, osteosarcoma, squamous cell carcinoma (e.g. squamous cell skin cancer, including NUT carcinoma), soft tissue sarcoma, Ewing's sarcoma, rhabdomyosarcoma, or esophageal cancer, among others.

[0064] The cancer, including any one of the above specific types of hematological or solid cancer, being treated may be a relapsed or refractory cancer. Furthermore, the cancer being treated may be a metastatic cancer, including any one of the specific types of hematological or solid cancers listed above.

[0065] In some embodiments, the cancer being treated is a hematological cancer. In some embodiments, the hematological cancer is selected from acute myeloid leukemia, acute lymphoblastic leukemia, chronic myeloid leukemia, chronic lymphocytic leukemia, mixed plasmatic leukemia, mixed phenotype leukemia, non-Hodgkin's lymphoma, myelodysplastic syndrome, and multiple myeloma.

[0066] In some embodiments, the hematological cancer is acute myeloid leukemia. In some aspects, the acute myeloid leukemia is relapsed or refractory acute myeloid leukemia.

[0067] In some embodiments, the acute myeloid leukemia is relapsed acute myeloid leukemia. In some embodiments, the acute myeloid leukemia is refractory acute myeloid leukemia. In some aspects, the acute myeloid leukemia is acute monocytic leukemia, acute myelomonocytic leukemia, acute monoblastic leukemia, acute megakaryoblastic leukemia, acute erythroid leukemia, or acute promyelocytic leukemia.

[0068] In some embodiments, the acute myeloid leukemia is acute monocytic leukemia. In some embodiments, the acute myeloid leukemia is acute myelomonocytic leukemia. In some embodiments, the acute myeloid leukemia is acute monoblastic leukemia.

[0069] In some embodiments, the acute myeloid leukemia is an acute myeloid leukemia having genetic, epigenetic, or post-transcriptional changes that affect (e.g., increase) FLT3 expression and / or FLT3 activity. In particular, the acute myeloid leukemia can be an acute myeloid leukemia having FLT3 mutations and / or genetic, epigenetic, or post-transcriptional changes that affect (e.g., increase) FLT3 expression and / or FLT3 activity. In some embodiments, the acute myeloid leukemia is an acute myeloid leukemia having genetic, epigenetic, or post-transcriptional changes that result in FLT3 mutations and / or increased FLT3 expression levels or increased FLT3 activity, where the increased FLT3 expression levels or increased FLT3 activity lead to uncontrolled cell proliferation.

[0070] In some embodiments, the acute myeloid leukemia is FLT3 mutated acute myeloid leukemia. In some embodiments, the acute myeloid leukemia is a relapsed or refractory acute myeloid leukemia with genetic, epigenetic, or post-transcriptional changes that affect (e.g., increase) FLT3 expression and / or FLT3 activity. For example, the acute myeloid leukemia can be a FLT3 mutation and / or a relapsed or refractory acute myeloid leukemia with genetic, epigenetic, or post-transcriptional changes that affect (e.g., increase) FLT3 expression and / or FLT3 activity.

[0071] In some embodiments, the acute myeloid leukemia is relapsed or refractory acute myeloid leukemia with a FLT3 mutation. In some embodiments, the acute myeloid leukemia is a relapsed acute myeloid leukemia with genetic, epigenetic, or post-transcriptional changes that affect (e.g., increase) FLT3 expression and / or FLT3 activity. For example, the acute myeloid leukemia can be a FLT3 mutation and / or a relapsed acute myeloid leukemia with genetic, epigenetic, or post-transcriptional changes that affect (e.g., increase) FLT3 expression and / or FLT3 activity.

[0072] In some embodiments, the acute myeloid leukemia is relapsed acute myeloid leukemia with a FLT3 mutation. In some embodiments, the acute myeloid leukemia is a refractory acute myeloid leukemia having a genetic, epigenetic, or post-transcriptional change that affects (e.g., increases) FLT3 expression and / or FLT3 activity. For example, the acute myeloid leukemia can be a refractory acute myeloid leukemia having a FLT3 mutation and / or a genetic, epigenetic, or post-transcriptional change that affects (e.g., increases) FLT3 expression and / or FLT3 activity.

[0073] In some embodiments, the acute myeloid leukemia is refractory acute myeloid leukemia with a FLT3 mutation. In some embodiments, the FLT3 mutation is an activating FLT3 mutation, particularly a mutation that results in ligand-independent FLT3 dimerization and constitutive activation of FLT3.

[0074] In some embodiments, the FLT3 mutation is an internal tandem duplication mutation in the juxtamembrane region (FLT3-ITD) or a point mutation or deletion in the tyrosine kinase domain (FLT3-TKD). In some embodiments, the FLT3 mutation is FLT3-ITD. In some embodiments, the FLT3 mutation is FLT3-TKD. In some embodiments, the FLT3 mutation is FLT3-ITD and FLT3-TKD.

[0075] In some embodiments, the FLT3 mutation is a mutation in the tyrosine kinase domain (FLT3-TKD), in particular a point mutation (e.g., a nucleotide substitution) affecting (or involving) the aspartic acid residue at position 835 of wild-type FLT3 (D835), or a deletion of D835, and / or a point mutation (e.g., a nucleotide substitution) affecting (or involving) the isoleucine residue at position 836 of wild-type FLT3 (I836), or a deletion of I836. Thus, the FLT3 mutation can be (or can include), for example, a D835 mutation, an I836 mutation, or a D835 / I836 mutation. In particular, the D835 mutation can be, for example, a D835Y mutation (i.e., a FLT3 mutation in which the aspartic acid (D) residue at position 835 (D835) is replaced / substituted with a tyrosine (Y) residue), a D835V mutation, a D835H mutation, a D835G mutation, a D835N mutation, or a deletion of D835. In some embodiments, the FLT3 mutation is (or comprises) a D835Y mutation.

[0076] Furthermore, the FLT3 mutation may be (or may include) a point mutation affecting / involving the tyrosine residue at position 842 (Y842) of wild-type FLT3 or a deletion of Y842, a point mutation affecting / involving the lysine residue at position 663 (K663) of wild-type FLT3 or a deletion of K663, and / or a point mutation affecting / involving the valine residue at position 592 (V592) of wild-type FLT3 or a deletion of V592, e.g., a Y842C mutation, a K663Q mutation, or a V592A mutation, or any combination thereof.

[0077] In some embodiments, the acute myeloid leukemia is KMT2A (also known as MLL1) rearranged acute myeloid leukemia. In some embodiments, the acute myeloid leukemia is NPM1-mutated acute myeloid leukemia.

[0078] In some embodiments, the acute myeloid leukemia is DNMT3-mutated acute myeloid leukemia. In some embodiments, the acute myeloid leukemia is p53-mutated acute myeloid leukemia. In some embodiments, the acute myeloid leukemia is TET1-mutated acute myeloid leukemia.

[0079] In some embodiments, the acute myeloid leukemia is TET2-mutated acute myeloid leukemia. In some embodiments, the acute myeloid leukemia is NRAS-mutated acute myeloid leukemia. In some embodiments, the acute myeloid leukemia is ASXL1-mutated acute myeloid leukemia.

[0080] In some embodiments, the acute myeloid leukemia is DOT1L-overexpressing acute myeloid leukemia. In some embodiments, the acute myeloid leukemia is HOXA9-overexpressing acute myeloid leukemia.

[0081] In some embodiments, the acute myeloid leukemia is MEIS1-overexpressing acute myeloid leukemia. In some embodiments, the acute myeloid leukemia is relapsed / refractory KMT2A-rearranged acute myeloid leukemia.

[0082] In some embodiments, the acute myeloid leukemia is relapsed / refractory NPM1-mutated acute myeloid leukemia. In some embodiments, the acute myeloid leukemia is relapsed / refractory DNMT3-mutated acute myeloid leukemia.

[0083] In some embodiments, the acute myeloid leukemia is relapsed / refractory p53-mutated acute myeloid leukemia. In some embodiments, the acute myeloid leukemia is relapsed / refractory TET1-mutated acute myeloid leukemia.

[0084] In some embodiments, the acute myeloid leukemia is relapsed / refractory TET2-mutated acute myeloid leukemia. In some embodiments, the acute myeloid leukemia is relapsed / refractory NRAS-mutated acute myeloid leukemia.

[0085] In some embodiments, the acute myeloid leukemia is relapsed / refractory ASXL1-mutated acute myeloid leukemia. In some embodiments, the acute myeloid leukemia is relapsed / refractory DOT1L-overexpressing acute myeloid leukemia.

[0086] In some embodiments, the acute myeloid leukemia is relapsed / refractory HOXA9-overexpressing acute myeloid leukemia. In some embodiments, the acute myeloid leukemia is relapsed / refractory MEIS1-overexpressing acute myeloid leukemia.

[0087] In some embodiments, the acute myeloid leukemia is any one of the specific types of acute myeloid leukemia described above (e.g., including any one of the specific types of mutant acute myeloid leukemia described above), which is further identified as selected from acute monocytic leukemia, acute myelomonocytic leukemia, acute monoblastic leukemia, acute megakaryoblastic leukemia, acute erythroid leukemia, and acute promyelocytic leukemia.

[0088] In some embodiments, the LSD1 inhibitor (or a pharmaceutically acceptable salt thereof) and the menin inhibitor (or a pharmaceutically acceptable salt thereof) are used as a second-line or third-line treatment for relapsed or refractory acute myeloid leukemia.

[0089] In some embodiments, the hematological cancer is acute lymphoblastic leukemia. In some embodiments, the hematological cancer is mixed phenotype leukemia. In some embodiments, the hematological cancer is mixed phenotype acute leukemia.

[0090] In some embodiments, the hematological cancer is a myelodysplastic syndrome. In some embodiments, the hematological cancer is a myelodysplastic syndrome with genetic, epigenetic, or post-transcriptional changes that affect (e.g., increase) FLT3 expression and / or FLT3 activity. In particular, the hematological cancer is a myelodysplastic syndrome with a FLT3 mutation and / or genetic, epigenetic, or post-transcriptional changes that affect (e.g., increase) FLT3 expression and / or FLT3 activity. In some embodiments, the hematological cancer is a myelodysplastic syndrome with a FLT3 mutation (e.g., any of the exemplary FLT3 mutations described above) and / or genetic, epigenetic, or post-transcriptional changes that result in an increased FLT3 expression level or increased FLT3 activity, which leads to uncontrolled cell proliferation. In some embodiments, the hematological cancer is a myelodysplastic syndrome with a FLT3 mutation (e.g., any of the exemplary FLT3 mutations described above).

[0091] In some embodiments, the LSD1 inhibitor (or a pharmaceutically acceptable salt thereof) and the menin inhibitor (or a pharmaceutically acceptable salt thereof) are administered as separate pharmaceutical formulations. To this end, the LSD1 inhibitor (or a pharmaceutically acceptable salt thereof) and the menin inhibitor (or a pharmaceutically acceptable salt thereof) are provided as separate pharmaceutical formulations.

[0092] Preferably, the LSD1 inhibitor, such as iadamstat (or a pharmaceutically acceptable salt thereof), is administered orally. Exemplary formulations that can be administered by oral ingestion are described in more detail below.

[0093] Preferably, the menin inhibitor (or a pharmaceutically acceptable salt thereof) is administered orally. Exemplary formulations that can be administered by oral ingestion are described in more detail below. As illustrated in the Examples, in the context of the present invention, it has been unexpectedly discovered that the combination of an LSD1 inhibitor and a menin inhibitor exerts a strong synergistic effect in inhibiting the growth of cancer, particularly hematological cancers such as AML. Thus, as described in Example 1, using three structurally unrelated different LSD1 inhibitors, namely, iadamdemstat and vomedemstat (both irreversible cyclopropylamine LSD1 inhibitors), and pleurodemstat (a reversible non-cyclopropylamine LSD1 inhibitor), treatment with a combination of an LSD1 inhibitor and a menin inhibitor exerted a synergistic effect in inhibiting the growth of AML cell lines with different genetic backgrounds. As illustrated in Example 1, a strong synergistic effect was observed in the combinations of iadamdemstat + a menin inhibitor and pleurodemstat + a menin inhibitor. These findings indicate that the combination of an LSD1 inhibitor, such as iadademstat (or a pharmaceutically acceptable salt thereof), with a menin inhibitor (or a pharmaceutically acceptable salt thereof) may be particularly useful for the treatment of AML and other hematological cancers, such as MDS, with or without FLT3 mutations, even in patients who are refractory to other therapies or who have relapsed.

[0094] The therapeutic efficacy of the combination of an LSD1 inhibitor and a menin inhibitor for the treatment of cancer, including hematological cancers such as AML, can be further confirmed in additional in vitro or in vivo experiments, as well as in human clinical trials, which can be easily set up by one skilled in the art of drug development.

[0095] LSD1 inhibitors As previously indicated, the term "LSD1 inhibitor" as used herein refers to a compound that reduces, decreases, blocks, or inhibits the gene expression, activity, or function of LSD1. Compounds that act as LSD1 inhibitors are known in the art. In principle, any molecule that acts as an LSD1 inhibitor can be used in the context of the combinations, methods, and uses according to the present invention. Preferably, the LSD1 inhibitor is a small molecule. As demonstrated by the results described in the Examples below, both irreversible and reversible LSD1 inhibitors are described and can be used in the context of the present invention, using combinations of menin inhibitors with both irreversible and reversible LSD1 inhibitors. Exemplary irreversible LSD1 inhibitors are cyclopropylamine-based compounds, such as iadamstat, one of the LSD1 inhibitors used in the Examples herein. A representative example of a reversible LSD1 inhibitor is the compound pleurodemstat, which is also used in the Examples herein. Preferably, the LSD1 inhibitor is a selective LSD1 inhibitor, and as used herein, "selective LSD1 inhibitor" means an LSD1 inhibitor that exhibits at least 10-fold (preferably at least 100-fold) selectivity for LSD1 over other FAD-dependent monoamine oxidases, particularly MAO-A and MAO-B (this means, for example, that the IC of LSD1, MAO-A, and MAO-B are higher). 50 can be evaluated by determining the value of

[0096] A list of exemplary small molecule LSD1 inhibitors is provided in the table below.

[0097] [Table A]

[0098] An LSD1 inhibitor for use in accordance with the present invention can thus be, for example, any one of the specific compounds listed in the table above, or a pharmaceutically acceptable salt of any one of these compounds.

[0099] In some embodiments, the LSD1 inhibitor is selected from the group consisting of compounds described in, for example, WO2010 / 043721, WO2010 / 084160, WO2010 / 143582, WO2011 / 035941, WO2011 / 042217, WO2011 / 131576, WO2011 / 131697, WO2012 / 013727, WO2012 / 013728, WO2012 / 045883, WO2012 / 135113, WO2013 / 022047, EP2743256A1, WO2013 / 025805, WO2013 / 057320, WO2013 / 057322, WO 2014 / 058071, EP2907802A1, WO2014 / 084298, EP2927212A1, WO2014 / 086790, WO2014 / 164867, WO2014 / 194280, WO2014 / 205213, WO2015 / 021128, WO2 015 / 031564, WO2015 / 089192, WO2015 / 120281, WO2015 / 123408, WO2015 / 123424, WO2015 / 123437, WO2015 / 123465, WO2015 / 134973, WO2015 / 168466, W O2015 / 181380, WO2015 / 200843, WO2016 / 003917, WO2016 / 004105, WO2016 / 007722, WO2016 / 007727, WO2016 / 007731, WO2016 / 007736, WO2016 / 03494 6, WO2016 / 037005, WO2016 / 123387, WO2016 / 130952, WO2016 / 161282, WO2016 / 172496, WO2016 / 177656, WO2017 / 004519, WO2017 / 027678, WO2017 / 079 476, WO2017 / 079670, WO2017 / 090756, EP3381896A1, WO2017 / 109061, WO2017 / 116558, WO2017 / 149463, WO2017 / 157322, EP3431471A1, WO2017 / 18493 4, WO2017 / 195216, WO2017 / 198780, WO2017 / 215464, EP3486244A1, WO2018 / 081342, WO2018 / 081343, WO2018 / 137644, EP3575285A1, WO2018 / 213211,WO2018 / 216800, EP3632897A1, WO2018 / 226053, WO2018 / 234978, WO2019 / 009412, WO2019 / 0347 74, WO2019 / 054766, WO2019 / 217972, WO2019 / 222069, WO2020 / 015745, EP3825309A1, WO2020 / 04 7198, WO2020 / 052647, WO2020 / 052649, EP3851440A1, WO2020 / 138398, WO2020 / 159285, EP39072 25A1, WO2021 / 058024, WO2021 / 095835, WO2021 / 175079, WO2022 / 072811, WO2022 / 171044, WO202 2 / 188709, WO2022 / 199662, WO2022 / 240886, WO2022 / 267495, WO2023 / 069884, WO2023 / 083269, W O2023 / 142641, WO2023 / 179078, WO2023 / 207447, WO2023 / 284651, US2017-0283397, US2022-006 4126, CN103054869, CN103319466, CN104119280, CN105541806, CN105924362, CN105985265, CN1 06045862, CN106045881, CN106432248, CN106478639, CN106831489, CN106928235, CN107033148 CN107174584, CN107176927, CN107459476, CN107474011, CN107501169, CN107936022, CN108530302, CN1 09265462, CN109293664, CN109535019, CN110204551, CN110478352, CN111072610, CN111454252, CN11211 CN113087712, CN113105479, CN113264903, CN113582906, CN113599380, CN114502561, CN114805205, CN114805261, KR20190040763, or KR20190040783,LSD1 inhibitors are known in the art. Each of the above documents is incorporated herein by reference in its entirety (including, inter alia, the compounds described in the Examples section of each of these documents). Thus, the LSD1 inhibitor can be, for example, a compound disclosed in any one of the above documents (including, for example, the Examples section of any one of these documents), and the compound can be used in its non-salt form or in the form of a pharmaceutically acceptable salt.

[0100] In some embodiments, the LSD1 inhibitor is a compound selected from the group consisting of iadamstat, plerodemstat, vomedemstat, seclidemstat, 1-((4-(methoxymethyl)-4-(((1R,2S)-2-phenylcyclopropylamino)methyl)piperidin-1-yl)methyl)cyclobutanecarboxylic acid, 3-(cyanomethyl)-3-(4-{[(1R,2S)-2-phenylcyclopropyl]amino}piperidin-1-yl)azetidine-1-sulfonamide, and pharmaceutically acceptable salts thereof.

[0101] Iadademstat is a selective and irreversible LSD1 inhibitor. Iadademstat has the formula:

[0102] [ka]

[0103] Iadademstat is the International Nonproprietary Name (INN) of the compound [CAS Registry Number 1431304-21-0], and 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 WO 2013 / 057322. Pharmaceutically acceptable salts thereof, including the hydrochloride salt, are also described therein.

[0104] Prurodemstat has the formula:

[0105] [ka]

[0106] A reversible LSD1 inhibitor [CAS Registry Number 1821307-10-1], also known as CC-90011, has the chemical name 4-[2-(4-aminopiperidin-1-yl)-5-(3-fluoro-4-methoxyphenyl)-1-methyl-6-oxo-1,6-dihydropyrimidin-4-yl]-2-fluorobenzonitrile. Plurodemstat is described, for example, in WO 2015 / 168466 and WO 2017 / 79670. Pharmaceutically acceptable salts thereof, including the besylate salt, are also described therein.

[0107] Vomedemstat has the formula:

[0108] [ka]

[0109] [CAS Registry Number 1990504-34-1] is an irreversible LSD1 inhibitor, also known as IMG-7289, and has the chemical name N-[(2S)-5-{[(1R,2S)-2-(4-fluorophenyl)cyclopropyl]amino}-1-(4-methylpiperazin-1-yl)-1-oxopentan-2-yl]-4-(1H-1,2,3-triazol-1-yl)benzamide. Vomedemstat is described, for example, in WO2016 / 130952 and WO2018 / 35259. Its pharmaceutically acceptable salts, including bistosylate salts, are also described therein.

[0110] Securidemstat has the formula:

[0111] [ka]

[0112] [CAS Registry Number 1423715-37-0] is an LSD1 inhibitor, also known as SP-2577, and has the chemical name (E)-N'-(1-(5-chloro-2-hydroxyphenyl)ethylidene)-3-((4-methylpiperazin-1-yl)sulfonyl)benzohydrazide. Secridemstat is described, for example, in WO2013 / 025805 and WO2014 / 205213.

[0113] 1-((4-(Methoxymethyl)-4-(((1R,2S)-2-phenylcyclopropylamino)methyl)piperidin-1-yl)methyl)cyclobutanecarboxylic acid is an irreversible LSD1 inhibitor that is described, for example, in WO2015 / 123465 and WO2017 / 27678. Pharmaceutically acceptable salts thereof, including the p-toluenesulfonate salt, are also described therein.

[0114] 3-(Cyanomethyl)-3-(4-{[(1R,2S)-2-phenylcyclopropyl]amino}piperidin-1-yl)azetidine-1-sulfonamide is an irreversible LSD1 inhibitor, and is described, for example, in WO2020 / 047198. Pharmaceutically acceptable salts thereof are also described therein.

[0115] Vafidemstat has the formula:

[0116] [ka]

[0117] and is also known as ORY-2001, 5-((((1R,2S)-2-(4-(benzyloxy)phenyl)cyclopropyl)amino)methyl)-1,3,4-oxadiazol-2-amine, or (-)5-((((trans)-2-(4-(benzyloxy)phenyl)cyclopropyl)amino)methyl)-1,3,4-oxadiazol-2-amine. Bufidemstat is described, for example, in Example 35 of WO2012 / 13728.

[0118] TAS1440 has the formula:

[0119] [ka]

[0120] It is a reversible LSD1 inhibitor with the chemical name (S)-5'-(3-aminopyrrolidine-1-carbonyl)-2",3-difluoro-4"-(2-hydroxy-2-methylpropyl)-[1,1':2',1"-terphenyl]-4-carbonitrile [CAS Registry Number 2098585-77-2]. The chemical family to which it belongs is described, for example, in WO2017090756 and US2018354960. Salts of this compound are described, for example, in WO2021095835.

[0121] In some embodiments, the LSD1 inhibitor is selected from the group consisting of iadamstat, pleurodemstat, vomedemstat, and pharmaceutically acceptable salts thereof. A particularly suitable LSD1 inhibitor is iadamstat or a pharmaceutically acceptable salt thereof. In some embodiments, iadamstat is used as the dihydrochloride salt.

[0122] Menin inhibitors As indicated above, the term "menin inhibitor" as used herein refers to a compound that reduces, decreases, blocks, antagonizes, or inhibits the gene expression, activity, or function of menin. Compounds that act as inhibitors of menin are known in the art. In principle, any molecule that acts as a menin inhibitor can be used in the context of the combinations, methods, and uses according to the present invention. Preferably, the menin inhibitor is a small molecule. Preferably, the menin inhibitor is a menin-MLL1 inhibitor compound (particularly a menin-MLL1 inhibitor small molecule), i.e., a protein-protein inhibitor that inhibits the interaction between menin and MLL1 (also known as histone-lysine N-methyltransferase 2A (KMT2A)). Therefore, it is preferred that the menin inhibitor is a menin-MLL1 inhibitor.

[0123] A list of exemplary small molecule menin inhibitors is provided in the table below.

[0124] [Table B]

[0125] A menin inhibitor used in accordance with the present invention can thus be, for example, any one of the specific compounds listed in the table above, or a pharmaceutically acceptable salt of any one of these compounds.

[0126] In some embodiments, the menin inhibitor is selected from the group consisting of, for example, WO2011 / 029054, WO2014 / 164543, WO2014 / 200479, WO2016 / 040330, WO2016 / 195776, WO2016 / 197027, WO2017 / 112768, WO2017 / 161002, WO2017 / 161028, WO2017 / 192543, WO2 017 / 207387, WO2017 / 214367, WO2018 / 024602, WO2018 / 050684, WO2018 / 050686, WO2018 / 053267, W O2018 / 109088, WO2018 / 183857, WO2018 / 226976, WO2019 / 060365, WO2019 / 120209, WO2019 / 189732, WO2019 / 191526, WO2020 / 032105, WO2020 / 045334, WO2020 / 116662, WO2020 / 142557, WO2020 / 14255 9, WO2021 / 060453, WO2021 / 121327, WO2021 / 207335, WO2022 / 133064, WO2022 / 237626, WO2022 / 2376 27, WO2022 / 241265, WO2023 / 098876, US2021 / 269454, or US2021 / 338668, each of which is incorporated herein by reference in its entirety (specifically including the compounds described in the Examples section of each of these documents). Thus, the menin inhibitor can be, for example, a compound disclosed in any one of the above documents (including, for example, the Examples section of any one of these documents), and the compound can be used in a non-salt form or in the form of a pharmaceutically acceptable salt.

[0127] In some embodiments, the menin inhibitor is a compound selected from the group consisting of revumenib, VTP50469, diftomenib, JNJ-75276617, DS-1594, DSP-5336, MI-136, menin-MLL inhibitor 20, BMF-219, MI-3454, BAY-155, MI-503, BN104, and pharmaceutically acceptable salts thereof. In some embodiments, the menin inhibitor is not diftomenib (or a pharmaceutically acceptable salt thereof).

[0128] Revumenib has the formula:

[0129] [ka]

[0130] [CAS Registry Number 2169919-21-3], or a menin inhibitor having the chemical name 2-{[4-(7-{[trans-4-(ethanesulfonamido)cyclohexyl]methyl}-2,7-diazaspiro[3.5]nonan-2-yl)pyrimidin-5-yl]oxy}-N-ethyl-5-fluoro-N-(propan-2-yl)benzamide, also known as SNDX-5613. Revumenib and pharmaceutically acceptable salts thereof are described, for example, in WO 2022 / 241122 (see in particular Examples 252 to 257 of WO 2022 / 241122). Thus, revumenib can also be used in the form of a pharmaceutically acceptable salt, such as the fumarate salt (particularly the sesquifumarate salt; see, e.g., Example 255 of WO 2022 / 241122), the methanesulfonic acid (or mesylate) salt (particularly the bismethanesulfonate salt; see, e.g., Example 256 of WO 2022 / 241122), or the hydrochloride salt (particularly the bishydrochloride salt; see, e.g., Example 257 of WO 2022 / 241122). In a preferred embodiment, revumenib is used in the form of a fumarate salt, particularly as revumenib sesquifumarate (i.e., revumenib·1.5C4H4O4).

[0131] VTP50469 has the formula:

[0132] [ka]

[0133] It is a menin inhibitor with the chemical name 5-fluoro-N,N-diisopropyl-2-({4-[7-({trans-4-[(methylsulfonyl)amino]cyclohexyl}methyl)-2,7-diazaspiro[3.5]non-2-yl]-5-pyrimidinyl}oxy)benzamide [CAS Registry Number 2169916-18-9], also known as SYN50469 or SNDX-50469. The compound VTP50469 (SYN50469 / SNDX-50469) and pharmaceutically acceptable salts thereof are described, for example, in WO2017 / 214367, WO2022 / 241122 and Krivtsov AV et al., Cancer Cell, 2019, 36(6):660-673.e11, doi:10.1016 / j.ccell.2019.11.001 (see in particular Example 6A and Examples 258-261 of WO2017 / 214367). Thus, VTP50469 can also be used in the form of a pharmaceutically acceptable salt, such as a fumarate (particularly a sesquifumarate; see, for example, Example 260 of WO2017 / 214367), a methanesulfonate (or mesylate) salt (particularly a bismethanesulfonate; see, for example, Example 259 of WO2017 / 214367), or a hydrochloride salt (particularly a bishydrochloride salt; see, for example, Example 261 of WO2017 / 214367), preferably in the form of a fumarate (particularly as VTP50469 sesquifumarate).

[0134] Diftomenib has the formula:

[0135] [ka]

[0136] [CAS Registry Number 2134675-36-6], or chemical name 4-methyl-5-[[4-[[2-(methylamino)-6-(2,2,2-trifluoroethyl)thieno[2,3-d]pyrimidin-4-yl]amino]piperidin-1-yl]methyl]-1-[(2S)-2-(4-methylsulfonylpiperazin-1-yl)propyl]indole-2-carbonitrile, and is also known as KO-539. Diftomenib and pharmaceutically acceptable salts thereof are described, for example, in WO2017 / 161028 (see in particular Example 135 of WO2017 / 161028).

[0137] DS-1594 has the formula:

[0138] [ka]

[0139] DS-1594 is a menin inhibitor with the chemical name (1R,2S,4R)-4-({[4-(5,6-dimethoxypyridazin-3-yl)phenyl]methyl}amino)-2-{methyl[6-(2,2,2-trifluoroethyl)thieno[2,3-d]pyrimidin-4-yl]amino}cyclopentan-1-ol [CAS Registry Number 2440018-29-9]. The non-salt form (free base) of DS-1594 is also known as "DS-1594a," while the succinate salt of DS-1594 is known as "DS-1594b." The compound DS-1594 and its pharmaceutically acceptable salts (including succinate and hydrochloride salts) are described, for example, in WO2020 / 116662 and US2021 / 269454 (see, in particular, Example 25 of WO2020 / 116662 and US2021 / 269454), and in Numata M et al., Cancer Cell Int, 2023, 23:36, doi:10.1186 / s12935-023-02877-y (and related "Supplementary Materials"). The hydrochloride salt of DS-1594 is known by CAS Registry Number 2440026-48-0. The formate salt (salt of formic acid) of DS-1594 is known by CAS Registry Number 2938875-58-0. The succinate salt of DS-1594 is known by CAS Registry Number 2440018-30-2. The benzenesulfonate salt of DS-1594 is known by CAS Registry Number 2440018-34-6. The fumarate salt of DS-1594 is known by CAS Registry Numbers 2440018-40-4 (salt with (E)-fumaric acid) and 2440018-37-9 (salt with (Z)-fumaric acid). Deuterated analogs of DS-1594, such as (1R,2S,4R)-4-({[4-(5,6-di-( 2 H3)-Methoxypyridazin-3-yl)phenyl]methyl}amino)-2-{methyl[6-(2,2,2-trifluoroethyl)thieno[2,3-d]pyrimidin-4-yl]amino}cyclopentan-1-ol (CAS Registry Number 2440018-22-2) and its pharmaceutically acceptable salts can also be used as menin inhibitors.

[0140] The DSP-5336 uses the formula:

[0141] [ka]

[0142] It is a menin inhibitor with the chemical name 5-fluoro-2-((4-(7-(((1S,3S,4R)-5-methylene-2-azabicyclo(2.2.2)oct-3-yl)carbonyl)-2,7-diazaspiro(3.5)non-2-yl)-5-pyrimidinyl)oxy)-N,N-bis(1-methylethyl)-benzamide [CAS Registry Number 2412555-70-3]. DSP-5336 and its pharmaceutically acceptable salts (including the L(+)-tartrate (particularly the mono-L(+)-tartrate), succinate (particularly the disuccinate), and hydrochloride salts) are described, for example, in WO 2020 / 045334 and US 2021 / 338668 (see, in particular, Example 6 of WO 2020 / 045334 and US 2021 / 338668). The hydrochloride salt of DSP-5336 is known under CAS Registry Number 2412556-01-3. The succinate salt of DSP-5336 is known under CAS Registry Number 2768840-62-4; the monosuccinate salt of DSP-5336 is known under CAS Registry Number 2412556-02-4; and the disuccinate salt of DSP-5336 is known under CAS Registry Number 2412555-90-7. The (2R,3R)-tartrate salt of DSP-5336 is known by the CAS Registry Number 2768840-33-9; the mono-(2R,3R)-tartrate salt of DSP-5336 is known by the CAS Registry Number 2412555-89-4.

[0143] Deuterated analogs of DSP-5336, such as 5-fluoro-2-((4-(7-(((1S,3S,4R)-5-( 2 H2)-methylene-2-azabicyclo(2.2.2)oct-3-yl)carbonyl)-2,7-diazaspiro(3.5)non-2-yl)-5-pyrimidinyl)oxy)-N,N-bis(1-methylethyl)-benzamide (CAS Registry Number 2412555-85-0) and its pharmaceutically acceptable salts can also be used as menin inhibitors. 5-fluoro-2-((4-(7-(((1S,3S,4R)-5-( 2H2)-methylene-2-azabicyclo(2.2.2)oct-3-yl)carbonyl)-2,7-diazaspiro(3.5)non-2-yl)-5-pyrimidinyl)oxy)-N,N-bis(1-methylethyl)-benzamide and pharmaceutically acceptable salts thereof (including L(+)-tartrate (particularly mono-L(+)-tartrate), succinate (particularly disuccinate), and hydrochloride salts) are described, for example, in WO2020 / 045334 and US2021 / 338668 (see in particular Example 20 of WO2020 / 045334 and US2021 / 338668). 5-fluoro-2-((4-(7-(((1S,3S,4R)-5-( 2 H2)-methylene-2-azabicyclo(2.2.2)oct-3-yl)carbonyl)-2,7-diazaspiro(3.5)non-2-yl)-5-pyrimidinyl)oxy)-N,N-bis(1-methylethyl)-benzamide hydrochloride is known under CAS Registry Number 2412556-09-1. 5-Fluoro-2-((4-(7-(((1S,3S,4R)-5-( 2 H2)-methylene-2-azabicyclo(2.2.2)oct-3-yl)carbonyl)-2,7-diazaspiro(3.5)non-2-yl)-5-pyrimidinyl)oxy)-N,N-bis(1-methylethyl)-benzamide succinate salt is known under the CAS registration number 2768840-68-0; the monosuccinate salt of this compound is known under the CAS registration number 2412556-11-5. 5-Fluoro-2-((4-(7-(((1S,3S,4R)-5-( 2 The (2R,3R)-tartrate salt of H2)-methylene-2-azabicyclo(2.2.2)oct-3-yl)carbonyl)-2,7-diazaspiro(3.5)non-2-yl)-5-pyrimidinyl)oxy)-N,N-bis(1-methylethyl)-benzamide is known under the CAS registration number 2768840-67-9; the mono-(2R,3R)-tartrate salt of this compound is known under the CAS registration number 2412556-10-4.

[0144] MI-136 has the formula:

[0145] [ka]

[0146] [CAS Registry Number 1628316-74-4], or chemical name 5-[[4-[[6-(2,2,2-trifluoroethyl)thieno[2,3-d]pyrimidin-4-yl]amino]piperidin-1-yl]methyl]-1H-indole-2-carbonitrile. MI-136 and pharmaceutically acceptable salts thereof are described, for example, in WO 2014 / 164543 (see in particular Example 175 of WO 2014 / 164543).

[0147] Menin-MLL inhibitor 20 has the formula:

[0148] [ka]

[0149] [CAS Registry Number 2448173-47-3], or chemical name tert-butyl N-[(3R)-1-[[2-[[4-(4-morpholin-4-yl-7H-pyrrolo[2,3-d]pyrimidin-6-yl)phenyl]carbamoyl]pyridin-4-yl]methyl]piperidin-3-yl]carbamate. Menin-MLL inhibitor 20 has been described in the literature (see, e.g., WO2020 / 142557).

[0150] BMF-219 has the formula:

[0151] [ka]

[0152] [CAS Registry Number 2448172-22-1], or the chemical name N-[4-(4-morpholin-4-yl-7H-pyrrolo[2,3-d]pyrimidin-6-yl)phenyl]-4-[[(3R)-3-(prop-2-enoylamino)piperidin-1-yl]methyl]pyridine-2-carboxamide. BMF-219 and pharmaceutically acceptable salts thereof are described, for example, in WO 2020 / 142557 (see, in particular, Examples 9 and 18 of WO 2020 / 142557).

[0153] MI-3454 has the formula:

[0154] [ka]

[0155] [CAS Registry Number 2134169-43-8], or chemical name N-[3-[[2-cyano-4-methyl-5-[[4-[[2-(methylamino)-6-(2,2,2-trifluoroethyl)thieno[2,3-d]pyrimidin-4-yl]amino]piperidin-1-yl]methyl]indol-1-yl]methyl]-1-bicyclo[1.1.1]pentanyl]formamide. MI-3454 and its pharmaceutically acceptable salts are described, for example, in WO2017 / 161002 (see, in particular, Example 85 of WO2017 / 161002).

[0156] BAY-155 has the formula:

[0157] [ka]

[0158] [CAS Registry Number 2163769-52-4], or chemical name 2-(2-cyano-4-methyl-5-((2-(6-(2,2,2-trifluoroethyl)thieno[2,3-d]pyrimidin-4-yl)-2,7-diazaspiro[3.5]nonan-7-yl)methyl)-1H-indol-1-yl)acetamide. BAY-155 and its pharmaceutically acceptable salts are described, for example, in WO 2017 / 207387 (see, in particular, Example 11) and Brzezinka K et al., Cancers (Basel), 2020, 12(1):201, doi:10.3390 / cancers12010201.

[0159] MI-503 has the formula:

[0160] [ka]

[0161] It is a menin inhibitor with the chemical name 4-methyl-1-(1H-pyrazol-4-ylmethyl)-5-[[4-[[6-(2,2,2-trifluoroethyl)thieno[2,3-d]pyrimidin-4-yl]amino]piperidin-1-yl]methyl]indole-2-carbonitrile [CAS Registry Number 1857417-13-0]. MI-503 and pharmaceutically acceptable salts thereof are described, for example, in WO2014 / 164543 (see especially Example 309); Borkin D et al., Cancer Cell, 2015, 27(4):589-602, doi:10.1016 / j.ccell.2015.02.016; and Brzezinka K et al., Cancers (Basel), 2020, 12(1):201, doi:10.3390 / cancers12010201.

[0162] BN104 has the formula:

[0163] [ka]

[0164] [CAS Registry Number 2938995-50-5], or chemical name (2-(6-(2-(4-cyclopropylpyrimidin-5-yl)-4-fluorophenoxy)-1,2,4-triazin-5-yl)-2,7-diazaspiro[3.5]nonan-7-yl)((1S,3aR,6aS)-octahydrocyclopenta[c]pyrrol-1-yl)methanone. BN104 and pharmaceutically acceptable salts thereof are described, for example, in WO 2023 / 098876 (see in particular Example 82).

[0165] In some embodiments, the menin inhibitor is selected from the group consisting of revumenib, diftomenib, JNJ-75276617, DS-1594, DSP-5336, MI-136, menin-MLL inhibitor 20, BMF-219, BN104, and pharmaceutically acceptable salts thereof.

[0166] In some embodiments, the menin inhibitor is selected from revumenib, diftomenib, DS-1594, DSP-5336, MI-136, menin-MLL inhibitor 20, BMF-219, BN104, and pharmaceutically acceptable salts thereof.

[0167] In some embodiments, the menin inhibitor is selected from revumenib, diftomenib, DS-1594, DSP-5336, BMF-219, BN104, and pharmaceutically acceptable salts thereof.

[0168] A particularly preferred menin inhibitor is revumenib or a pharmaceutically acceptable salt thereof. A more particularly preferred menin inhibitor is diftomenib or a pharmaceutically acceptable salt thereof. It should be understood that the present invention specifically and individually relates to each combination of any one of the above LSD1 inhibitors and any one of the above menin inhibitors. Thus, for example, the present invention specifically relates to the following combinations: a combination of iademstat or a pharmaceutically acceptable salt thereof and revumenib or a pharmaceutically acceptable salt thereof; a combination of iademstat or a pharmaceutically acceptable salt thereof and diftomenib or a pharmaceutically acceptable salt thereof; a combination of iademstat or a pharmaceutically acceptable salt thereof and JNJ-75276617 or a pharmaceutically acceptable salt thereof; a combination of iademstat or a pharmaceutically acceptable salt thereof and DS-1594 or a pharmaceutically acceptable salt thereof. a combination of iadamstat or a pharmaceutically acceptable salt thereof with DSP-5336 or a pharmaceutically acceptable salt thereof; a combination of iadamstat or a pharmaceutically acceptable salt thereof with MI-136 or a pharmaceutically acceptable salt thereof; a combination of iadamstat or a pharmaceutically acceptable salt thereof with menin-MLL inhibitor 20 or a pharmaceutically acceptable salt thereof; a combination of iadamstat or a pharmaceutically acceptable salt thereof with BMF-219 or a pharmaceutically acceptable salt thereof; ... or a pharmaceutically acceptable salt thereof and BN104 or a pharmaceutically acceptable salt thereof; a combination of pleurodemstat or a pharmaceutically acceptable salt thereof and revumenib or a pharmaceutically acceptable salt thereof; a combination of pleurodemstat or a pharmaceutically acceptable salt thereof and diftomenib or a pharmaceutically acceptable salt thereof; a combination of pleurodemstat or a pharmaceutically acceptable salt thereof and JNJ-75276617 or a pharmaceutically acceptable salt thereof; a combination of pleurodemstat or a pharmaceutically acceptable salt thereof and DS-1594 or a combination of pleurodemstat or a pharmaceutically acceptable salt thereof and DSP-5336 or a pharmaceutically acceptable salt thereof; a combination of pleurodemstat or a pharmaceutically acceptable salt thereof and MI-136 or a pharmaceutically acceptable salt thereof; a combination of pleurodemstat or a pharmaceutically acceptable salt thereof and menin-MLL inhibitor 20 or a pharmaceutically acceptable salt thereof; a combination of pleurodemstat or a pharmaceutically acceptable salt thereof and BMF-219 or a pharmaceutically acceptable salt thereof;A combination of prurodemstat or a pharmaceutically acceptable salt thereof and BN104 or a pharmaceutically acceptable salt thereof; a combination of vomedemstat or a pharmaceutically acceptable salt thereof and revumenib or a pharmaceutically acceptable salt thereof; a combination of vomedemstat or a pharmaceutically acceptable salt thereof and diftomenib or a pharmaceutically acceptable salt thereof; a combination of vomedemstat or a pharmaceutically acceptable salt thereof and JNJ-75276617 or a pharmaceutically acceptable salt thereof; a combination of vomedemstat or a pharmaceutically acceptable salt thereof and DS-1594 or a pharmaceutically acceptable salt thereof; vomedemstat a combination of bomedemstat or a pharmaceutically acceptable salt thereof with DSP-5336 or a pharmaceutically acceptable salt thereof; a combination of bomedemstat or a pharmaceutically acceptable salt thereof with MI-136 or a pharmaceutically acceptable salt thereof; a combination of bomedemstat or a pharmaceutically acceptable salt thereof with menin-MLL inhibitor 20 or a pharmaceutically acceptable salt thereof; a combination of bomedemstat or a pharmaceutically acceptable salt thereof with BMF-219 or a pharmaceutically acceptable salt thereof; or a combination of bomedemstat or a pharmaceutically acceptable salt thereof with BN104 or a pharmaceutically acceptable salt thereof;

[0169] Unless otherwise specified, throughout this description and claims, any reference to an LSD1 inhibitor (e.g., iadamstat) includes the LSD1 inhibitor in its non-salt form and any pharmaceutically acceptable salts thereof. When the LSD1 inhibitor is iadamstat, it is preferably used in the form of a pharmaceutically acceptable salt, preferably the hydrochloride salt, more preferably the dihydrochloride salt.

[0170] Similarly, throughout this description and claims, any reference to a menin inhibitor also includes menin inhibitor (non-salt form) and any pharmaceutically acceptable salts thereof. Administration of a combination of an LSD1 inhibitor and a menin inhibitor may include administering the composition in any useful form. For example, the combination of the present invention may be administered using separate pharmaceutical formulations for each active ingredient (i.e., separate formulations for the LSD1 inhibitor and the menin inhibitor), or may be administered using a pharmaceutical formulation containing both an LSD1 inhibitor and a menin inhibitor. When separate pharmaceutical formulations are used, for example, when a first formulation containing an LSD1 inhibitor and a second formulation containing a menin inhibitor are used, the formulations can be administered in any order, either sequentially or simultaneously. In such cases, it is preferred that there is a time interval during which the two (or all) active agents simultaneously exert their biological activities.

[0171] In some embodiments, one or more additional therapeutic agents may also be administered to the patient. The additional therapeutic agent(s) may include one or more additional anti-cancer agents, such as any agent used to treat hematological cancers, particularly AML, including any corresponding agent listed in the FDA Orange Book or other references listing approved drugs in other countries. The additional therapeutic agent(s) may also include one or more antiemetic agents, such as a 5-HT3 antagonist (e.g., palonosetron, ramosetron, alosetron, ondansetron, tropisetron, granisetron, or dolasetron), olanzapine, a corticosteroid (e.g., methylprednisolone or dexamethasone), or prochlorperazine.

[0172] Pharmaceutical preparations The LSD1 inhibitor and menin inhibitor used in combination as described herein, as well as the pharmaceutical compositions described herein comprising the combinations of the invention, can be administered by any route appropriate to the condition being treated. Suitable routes include oral, parenteral (including subcutaneous, intramuscular, intravenous, intraarterial, inhalation, intradermal, intrathecal, epidural, and injection techniques), transdermal, rectal, nasal, topical (including buccal and sublingual), vaginal, intraperitoneal, intrapulmonary, and intranasal. Preferably, both components of the combination (the LSD1 inhibitor and the menin inhibitor) are administered orally if formulated separately, or the combination if both active ingredients are formulated in a single formulation.

[0173] The LSD1 inhibitors and menin inhibitors for use in the combinations described herein, as well as the pharmaceutical compositions described herein comprising the combinations of the invention, can be administered in any convenient pharmaceutical composition or formulation, for example, as tablets, powders, capsules, solutions, dispersions, suspensions, syrups, sprays, suppositories, gels, emulsions, patches, etc. Such compositions / formulations may contain ingredients conventional in pharmaceutical manufacturing, such as diluents, carriers, pH adjusters, preservatives, solubilizers, stabilizers, wetting agents, emulsifiers, sweeteners, colorants, flavoring agents, salts for varying osmotic pressure, buffers, masking agents, antioxidants, and / or additional active agents. They may also contain other therapeutically effective or therapeutically valuable substances.

[0174] A typical formulation is prepared by mixing an LSD1 inhibitor or menin inhibitor or a combination described herein with one or more pharmaceutically acceptable excipients. 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, opaquing agents, glidants, processing aids, colorants, sweeteners, fragrances, flavoring agents, diluents, and / or other known additives to enhance the presentation of the drug or to aid in the manufacture of a pharmaceutical product (i.e., a drug product).

[0175] For oral delivery of LSD1 inhibitors and / or menin inhibitors, each compound can be formulated into a formulation containing a pharmaceutically acceptable carrier, such as a binder (e.g., gelatin, cellulose, gum tragacanth), an excipient (e.g., starch, lactose), a lubricant (e.g., magnesium stearate, silicon dioxide), a disintegrant (e.g., alginate, Primogel, and corn starch), and a sweetener or flavoring agent (e.g., glucose, sucrose, saccharin, methyl salicylate, and peppermint). The formulation can be orally administered, for example, in the form of a sealed gelatin capsule or a compressed tablet. Capsules and tablets can be manufactured by any conventional technology. 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. Additionally, a liquid carrier, such as a fatty oil, can be included in the capsule.

[0176] Suitable oral preparations may be in the form of suspension, syrup, chewing gum, wafer, elixir, etc. If desired, conventional agents for modifying flavor, taste, color, and shape of special forms can also be included.In addition, for convenient administration to patients who cannot swallow through enteral feeding tubes, active compounds can also be dissolved in acceptable lipophilic vegetable oil vehicles, such as olive oil, corn oil, or safflower oil.

[0177] The compounds can also be administered parenterally in solution or suspension form, or in lyophilized form, which can be converted into a solution or suspension before use. Such formulations can use diluents or pharmaceutically acceptable carriers, such as sterile water and physiological saline buffer. Other conventional solvents, pH buffers, stabilizers, antibacterial agents, surfactants, and antioxidants can also be included. For example, useful ingredients include sodium chloride, acetic acid, citric acid or phosphate buffer, glycerin, dextrose, fixed oils, methylparaben, polyethylene glycol, propylene glycol, sodium hydrogen sulfate, benzyl alcohol, ascorbic acid, and the like. Parenteral formulations can be stored in any conventional container, such as a vial or ampule.

[0178] 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, for example, under the anterior abdominal wall. Hydrogels can be used as carriers for sustained release of active compounds. Hydrogels are generally known in the art. They are typically prepared by crosslinking high molecular weight biocompatible polymers into a network, which forms a gel-like material when swollen with water. Preferably, the hydrogel is biodegradable or bioabsorbable. For the purposes of the present invention, hydrogels made of polyethylene glycol, collagen, or poly(glycol-co-L-lactic acid) may be useful.

[0179] Pharmaceutical compositions, such as oral and parenteral compositions, can be formulated into unit dosage forms for ease of administration and uniformity of dosage. As used herein, the term "unit dosage form" refers to physically discrete units suitable as unit dosages for administration to a subject, each containing a predetermined amount of active ingredient calculated to produce a desired therapeutic effect, together with one or more suitable pharmaceutical carriers.

[0180] Suitable oral dosage forms of iadamstat are disclosed, for example, in WO2013 / 057322. In particular, iadamstat can be provided in the form of tablets. Alternatively, iadamstat can be provided in the form of an oral aqueous solution (e.g., prepared from a powder for reconstitution). As explained above, iadamstat is preferably used in the form of iadamstat dihydrochloride.

[0181] In therapeutic use, the combination and pharmaceutical composition of the present invention are administered in a manner appropriate to the disease being treated, as determined by a medical expert. The appropriate dose and the appropriate duration and frequency of administration can vary within wide limits and are determined, inter alia, 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 administration regimen provides the active ingredients of the combination of the present invention in an amount sufficient to provide a therapeutic benefit, for example, an improved clinical outcome, for example, more frequent complete or partial remission, or a longer disease-free period and / or overall survival, or a reduction in the severity of symptoms, or any other objectively identifiable improvement as perceived by a clinician. Therapeutically effective amounts can generally be assessed or estimated using experimental models, such as dose-response curves derived from in vitro or animal model test systems, or from human clinical trials.

[0182] As an example, an appropriate dose of a menin inhibitor may be the dose used in clinical trials for cancer treatment of menin inhibitors such as SNDX-5613 or KO-539. The dose of the menin inhibitor may be reduced due to the newly identified synergistic effect of the combination of a menin inhibitor and an LSD1 inhibitor.

[0183] Appropriate doses and administration regimens for LSD1 inhibitors will depend on the particular LSD1 inhibitor used, its LSD1 inhibitory potency, its pharmacokinetic profile, and other factors, as will be known to those skilled in the art.

[0184] Iadademstat is a highly potent active pharmaceutical ingredient (HPAPI). Therefore, the expected daily dose is very low, e.g., less than 1 mg per day. Accordingly, the drug load in the solid form is also very low, e.g., less than 1 mg of API per 100 mg tablet. Generally, for oral administration (e.g., as a tablet or as an oral aqueous solution), a daily dose of about 50 μg to about 300 μg, preferably about 75 μg to about 300 μg (e.g., about 75 μg, about 100 μg, about 125 μg, about 150 μg, about 175 μg, about 200 μg, about 225 μg, about 250 μg, about 275 μg, or about 300 μg, or any range between any two of the aforementioned daily doses) of iadademstat described herein should be appropriate, although these limits can be adjusted if necessary. As used herein, the term "ug" refers to micrograms and is used synonymously with the term "μg."

[0185] In some embodiments, the LSD1 inhibitor is iademstat (or a pharmaceutically acceptable salt thereof, such as iademstat dihydrochloride) administered 5 days on / 2 days off (5 / 2) per week.

[0186] In some embodiments, the LSD1 inhibitor is iadamstat (or a pharmaceutically acceptable salt thereof, e.g., iadamstat dihydrochloride), administered orally at a daily dose of about 50 μg to about 300 μg, preferably about 75 μg to about 300 μg (e.g., about 100 μg to about 300 μg), 5 days on / 2 days off (5 / 2) per week. Doses of iadamstat reflected herein relate to the corresponding amount of iadamstat free base. In some embodiments, iadamstat is administered orally at a daily dose of about 75 μg, 5 days on / 2 days off (5 / 2) per week. In some embodiments, iadamstat is administered orally at a daily dose of about 100 μg, 5 days on / 2 days off (5 / 2) per week. In some embodiments, iadademstat is administered orally at a daily dose of about 150 μg, 5 days on / 2 days off (5 / 2) per week. In some embodiments, iadademstat is administered orally at a daily dose of about 200 μg, 5 days on / 2 days off (5 / 2) per week. In some embodiments, iadademstat is administered orally at a daily dose of about 250 μg, 5 days on / 2 days off (5 / 2) per week. In some embodiments, iadademstat is administered orally at a daily dose of about 300 μg, 5 days on / 2 days off (5 / 2) per week.

[0187] manufactured goods The compounds, combinations, and pharmaceutical compositions of the invention can be included in a container, pack, or dispenser together with instructions for administration.

[0188] In another aspect of the present invention, articles of manufacture or "kits" are provided which contain the combinations described herein. In some embodiments, the article of manufacture or kit comprises a container and a combination according to the invention described herein.

[0189] In some embodiments, the article of manufacture or kit comprises a) a container comprising an LSD1 inhibitor (or a pharmaceutically acceptable salt thereof), and b) a container comprising a menin inhibitor (or a pharmaceutically acceptable salt thereof).

[0190] The article of manufacture or kit may further include a label or package insert. The term "package insert" refers to instructions customarily included in the packaging of commercially available therapeutic products, containing information regarding the indications, usage, dosage, administration, contraindications, and / or warnings for the use of such therapeutic products. Suitable containers include, for example, blister packs, bottles, vials, syringes, etc. The container can be formed from a variety of materials, such as glass or plastic. The container can hold a combination effective for treating a disease, or a formulation thereof, and can also include a sterile access port (e.g., the container can 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 for treating a selected disease, such as AML. Alternatively or additionally, the article of manufacture can further include a second container containing a pharmaceutically acceptable buffer, such as bacteriostatic water for injection (BWFI), phosphate-buffered saline, Ringer's solution, and dextrose solution. Additionally, other materials desirable from a commercial and user standpoint may be included, including other buffers, diluents, filters, needles, and syringes.

[0191] The kit may further include instructions for administering the combination and, if present, the second pharmaceutical formulation. For example, if the kit includes a first pharmaceutical composition / formulation comprising an LSD1 inhibitor or a pharmaceutically acceptable salt thereof and a second pharmaceutical composition / formulation comprising a menin inhibitor or a pharmaceutically acceptable salt thereof, the kit may further include instructions for the simultaneous, sequential or separate administration of the first and second pharmaceutical compositions / formulations to a patient in need thereof.

[0192] In another aspect, the kit is suitable for delivering a combination of solid oral dosage forms, such as tablets or capsules. Such a kit preferably contains several unit dosage forms. Such a kit may include a card with the dosage forms arranged 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 pharmaceutical unit dosage forms. If desired, a memory aid can be provided using numbers, letters, or other markings, or a calendar insert, to designate the days in a treatment schedule on which the dosage forms can be administered.

[0193] According to one embodiment, the kit may include (a) a first container containing an LSD1 inhibitor or a pharmaceutically acceptable salt thereof; (b) a second container containing a menin inhibitor or a pharmaceutically acceptable salt thereof; and (c) a third container containing a third pharmaceutical formulation, wherein the third pharmaceutical formulation comprises another compound having anti-cancer activity. Alternatively, or additionally, the kit may include another container containing a pharmaceutically acceptable buffer, such as bacteriostatic water for injection (BWFI), phosphate-buffered saline, Ringer's solution, and dextrose solution. Furthermore, other materials desirable from a commercial and user standpoint may be included, such as other buffers, diluents, filters, needles, and syringes.

[0194] When the kit includes a composition of an LSD1 inhibitor or a pharmaceutically acceptable salt thereof and a composition of a menin inhibitor or a pharmaceutically acceptable salt thereof, the kit may include containers for containing the separate compositions, such as divided bottles or divided foil packets. However, the separate compositions may also be contained in a single, undivided container. Typically, the kit includes instructions for administering 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), at different dosage intervals, or when titration of the individual components of the combination is desired by the prescribing physician.

[0195] 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.

[0196] The following definitions apply throughout the present specification and claims, unless stated otherwise. 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 therapy and veterinary use. In a preferred aspect, the subject or patient is a mammal, and in a most preferred aspect, the subject or patient is human (e.g., a male or female human).

[0197] The terms "treatment," "treating," and the like are used generally herein to mean obtaining a desired pharmacological and / or physiological effect. This includes partial or complete cure or amelioration of a disease (i.e., cancer) and / or symptoms or adverse effects resulting from the disease, or partial or complete halting of the progression of the disease and / or symptoms or adverse effects resulting from the disease. As used herein, the term "treatment" encompasses any treatment of a disease (i.e., cancer) in a patient. For example, this includes, but is not limited to, inhibiting cancer, i.e., arresting, delaying, or slowing its onset / progression; or palliating cancer, i.e., causing its (complete or partial) regression, correction, or alleviation. The present invention specifically and expressly relates to each of these forms of treatment.

[0198] As used herein, the terms "therapeutically effective amount" or "effective amount" of a compound or combination according to the invention refers to an amount sufficient to produce a desired biological effect (e.g., a therapeutic effect or benefit) in a subject. Thus, a therapeutically effective amount of a compound or combination can be the amount that, when administered to a subject suffering from or susceptible to a disease, is sufficient to treat the disease (i.e., cancer) and / or delay the onset or progression of the disease and / or alleviate one or more symptoms of the disease. The therapeutically effective amount will vary depending on the compound, the state of the disease being treated, the severity of the disease being treated, the age and relative health of the subject, the route and form of administration, the judgment of the attending physician or veterinarian, and other factors.

[0199] The term "pharmaceutically acceptable" refers to the properties of a material useful in preparing a pharmaceutical composition that is generally safe, non-toxic, and not biologically or otherwise harmful, and acceptable for veterinary and / or human pharmaceutical use.

[0200] As used herein, "pharmaceutically acceptable salts" is intended to mean salts that retain the biological effectiveness of the free acids and / or free bases of the specified compound and that are not biologically or otherwise undesirable. Compounds may have sufficiently acidic, sufficiently basic, or both functional groups and thus can react with any of a number of inorganic or organic bases and inorganic or organic acids to form pharmaceutically acceptable salts. Exemplary pharmaceutically acceptable salts include salts prepared by reaction of a compound according to the invention, such as iadamstat, with a mineral or organic acid, such as hydrochloride, hydrobromide, sulfate, pyrosulfate, hydrogensulfate, sulfite, bisulfite, phosphate, monohydrogenphosphate, dihydrogenphosphate, metaphosphate, pyrophosphate, chloride, bromide, iodide, nitrate, acetate, propionate, decanoate, caprylate, acrylate, formate, isobutyrate, caproate, heptanoate, propiolate, oxalate, malonate, succinate, suberate, sebacate, fumarate, maleate, butyne-1,4-dioate, hexyne-1,6-dioate, benzoate, salts, chlorobenzoate, methylbenzoate, dinitrobenzoate, hydroxybenzoate, methoxybenzoate, phthalate, sulfonate, xylenesulfonate, phenylacetate, phenylpropionate, phenylbutyrate, citrate, lactate, gamma hydroxybutyrate, glycolate, tartrate, methanesulfonate (or mesylate), ethanesulfonate, propanesulfonate, benzenesulfonate (or besylate), toluenesulfonate, trifluoromethanesulfonate, naphthalene-1-sulfonate, naphthalene-2-sulfonate, mandelate, pyruvate, stearate, ascorbate, or salicylate. Where the compound contains an acidic moiety, suitable pharmaceutically acceptable salts thereof can be 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.

[0201] The terms "pharmaceutical composition" and "pharmaceutical formulation" (or "formulation") are used interchangeably and refer to a mixture or solution containing a therapeutically effective amount of an active pharmaceutical ingredient (active pharmaceutical ingredient) or combination of the present invention together with one or more pharmaceutically acceptable excipients, to be administered to a mammal, e.g., a human, in need thereof.

[0202] The terms "pharmaceutically acceptable excipient" or "pharmaceutically acceptable carrier" are used interchangeably and refer to any pharmaceutically acceptable ingredient in a pharmaceutical composition that has no therapeutic activity and is non-toxic to a subject to which it is administered. For example, disintegrants, binders, fillers, solvents, buffers, tonicity agents, stabilizers, antioxidants, surfactants, carriers, diluents, lubricants, etc., used in formulating pharmaceutical products, which 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 skilled in the art.

[0203] As used herein, the term "inhibitor" refers to a compound that competes with, reduces, blocks, inhibits, abolishes or interferes in any way with the binding of a particular ligand to a particular receptor or enzyme, and / or reduces, blocks, inhibits, abolishes or interferes in any way with the activity or function of a particular protein, e.g., receptor or enzyme.

[0204] As used herein, a "small molecule" refers to an organic compound having a molecular weight of 900 Daltons or less, preferably less than 500 Daltons. Molecular weight (expressed in Daltons) is the mass of a molecule, calculated by multiplying the atomic weight of each constituent element in the molecular formula by the number of atoms of that element.

[0205] As used herein, the word "comprising" (or "comprise," "comprises," "contain," "contains," or "containing") has the meaning "containing, among other things," i.e., "containing, among other optional further elements," unless expressly stated otherwise or the context indicates otherwise. In addition, the term also includes the narrower meanings of "consisting essentially of" and "consisting of." For example, the term "A comprising B and C" means "A containing, among other things, B and C," and A may contain optional further elements (e.g., "A containing B, C, and D" is also included), but the term also includes the meanings "A consisting essentially of B and C" and "A consisting of B and C" (i.e., A does not contain any other components other than B and C).

[0206] As used herein, the indefinite articles "a" and "an" and the definite article "the" include plural referents as well as singular referents, unless the context clearly requires otherwise.

[0207] The term "about" or "approximately" refers to an acceptable error for a particular value as determined by one of ordinary skill in the art. The error depends, in part, on how the value is measured or determined. In certain embodiments, the term "about" or "approximately" means within 1, 2, 3, or 4 standard deviations. In certain embodiments, the term "about" or "approximately" means within 25%, 20%, 15%, 10%, 9%, 8%, 7%, 6%, 5%, 4%, 3%, 2%, 1%, 0.5%, 0.1%, or 0.05% of a given value or range. Any reference to a numerical value or range provided with the term "about" also includes a reference to the corresponding specific value or range.

[0208] In the foregoing text, various compounds are described by their chemical name, their CAS Registry Number, and / or their chemical formula. In the event of any discrepancy or difference between the structures thus identified, the present invention specifically relates to each of the compounds defined by their respective chemical name, their respective CAS Registry Number, and their respective chemical formula.

[0209] All publications, patent applications, patents, and other references mentioned herein are each incorporated by reference in their entirety. [Example]

[0210] The following examples are provided to illustrate the present invention, but are merely representative of the invention and should not be construed as limiting the scope of the invention. Example 1: Matrix assay to determine synergy between LSD1 inhibitors and menin inhibitors in AML cell lines The purpose of this assay is to determine the synergistic effects that exist between LSD1 and menin inhibitors. As a first step, the compounds of interest were evaluated as single agents before setting up matrix experiments to determine synergistic effects.

[0211] 1.1 Experimental design 1.1.1 Cell lines and culture conditions Mycoplasma-free AML cell lines were maintained in RPMI 10% FBS medium at 37°C in a humidified incubator with a controlled 5% CO2 atmosphere. Freezing and thawing of cells was performed according to ATCC recommendations. The genetic profile of the cell lines used can be found in Table 1.

[0212] [Table 1]

[0213] 1.1.2 Single-drug viability assay (96 hours) Cells were seeded in 50 μL of medium into 96-well plates at an optimal density (8000 cells / well for MV(4;11) and 4000 cells / well for MOLM-13 and OCI-AML3) to ensure linear growth throughout the assay. Each experimental condition was tested in three technical triplicates, including medium-only and vehicle-treated controls for background correction and normalization, respectively. After seeding, 50 μL of medium containing nine serial dilutions of 2x concentrated compounds was added to the cells, resulting in 100 μL of cells with 1x concentrated compound per dilution (DMSO% <0.5%). Cells were then incubated at 37°C in a controlled 5% CO2 atmosphere for 96 hours, after which cell viability was assessed using alamarBlue. TM Cell viability was assessed using a cell viability reagent (ThermoFisher Scientific, Waltham, MA, USA). TM is an indicator that uses the natural reducing power of living cells to convert resazurin into the fluorescent molecule resorufin. TM The stock solution was diluted 1:20 in culture medium, and after 3 h, incubation fluorescence was measured using a TECAN Infinity 2000 plate reader (Tecan Group Ltd., Männedorf, Switzerland; 540–570 nm excitation wavelength, 580–610 nm emission wavelength). For each condition, mean fluorescence was calculated from three technical replicates; background correction was calculated from the fluorescence of the medium-only control. Data were analyzed using GraphPad PRISM® version 9.0.1 (GraphPad Software, Inc., La Jolla, CA, USA), and best-fit curves and EC 50 values ​​were calculated.

[0214] 1.1.3 9x9 Matrix Viability Assay (96 hours) Each matrix assay was assigned to two plates according to the scheme shown in Figure 1. One compound was added in increasing concentrations from left to right, and the other compound was added in increasing concentrations from top to bottom.

[0215] For the assay, cells were seeded in 50 μL of medium in a 96-well plate at the optimal density specified in the previous section. The edge wells of the plate were filled with 100 μL of medium only for background correction. Two compounds were added at 4x concentrations in 25 μL, resulting in a final volume of 100 μL and a final concentration of 1x for each dilution (DMSO% <0.5%). As shown in Figure 1, the matrix was designed with increasing concentrations of the LSD1 inhibitor from left to right and increasing concentrations of the menin inhibitor from top to bottom. The first and last rows of plate #1 were repeated on plate #2 (indicated by arrows in Figure 1) to confirm reproducibility between the two plates. The concentration range tested for each compound pair was determined based on the EC2 of the two compounds. 50 The values ​​were designed to be centered horizontally and vertically in the matrix (as shown in Figure 1). 50 (The values ​​correspond to the fifth well from the right and the fifth well from the bottom, respectively.) In this way, the diagonal wells of the plate (marked with horizontal lines in Figure 1) represent the fixed EC 50 The EC of the compounds tested in the matrix assay corresponds to the ratio 50 Values ​​were previously obtained through single agent assays performed as detailed in section 1.1.2.

[0216] Viability was then assessed using alamarBlue as detailed in Section 1.1.2. TM Staining was performed using at least two independent biological replicates (N=2).

[0217] 1.1.3.1 9x9 Matrix Viability Assay (Data Analysis) For each matrix assay, data were then normalized to vehicle-treated controls (<0.5% DMSO, top left corner) to obtain percentage values ​​of relative remaining viability according to the formula:

[0218] % relative remaining viability = background-corrected RFU treated cells / background-corrected RFU vehicle control × 100 The percentage survival values ​​were then analyzed using GraphPad PRISM® version 9.0.1 (GraphPad Software, Inc., La Jolla, CA, USA) to generate best-fit curves for single agents and EC 50 values ​​were calculated.

[0219] At this point, the fraction affected (Fa) (also known as the fractional effect) was calculated for the following conditions using the following formula: Fa = 1-(% relative survival rate / 100) Cells treated with serial dilutions of LSD1 inhibitors as single agents (average of first row of first and second plates for each matrix assay).

[0220] · Cells treated with serial dilutions of menin inhibitors as single agents (first column of matrix assay). ·EC 50 Cells treated with LSD1 inhibitor and menin inhibitor at a fixed ratio corresponding to the ratio of values ​​(% relative remaining viability values ​​on the diagonal of the matrix assay; highlighted in Figure 1 ).

[0221] CalcuSyn software (http: / / www.biosoft.com / w / calcusyn.htm, Biosoft, Cambridge, UK) is designed to determine the nature of the interaction (synergistic, additive, or antagonistic) between two compounds by calculating the Combination Index (CI). This analysis is based on the Median Effect Principle and Combination Index Theorem, as explained by the Chou-Talalay method (Chou TC, Pharmacol Rev, 2006, 58(3):621-681, doi:10.1124 / pr.58.3.10). According to this, a resulting CI < 1 indicates synergy, a CI = 1 indicates additive effects, while a CI > 1 reflects antagonism. In the case of synergy (CI < 1), the smaller the CI value, the greater the synergistic effect. Furthermore, the strength of drug interactions can be further classified based on the CI range, as shown in Table 2.

[0222] [Table 2]

[0223] To generate informative and consistent results, the data processed by CalcuSyn (both single drugs and drug combinations) must fit the theoretical models of the median effect principle and the combination coefficient theorem. For this reason, it is important to remove what appear to be outliers or data points characterized as poorly fitting the median effect principle (Chou TC, Pharmacol Rev, 2006, 58(3):621-681, doi:10.1124 / pr.58.3.10). To achieve this, the following strategy was adopted for data filtering:

[0224] As a first step, we reduced the data variance by removing points characterized by: 1) Fa<0.1 2) An increase of Fa<0.03 compared to the previous point (if Fa>0.9).

[0225] These conditions define the plateaus of the dose-response curve where cells are treated with very low or very high concentrations of the compound (or combination) resulting in a loss of viability of 0% or near 100% (corresponding to Fa values ​​near 0 or 1, respectively). Note that in these regions of the dose-response curve, alamarBlue TM The signal variations are very small and are likely due to random noise with little biological significance.

[0226] Then, for each data point, Log 10 (concentration) and Log 10 (Fa / (1-Fa)) was calculated and a dot plot graph was generated reporting the former value on the x-axis and the latter value on the y-axis. A regression line was then obtained using Excel (corresponding to the median effect formula).

[0227] At this point, the distance from the regression line for each data point was calculated using the formula: Distance(ax+by+c=0;X,Y)=(aX+bY+c) / √(a 2 +b 2 ) Outliers are identified using a Grubbs test based on their distance from the median effect equation. For each data point, a Grubbs test is performed on the absolute value of the distance according to the following formula (note: the variables for the Grubbs test can be referred to interchangeably as G or Z):

[0228] G=(X n -X average ) / s In the formula, X n represents the absolute value of the distance of each point from the regression line; X average is all X n represents the mean of the values, and s represents the standard deviation. crit Values ​​of G above (calculated with α=0.2 as shown below) are identified as outliers that do not fit the median effect equation. Such data points are removed to successfully calculate the combination coefficients by CalcuSyn.

[0229]

number

[0230] If possible, 1. No further outliers are identified, or 2.R 2 >0.95 The test is repeated two or more times to remove multiple outliers until the R value is 0.95. To measure data quality, the R value is also calculated in CalcuSyn software (good data is characterized by an R value higher than 0.95).

[0231] 1.1.3.2 CalcuSyn output results CalcuSyn results are shown for fixed EC 50 The experimental fractional effect (referred to as Fa), which represents the proportion of cells affected by the combination treatment in a ratio (for cytotoxic treatments, the fractional effect corresponds to a reduction in viability compared to the vehicle control, with Fa = 1 equal to a 100% reduction in viability), and the associated combination coefficient (CI) are provided. As shown in Table 2 above, the CI value is an indicator of the nature and strength of the compound interaction, with values ​​less than 1 indicating a synergistic interaction (values ​​closer to 0 are more synergistic), values ​​equal to 1 indicating an additive interaction, and values ​​greater than 1 indicating an antagonistic interaction.

[0232] 1.2 Results 1.2.1 Single-agent viability: iadamstat, purlodemstat, vomedemstat, revmenib, menin-MLL inhibitor 20, and MI-136 MV(4;11), OCI-AML3, and MOLM-13 cell lines were seeded as described in Section 1.1.2 and incubated with either vehicle or serial dilutions of LSD1 inhibitors (iadademstat, pleurodemstat, or vomedemstat) or menin inhibitors (revumenib, menin-MLL inhibitor 20, or MI-136). The concentration ranges used for each compound were as follows: The following LSD1 inhibitors were used: iadamantane, 0.002–12.5 nM; pleurodemstat, 0.045–300 nM; vomedemstat, 0.045–300 nM; revumenib, 0.14–900 nM; menin-MLL inhibitors 20, 27–7,000 nM; MI-136, 27–7,000 nM (for MV(4;11) cells) and 80–20,000 nM (for MOLM-13 cells). In all cases, the LSD1 inhibitors used induced a >20% reduction in viability (compared to vehicle control) and showed EC values ​​above 100 in at least two biological replicates. 50 In the MLL-translocated cell lines MOLM-13 and MV(4;11), the menin inhibitor revumenib significantly reduced mean survival by nearly 100% in MV(4;11) and approximately 70% in MOLM-13, and significantly reduced EC 50 The menin-MLL inhibitors 20 and MI-136 induced a 100% loss of cell viability in both cell lines, but were less potent than SNDX-5613 (EC 50 In OCI-AML-3 with NPM1 mutations, the menin inhibitor revumenib showed an EC 50 induced an average viability reduction of approximately 50%. Experiments were performed in at least two biological replicates.

[0233] Table 3 shows the experimentally determined mean EC20 values ​​after 96 hours of incubation in selected cell lines with the LSD1 inhibitors iadamstat, pleurodemstat, and vomedemstat, and the menin inhibitors revumenib, menin-MLL inhibitor 20, and MI-136. 50 The values ​​are shown (all N=2).

[0234] [Table 3]

[0235] 1.2.2 Combination of the LSD1 inhibitor iadademstat and the menin inhibitor revmenib Matrix processing with the menin inhibitor revumenib and the LSD1 inhibitors iadamdemstat, vomedemstat (see 1.2.4), and pleurodemstat (see 1.2.3) was performed as described in Section 1.1.3. Data analysis and calculation of combination coefficients were performed as described in Section 1.1.3.1.

[0236] Iadademstat was tested over a concentration range of 0.002 to 12.5 nM, and revumenib was tested over a concentration range of 0.14 to 900 nM. The results of the combination index (CI) associated with the specific effect rate (Fa) and the respective classifications (listed in Table 2) obtained from the combination of iadamstat and revumenib are shown in Table 4.

[0237] In summary, the combination of iadamstat plus revumenib demonstrated potent synergy across a wide range of effect rates (Fa) in revumenib-sensitive cell lines harboring MLL translocations (MOLM-13, N=2; MV(4;11), N=2) or NPM1 mutations (OCI-AML3, N=2).

[0238] [Table 4]

[0239] 1.2.3 LSD1 inhibitor pleurodemstat + menin inhibitor revmenib combination The synergistic effect between the LSD1 inhibitors described in Section 1.2.2 and the menin inhibitor revumenib was further confirmed using another LSD1 inhibitor, specifically the structurally unrelated reversible LSD1 inhibitor pleurodemstat. Matrix treatment with revumenib (concentration range 0.14–900 nM) and pleurodemstat (concentration range 0.045–300 nM) was performed as described in Section 1.1.3. Data analysis and calculation of combination coefficients were performed as described in Section 1.1.3.1. The combination coefficients (CI) related to the specific effect ratios (Fa) and their respective classifications (listed in Table 2) obtained for the combination of pleurodemstat and revumenib are shown in Table 5.

[0240] In summary, the combination of plerodemstat + revmenib also showed strong synergistic effects across a wide range of effect rates (Fa) in the cancer cell lines tested (MOLM-13, N = 2; MV(4;11), N = 2; OCI-AML3, N = 2).

[0241] [Table 5]

[0242] 1.2.4 Combination of the LSD1 inhibitor bomedemstat and the menin inhibitor revmenib The synergistic effect between the LSD1 inhibitors and the menin inhibitor revumenib described in sections 1.2.2 and 1.2.3 was further confirmed using another LSD1 inhibitor, bomedemstat.

[0243] Matrix treatment with revumenib (concentration range 0.14-900 nM) and vomedemstat (concentration range 0.045-300 nM) was performed as described in Section 1.1.3. Data analysis and calculation of combination coefficients were performed as described in Section 1.1.3.1. The combination coefficients (CI) associated with the specific effect rates (Fa) and their respective classifications (described in Table 2) obtained for the combination of vomedemstat and revumenib are shown in Table 6.

[0244] In summary, the combination of vomedemstat + revmenib demonstrated potent synergistic effects across a wide range of effect rates (Fa) in the cancer cell lines tested (MOLM-13, N = 2; MV(4;11), N = 2; OCI-AML3, N = 2).

[0245] [Table 6]

[0246] 1.2.5 LSD1 inhibitor iadamstat + menin inhibitor menin-MLL inhibitor 20 combination The synergy between LSD1 inhibitors and menin inhibitors was further tested using another menin inhibitor, menin-MLL inhibitor 20, as described in sections 1.2.2 and 1.2.3.

[0247] Matrix treatment with menin-MLL inhibitor 20 (concentration range 27-7,000 nM) and iadamstat (concentration range 0.006-1.6 nM) was performed as described in Section 1.1.3. Data analysis and calculation of combination coefficients were performed as described in Section 1.1.3.1. The combination coefficients (CI) associated with the specific effect ratios (Fa) and their respective classifications (listed in Table 2) obtained for the combination of iadamstat and menin-MLL inhibitor 20 are shown in Table 7.

[0248] [Table 7]

[0249] In summary, the combination of iadamstat + menin-MLL inhibitor 20 showed synergistic effects across a wide range of effect rates (Fa) in the cancer cell lines tested (MOLM-13, N = 2; MV(4;11), N = 2).

[0250] 1.2.6 Combination of the LSD1 inhibitor iadamstat and the menin inhibitor MI-136 The synergistic effect between LSD1 inhibitors and menin inhibitors was further tested using yet another menin inhibitor, MI-136, as described in sections 1.2.2 and 1.2.3.

[0251] Matrix treatments with MI-136 (concentration range 27-7,000 nM for MV(4;11) and 80-20,000 nM for MOLM-13) and iadademstat (concentration range 0.006-1.6 nM) were performed as described in Section 1.1.3. Data analysis and calculation of combination coefficients were performed as described in Section 1.1.3.1. The results of combination coefficients (CI) related to specific effect rates (Fa) and their respective classifications (described in Table 2) obtained for the combination of iadademstat and MI-136 are shown in Table 8.

[0252] [Table 8]

[0253] In summary, the combination of iadamstat + MI-136 demonstrated synergistic effects across a wide range of effect rates (Fa) in the cancer cell lines tested (MOLM-13, N=2; MV(4;11), N=2).

[0254] Overall, the results presented above demonstrate that the menin inhibitor revumenib, when used in combination with a range of different LSD1 inhibitors, exhibits particularly strong synergistic effects compared with combinations of LSD1 inhibitors with other menin inhibitors.

[0255] By using the methods described in Example 1, the superior therapeutic effects of further combinations of LSD1 inhibitors and menin inhibitors (including further combinations of other LSD1 inhibitors with the menin inhibitor revumenib) can be demonstrated.

[0256] Similarly, by using methods similar to those described in Example 1, the superior therapeutic effect of the combination of an LSD1 inhibitor and a menin inhibitor in other cancers, including other hematological cancers such as MDS, can be demonstrated.

[0257] While the invention has been described in relation to specific embodiments thereof, it will be understood that further modifications are possible, and that this patent or this patent application is intended to cover generally any variations, uses, or adaptations of the invention in accordance with the principles of the invention, including such departures from the present disclosure as come within known or customary practice in the art to which this invention pertains and as are applicable to the essential features described herein and as fall within the scope of the appended claims.

Claims

1. A combination product comprising an LSD1 inhibitor, or a pharmaceutically acceptable salt thereof, and a menin inhibitor, or a pharmaceutically acceptable salt thereof, in the same or separate pharmaceutical formulations.

2. 2. The combination product of claim 1, wherein the LSD1 inhibitor is a small molecule.

3. 3. The combination product according to claim 1 or 2, wherein the LSD1 inhibitor is selected from the group consisting of iadamstat, pleurodemstat, vomedemstat, seclidemstat, 1-((4-(methoxymethyl)-4-(((1R,2S)-2-phenylcyclopropylamino)methyl)piperidin-1-yl)methyl)cyclobutanecarboxylic acid, 3-(cyanomethyl)-3-(4-{[(1R,2S)-2-phenylcyclopropyl]amino}piperidin-1-yl)azetidine-1-sulfonamide, and pharmaceutically acceptable salts thereof.

4. 2. The combination product of claim 1, wherein the LSD1 inhibitor is iadamstat or a pharmaceutically acceptable salt thereof.

5. 5. The combination product of claim 4, wherein the LSD1 inhibitor is iademstat dihydrochloride.

6. The combination product according to any one of claims 1 to 5, wherein the menin inhibitor is selected from the group consisting of revumenib, VTP50469, diftomenib, JNJ-75276617, DS-1594, DSP-5336, MI-136, menin-MLL inhibitor 20, BMF-219, MI-3454, BAY-155, MI-503, BN104, and pharmaceutically acceptable salts thereof.

7. The combination product according to any one of claims 1 to 5, wherein the menin inhibitor is selected from the group consisting of revumenib, diftomenib, DS-1594, DSP-5336, BMF-219, BN104, and pharmaceutically acceptable salts thereof.

8. 8. The combination product according to any one of claims 1 to 7, wherein the LSD1 inhibitor, or a pharmaceutically acceptable salt thereof, and the menin inhibitor, or a pharmaceutically acceptable salt thereof, are provided in the same pharmaceutical formulation.

9. 8. The combination product according to any one of claims 1 to 7, wherein the LSD1 inhibitor or a pharmaceutically acceptable salt thereof and the menin inhibitor or a pharmaceutically acceptable salt thereof are provided in separate pharmaceutical formulations.

10. A pharmaceutical composition comprising an LSD1 inhibitor or a pharmaceutically acceptable salt thereof and a menin inhibitor or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable excipients.

11. 11. The pharmaceutical composition of claim 10, wherein the LSD1 inhibitor is a small molecule.

12. 12. The pharmaceutical composition according to claim 10 or 11, wherein the LSD1 inhibitor is selected from the group consisting of iadamstat, plerodemstat, vomedemstat, seclidemstat, 1-((4-(methoxymethyl)-4-(((1R,2S)-2-phenylcyclopropylamino)methyl)piperidin-1-yl)methyl)cyclobutanecarboxylic acid, 3-(cyanomethyl)-3-(4-{[(1R,2S)-2-phenylcyclopropyl]amino}piperidin-1-yl)azetidine-1-sulfonamide, and pharmaceutically acceptable salts thereof.

13. 11. The pharmaceutical composition according to claim 10, wherein the LSD1 inhibitor is iadamstat or a pharmaceutically acceptable salt thereof.

14. 11. The pharmaceutical composition of claim 10, wherein the LSD1 inhibitor is iademstat dihydrochloride.

15. The pharmaceutical composition according to any one of claims 10 to 14, wherein the menin inhibitor is selected from the group consisting of revumenib, VTP50469, diftomenib, JNJ-75276617, DS-1594, DSP-5336, MI-136, menin-MLL inhibitor 20, BMF-219, MI-3454, BAY-155, MI-503, BN104, and pharmaceutically acceptable salts thereof.

16. The pharmaceutical composition according to any one of claims 10 to 14, wherein the menin inhibitor is selected from the group consisting of revumenib, diftomenib, DS-1594, DSP-5336, BMF-219, BN104, and pharmaceutically acceptable salts thereof.

17. An article of manufacture comprising an LSD1 inhibitor, or a pharmaceutically acceptable salt thereof, and a menin inhibitor, or a pharmaceutically acceptable salt thereof, in the same or separate pharmaceutical formulations.

18. 18. The article of manufacture of claim 17, wherein the LSD1 inhibitor is a small molecule.

19. 19. The article of manufacture of claim 17 or 18, wherein the LSD1 inhibitor is selected from the group consisting of iadamstat, plerodemstat, vomedemstat, seclidemstat, 1-((4-(methoxymethyl)-4-(((1R,2S)-2-phenylcyclopropylamino)methyl)piperidin-1-yl)methyl)cyclobutanecarboxylic acid, 3-(cyanomethyl)-3-(4-{[(1R,2S)-2-phenylcyclopropyl]amino}piperidin-1-yl)azetidine-1-sulfonamide, and pharmaceutically acceptable salts thereof.

20. 18. The article of manufacture of claim 17, wherein the LSD1 inhibitor is iadademstat or a pharmaceutically acceptable salt thereof.

21. 18. The article of manufacture of claim 17, wherein the LSD1 inhibitor is iademstat dihydrochloride.

22. 22. The article of manufacture of any one of claims 17 to 21, wherein the menin inhibitor is selected from the group consisting of revumenib, VTP50469, diftomenib, JNJ-75276617, DS-1594, DSP-5336, MI-136, menin-MLL inhibitor 20, BMF-219, MI-3454, BAY-155, MI-503, BN104, and pharmaceutically acceptable salts thereof.

23. 22. The article of manufacture of any one of claims 17 to 21, wherein the menin inhibitor is selected from the group consisting of revumenib, diftomenib, DS-1594, DSP-5336, BMF-219, BN104, and pharmaceutically acceptable salts thereof.

24. A combination product according to any one of claims 1 to 9 or an article of manufacture according to any one of claims 17 to 23 for use in therapy.

25. A combination product according to any one of claims 1 to 9 or a pharmaceutical composition according to any one of claims 10 to 16 or an article of manufacture according to any one of claims 17 to 23 for use in the treatment of cancer.

26. 1. A compound which is an LSD1 inhibitor or a pharmaceutically acceptable salt thereof for use in the treatment of cancer, wherein said LSD1 inhibitor or a pharmaceutically acceptable salt thereof is used in combination with a menin inhibitor or a pharmaceutically acceptable salt thereof.

27. 1. A compound which is a menin inhibitor or a pharmaceutically acceptable salt thereof for use in the treatment of cancer, wherein said menin inhibitor or a pharmaceutically acceptable salt thereof is used in combination with an LSD1 inhibitor or a pharmaceutically acceptable salt thereof.

28. 28. The compound for use according to claim 26 or 27, wherein the LSD1 inhibitor is a small molecule.

29. 28. The compound for use according to claim 26 or 27, wherein the LSD1 inhibitor is selected from the group consisting of iadamstat, plerodemstat, vomedemstat, seclidemstat, 1-((4-(methoxymethyl)-4-(((1R,2S)-2-phenylcyclopropylamino)methyl)piperidin-1-yl)methyl)cyclobutanecarboxylic acid, 3-(cyanomethyl)-3-(4-{[(1R,2S)-2-phenylcyclopropyl]amino}piperidin-1-yl)azetidine-1-sulfonamide, and pharmaceutically acceptable salts thereof.

30. 28. The compound for use according to claim 26 or 27, wherein the LSD1 inhibitor is iadamstat or a pharmaceutically acceptable salt thereof.

31. 31. The compound for use according to claim 30, wherein the LSD1 inhibitor is iademstat dihydrochloride.

32. 32. The compound for use according to any one of claims 26 to 31, wherein the menin inhibitor is selected from the group consisting of revumenib, VTP50469, diftomenib, JNJ-75276617, DS-1594, DSP-5336, MI-136, menin-MLL inhibitor 20, BMF-219, MI-3454, BAY-155, MI-503, BN104, and pharmaceutically acceptable salts thereof.

33. 32. The compound for use according to any one of claims 26 to 31, wherein the menin inhibitor is selected from the group consisting of revumenib, diftomenib, DS-1594, DSP-5336, BMF-219, BN104, and pharmaceutically acceptable salts thereof.

34. 34. A combination product for use according to claim 25, a pharmaceutical composition for use according to claim 25, an article of manufacture for use according to claim 25, or a compound for use according to any one of claims 26 to 33, wherein the cancer is a blood cancer.

35. 35. A combination product for use according to claim 25 or 34, a pharmaceutical composition for use according to claim 25 or 34, an article of manufacture for use according to claim 25 or 34, or a compound for use according to any one of claims 26 to 34, wherein the cancer is selected from acute myeloid leukemia, acute lymphoblastic leukemia, chronic myeloid leukemia, chronic lymphocytic leukemia, mixed plasmatic leukemia, mixed phenotype leukemia, non-Hodgkin's lymphoma, myelodysplastic syndrome, and multiple myeloma.

36. 36. A combination product for use according to claim 35, a pharmaceutical composition for use according to claim 35, an article of manufacture for use according to claim 35, or a compound for use according to claim 35, wherein the cancer is selected from acute myeloid leukemia and myelodysplastic syndrome.

37. 36. A combination product for use according to claim 35, a pharmaceutical composition for use according to claim 35, an article of manufacture for use according to claim 35, or a compound for use according to claim 35, wherein the cancer is acute myeloid leukemia.

38. 38. A combination product for use according to claim 37, a pharmaceutical composition for use according to claim 37, an article of manufacture for use according to claim 37, or a compound for use according to claim 37, wherein the acute myeloid leukemia is relapsed or refractory acute myeloid leukemia.

39. A combination product for use according to claim 37 or 38, a pharmaceutical composition for use according to claim 37 or 38, an article of manufacture for use according to claim 37 or 38, or a compound for use according to claim 37 or 38, wherein the acute myeloid leukemia is acute myeloid leukemia with a FLT3 mutation.

40. A combination product for use according to claim 37, a pharmaceutical composition for use according to claim 37, an article of manufacture for use according to claim 37, or a compound for use according to claim 37, wherein the acute myeloid leukemia is relapsed or refractory acute myeloid leukemia with a FLT3 mutation.

41. A method for treating cancer in a patient in need thereof, comprising administering to said patient a therapeutically effective amount of a combination product according to any one of claims 1 to 9 or a pharmaceutical composition according to any one of claims 10 to 16.

42. 1. A method of treating cancer in a patient in need of cancer treatment, comprising administering to the patient a therapeutically effective amount of an LSD1 inhibitor, or a pharmaceutically acceptable salt thereof, and a therapeutically effective amount of a menin inhibitor, or a pharmaceutically acceptable salt thereof.

43. 43. The method of claim 41 or 42, wherein the LSD1 inhibitor is a small molecule.

44. 43. The method of claim 41 or 42, wherein the LSD1 inhibitor is selected from the group consisting of iadamstat, plerodemstat, vomedemstat, seclidemstat, 1-((4-(methoxymethyl)-4-(((1R,2S)-2-phenylcyclopropylamino)methyl)piperidin-1-yl)methyl)cyclobutanecarboxylic acid, 3-(cyanomethyl)-3-(4-{[(1R,2S)-2-phenylcyclopropyl]amino}piperidin-1-yl)azetidine-1-sulfonamide, and pharmaceutically acceptable salts thereof.

45. 43. The method of claim 41 or 42, wherein the LSD1 inhibitor is iadamstat or a pharmaceutically acceptable salt thereof.

46. 46. ​​The method of claim 45, wherein the LSD1 inhibitor is iademstat dihydrochloride.

47. The method of any one of claims 41 to 46, wherein the menin inhibitor is selected from the group consisting of revumenib, VTP50469, diftomenib, JNJ-75276617, DS-1594, DSP-5336, MI-136, menin-MLL inhibitor 20, BMF-219, MI-3454, BAY-155, MI-503, BN104, and pharmaceutically acceptable salts thereof.

48. The method of any one of claims 41 to 46, wherein the menin inhibitor is selected from the group consisting of revumenib, diftomenib, DS-1594, DSP-5336, BMF-219, BN104, and pharmaceutically acceptable salts thereof.

49. The method of any one of claims 41 to 48, wherein the cancer is a blood cancer.

50. 50. The method of any one of claims 41 to 49, wherein the cancer is selected from acute myeloid leukemia, acute lymphoblastic leukemia, chronic myeloid leukemia, chronic lymphocytic leukemia, mixed plasmatic leukemia, mixed phenotype leukemia, non-Hodgkin's lymphoma, myelodysplastic syndrome, and multiple myeloma.

51. 51. The method of claim 50, wherein the cancer is selected from acute myeloid leukemia and myelodysplastic syndrome.

52. 51. The method of claim 50, wherein the cancer is acute myeloid leukemia.

53. 53. The method of claim 52, wherein the acute myeloid leukemia is relapsed or refractory acute myeloid leukemia.

54. 54. The method of claim 52 or 53, wherein the acute myeloid leukemia is FLT3 mutated acute myeloid leukemia.

55. 53. The method of claim 52, wherein the acute myeloid leukemia is relapsed or refractory acute myeloid leukemia with a FLT3 mutation.

56. 56. The method of any one of claims 41 to 55, wherein the patient to be treated is a human.

57. 57. The method of any one of claims 41 to 56, wherein the LSD1 inhibitor, or a pharmaceutically acceptable salt thereof, and the menin inhibitor, or a pharmaceutically acceptable salt thereof, are administered in the same pharmaceutical formulation.

58. 57. The method of any one of claims 41 to 56, wherein the LSD1 inhibitor, or a pharmaceutically acceptable salt thereof, and the menin inhibitor, or a pharmaceutically acceptable salt thereof, are administered in separate pharmaceutical formulations.

59. 1. Use of a combination comprising an LSD1 inhibitor or a pharmaceutically acceptable salt thereof and a menin inhibitor or a pharmaceutically acceptable salt thereof for the manufacture of a medicament for treating cancer.

60. 1. Use of an LSD1 inhibitor or a pharmaceutically acceptable salt thereof for the manufacture of a medicament for the treatment of cancer, wherein said medicament is used in combination with a menin inhibitor or a pharmaceutically acceptable salt thereof.

61. 1. Use of a menin inhibitor, or a pharmaceutically acceptable salt thereof, for the manufacture of a medicament for the treatment of cancer, wherein said medicament is used in combination with an LSD1 inhibitor, or a pharmaceutically acceptable salt thereof.

62. 1. Use of a combination comprising an LSD1 inhibitor or a pharmaceutically acceptable salt thereof and a menin inhibitor or a pharmaceutically acceptable salt thereof for the treatment of cancer.

63. 1. Use of an LSD1 inhibitor or a pharmaceutically acceptable salt thereof in combination with a menin inhibitor or a pharmaceutically acceptable salt thereof for the treatment of cancer.

64. 1. Use of a menin inhibitor or a pharmaceutically acceptable salt thereof in combination with an LSD1 inhibitor or a pharmaceutically acceptable salt thereof for the treatment of cancer.

65. 65. The use according to any one of claims 59 to 64, wherein the LSD1 inhibitor is a small molecule.

66. 66. The use according to any one of claims 59 to 65, wherein the LSD1 inhibitor is selected from the group consisting of iadamstat, plerodemstat, vomedemstat, seclidemstat, 1-((4-(methoxymethyl)-4-(((1R,2S)-2-phenylcyclopropylamino)methyl)piperidin-1-yl)methyl)cyclobutanecarboxylic acid, 3-(cyanomethyl)-3-(4-{[(1R,2S)-2-phenylcyclopropyl]amino}piperidin-1-yl)azetidine-1-sulfonamide, and pharmaceutically acceptable salts thereof.

67. The use according to any one of claims 59 to 65, wherein the LSD1 inhibitor is iadamstat or a pharmaceutically acceptable salt thereof.

68. 68. The use according to claim 67, wherein the LSD1 inhibitor is iademstat dihydrochloride.

69. 69. The use according to any one of claims 59 to 68, wherein the menin inhibitor is selected from the group consisting of revumenib, VTP50469, diftomenib, JNJ-75276617, DS-1594, DSP-5336, MI-136, menin-MLL inhibitor 20, BMF-219, MI-3454, BAY-155, MI-503, BN104, and pharmaceutically acceptable salts thereof.

70. The use according to any one of claims 59 to 68, wherein the menin inhibitor is selected from the group consisting of revumenib, diftomenib, DS-1594, DSP-5336, BMF-219, BN104, and pharmaceutically acceptable salts thereof.

71. 71. The use according to any one of claims 59 to 70, wherein the cancer is a blood cancer.

72. 72. The use according to any one of claims 59 to 71, wherein the cancer is selected from acute myeloid leukemia, acute lymphoblastic leukemia, chronic myeloid leukemia, chronic lymphocytic leukemia, mixed plasmatic leukemia, mixed phenotype leukemia, non-Hodgkin's lymphoma, myelodysplastic syndrome, and multiple myeloma.

73. 73. The use of claim 72, wherein the cancer is selected from acute myeloid leukemia and myelodysplastic syndrome.

74. 73. The use of claim 72, wherein the cancer is acute myeloid leukemia.

75. 75. The use according to claim 74, wherein the acute myeloid leukemia is relapsed or refractory acute myeloid leukemia.

76. 76. The use of claim 74 or 75, wherein the acute myeloid leukemia is FLT3 mutated acute myeloid leukemia.

77. 75. The use of claim 74, wherein the acute myeloid leukemia is relapsed or refractory acute myeloid leukemia with a FLT3 mutation.

78. A combination product for use according to any one of claims 24, 25 or 34 to 40, an article of manufacture for use according to any one of claims 24, 25 or 34 to 40, a compound for use according to any one of claims 26 to 40, a method according to any one of claims 41 to 58, or a use according to any one of claims 59 to 77, wherein the LSD1 inhibitor, or a pharmaceutically acceptable salt thereof, and the menin inhibitor, or a pharmaceutically acceptable salt thereof, are administered orally.

79. A combination product for use according to any one of claims 24, 25 or 34 to 40, an article of manufacture for use according to any one of claims 24, 25 or 34 to 40, a compound for use according to any one of claims 26 to 40, a method according to any one of claims 41 to 58, or a use according to any one of claims 59 to 77, wherein the LSD1 inhibitor, or a pharmaceutically acceptable salt thereof, and the menin inhibitor, or a pharmaceutically acceptable salt thereof, are administered using separate pharmaceutical formulations.

80. 80. A combination product for use according to claim 79, an article of manufacture for use according to claim 79, a compound for use according to claim 79, a method according to claim 79, or a use according to claim 79, wherein the LSD1 inhibitor, or a pharmaceutically acceptable salt thereof, and the menin inhibitor, or a pharmaceutically acceptable salt thereof, are administered simultaneously using separate pharmaceutical formulations.

81. 80. A combination product for use according to claim 79, an article of manufacture for use according to claim 79, a compound for use according to claim 79, a method according to claim 79, or a use according to claim 79, wherein the LSD1 inhibitor, or a pharmaceutically acceptable salt thereof, and the menin inhibitor, or a pharmaceutically acceptable salt thereof, are administered sequentially using separate pharmaceutical formulations.

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