Combination of LSD1 inhibitors for the treatment of myeloid cancer

Abstract

The present invention relates to a combination of an LSD1 inhibitor (or a pharmaceutically acceptable salt thereof) and gilteritinib (or a pharmaceutically acceptable salt thereof). This combination is particularly useful for the treatment of bone marrow cancers, such as acute myeloid leukemia or myelodysplastic syndromes.

Description

[Technical field]

[0001] Field The present invention relates to a combination of an LSD1 inhibitor and gilteritinib. The combination is useful for the treatment of myeloid cancers, particularly acute myeloid leukemia and myelodysplastic syndromes. [Background technology]

[0002] background Acute myeloid leukemia (AML) is an aggressive bone marrow cancer that causes uncontrolled proliferation and accumulation of undifferentiated hematopoietic cells (blasts) leading to bone marrow failure, affecting normal blood cell production, and ultimately, if untreated, causing the patient's death within months of diagnosis. AML is the most common acute leukemia in adults and is primarily a disease of older adults, with a median age at diagnosis of 68 years. Due to the growing population and increased life expectancy worldwide, more and more patients are diagnosed with AML every year. In fact, AML accounts for 1.1% of all new cancer diagnoses, with approximately 135,000 new cases of AML diagnosed worldwide in 2019.

[0003] Treatment of AML in people under 60 years of age is standard with intensive chemotherapy to induce remission followed by bone marrow transplantation, the only treatment considered curative in these patients. However, older patients or those in poor health may not be able to tolerate this treatment, and treatment options are limited to non-curative approaches such as low-intensity chemotherapy, for example with azacitidine alone or in combination with venetoclax (only the latter is approved in the USA), or specific drugs aimed at specific populations harboring specific mutations.

[0004] The prognosis of AML is poor, with survival rates ranging from 35-40% in adults <60 years of age to as low as 5-15% in elderly patients. It is estimated that 25% of patients with AML are refractory to treatment, and over 50% will relapse with current treatments. When patients relapse with or fail to benefit from first-line treatment, they continue with second-line regimens, which are largely unstandardized and inefficient; in fact, most of these patients enter clinical trials in light of the lack of effective treatments. Even with aggressive treatment, the prognosis of these relapsed / refractory (R / R) patients is extremely poor, with a median survival of 6 months. A large proportion of this R / R population (30-50% of all R / R AML cases) exhibits mutations in the FMS-like tyrosine kinase 3 (FLT3) gene, considered a marker of poor prognosis.

[0005] Myelodysplastic syndrome (MDS) is another type of bone marrow cancer in which differentiation of blood progenitor cells is impaired and a marked increase in the level of apoptotic cell death occurs in bone marrow cells. Over time, approximately one-third of all MDS cases progress to AML. FLT3 mutations are also found in MDS.

[0006] Gilteritinib is an FLT3 inhibitor approved for the treatment of R / R AML patients with FLT3 mutations and MDS is being evaluated in clinical trials. However, outcomes after gilteritinib treatment remain poor, with only 21% of R / R AML patients achieving complete remission when treated with gilteritinib, and relapse-free survival being only about 4 months. Summary of the Invention [Problem to be solved by the invention]

[0007] Thus, there is a strong and unmet need for new and improved therapeutic options for myeloid cancers, particularly AML and MDS, that address the problems of resistance and lack of responsiveness to current treatments. The present invention addresses these and other needs. [Means for solving the problem]

[0008] Summary of the Invention The present invention is based on the unexpected discovery that the combination of LSD1 inhibitors described herein and gilteritinib shows outstanding activity in suppressing myeloid cancer cell proliferation compared with treatment with LSD1 inhibitors alone or gilteritinib alone.Therefore, the present invention relates to a novel combination for treating myeloid malignancies such as AML and MDS by using the combination of LSD1 inhibitors and gilteritinib.

[0009] Thus, the present invention provides a combination product comprising an LSD1 inhibitor, or a pharma- ceutically acceptable salt thereof, and gilteritinib, or a pharma- ceutically acceptable salt thereof, in the same or in different pharmaceutical formulations.

[0010] The present invention further provides a pharmaceutical composition comprising an LSD1 inhibitor or a pharma- ceutically acceptable salt thereof and gilteritinib or a pharma- ceutically acceptable salt thereof and one or more pharma- ceutically acceptable excipients.

[0011] The present invention further provides an article of manufacture (or "kit") comprising an LSD1 inhibitor, or a pharma- ceutically acceptable salt thereof, and gilteritinib, or a pharma- ceutically acceptable salt thereof, in the same or different pharmaceutical formulations.

[0012] The present invention further relates to the above combination product, pharmaceutical composition or article of manufacture for use in therapy (or for use as a medicine / drug).Thus, the present invention provides a combination product comprising an LSD1 inhibitor or a pharma- ceutically acceptable salt thereof and gilteritinib or a pharma- ceutically acceptable salt thereof, in the same or different pharmaceutical formulations, in particular for use in therapy.

[0013] The present invention further provides a combination product comprising an LSD1 inhibitor or a pharma- ceutically acceptable salt thereof and gilteritinib or a pharma- ceutically acceptable salt thereof, in the same or in different pharmaceutical formulations, for use in the treatment of a myeloid cancer, preferably selected from acute myeloid leukemia and myelodysplastic syndrome.

[0014] The present invention further provides a method for treating bone marrow cancer (preferably selected from acute myeloid leukemia and myelodysplastic syndrome) in a patient in need of treatment, comprising administering to the patient a therapeutically effective amount of the combination product, pharmaceutical composition or product of manufacture described above.In particular, the present invention provides a method for treating bone marrow cancer (preferably selected from acute myeloid leukemia and myelodysplastic syndrome) in a patient in need of treatment, comprising administering to the patient a therapeutically effective amount of a combination product comprising an LSD1 inhibitor or a pharmaceutically acceptable salt thereof and gilteritinib or a pharmaceutically acceptable salt thereof in the same pharmaceutical formulation or in different pharmaceutical formulations.

[0015] The present invention further provides a method for treating myeloid cancer, preferably selected from acute myeloid leukemia and myelodysplastic syndrome, in a patient in need of such treatment, comprising administering to the patient a therapeutically effective amount of an LSD1 inhibitor or a pharma- ceutically acceptable salt thereof and a therapeutically effective amount of gilteritinib or a pharma- ceutically acceptable salt thereof.

[0016] The present invention further provides the use of a combination comprising an LSD1 inhibitor or a pharma- ceutically acceptable salt thereof and gilteritinib or a pharma- ceutically acceptable salt thereof in the manufacture of a medicament for the treatment of a bone marrow cancer, preferably selected from acute myeloid leukemia and myelodysplastic syndrome.

[0017] The present invention further provides the use of a combination comprising an LSD1 inhibitor or a pharma- ceutically acceptable salt thereof and gilteritinib or a pharma- ceutically acceptable salt thereof for the treatment of a bone marrow cancer, preferably selected from acute myeloid leukemia and myelodysplastic syndrome.

[0018] In a preferred embodiment, the LSD1 inhibitor is iademstat or a pharma- ceutically acceptable salt thereof (eg, iademstat dihydrochloride). [Brief description of the drawings]

[0019] [Figure 1]FIG. 1 shows the plate organization for the matrix assay used to determine the synergistic effect of the combination of the present invention, as described in Example 1. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0020] Detailed Description of the Invention As noted above, the present invention is based on the surprising discovery that an LSD1 inhibitor and gilteritinib, as described herein, can be used in combination to treat myeloid malignancies with greater anti-cancer efficacy than obtained with treatment with an LSD1 inhibitor alone or with gilteritinib alone, as described in more detail below and in the Examples.

[0021] According to the present invention, an "LSD1 inhibitor" is 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 preferred LSD1 inhibitor is iademstat or a pharma- ceutically acceptable salt thereof (e.g., iademstat dihydrochloride).

[0022] In particular, the present invention provides a combination product comprising an LSD1 inhibitor or a pharma- ceutically acceptable salt thereof and gilteritinib or a pharma- ceutically acceptable salt thereof in the same or different pharmaceutical formulations.Thus, the LSD1 inhibitor (or a pharma- ceutically acceptable salt thereof) and gilteritinib (or a pharma- ceutically acceptable salt thereof) can be present in a single pharmaceutical formulation (i.e., in the same pharmaceutical formulation) or can be provided in different (separate) pharmaceutical formulations.

[0023] The present invention further provides a pharmaceutical composition comprising an LSD1 inhibitor or a pharma- ceutically acceptable salt thereof and gilteritinib or a pharma- ceutically acceptable salt thereof and one or more pharma- ceutically acceptable excipients.

[0024] The present invention further provides an article of manufacture comprising an LSD1 inhibitor, or a pharma- ceutically acceptable salt thereof, and gilteritinib, or a pharma- ceutically acceptable salt thereof, in the same pharmaceutical formulation or in separate pharmaceutical formulations.

[0025] The present invention further provides a combination product comprising an LSD1 inhibitor or a pharma- ceutically acceptable salt thereof and gilteritinib or a pharma- ceutically acceptable salt thereof, in the same or different 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).

[0026] The invention further provides the above combination product, pharmaceutical composition or article of manufacture for use in the treatment of cancer, preferably for use in the treatment of a bone marrow cancer such as acute myeloid leukemia or myelodysplastic syndrome.

[0027] Thus, the present invention provides a combination product comprising an LSD1 inhibitor or a pharma- ceutically acceptable salt thereof and gilteritinib or a pharma- ceutically acceptable salt thereof, in the same or in different pharmaceutical formulations, in particular for use in the treatment of a myeloid cancer, preferably selected from acute myeloid leukemia and myelodysplastic syndrome.

[0028] The present invention further provides an LSD1 inhibitor or a pharmaceutically acceptable salt thereof for use in the treatment of bone marrow cancer, which is preferably selected from acute myeloid leukemia and myelodysplastic syndrome, wherein the LSD1 inhibitor or a pharmaceutically acceptable salt thereof is for use in combination with gilteritinib or a pharmaceutically acceptable salt thereof.Thus, the present invention provides an LSD1 inhibitor or a pharmaceutically acceptable salt thereof for use in the treatment of bone marrow cancer, which is preferably selected from acute myeloid leukemia and myelodysplastic syndrome, wherein the LSD1 inhibitor or a pharmaceutically acceptable salt thereof is administered in combination with gilteritinib or a pharmaceutically acceptable salt thereof.The LSD1 inhibitor (or a pharmaceutically acceptable salt thereof) and gilteritinib (or a pharmaceutically acceptable salt thereof) can be provided in the same pharmaceutical formulation or in separate pharmaceutical formulations.

[0029] The present invention further provides gilteritinib or its pharmaceutically acceptable salt for use in the treatment of bone marrow cancer, which is preferably selected from acute myeloid leukemia and myelodysplastic syndrome, wherein gilteritinib or its pharmaceutically acceptable salt is for use in combination with LSD1 inhibitor or its pharmaceutically acceptable salt.Thus, the present invention provides gilteritinib or its pharmaceutically acceptable salt for use in the treatment of bone marrow cancer, which is preferably selected from acute myeloid leukemia and myelodysplastic syndrome, wherein gilteritinib or its pharmaceutically acceptable salt is administered in combination with LSD1 inhibitor or its pharmaceutically acceptable salt.Gilteritinib (or its pharmaceutically acceptable salt) and LSD1 inhibitor (or its pharmaceutically acceptable salt) can be provided in the same pharmaceutical formulation or in separate pharmaceutical formulations.

[0030] The present invention further provides a method of treating cancer, in particular myeloid cancer, which is preferably selected from acute myeloid leukemia and myelodysplastic syndrome, comprising administering to a patient a therapeutically effective amount of the above combination product, pharmaceutical composition or article of manufacture.

[0031] In particular, the present invention provides a method for treating myeloid cancer, which is preferably selected from acute myeloid leukemia and myelodysplastic syndrome, comprising administering to a patient a therapeutically effective amount of a combination product comprising an LSD1 inhibitor or a pharma- ceutically acceptable salt thereof and gilteritinib or a pharma- ceutically acceptable salt thereof, in the same or different pharmaceutical formulations.

[0032] The present invention further provides a method for treating bone marrow cancer (preferably selected from acute myeloid leukemia and myelodysplastic syndrome) in a patient in need of 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 gilteritinib or a pharmaceutically acceptable salt thereof. The LSD1 inhibitor (or a pharmaceutically acceptable salt thereof) and gilteritinib (or a pharmaceutically acceptable salt thereof) can be provided / administered in the same pharmaceutical formulation or in different pharmaceutical formulations.

[0033] The present invention further provides the use of a combination comprising an LSD1 inhibitor or a pharma- ceutically acceptable salt thereof and gilteritinib or a pharma- ceutically acceptable salt thereof for the manufacture of a medicament for the treatment of a bone marrow cancer, preferably selected from acute myeloid leukemia and myelodysplastic syndrome.

[0034] The present invention further provides the use of an LSD1 inhibitor or a pharma- ceutically acceptable salt thereof in combination with gilteritinib or a pharma- ceutically acceptable salt thereof for the manufacture of a medicament comprising said LSD1 inhibitor or a pharma- ceutically acceptable salt thereof and said gilteritinib or a pharma- ceutically acceptable salt thereof in the same or different pharmaceutical formulations, preferably for the treatment of a bone marrow cancer selected from acute myeloid leukemia and myelodysplastic syndrome.

[0035] The present invention further provides the use of an LSD1 inhibitor or a pharma- ceutically acceptable salt thereof in combination with gilteritinib or a pharma- ceutically acceptable salt thereof for the manufacture of a medicament for the treatment of a bone marrow cancer, which is preferably selected from acute myeloid leukemia and myelodysplastic syndrome, wherein the medicament comprises an LSD1 inhibitor or a pharma- ceutically acceptable salt thereof and gilteritinib or a pharma- ceutically acceptable salt thereof in the same pharmaceutical formulation or in different pharmaceutical formulations.

[0036] The present invention further provides the use of an LSD1 inhibitor or a pharma- ceutically acceptable salt thereof for the manufacture of a medicament for the treatment of a bone marrow cancer, preferably selected from acute myeloid leukemia and myelodysplastic syndrome, for use in combination with gilteritinib or a pharma- ceutically acceptable salt thereof.

[0037] The present invention further provides the use of an LSD1 inhibitor or a pharma- ceutically acceptable salt thereof in combination with gilteritinib or a pharma- ceutically acceptable salt thereof for the manufacture of a medicament for the treatment of a myeloid cancer, which is preferably selected from acute myeloid leukemia and myelodysplastic syndrome.

[0038] The present invention further provides the use of an LSD1 inhibitor or a pharma- ceutically acceptable salt thereof for the manufacture of a medicament for the treatment of a bone marrow cancer, preferably selected from acute myeloid leukemia and myelodysplastic syndrome, wherein the medicament is manufactured for (or is manufactured for) combined use with gilteritinib or a pharma- ceutically acceptable salt thereof.

[0039] The present invention further provides the use of gilteritinib or a pharma- ceutically acceptable salt thereof for the manufacture of a medicament for the treatment of bone marrow cancer, preferably selected from acute myeloid leukemia and myelodysplastic syndrome, for use in combination with an LSD1 inhibitor or a pharma- ceutically acceptable salt thereof.

[0040] The present invention further provides the use of gilteritinib or a pharma- ceutically acceptable salt thereof in combination with an LSD1 inhibitor or a pharma- ceutically acceptable salt thereof for the manufacture of a medicament for the treatment of a bone marrow cancer, which is preferably selected from acute myeloid leukemia and myelodysplastic syndrome.

[0041] The present invention further provides the use of gilteritinib or a pharma- ceutically acceptable salt thereof for the manufacture of a medicament for the treatment of a bone marrow cancer, which is preferably selected from acute myeloid leukemia and myelodysplastic syndrome, wherein the medicament is manufactured for (or is manufactured for use in combination with) an LSD1 inhibitor or a pharma- ceutically acceptable salt thereof.

[0042] The present invention further provides the use of a combination comprising an LSD1 inhibitor or a pharma- ceutically acceptable salt thereof and gilteritinib or a pharma- ceutically acceptable salt thereof for the treatment of a bone marrow cancer, preferably selected from acute myeloid leukemia and myelodysplastic syndrome.

[0043] The present invention further provides the use of an LSD1 inhibitor or a pharma- ceutically acceptable salt thereof in combination with gilteritinib or a pharma- ceutically acceptable salt thereof for the treatment of bone marrow cancer, which is preferably selected from acute myeloid leukemia and myelodysplastic syndrome, wherein said LSD1 inhibitor or a pharma- ceutically acceptable salt thereof and said gilteritinib or a pharma- ceutically acceptable salt thereof are provided in the same pharmaceutical formulation or in different pharmaceutical formulations.

[0044] The present invention further provides the use of an LSD1 inhibitor or a pharma- ceutically acceptable salt thereof for the treatment of bone marrow cancer, which is preferably selected from acute myeloid leukemia and myelodysplastic syndrome, in combination with gilteritinib or a pharma- ceutically acceptable salt thereof.

[0045] The present invention further provides the use of an LSD1 inhibitor or a pharma- ceutically acceptable salt thereof in combination with gilteritinib or a pharma- ceutically acceptable salt thereof for the treatment of bone marrow cancer, which is preferably selected from acute myeloid leukemia and myelodysplastic syndrome.

[0046] The present invention further provides the use of an LSD1 inhibitor or a pharma- ceutically acceptable salt thereof for the treatment of bone marrow cancer, which is preferably selected from acute myeloid leukemia and myelodysplastic syndrome, wherein the LSD1 inhibitor or a pharma- ceutically acceptable salt thereof is administered in combination with gilteritinib or a pharma- ceutically acceptable salt thereof.

[0047] The present invention further provides the use of gilteritinib or a pharma- ceutically acceptable salt thereof for the treatment of bone marrow cancer, which is preferably selected from acute myeloid leukemia and myelodysplastic syndrome, in combination with an LSD1 inhibitor or a pharma- ceutically acceptable salt thereof.

[0048] The present invention further provides the use of gilteritinib, or a pharma- ceutically acceptable salt thereof, in combination with an LSD1 inhibitor, or a pharma- ceutically acceptable salt thereof, for the treatment of a myeloid cancer, which is preferably selected from acute myeloid leukemia and myelodysplastic syndrome.

[0049] The present invention further provides the use of gilteritinib or a pharmaceutically acceptable salt thereof for the treatment of bone marrow cancer, which is preferably selected from acute myeloid leukemia and myelodysplastic syndrome, wherein said gilteritinib or a pharmaceutically acceptable salt thereof is administered in combination with an LSD1 inhibitor or a pharmaceutically acceptable salt thereof.

[0050] In the methods and uses according to the invention, the patient is a human or an animal (eg a non-human mammal), preferably a human.

[0051] In certain embodiments, the LSD1 inhibitor is a small molecule.

[0052] In certain embodiments, the LSD1 inhibitor is selected from the group consisting of iademstat, plerodemstat (CC-90011), bomedemstat, secridemstat, 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 of the above agents).

[0053] In certain embodiments, the LSD1 inhibitor is selected from the group consisting of iademstat, plerodemstat (CC-90011), vomedemstat, and pharma- ceutically acceptable salts thereof.

[0054] In certain embodiments, the LSD1 inhibitor is plerodemstat (CC-90011) or a pharma- ceutically acceptable salt thereof.

[0055] In certain embodiments, the LSD1 inhibitor is bomedemstat or a pharma- ceutically acceptable salt thereof.

[0056] Preferably, the LSD1 inhibitor is iademstat or a pharma- ceutically acceptable salt thereof. In one embodiment, the LSD1 inhibitor is iademstat dihydrochloride.

[0057] In some embodiments, the bone marrow cancer is acute myeloid leukemia.

[0058] In certain embodiments, the acute myeloid leukemia is relapsed or refractory acute myeloid leukemia.

[0059] In certain embodiments, the acute myeloid leukemia is relapsed acute myeloid leukemia.

[0060] In certain embodiments, the acute myeloid leukemia is refractory acute myeloid leukemia.

[0061] In some embodiments, acute myeloid leukemia is acute myeloid leukemia with genetic, epigenetic or post-transcriptional alteration that affects (for example, increases) FLT3 expression and / or FLT3 activity.In particular, acute myeloid leukemia can be acute myeloid leukemia with FLT3 mutation and / or genetic, epigenetic or post-transcriptional alteration that affects (for example, increases) FLT3 expression and / or FLT3 activity.In some embodiments, acute myeloid leukemia is acute myeloid leukemia with FLT3 mutation and / or genetic, epigenetic or post-transcriptional alteration that causes FLT3 expression level increase or FLT3 activity increase, where said FLT3 expression level increase or said FLT3 activity increase leads to uncontrolled cell proliferation.

[0062] In certain embodiments, the acute myeloid leukemia is FLT3 mutated acute myeloid leukemia.

[0063] In some embodiments, acute myeloid leukemia is relapsed or refractory acute myeloid leukemia with genetic, epigenetic or post-transcriptional alteration that affects (e.g., increases) FLT3 expression and / or FLT3 activity.For example, acute myeloid leukemia can be relapsed or refractory acute myeloid leukemia with FLT3 mutation and / or genetic, epigenetic or post-transcriptional alteration that affects (e.g., increases) FLT3 expression and / or FLT3 activity.

[0064] In certain embodiments, the acute myeloid leukemia is relapsed or refractory acute myeloid leukemia with a FLT3 mutation.

[0065] In some embodiments, acute myeloid leukemia is relapsed acute myeloid leukemia with genetic, epigenetic or post-transcriptional alteration that affects (e.g., increases) FLT3 expression and / or FLT3 activity.For example, acute myeloid leukemia can be relapsed acute myeloid leukemia with FLT3 mutation and / or genetic, epigenetic or post-transcriptional alteration that affects (e.g., increases) FLT3 expression and / or FLT3 activity.

[0066] In certain embodiments, the acute myeloid leukemia is relapsed acute myeloid leukemia with a FLT3 mutation.

[0067] In some embodiments, acute myeloid leukemia is refractory acute myeloid leukemia with genetic, epigenetic or post-transcriptional alteration that affects (e.g., increases) FLT3 expression and / or FLT3 activity.For example, acute myeloid leukemia can be refractory acute myeloid leukemia with FLT3 mutation and / or genetic, epigenetic or post-transcriptional alteration that affects (e.g., increases) FLT3 expression and / or FLT3 activity.

[0068] In certain embodiments, the acute myeloid leukemia is refractory acute myeloid leukemia with a FLT3 mutation.

[0069] In certain embodiments, the FLT3 mutation is an activating FLT3 mutation, particularly a mutation that results in ligand-independent FLT3 dimerization and constitutive activation of FLT3.

[0070] In some embodiments, FLT3 mutation is juxtamembrane domain intragenic tandem duplication mutation (FLT3-ITD) or tyrosine kinase domain point mutation or deletion (FLT3-TKD).In some embodiments, FLT3 mutation is FLT3-ITD.In some embodiments, FLT3 mutation is FLT3-TKD.In some embodiments, FLT3 mutation is FLT3-ITD and FLT3-TKD.

[0071] In some embodiments, FLT3 mutation is a mutation in tyrosine kinase domain (FLT3-TKD), particularly a point mutation (e.g., nucleotide substitution) that affects (or involves) the aspartic acid residue at position 835 of wild-type FLT3 (D835) or a deletion of D835 and / or a point mutation (e.g., nucleotide substitution) that affects (or involves) the isoleucine residue at position 836 of wild-type FLT3 (I836) or a deletion of I836. Thus, FLT3 mutation can be (or can include), for example, D835 mutation, I836 mutation, or D835 / I836 mutation. In particular, the D835 mutation can be, for example, a D835Y mutation (i.e., an 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. Furthermore, the FLT3 mutation may also be (or may include) a point mutation affecting (or involving) the tyrosine residue at position 842 of wild-type FLT3 (Y842) or a deletion of Y842, a point mutation affecting (or involving) the lysine residue at position 663 of wild-type FLT3 (K663) or a deletion of K663 and / or a point mutation affecting (or involving) the valine residue at position 592 of wild-type FLT3 (V592) or a deletion of V592, e.g., a Y842C mutation, a K663Q mutation or a V592A mutation or any combination of these.

[0072] In certain embodiments, the LSD1 inhibitor (or a pharma- ceutically acceptable salt thereof) and gilteritinib (or a pharma- ceutically acceptable salt thereof) are used as second-line or third-line treatment of relapsed or refractory acute myeloid leukemia.

[0073] In some embodiments, bone marrow cancer is myelodysplastic syndrome.In some embodiments, bone marrow cancer is myelodysplastic syndrome with genetic, epigenetic or post-transcriptional alteration that affects (e.g., increases) FLT3 expression and / or FLT3 activity.In particular, bone marrow cancer can be myelodysplastic syndrome with FLT3 mutation and / or genetic, epigenetic or post-transcriptional alteration that affects (e.g., increases) FLT3 expression and / or FLT3 activity.In some embodiments, bone marrow cancer is myelodysplastic syndrome with FLT3 mutation (e.g., any of the above-mentioned FLT3 mutation examples) and / or genetic, epigenetic or post-transcriptional alteration that leads to FLT3 expression level increase or FLT3 activity increase, where the FLT3 expression level increase or the FLT3 activity increase leads to uncontrolled cell proliferation.In some embodiments, bone marrow cancer is myelodysplastic syndrome with FLT3 mutation (e.g., any of the above-mentioned FLT3 mutation examples).

[0074] In some embodiments, the LSD1 inhibitor (or its pharmaceutically acceptable salt) and gilteritinib (or its pharmaceutically acceptable salt) are administered as separate pharmaceutical formulations.For this purpose, the LSD1 inhibitor (or its pharmaceutically acceptable salt) and gilteritinib (or its pharmaceutically acceptable salt) are provided as different pharmaceutical formulations.

[0075] Preferably, the LSD1 inhibitor, such as iadamstat (or a pharma- ceutically acceptable salt thereof), is administered orally. Examples of formulations that may be administered via oral ingestion are described in further detail below.

[0076] Preferably, gilteritinib (or a pharma- ceutically acceptable salt thereof) is administered orally. Examples of formulations that may be administered via oral ingestion are further detailed below.

[0077] As described in the Examples, the present invention has unexpectedly discovered that the combination of LSD1 inhibitor and gilteritinib shows strong synergistic effect in inhibiting the proliferation of myeloid cancer such as AML. As described in Example 1, treatment with the combination of LSD1 inhibitor and gilteritinib using two structurally unrelated and dissimilar LSD1 inhibitors, i.e., irreversible cyclopropylamine-based LSD1 inhibitor iademstat and reversible non-cyclopropylamine-based LSD1 inhibitor pleurodemstat (CC-90011), shows synergistic effect in inhibiting the proliferation of AML cell lines of various genetic backgrounds. Strong synergistic effect of the combination of iademstat and gilteritinib and pleurodemstat (CC-90011) and gilteritinib was observed in FLT3-mutant AML cell lines, MOLM-13 and MV(4;11). Notably, synergy was also observed in the FLT3-wild type (i.e., no FLT3 mutation) AML cell lines OCI-AML3 and TF-1a, which are resistant or poorly responsive to treatment with other current AML therapies, such as gilteritinib or venetoclax, as shown in Example 1. These findings indicate that the combination of an LSD1 inhibitor, such as iademstat (or a pharma- ceutically acceptable salt thereof), with gilteritinib (or a pharma- ceutically acceptable salt thereof) is particularly useful for the treatment of AML with or without FLT3 mutations and other myeloid cancers, such as MDS, even in patients who are refractory or have relapsed to other treatments.

[0078] The therapeutic effect of the combination of LSD1 inhibitor and gilteritinib for the treatment of myeloid cancer such as AML may be further confirmed in further in vitro or in vivo experiments and human clinical trials, which may be easily set up by those skilled in the art of drug development.

[0079] LSD1 inhibitors As indicated above, "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. Any molecule that acts as an LSD1 inhibitor can in principle be used in the combinations, methods and uses of the present invention. Preferably, the LSD1 inhibitor is a small molecule. Irreversible and reversible LSD1 inhibitors have been described and can be used in the present invention, as shown by the results described in the examples below, using a combination of gilteritinib with both irreversible and reversible LSD1 inhibitors. Prototypical irreversible LSD1 inhibitors are cyclopropylamine-based compounds, such as iademstat, which is one of the LSD1 inhibitors used in the examples herein. A representative example of a reversible LSD1 inhibitor is the compound plerodemstat (CC-90011), which is also used in the examples herein. Preferably, the LSD1 inhibitor is a selective LSD1 inhibitor; as used herein, "selective LSD1 inhibitor" refers to an LSD1 inhibitor that exhibits at least 10-fold selectivity for LSD1 over other FAD-dependent monoamine oxidases, particularly MAO-A and MAO-B.

[0080] An exemplary list of small molecule LSD1 inhibitors is provided in the table below. [Table 1]

[0081] The LSD1 inhibitor for use in accordance with the present invention may thus be, for example, a specific compound named in the table above, or a pharma- ceutically acceptable salt of any of these compounds.

[0082] In certain embodiments, the LSD1 inhibitors are 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, W O2014 / 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 / 034774, WO2019 / 054766, WO2019 / 217972, WO2019 / 222069, WO2020 / 015745, EP3825309A1, WO2020 / 047198, WO2020 / 052647, WO2020 / 052649, EP3851440A1, WO2020 / 138398, WO2020 / 159285, EP3 907225A1, WO2021 / 058024, WO2021 / 095835, WO2021 / 175079, US2017-0283397, US2022-0064126, CN103054869, CN103319466, CN104119280, C N105541806, CN105924362, CN105985265, CN106045862, CN106045881, CN106432248, CN106478639, CN106831489, CN106928235, CN107033148 CN107174584, CN107176927, CN107459476, CN107474011, CN107501169, CN107936022, CN108530302, CN109265462, C N109293664, CN109535019, CN110204551, CN110478352, CN111072610, CN111454252, CN112110936, CN112409310, CN CN112920130, CN113087712, CN113105479, CN113264903, CN113582906, CN113599380, KR20190040763 or KR20190040783, each of which is incorporated herein by reference in its entirety (particularly including compounds described in the Examples section of each of these documents). Thus, the LSD1 inhibitor may be, for example, a compound disclosed in any of the above documents (including, for example, in the Examples section of any of these documents), where the compound may be used in a non-salt form or in the form of a pharma- ceutically acceptable salt.

[0083] In certain embodiments, the LSD1 inhibitor is a compound selected from the group consisting of iademstat, plerodemstat (CC-90011), bomedemstat, secridemstat, 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.

[0084] Iadademstat is a selective and irreversible LSD1 inhibitor. Iadademstat has the formula: [ka] INN is the compound of [CAS Reg. No. 1431304-21-0], 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 WO2013 / 057322. Its pharmaceutically acceptable salts, including the hydrochloride, are also described therein.

[0085] Plurodemstat has the formula [ka] It is a reversible LSD1 inhibitor of [CAS Reg. No. 1821307-10-1], also known as CC-90011, with 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 (CC-90011) is described, for example, in WO2015 / 168466 and WO2017 / 79670. Its pharma-ceutically acceptable salts, including the besylate, are also described therein.

[0086] Bomedemstat is a [ka] It is an irreversible LSD1 inhibitor of [CAS Reg. No. 1990504-34-1], 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. Bomedemstat is described, for example, in WO2016 / 130952 and WO2018 / 35259. Its pharma-ceutically acceptable salts, including bistosilate, are also described therein.

[0087] Seclidemstat has the formula [ka] It is an LSD1 inhibitor of [CAS Reg. No. 1423715-37-0], 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.

[0088] 1-((4-(Methoxymethyl)-4-(((1R,2S)-2-phenylcyclopropylamino)methyl)piperidin-1-yl)methyl)cyclobutanecarboxylic acid is an irreversible LSD1 inhibitor described, for example, in WO2015 / 123465 and WO2017 / 27678. Pharmaceutically acceptable salts thereof, including the p-toluenesulfonate salt, are also described therein.

[0089] 3-(cyanomethyl)-3-(4-{[(1R,2S)-2-phenylcyclopropyl]amino}piperidin-1-yl)azetidine-1-sulfonamide is an irreversible LSD1 inhibitor, for example, as described in WO2020 / 047198. Pharmaceutically acceptable salts thereof are also described therein.

[0090] Vafidemstat has the formula: [ka] is an irreversible LSD1 inhibitor of the formula: 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. Bafidemstat is also known as, for example, as described in Example 35 of WO2012 / 13728.

[0091] In certain embodiments, the LSD1 inhibitor is selected from the group consisting of iademstat, plerodemstat (CC-90011), vomedemstat, and pharma- ceutically acceptable salts thereof.

[0092] A particularly preferred LSD1 inhibitor is iademstat or a pharma- ceutically acceptable salt thereof. In some embodiments, iademstat is used as the dihydrochloride salt.

[0093] Gilteritinib Gilteritinib has the formula: [ka] It is the compound INN of [CAS Reg. No. 1254053-43-4], also known as ASP2215 or 6-ethyl-3-[[3-methoxy-4-[4-(4-methylpiperazinyl)piperidin-1-yl]phenyl]amino]-5-[(tetrahydro-2H-pyran-4-yl)amino]pyrazine-2-carboxamide. Gilteritinib is an FLT3 inhibitor, in particular a type I FLT3 inhibitor, and corresponds to the drug sold under the trade name XOSPATA®. Gilteritinib is preferably used as the fumarate salt.

[0094] Unless otherwise specified, all references to an LSD1 inhibitor (e.g., iadamstat) throughout this specification and claims include the LSD1 inhibitor in either non-salt form or in a pharma- ceutically acceptable salt thereof. When the LSD1 inhibitor is iadamstat, it is preferably used in the form of a pharma- ceutically acceptable salt, preferably the hydrochloride salt, more preferably the dihydrochloride salt.

[0095] Similarly, any reference to gilteritinib throughout this specification and claims includes gilteritinib (non-salt form) and any of its pharmaceutically acceptable salts. Preferably, gilteritinib is used in the form of a pharmaceutically acceptable salt, preferably the fumarate salt.

[0096] The administration of the combination of LSD1 inhibitor and gilteritinib can include the administration of the composition in any useful form.For example, the combination of the present invention can be administered using different formulations for each active ingredient (i.e., separate formulations for LSD1 inhibitor and gilteritinib) or can be administered using pharmaceutical formulations that contain both LSD1 inhibitor and gilteritinib.When using different formulations, such as a first formulation that contains LSD1 inhibitor and a second formulation that contains gilteritinib, the formulations can be administered in any order, whether sequentially or simultaneously, where preferably both (or all) active agents are allowed to exert their biological activity at the same time.

[0097] In some embodiments, one or more additional therapeutic agents can be administered to patient.The additional therapeutic agent can include one or more additional anticancer agents, including any of the drugs used to treat myeloid cancer, especially AML, including any of the corresponding drugs listed in the FDA Orange Book or other documents that list approved drugs in other countries.The additional therapeutic agent can also include one or more antiemetic agents, such as, for example, 5-HT3 antagonists (e.g., palonosetron, ramosetron, alosetron, ondansetron, tropisetron, granisetron or dolasetron), olanzapine, corticosteroids (e.g., methylprednisolone or dexamethasone) or prochlorperazine.

[0098] Pharmaceutical preparations The LSD1 inhibitor and gilteritinib for use in the combinations described herein and the pharmaceutical compositions described herein that comprise the combination of the present invention can be administered by any route suitable for the condition to be treated.Suitable routes include oral, parenteral (including subcutaneous, intramuscular, intravenous, intraarterial, inhalation, intradermal, intrathecal, epidural and infusion techniques), transdermal, rectal, nasal, topical (including buccal and sublingual), vaginal, intraperitoneal, intrapulmonary and intranasal.Preferably, both components of the combination (LSD1 inhibitor and gilteritinib) are administered orally when formulated separately or when both active ingredients are formulated in a single formulation.

[0099] The LSD1 inhibitors and gilteritinib for use in the combinations described herein and the pharmaceutical compositions described herein that include the combinations of the present invention can be administered in any conventional pharmaceutical composition or formulation, such as tablets, powders, capsules, solutions, dispersions, suspensions, syrups, sprays, suppositories, gels, emulsions, patches, etc. Such compositions / formulations may contain ingredients conventional in pharmaceutical formulations, such as diluents, carriers, pH modifiers, preservatives, solubilizers, stabilizers, wetting agents, emulsifiers, sweeteners, colorants, flavorings, salts for modifying osmotic pressure, buffers, masking agents, antioxidants, and / or further active agents. They may also contain other therapeutically active or therapeutically valuable substances.

[0100] A typical formulation is prepared by mixing the LSD1 inhibitor or gilteritinib or a combination described herein with one or more pharma- ceutically acceptable additives. Suitable additives 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, opacifying agents, glidants, processing aids, colorants, sweeteners, fragrances, flavorings, diluents, and / or other known additives that provide an elegant appearance of the drug (i.e., the compound of the present invention or a pharmaceutical composition thereof) or aid in the manufacture of a pharmaceutical product (i.e., a drug product).

[0101] For oral delivery, the compound can be included in a formulation that includes a pharma- ceutically acceptable carrier, such as a binder (e.g., gelatin, cellulose, tragacanth gum), an additive (e.g., starch, lactose), a lubricant (e.g., magnesium stearate, silicon dioxide), a disintegrant (e.g., alginic acid, Primogel, and corn starch), and a sweetener or flavoring agent (e.g., glucose, sucrose, saccharin, methyl salicylate, and peppermint). The formulation can be delivered orally, for example, in the form of an enclosed gelatin capsule or a compressed tablet. Capsules and tablets can be manufactured using 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. In addition, liquid carriers, such as fatty oils, can also be included in the capsule.

[0102] Suitable oral preparations can also be in the form of suspension, syrup, chewing gum, wafer, elixir, etc. If desired, can also include the conventional agent for modifying the flavor, taste, color and shape of specific form.Furthermore, for conventional administration by enteral feeding tube in the patient who cannot swallow, active compound can be dissolved in acceptable lipophilic vegetable oil medium such as olive oil, corn oil and safflower oil.

[0103] Compounds can be administered parenterally in the form of solution or suspension or in lyophilized form that can be converted into solution or suspension before use.In such preparations, diluents or pharma- ceutically acceptable carriers such as sterile water and physiological saline buffer can be used.Other conventional solvents, pH buffers, stabilizers, antibacterial agents, surfactants and antioxidants can all be included.For example, useful components include sodium chloride, acetic acid, citric acid or phosphate buffer, glycerin, dextrose, fixed oil, methylparaben, polyethylene glycol, propylene glycol, sodium bisulfate, benzyl alcohol, ascorbic acid, etc.Parenteral preparations can be stored in any conventional container, such as vials and ampoules.

[0104] Subcutaneous implantation for sustained release of compound may also be a suitable route of administration. This includes surgical procedures for implantation of active compound in any suitable formulation into subcutaneous space, e.g., under the anterior abdominal wall. See, e.g., Wilson et al. (1984) J. Clin. Psych. 45:242-247. Hydrogels can be used as carriers for sustained release of active compound. Hydrogels are generally known in the art. They are typically made by crosslinking a network of high molecular weight biocompatible polymers, which swell in water to form a gel-like material. Preferably, hydrogels are biodegradable or bioabsorbable. For the purposes of the present invention, hydrogels made of polyethylene glycol, collagen, or poly(glycolic acid-co-L-lactic acid) may be useful. See, e.g., Phillips et al. (1984) J. Pharmaceut. Sci., 73: 1718-1720.

[0105] 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, "unit dosage form" refers to physically discrete units suitable for administration as unitary dosages to subjects, each unit containing a predetermined amount of active ingredient calculated to produce a desired therapeutic effect, together with one or more suitable pharmaceutical carriers.

[0106] Suitable oral dosage forms of iademstat are disclosed, for example, in WO2019 / 211491A1.

[0107] In particular, iademstat may be provided in the form of tablets. Alternatively, iademstat may be provided in the form of an oral aqueous solution (which may be prepared, for example, from a powder for reconstitution). As mentioned above, iademstat is preferably used in the form of iademstat dihydrochloride.

[0108] Suitable oral dosage forms of gilteritinib that can be used in the present invention include, for example, those marketed under the name XOSPATA®. Gilteritinib is marketed as a film-coated tablet containing 40 mg of gilteritinib (as the fumarate salt). Such tablets for oral use contain, for example, mannitol (E421), hydroxypropylcellulose, hydroxypropylcellulose (low-substituted) and magnesium stearate as tablet core additives and hypromellose, talc, macrogol, titanium dioxide and iron oxide yellow (E172) as film coating additives, as described in the Product Description for XOSPATA®, which is incorporated herein by reference in its entirety (particularly the latest version available on April 1, 2021). Thus, in some embodiments, gilteritinib is provided in the form of a tablet (e.g., a tablet containing 40 mg of gilteritinib, preferably as the fumarate salt).

[0109] In therapeutic applications, the combination and pharmaceutical composition of the present invention are administered in a manner suitable for the disease to be treated, as determined by those skilled in the medical field.The appropriate dose and the appropriate administration period and frequency can vary within wide limits and are determined by factors such as the condition of the patient, the type and severity of the disease, the specific form of the active ingredient, the administration method, among others.In general, the appropriate dose and administration regimen is an amount of the active ingredient of the combination of the present invention sufficient to provide therapeutic benefit, for example, improved clinical outcome, such as more frequent complete or partial remission, or longer disease-free and / or overall survival, or reduced symptom severity, or any other objectively identifiable improvement as indicated by the clinician.Therapeutically effective doses can generally be estimated or extrapolated using experimental models, such as in vitro or animal model test systems or dose-response curves derived from human clinical trials.

[0110] For example, suitable doses of gilteritinib are those used in current clinical practice for the treatment of AML. The current recommended dose of gilteritinib as monotherapy for the treatment of R / R AML is 120 mg per day, and can be increased to 200 mg per day. Thus, gilteritinib can be administered orally, for example, at a dose of about 120 mg per day. Other doses may be possible, for example, the dose of gilteritinib can be reduced due to the combined action (synergism) of the newly identified combination of gilteritinib and LSD1 inhibitor. The doses shown here for gilteritinib are the amounts of the corresponding gilteritinib free base.

[0111] Appropriate doses and administration regimens of LSD1 inhibitors depend on the particular LSD1 inhibitor used, its LSD1 inhibitory potency, its pharmacokinetic profile, and other factors, as will be known to those of skill in the art.

[0112] Iadademstat is a highly potent active pharmaceutical ingredient (HPAPI). Thus, the expected daily dose is very low, e.g., less than 1 mg per day. Thus, the amount of drug in solid form is also very low, e.g., less than 1 mg API per 100 mg tablet. In general, for oral administration (e.g., as a tablet or oral aqueous solution), a daily dose of about 50 ug to about 300 ug, preferably about 75 ug to about 300 ug (e.g., about 75 ug, about 100 ug, about 125 ug, about 150 ug, about 175 ug, about 200 ug, about 225 ug, about 250 ug, about 275 ug or about 300 ug or any range between any two of the above daily doses) of Iadademstat as described herein is appropriate, although these limits may be adjusted as necessary. As used herein, the term "ug" refers to micrograms and is used synonymously with the term "μg."

[0113] In certain embodiments, the LSD1 inhibitor is iademstat (or a pharma- ceutically acceptable salt thereof, e.g., iademstat dihydrochloride), and is administered 5 days on / 2 days off (5 / 2) per week.

[0114] In certain embodiments, the LSD1 inhibitor is iademstat (or a pharma- ceutically acceptable salt thereof, e.g., iademstat dihydrochloride), and is orally administered 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 per week (5 / 2). The doses described herein for iademstat relate to the corresponding amount of iademstat free base. In certain embodiments, iademstat is orally administered at a daily dose of about 75 μg, 5 days on / 2 days off per week (5 / 2). In certain embodiments, iademstat is orally administered at a daily dose of about 100 μg, 5 days on / 2 days off per week (5 / 2). In some embodiments, iademstat is orally administered at a daily dose of about 150 μg, 5 days on / 2 days off (5 / 2) per week. In some embodiments, iademstat is orally administered at a daily dose of about 200 μg, 5 days on / 2 days off (5 / 2) per week. In some embodiments, iademstat is orally administered at a daily dose of about 250 μg, 5 days on / 2 days off (5 / 2) per week. In some embodiments, iademstat is orally administered at a daily dose of about 300 μg, 5 days on / 2 days off (5 / 2) per week.

[0115] manufactured goods The combinations and pharmaceutical compositions of the invention may be included in a container, pack, or dispenser together with instructions for administration.

[0116] In other embodiments of the present invention, articles of manufacture or "kits" are provided which contain the combinations described herein.

[0117] In one embodiment, the article of manufacture or kit comprises a container and an inventive combination described herein.

[0118] In certain embodiments, the article of manufacture or kit comprises: a) a container comprising an LSD1 inhibitor (or a pharma- ceutically acceptable salt thereof); and b) a container comprising gilteritinib (or a pharma- ceutically acceptable salt thereof).

[0119] The article of manufacture or kit may further include a label or package insert. The term "package insert" refers to instructions customarily included in commercial packaging of a therapeutic agent, including information about indications, uses, dosage, administration, contraindications, and / or warnings regarding the use of such therapeutic agent. Suitable containers include, for example, blister packs, bottles, vials, syringes, and the like. The containers may be formed from a variety of materials, such as glass or plastic. The containers may contain a combination or a formulation thereof effective for treating a condition and may have a sterile access port (e.g., the container may be an intravenous solution bag or vial having a stopper pierceable by a hypodermic injection needle). The label or package insert indicates that the composition is for treating a selected condition, such as AML. Alternatively or in addition, the article of manufacture may further include a second container containing a pharmacologic acceptable buffer, such as sterile water for injection (BWFI), phosphate buffered saline, Ringer's solution, and dextrose solution. It may further include other materials desirable for marketing and use, including other buffers, diluents, filters, needles, and syringes.

[0120] The kit may further include instructions for administration of the combination and, if present, a second pharmaceutical formulation. If the kit includes a first pharmaceutical composition / formulation comprising an LSD1 inhibitor or a pharma- ceutically acceptable salt thereof and a second pharmaceutical composition / formulation comprising gilteritinib or a pharma- ceutically acceptable salt thereof, the kit may further include instructions for simultaneous, sequential or separate administration of the first and second pharmaceutical compositions / formulations to a patient in need of treatment.

[0121] In other embodiments, the kit is suitable for delivery of the combined solid oral form, such as tablets or capsules. Such a kit preferably includes several unit doses. Such a kit may include a card with doses that are adapted to the order of intended use. An example of such a kit is a "blister pack". Blister packs are well known in the packaging industry and are widely used to package pharmaceutical unit dosage forms. Optionally, memory aids may be provided, such as by inserting numbers, letters or other marks or calendars that indicate the days on which doses in a treatment schedule can be administered.

[0122] In some embodiments, the kit can include: (a) a first container that contains an LSD1 inhibitor or a pharmaceutically acceptable salt thereof; (b) a second container that contains gilteritinib or a pharmaceutically acceptable salt thereof; and (c) a third container that contains a third pharmaceutical preparation, wherein the third pharmaceutical preparation contains another compound that has anticancer activity.Alternatively or in addition, the kit can include another container that contains a pharmaceutically acceptable buffer solution, such as sterile water for injection (BWFI), phosphate buffered saline, Ringer's solution and dextrose solution.It can also include other materials that are desired for commercialization and by users, including other buffer solutions, diluents, filters, needles and syringes.

[0123] When the kit comprises a composition of an LSD1 inhibitor or a pharma- ceutically acceptable salt thereof and a composition of gilteritinib or a pharma- ceutically acceptable salt thereof, the kit may comprise a container for containing the separate compositions, such as a divided bottle or a divided foil packet, but the separate compositions may also be placed in a single undivided container.Typically, the kit comprises instructions for the administration of the separate components.The kit form is particularly advantageous when the separate components are preferably administered in different dosage forms (e.g., oral and parenteral), administered at different dosage intervals, or titration of the individual components of the combination is desired by the treating physician.

[0124] 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 belongs.

[0125] The following definitions apply throughout the specification and claims, unless otherwise stated.

[0126] A "patient" or "subject" for the purposes of the present invention 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 applications. In a preferred embodiment, the subject or patient is a mammal, and in a most preferred embodiment, the subject or patient is a human (e.g., a male or female human).

[0127] The terms "treatment", "treating" and the like are used herein to generally mean obtaining a desired pharmacological and / or physiological effect, including partial or complete cure or alleviation of a disease (i.e., cancer) and / or symptoms or deleterious effects associated with the disease, or partial or complete halting of progression of the disease and / or symptoms or deleterious effects associated with the disease. The term "treatment" as used herein encompasses any treatment of a disease (i.e., cancer) in a patient, including, but not limited to, preventing cancer, i.e., arresting, retarding or slowing its development / progression; or alleviating cancer, i.e., regression (complete or partial), correction or remission of cancer. The present invention is particularly and specifically related to each and every one of these forms of treatment.

[0128] As used herein, the term "therapeutically effective amount" or "effective amount" of a compound or combination of 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 an amount that, when administered to a subject suffering from or susceptible to a disease (i.e., cancer), treats the disease and / or delays the onset or progression of the disease and / or relieves one or more symptoms of the disease. The therapeutically effective amount will vary depending on the compound, the disease state 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 treating physician or veterinarian, and other factors.

[0129] The term "pharmaceutical acceptable" generally refers to the characteristics of a material useful in the preparation of pharmaceutical compositions that are safe, non-toxic, and not biologically or otherwise undesirable, and that are acceptable for veterinary and / or human medical use.

[0130] As used herein, "pharmaceutically acceptable salts" is intended to mean salts that retain the biological effectiveness of the free acids and / or bases of the particular compound and are not biologically or otherwise undesirable. The compounds may possess functional groups that are sufficiently acidic, sufficiently basic, or both, and thus capable of reacting with any number of inorganic or organic bases and inorganic or organic acids to form pharmaceutically acceptable salts. Examples of pharma- ceutically acceptable salts include those of the compounds of the invention, e.g., iadamstat, with hydrochloric acid, hydrobromic acid, sulfuric acid, pyrosulfuric acid, bisulfate, sulfurous acid, bisulfite, phosphoric acid, monohydrogen phosphate, dihydrogen phosphate, metaphosphoric acid, pyrophosphate, chloride, bromide, iodide, nitric acid, acetic acid, propionic acid, decanoic acid, caprylic acid, acrylic acid, formic acid, isobutyric acid, caproic acid, heptanoic acid, propiolic acid, oxalic acid, malonic acid, succinic acid, suberic acid, sebacic acid, fumaric acid, maleic acid, butyne-1,4-dioic acid, hexyne-1,6-dioic acid, benzoic acid, chlorobenzoic acid, methylbenzoic acid, dinitrobenzoic acid, hydroxybenzoic acid, ... These include salts prepared by reaction with inorganic or organic acids such as benzoic acid, methoxybenzoic acid, phthalic acid, sulfonic acid, xylenesulfonic acid, phenylacetic acid, phenylpropionic acid, phenylbutyric acid, citric acid, lactic acid, gamma-hydroxybutyric acid, glycolic acid, tartaric acid, methanesulfonic acid (or mesylic acid), ethanesulfonic acid, propanesulfonic acid, benzenesulfonic acid (or besylic acid), toluenesulfonic acid, trifluoromethanesulfonic acid, naphthalene-1-sulfonic acid, naphthalene-2-sulfonic acid, mandelic acid, pyruvic acid, stearic acid, ascorbic acid, or salicylic acid. When the compound contains an acidic moiety, suitable pharma- ceutically acceptable salts thereof may include alkali metal salts, e.g., sodium or potassium salts; alkaline earth metal salts, e.g., calcium or magnesium salts; and salts formed with suitable organic ligands, such as ammonia, alkylamines, hydroxyalkylamines, lysine, arginine, N-methylglucamine, procaine, and the like. Pharmaceutically acceptable salts are well known in the art.

[0131] 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 or combination of the present invention together with one or more pharma- ceutically acceptable excipients, to be administered to a mammal, e.g., a human in need of treatment.

[0132] The terms "pharmaceutically acceptable excipient" or "pharmaceutically acceptable carrier" may be used interchangeably and refer to pharmaceutically acceptable ingredients in pharmaceutical compositions, such as disintegrants, binders, fillers, solvents, buffers, isotonicity agents, stabilizers, antioxidants, surfactants, carriers, diluents, lubricants, etc., used in the formulation of pharmaceutical products, which have no therapeutic activity and are non-toxic to the subject to which they are administered. Generally, they are safe for human use according to established governmental regulations, 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 of skill in the art.

[0133] As used herein, the term "inhibitor" refers to a compound that competes with, reduces, blocks, inhibits, eliminates or interferes in any way with the binding of a particular ligand to a particular receptor or enzyme and / or that reduces, blocks, inhibits, eliminates or interferes in any way with the activity or function of a particular protein, e.g., a receptor or enzyme.

[0134] As used herein, a "small molecule" refers to an organic compound with a molecular weight of 900 Daltons or less, preferably 500 Daltons or less. Molecular weight is the mass of a molecule, calculated as the sum of the atomic weights of each of the constituent elements multiplied by the number of atoms of that element in the molecular formula.

[0135] As used herein, the term "comprise" (or "comprises", "including", "including", "including" or "comprising") means "comprises", i.e., "including, among other optional elements", unless otherwise specified or contrary to context. In addition, the term includes the narrower meanings of "consisting essentially of" and "consisting of". For example, the term "A comprising B and C" means "A comprising, among other elements, B and C", where A may include additional optional elements (e.g., "A comprising B, C and D" is also included), but the term also includes the meaning of "A consisting essentially of B and C" and "A consisting of B and C" (i.e., A does not include any components other than B and C).

[0136] As used herein, the singular terms "a," "an," and "the" include plural and singular elements unless the context clearly indicates otherwise.

[0137] The term "about" or "approximately" refers to the allowable error of a particular value as determined by those skilled in the art, which depends in part on how the value is measured or determined. In some embodiments, the term "about" or "approximately" refers to within 1, 2, 3 or 4 standard deviations. In some embodiments, the term "about" or "approximately" refers to within 25%, 20%, 15%, 10%, 9%, 8%, 7%, 6%, 5%, 4%, 3%, 2%, 1%, 0.5%, 0.1% or 0.05% of a value or range. Any description of a numerical value or range indicated with the term "about" also includes the description of the corresponding particular value or range.

[0138] All publications, patent applications, patents, and other references mentioned herein are incorporated by reference in their entirety. EXAMPLES

[0139] The following examples are offered by way of illustration of the present invention and should not be construed as limiting the scope of the invention, but merely as being representative thereof.

[0140] Example 1 – Matrix assay for determining synergy between LSD1 inhibitors and gilteritinib in AML cell lines The purpose of this assay is to determine the synergy that exists between LSD1 inhibitors and gilteritinib. As a first step, compounds of interest were evaluated as single agents before setting up matrix experiments to determine synergy.

[0141] 1.1 Experimental design 1.1.1 Cell lines and culture conditions Mycoplasma-free AML cell lines were maintained in RPMI 10% FBS medium in a humidified incubator with a controlled 5% CO2 atmosphere at 37°C. Cell freezing and thawing was performed according to ATCC recommendations. Genetic profiling of the cell lines used is available in Table 1. [Table 2]

[0142] 1.1.2 Single-drug viability assay (96 hours) Cells were seeded in 96-well plates at optimal densities to ensure linear growth throughout the assay in 50 μL of medium (8000 cells / well for MV(4;11), 4000 cells / well for MOLM-13 and OCI-AML3, and 2000 cells / well for TF1a). Each experimental condition was tested in technical triplicates, including medium only and vehicle-treated controls for background correction and normalization, respectively. After seeding, 50 μL of medium containing 9 serial dilutions (1:3) of 2x concentrated compounds were added to the cells to obtain 100 μL of cells with 1x concentrated compound at each dilution. Cells were then incubated for 96 hours at 37°C in a controlled 5% CO2 atmosphere, followed by incubation with alamarBlue. TM Cell viability was assessed using the Cell Viability Reagent (ThermoFisher Scientific, Waltham, MA / USA). TM AlamarBlue is a cell viability indicator that uses the natural reducing power of viable cells to convert resazurin into a fluorescent molecule, resorufin. TMStock solutions were diluted 1:20 in culture medium and after 3 h of incubation, fluorescence was measured using a TECAN Infinity 2000 plate reader (Tecan Group Ltd., Maennedorf, CH; 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) to generate best fit curves and EC 50 values ​​were calculated.

[0143] 1.1.3 9x9 matrix viability assay (96 hours) Each matrix assay was distributed across two plates according to the scheme described in Figure 1, with one compound added in increasing concentrations from left to right and the other compound added in increasing concentrations from top to bottom. For the assay, cells were seeded in 50 μL of medium in 96-well plates at the optimal density identified in the section above; wells at the edge of the plate were left with 100 μL of medium only for background correction. Each of the two compounds was added at 25 μL of 4x concentration, resulting in a final volume of 100 μL and a final concentration of 1x at each dilution. As shown in Figure 1, a matrix was designed with increasing concentrations from left to right for the LSD1 inhibitor and from top to bottom for gilteritinib. The first and last rows of plate #1 were repeated in plate #2 (indicated by arrows in Figure 1) to ensure reproducibility across the two plates. The concentrations tested for both compounds were EC 50 A total of 9 × 1:3 dilutions were made to encompass a 6561-fold range, with the EC values ​​for LSD1 inhibitors and gilteritinib designed to be centered horizontally and vertically in the matrix. 50 (The wells in the diagonal of the plate (shown by horizontal lines in Fig. 1) correspond to the fifth well from the right and the fifth well from the bottom, respectively.) In this way, the wells in the diagonal of the plate (shown by horizontal lines in Fig. 1) correspond to the fixed EC 50 The EC of the compounds tested in the matrix assay corresponds to the ratio 50Values ​​were previously obtained via single agent assays performed as detailed in section 1.1.2. Viability was then assessed in at least two independent biological replicates (N=2) using alamarBlue TM This was determined using staining.

[0144] 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 a percentage value of relative remaining viability according to the following formula: % relative remaining viability = background-corrected RFU treated cells / background-corrected RFU vehicle control x 100 The percentage residual viability values ​​were then analyzed using GraphPad PRISM® version 9.0.1 (GraphPad Software, Inc., La Jolla, CA / USA) to generate single agent best fit curves and EC 50 values ​​were calculated.

[0145] The influence factor (Fa), also known as the effectiveness ratio, is calculated using the formula: Fa=1-(% relative residual viability / 100) was used to calculate the following conditions: Cells treated with serial dilutions of LSD1 inhibitors as single agents (average of the first row of the first and second plates of each matrix assay) Cells treated with serial dilutions of gilteritinib as a single agent (first row of matrix assay) Cells, EC 50 The mice were treated with the LSD1 inhibitor and gilteritinib at a fixed ratio corresponding to the value ratio (% relative remaining viability values ​​in the diagonal of the matrix assay; highlighted in Figure 1 ).

[0146] CalcuSyn software (http: / / www.biosoft.com / w / calcusyn.htm, Biosoft, Cambridge, UK) is designed to determine the nature of the interaction between two compounds (synergistic, additive or antagonistic) by calculating the combination index (CI). This analysis is based on the median effect principle and the combination index theorem described in the Chou-Talalay method (TC Chou, Pharmacol Rev. 2006;58(3):621-681), where a resulting CI<1 indicates synergistic effect, CI=1 indicates additive effect, while CI>1 reflects antagonistic effect. In the case of synergistic effect (CI<1), the smaller the CI value, the stronger the synergistic effect. Furthermore, the drug interaction strength can be further classified based on the CI range, as shown in Table 2. [Table 3]

[0147] To produce informative and consistent results, the Calcusyn processed data (both single agents and drug combinations) need to be fitted to the median effect principle and combination index theorem theoretical models. For this reason, it is important to remove potential outliers and data points that are characterized by poor fit to the median effect principle (TC Chou, Pharmacol Rev. 2006;58(3):621-681). To achieve this, the following strategy was adopted for data selection: In the first step, data variability 1) Fa<0.1 2) Increase in Fa compared to the previous point is <0.03 (if Fa>0.9) The reduction is achieved by removing points characterized by These conditions define the plateau of the dose-response curve where cells are treated with very low or very high concentrations of compounds (or combinations) resulting in near 0% or 100% reduction in viability (corresponding to Fa values ​​close to 0 or 1, respectively). TMThe signal variations are minimal and likely due to random noise of minimal biological significance.

[0148] 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 on the y-axis. The regression line was then obtained in Excel (corresponding to the median effect equation). At this point, the distance of each data point from the regression line is calculated using the formula: Distance(ax+by+c=0;X,Y)=(aX+bY+c) / √(a 2 +b 2 ) was used to calculate. Outliers are identified based on their distance from the median effect equation using the Grubbs test. For each data point, the Grubbs test was performed on the absolute value of the distance according to the following formula (note that the variables for the Grubbs test are interchangeably referred to as G or Z): G=(X n -X 平均 ) / s Where X n means the absolute value of the distance of each point from the regression line;X 平均 is all X n means the mean of the values, and s means the standard deviation. crit G values ​​above (calculated for α=0.2 as below) identify outliers that do not fit the median effect equation. Such data points are successfully excluded from combination index calculations using CalcuSyn.

number

[0149] 1.1.3.2 CalcuSyn Output CalcuSyn results, fixed EC 50 The experimental effect ratio (designated Fa) expressing the proportion of cells affected by the combination treatment in ratio (for cytotoxic treatments, the effect ratio corresponds to the reduction in viability compared to the vehicle control, where Fa=1 corresponds to 100% reduction in viability) and the associated combination index (CI) are provided. As shown in Table 2 above, the CI value is an indication of the nature and strength of the compound interaction, with values ​​less than 1 representing a synergistic interaction (the closer the value is to 0, the stronger the synergistic effect), values ​​equal to 1 representing an additive interaction, and values ​​greater than 1 representing an antagonistic interaction.

[0150] 1.2 Results 1.2.1 Single-agent viability: iadamstat, pleurodemstat (CC-90011), gilteritinib, and vomedemstat MV(4;11), OCI-AML3, MOLM-13 and TF1a cell lines were seeded as described in section 1.1.2 and incubated with vehicle (DMSO 0.05%) or serial 1:3 dilutions of iadamstat (concentration range 0.0014 to 9 nM). In all cases, iadamstat induced a greater than 20% (compared to vehicle control) decrease in viability and exceeded the EC 50 Values ​​were in the subnanomolar range. For CC-90011, MV(4;11) and MOLM-13 cells were treated with vehicle (DMSO 0.05%) or serial 1:3 dilutions (concentration range 0.045–300 nM) as described in section 1.1.2. In all cases, CC-90011 induced a greater than 20% decrease in viability (compared to vehicle control) and was greater than the EC 50 Values ​​were in the nanomolar range. Gilteritinib EC 50For determination, MV(4;11), OCI-AML3, MOLM-13 and TF1a cell lines were incubated with vehicle (DMSO 0.45%) or serial 1:3 dilutions (concentration range 0.014-90 nM for MOLM-13 and MV(4;11) and 1.4-9000 nM for TF1a and OCI-AML3) as described in section 1.1.2. For cell lines harboring FLT3-ITD, MOLM-13 and MV(4;11), gilteritinib showed a significant reduction in viability of nearly 100% in both cell lines, resulting in an EC 50 In cells lacking FLT3 mutations, such as TF1a or OCI-AML3 cells, gilteritinib induced a >70% decrease in viability and EC 50 was in the micromolar range for both cell lines. For bomedemstat, MV(4;11) and MOLM-13 cells were treated with vehicle (DMSO 0.05%) or serial 1:3 dilutions (concentration range 0.045–300 nM) as described in section 1.1.2. In all cases, bomedemstat induced a greater than 20% (compared to vehicle control) decrease in viability and an EC 50 Values ​​were in the nanomolar range. Experiments were performed in at least two biological replicates. Table 3 shows the experimentally determined EC values ​​after 96 h incubation with iadamdemstat, CC-90011, gilteritinib, and vomedemstat in specific cell lines. 50 Indicates the value. [Table 4]

[0151] 1.2.2 Combination of LSD1 inhibitor iademstat + gilteritinib Matrix treatments with gilteritinib (concentration range 0.014-90 nM for MOLM-13 and MV(4;11) and 1.4-9000 nM for TF1a and OCI-AML3) and the covalent and irreversible LSD1 inhibitor iademstat (concentration range 0.0014-9 nM for all four cell lines) were performed as described in section 1.1.3. Data analysis and combination index calculations were performed as described in section 1.1.3.1. Combination index (CI) results from the combination of iademstat and gilteritinib are shown in Table 4 along with the specific efficacy ratio (Fa) and respective classifications (as described in Table 2). In summary, the combination iademstat + gilteritinib demonstrated strong synergy with a wide range of efficacy ratios (Fa) in gilteritinib-sensitive cell lines harboring FLT3 mutations (MOLM-13, N=3 and MV(4;11), N=2). Importantly, strong synergy was also observed in cell lines lacking FLT3 mutations (WT FLT3) that are poorly responsive to gilteritinib as a single agent (OCI-AML3, N=2 and TF1a, N=3). These cell lines are also resistant to other current AML treatments. Notably, OCI-AML3 and TF1a cells were resistant to venetoclax (EC 50 (>10 μM, tested according to the methods described above). These results open the possibility of successful combination of gilteritinib with an LSD1 inhibitor such as iadamstat in AML patients with or without FLT3 mutations or in the refractory / relapsed setting. [Table 5]

[0152] 1.2.3 Combination of LSD1 inhibitor pleurodemstat (CC-90011) + gilteritinib The synergy between the LSD1 inhibitors described in section 1.2.2 and gilteritinib was further confirmed using other LSD1 inhibitors, in particular the structurally unrelated, reversible LSD1 inhibitor CC-90011. Matrix processing with gilteritinib (concentration range 0.014-90 nM for MOLM-13 and MV(4;11)) and CC-90011 (concentration range 0.045-300 nM for both cell lines) was performed as described in section 1.1.3. Data analysis and combination index calculations were performed as described in section 1.1.3.1. Combination index (CI) results from the combination of CC-90011 and gilteritinib are shown in Table 5 along with the specific efficacy ratio (Fa) and respective classifications (as described in Table 2). In summary, the combination CC-90011 + gilteritinib also showed strong synergy with a wide range of efficacy ratios (Fa) in the cell lines tested (MOLM-13, N=2 and MV(4;11), N=2). [Table 6]

[0153] 1.2.4 LSD1 inhibitor bomedemstat + gilteritinib combination The synergy between the LSD1 inhibitors described in sections 1.2.2 and 1.2.3 and gilteritinib was further confirmed using another LSD1 inhibitor, bomedemstat. Matrix treatment with gilteritinib (concentration range 0.014-90 nM for MOLM-13 and MV(4;11)) and bomedemstat (concentration range 0.045-300 nM for both cell lines) was performed as described in section 1.1.3. Data analysis and combination index calculations were performed as described in section 1.1.3.1. Combination index (CI) results from the combination of bomedemstat and gilteritinib are shown in Table 6 along with the specific efficacy ratio (Fa) and respective classifications (as described in Table 2). In summary, the combination vomedemstat + gilteritinib showed strong synergy with a wide range of efficacy ratios (Fa) in the cell lines tested (MOLM-13, N=2 and MV(4;11), N=2). [Table 7]

[0154] Using the method described in Example 1, the superior therapeutic effect of the combination of gilteritinib with other LSD1 inhibitors can be confirmed. Similarly, methods similar to those described in this Example 1 can be used to confirm the superior therapeutic effect of a combination of an LSD1 inhibitor and gilteritinib in other myeloid malignancies, such as MDS.

[0155] While the invention has been described in connection with specific embodiments thereof, it will be understood that further modifications are possible, and that this patent or patent application is generally intended to cover any changes, uses, or adaptations of the invention in accordance with the principles of the invention, including departures from the disclosure of the invention that are within known or customary practice in the art to which the invention pertains, and which may be applied to the essential features set forth above and in the following claims.

Claims

1. A combination product comprising an LSD1 inhibitor, or a pharma- ceutically acceptable salt thereof, and gilteritinib, or a pharma- ceutically acceptable salt thereof, in the same or different pharmaceutical formulations.

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

3. 3. The combination product of claim 1 or 2, wherein the LSD1 inhibitor is selected from the group consisting of iademstat, plerodemstat, bomedemstat, secridemstat, 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 iademstat or a pharma- ceutically acceptable salt thereof.

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

6. 6. The combination product of any of claims 1 to 5, wherein the LSD1 inhibitor or a pharma- ceutically acceptable salt thereof and gilteritinib or a pharma- ceutically acceptable salt thereof are provided in different pharmaceutical formulations.

7. A pharmaceutical composition comprising an LSD1 inhibitor or a pharma- ceutically acceptable salt thereof and gilteritinib or a pharma- ceutically acceptable salt thereof and one or more pharma- ceutically acceptable excipients.

8. 8. The pharmaceutical composition of claim 7, wherein the LSD1 inhibitor is a small molecule.

9. 9. The pharmaceutical composition of claim 7 or 8, wherein the LSD1 inhibitor is selected from the group consisting of iademstat, plerodemstat, bomedemstat, secridemstat, 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.

10. 8. The pharmaceutical composition of claim 7, wherein the LSD1 inhibitor is iademstat or a pharma- ceutically acceptable salt thereof.

11. 8. The pharmaceutical composition of claim 7, wherein the LSD1 inhibitor is iademstat dihydrochloride.

12. An article of manufacture comprising an LSD1 inhibitor, or a pharma- ceutically acceptable salt thereof, and gilteritinib, or a pharma- ceutically acceptable salt thereof, in the same or different pharmaceutical formulations.

13. 13. The article of manufacture of claim 12, wherein the LSD1 inhibitor is a small molecule.

14. 14. The article of manufacture of claim 12 or 13, wherein the LSD1 inhibitor is selected from the group consisting of iademstat, plerodemstat, bomedemstat, secridemstat, 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.

15. 13. The article of manufacture of claim 12, wherein the LSD1 inhibitor is iademstat or a pharma- ceutically acceptable salt thereof.

16. 13. The article of manufacture of claim 12, wherein the LSD1 inhibitor is iademstat dihydrochloride.

17. A combination product according to any of claims 1 to 6 for use in the treatment of myeloid cancer.

18. 1. A pharmaceutical composition comprising a LSD1 inhibitor, or a pharma- ceutical acceptable salt thereof, in combination with gilteritinib, or a pharma- ceutical acceptable salt thereof, for use in the treatment of myeloid cancer.

19. A pharmaceutical composition comprising gilteritinib or a pharma- ceutical acceptable salt thereof in combination with a LSD1 inhibitor or a pharma- ceutical acceptable salt thereof for use in the treatment of myeloid cancer.

20. 20. The pharmaceutical composition of claim 18 or 19, wherein the LSD1 inhibitor is a small molecule.

21. 20. The pharmaceutical composition of claim 18 or 19, wherein the LSD1 inhibitor is selected from the group consisting of iademstat, plerodemstat, bomedemstat, secridemstat, 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.

22. 20. The pharmaceutical composition of claim 18 or 19, wherein the LSD1 inhibitor is iademstat or a pharma- ceutically acceptable salt thereof.

23. 23. The pharmaceutical composition of claim 22, wherein the LSD1 inhibitor is iademstat dihydrochloride.

24. The combination product of claim 17 or any of claims 18 to 23, wherein the myeloid cancer is selected from acute myeloid leukemia and myelodysplastic syndrome.

25. The combination product of claim 17 or the pharmaceutical composition of any of claims 18 to 23, wherein the myeloid cancer is acute myeloid leukemia.

26. 26. The combination product of claim 25; or the pharmaceutical composition of claim 25, wherein the acute myeloid leukemia is relapsed or refractory acute myeloid leukemia.

27. 27. The combination product of claim 25 or 26, or the pharmaceutical composition of claim 25 or 26, wherein the acute myeloid leukemia is FLT3 mutated acute myeloid leukemia.

28. 26. The combination product of claim 25; or the pharmaceutical composition of claim 25, wherein the acute myeloid leukemia is relapsed or refractory acute myeloid leukemia with a FLT3 mutation.

29. 23. Use of a combination comprising an LSD1 inhibitor or a pharma- ceutically acceptable salt thereof and gilteritinib or a pharma- ceutically acceptable salt thereof for the manufacture of a medicament for the treatment of myeloid cancer.

30. 2. The use of an LSD1 inhibitor or a pharma- ceutically acceptable salt thereof for the manufacture of a medicament for the treatment of bone marrow cancer, wherein the LSD1 inhibitor or a pharma- ceutically acceptable salt thereof is for use in combination with gilteritinib or a pharma- ceutically acceptable salt thereof.

31. 2. The use of gilteritinib or a pharma- ceutically acceptable salt thereof for the manufacture of a medicament for the treatment of bone marrow cancer, wherein the use is for use in combination with a LSD1 inhibitor or a pharma- ceutically acceptable salt thereof.

32. 32. The use of any of claims 29 to 31, wherein the LSD1 inhibitor is a small molecule.

33. 32. The use of any of claims 29 to 31, wherein the LSD1 inhibitor is selected from the group consisting of iademstat, plerodemstat, bomedemstat, secridemstat, 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 pharma-ceutical acceptable salts thereof.

34. The use of any of claims 29 to 31, wherein the LSD1 inhibitor is iademstat or a pharma- ceutically acceptable salt thereof.

35. 35. The use of claim 34, wherein the LSD1 inhibitor is iademstat dihydrochloride.

36. The use of any one of claims 29 to 35, wherein the myeloid cancer is selected from acute myeloid leukemia and myelodysplastic syndrome.

37. The use of any one of claims 29 to 36, wherein the myeloid cancer is acute myeloid leukemia.

38. 38. The use of claim 37, wherein the acute myeloid leukemia is relapsed or refractory acute myeloid leukemia.

39. 39. The use of claim 37 or 38, wherein the acute myeloid leukemia is FLT3 mutated acute myeloid leukemia.

40. 38. The use of claim 37, wherein the acute myeloid leukemia is relapsed or refractory acute myeloid leukemia with a FLT3 mutation.

41. A combination product for use according to claim 17 or any of claims 24 to 28, a pharmaceutical composition according to any of claims 18 to 28, or a use according to any of claims 29 to 40, wherein the LSD1 inhibitor or a pharma- ceutically acceptable salt thereof and gilteritinib or a pharma- ceutically acceptable salt thereof are administered orally.

42. The combination product of any of claims 17, 24 to 28 or 41, the pharmaceutical composition of any of claims 18 to 28 or 41, or the use of any of claims 29 to 41, wherein the LSD1 inhibitor or a pharma- ceutically acceptable salt thereof and gilteritinib or a pharma- ceutically acceptable salt thereof are administered in separate pharmaceutical formulations.

43. 43. The combination product of claim 42, the pharmaceutical composition of claim 42, or the use of claim 42, wherein the LSD1 inhibitor or a pharma- ceutically acceptable salt thereof and gilteritinib or a pharma- ceutically acceptable salt thereof are administered simultaneously using separate pharmaceutical formulations.

44. The combination product of claim 42, the pharmaceutical composition of claim 42, or the use of claim 61, wherein the LSD1 inhibitor or a pharma- ceutically acceptable salt thereof and gilteritinib or a pharma- ceutically acceptable salt thereof are administered sequentially using separate pharmaceutical formulations.

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