Combination products comprising iadademstat and gilteritinib, pharmaceutical compositions comprising iadademstat and gilteritinib, and uses of iadademstat and gilteritinib for the manufacture of medicaments for the treatment of myeloid cancers

Abstract

This invention relates to a combination of an LSD1 inhibitor (or a pharmaceutically acceptable salt thereof) and gidatetinib (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] This invention relates to a combination of an LSD1 inhibitor and gipretinib. This combination can be used to treat bone marrow cancer, particularly acute myeloid leukemia and myelodysplastic syndrome. Prior Technology

[0002] Acute myeloid leukemia (AML) is an aggressive myeloid cancer that causes the uncontrolled growth and accumulation of undifferentiated hematopoietic cells (blast cells), leading to bone marrow failure, impairing normal blood cell production, and ultimately causing death within months of diagnosis unless treated. AML is the most common acute leukemia in adults, and primarily affects older populations, with a median age at diagnosis of 68 years. With a growing global population and increased life expectancy, more patients are diagnosed with AML each year. In fact, AML accounts for 1.1% of all new cancer diagnoses, and there were approximately 135,000 new AML diagnoses worldwide in 2019.

[0003] Treatment for AML in individuals under 60 years of age is standard, involving intensive chemotherapy to induce remission, thus enabling subsequent bone marrow transplantation. This is considered the only curative treatment for these patients. However, older patients or those in poor health may not tolerate this treatment, and their treatment options are limited to non-curative approaches, such as low-intensity chemotherapy, such as azacitidine alone or in combination with venetoclax (the latter approved only in the United States), or certain drugs targeting specific subgroups with certain mutations.

[0004] AML has a poor prognosis, with a survival rate of 35-40% in adults under 60 years of age and as low as 5-15% in older patients. It is estimated that 25% of AML patients are refractory, and over 50% relapse after treatment with current therapies. When patients on first-line therapy relapse or fail to benefit from treatment, they are continued with second-line treatment regimens, which are far less standardized and efficient; in fact, many of these patients are placed in clinical trials due to the lack of effective treatments. Even with aggressive treatment, the prognosis for these relapsed / refractory (R / R) patients is 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 syndromes (MDS) are another type of bone marrow cancer in which the differentiation of blood progenitor cells is impaired, and the level of apoptotic cell death in bone marrow cells is significantly increased. Over time, about one-third of all MDS cases develop into AML. FLT3 mutations have also been found in MDS.

[0006] Gefitinib is an FLT3 inhibitor approved for the treatment of relapsed / relapsed AML patients with FLT3 mutations and is being evaluated in a clinical trial at MDS. However, outcomes remain poor after gefitinib treatment, with only 21% of relapsed / relapsed AML patients showing complete remission and a relapse-free survival of only about 4 months.

[0007] Therefore, there is a strong and unmet need for new and improved treatment options for myeloma, particularly AML and MDS, addressing the problems of resistance and lack of response to current therapies. This invention addresses these and other needs. Summary of the Invention

[0008] This invention is based on the unexpected discovery that the combination of an LSD1 inhibitor and gipretinib, as described herein, exhibits superior activity in inhibiting the growth of bone marrow cancer cells compared to treatment with either an LSD1 inhibitor or gipretinib alone. Therefore, this invention relates to a novel combination of an LSD1 inhibitor and gipretinib for the treatment of myeloma malignancies such as AML and MDS.

[0009] Therefore, the present invention provides a combination product comprising an LSD1 inhibitor or a pharmaceutically acceptable salt thereof and giretinib or a pharmaceutically acceptable salt thereof in the same pharmaceutical formulation or separate pharmaceutical formulations.

[0010] The present invention also provides a pharmaceutical composition comprising an LSD1 inhibitor or a pharmaceutically acceptable salt thereof and giretinib or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable excipients.

[0011] The present invention also provides an article (or “pharmaceutical box”) comprising an LSD1 inhibitor or a pharmaceutically acceptable salt thereof and giretinib or a pharmaceutically acceptable salt thereof in the same pharmaceutical formulation or separate pharmaceutical formulations.

[0012] This invention also relates to the above-described combination products, pharmaceutical compositions, or articles for treatment (or as medicines / pharmaceuticals). Therefore, this invention particularly provides a combination product for treatment comprising an LSD1 inhibitor or a pharmaceutically acceptable salt thereof and giretinib or a pharmaceutically acceptable salt thereof in the same pharmaceutical formulation or separate pharmaceutical formulations.

[0013] The present invention also provides a combination product for treating myeloma, comprising an LSD1 inhibitor or a pharmaceutically acceptable salt thereof and giretinib or a pharmaceutically acceptable salt thereof in the same pharmaceutical formulation or separate pharmaceutical formulations, wherein the myeloma is preferably selected from acute myeloid leukemia and myelodysplastic syndrome.

[0014] The present invention also provides a method for treating bone marrow cancer (preferably selected from acute myeloid leukemia and myelodysplastic syndrome) in patients in need, comprising administering to the patient a therapeutically effective amount of the above-described combination product, pharmaceutical composition, or article of manufacture. Specifically, the present invention provides a method for treating bone marrow cancer (preferably selected from acute myeloid leukemia and myelodysplastic syndrome) in patients in need, comprising administering to the patient a therapeutically effective amount of a combination product, wherein the combination product comprises an LSD1 inhibitor or a pharmaceutically acceptable salt thereof and giretinib or a pharmaceutically acceptable salt thereof in the same pharmaceutical formulation or separate pharmaceutical formulations.

[0015] The present invention also provides a method for treating bone marrow cancer (preferably selected from acute myeloid leukemia and myelodysplastic syndrome) in patients in need, the method comprising administering to the patient a therapeutically effective amount of an LSD1 inhibitor or a pharmaceutically acceptable salt thereof and a therapeutically effective amount of giretinib or a pharmaceutically acceptable salt thereof.

[0016] The present invention also provides the use of a combination comprising an LSD1 inhibitor or a pharmaceutically acceptable salt thereof and giretinib or a pharmaceutically acceptable salt thereof in the preparation of a medicament for treating bone marrow cancer, preferably selected from acute myeloid leukemia and myelodysplastic syndrome.

[0017] The present invention also provides the use of a combination comprising an LSD1 inhibitor or a pharmaceutically acceptable salt thereof and giretinib or a pharmaceutically acceptable salt thereof for the treatment of myeloma, preferably selected from acute myeloid leukemia and myelodysplastic syndrome.

[0018] In a preferred embodiment, the LSD1 inhibitor is idastat or a pharmaceutically acceptable salt thereof (e.g., idastat dihydrochloride). Simple Explanation of the Diagram

[0019]

[0020] Figure 1 shows a flat plate configuration for matrix determination of the synergistic effect of the combination of the present invention, as described in Example 1. Implementation

[0021] Invention Details

[0022] As described above, the present invention is based on the following surprising discovery: as described herein, LSD1 inhibitors and gipretinib can be used in combination to treat myeloma, and their anticancer efficacy is superior to that obtained by using LSD1 inhibitors or gipretinib alone, as explained in more detail below and in the examples.

[0023] According to the present invention, "LSD1 inhibitor" refers to a compound that reduces, decreases, blocks, or inhibits the gene expression, activity, or function of LSD1. Examples of such compounds are provided under the heading "LSD1 Inhibitor" below. Preferred LSD1 inhibitors are idastat or pharmaceutically acceptable salts thereof (e.g., idastat dihydrochloride).

[0024] In detail, the present invention provides a combination product comprising an LSD1 inhibitor or a pharmaceutically acceptable salt thereof and gigritinib or a pharmaceutically acceptable salt thereof in the same pharmaceutical formulation or separate pharmaceutical formulations. Therefore, the LSD1 inhibitor (or a pharmaceutically acceptable salt thereof) and gigritinib (or a pharmaceutically acceptable salt thereof) may be present in a single pharmaceutical formulation (i.e., in the same pharmaceutical formulation), or they may be provided in separate pharmaceutical formulations.

[0025] The present invention also provides a pharmaceutical composition comprising an LSD1 inhibitor or a pharmaceutically acceptable salt thereof and giretinib or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable excipients.

[0026] The present invention also provides an article comprising an LSD1 inhibitor or a pharmaceutically acceptable salt thereof and giretinib or a pharmaceutically acceptable salt thereof in the same pharmaceutical formulation or separate pharmaceutical formulations.

[0027] This invention also provides a combination product for treatment (or use as a medicine / pharmaceutical) comprising an LSD1 inhibitor or a pharmaceutically acceptable salt thereof and giretinib or a pharmaceutically acceptable salt thereof in the same pharmaceutical formulation or separate pharmaceutical formulations. This invention also relates to the above-described pharmaceutical composition or article for treatment (or use as a medicine / pharmaceutical).

[0028] The present invention also provides the above-described combination products, pharmaceutical compositions or articles for the treatment of cancer, preferably for the treatment of bone marrow cancer, such as acute myeloid leukemia or myelodysplastic syndrome.

[0029] Therefore, the present invention specifically provides a combination product comprising an LSD1 inhibitor or a pharmaceutically acceptable salt thereof and giretinib or a pharmaceutically acceptable salt thereof in the same pharmaceutical formulation or separate pharmaceutical formulations for the treatment of myeloma, preferably selected from acute myeloid leukemia and myelodysplastic syndrome.

[0030] This invention also provides an LSD1 inhibitor or a pharmaceutically acceptable salt thereof for the treatment of myeloma (preferably selected from acute myeloid leukemia and myelodysplastic syndrome), wherein the LSD1 inhibitor or a pharmaceutically acceptable salt thereof is used in combination with gipretinib or a pharmaceutically acceptable salt thereof. Therefore, this invention provides an LSD1 inhibitor or a pharmaceutically acceptable salt thereof for the treatment of myeloma (preferably selected from acute myeloid leukemia and myelodysplastic syndrome), wherein the LSD1 inhibitor or a pharmaceutically acceptable salt thereof is administered in combination with gipretinib or a pharmaceutically acceptable salt thereof. The LSD1 inhibitor (or a pharmaceutically acceptable salt thereof) and gipretinib (or a pharmaceutically acceptable salt thereof) may be provided in the same pharmaceutical formulation, or they may be provided in separate pharmaceutical formulations.

[0031] This invention also provides giretinib or a pharmaceutically acceptable salt thereof for the treatment of myeloma (preferably selected from acute myeloid leukemia and myelodysplastic syndrome), wherein giretinib or a pharmaceutically acceptable salt thereof is used in combination with an LSD1 inhibitor or a pharmaceutically acceptable salt thereof. Therefore, this invention provides giretinib or a pharmaceutically acceptable salt thereof for the treatment of myeloma (preferably selected from acute myeloid leukemia and myelodysplastic syndrome), wherein the giretinib or a pharmaceutically acceptable salt thereof is administered in combination with an LSD1 inhibitor or a pharmaceutically acceptable salt thereof. Giretinib (or a pharmaceutically acceptable salt thereof) and an LSD1 inhibitor (or a pharmaceutically acceptable salt thereof) may be provided in the same pharmaceutical formulation, or they may be provided in separate pharmaceutical formulations.

[0032] The present invention also provides a method for treating cancer, particularly bone marrow cancer (preferably selected from acute myeloid leukemia and myelodysplastic syndrome) in patients in need, comprising administering to the patient a therapeutically effective amount of the above-described combination product, pharmaceutical composition or article.

[0033] In particular, the present invention provides a method for treating bone marrow cancer (preferably selected from acute myeloid leukemia and myelodysplastic syndrome) in patients in need, comprising administering to the patient a therapeutically effective amount of a combination product comprising an LSD1 inhibitor or a pharmaceutically acceptable salt thereof and giretinib or a pharmaceutically acceptable salt thereof in the same pharmaceutical formulation or separate pharmaceutical formulations.

[0034] The present invention also provides a method for treating bone marrow cancer (preferably selected from acute myeloid leukemia and myelodysplastic syndrome) in patients in need, the method comprising administering to the patient a therapeutically effective amount of an LSD1 inhibitor or a pharmaceutically acceptable salt thereof and a therapeutically effective amount of giretinib or a pharmaceutically acceptable salt thereof. The LSD1 inhibitor (or a pharmaceutically acceptable salt thereof) and giretinib (or a pharmaceutically acceptable salt thereof) may be provided / administered in the same pharmaceutical formulation, or they may be provided / administered in separate pharmaceutical formulations.

[0035] The present invention also provides the use of a combination comprising an LSD1 inhibitor or a pharmaceutically acceptable salt thereof and giretinib or a pharmaceutically acceptable salt thereof in the preparation of a medicament for treating bone marrow cancer, preferably selected from acute myeloid leukemia and myelodysplastic syndrome.

[0036] The present invention also provides the use of a combination of an LSD1 inhibitor or a pharmaceutically acceptable salt thereof and giretinib or a pharmaceutically acceptable salt thereof in the preparation of a medicament for treating myeloma, preferably selected from acute myeloid leukemia and myelodysplastic syndrome, wherein the medicament comprises the LSD1 inhibitor or a pharmaceutically acceptable salt thereof and giretinib or a pharmaceutically acceptable salt thereof in the same pharmaceutical preparation or in separate pharmaceutical preparations.

[0037] The present invention further provides the use of a combination of an LSD1 inhibitor or a pharmaceutically acceptable salt thereof and giretinib or a pharmaceutically acceptable salt thereof in the preparation of a medicament for the treatment of bone marrow cancer (preferably selected from acute myeloid leukemia and myelodysplastic syndrome), wherein the medicament comprises an LSD1 inhibitor or a pharmaceutically acceptable salt thereof and giretinib or a pharmaceutically acceptable salt thereof in the same pharmaceutical formulation or in separate pharmaceutical formulations.

[0038] The present invention also provides the use of an LSD1 inhibitor or a pharmaceutically acceptable salt thereof in the preparation of a medicament for the treatment of bone marrow cancer (preferably selected from acute myeloid leukemia and myelodysplastic syndrome) in combination with giretinib or a pharmaceutically acceptable salt thereof.

[0039] The present invention also provides the use of an LSD1 inhibitor or a pharmaceutically acceptable salt thereof in combination with giretinib or a pharmaceutically acceptable salt thereof for the preparation of a medicament for the treatment of bone marrow cancer (preferably selected from acute myeloid leukemia and myelodysplastic syndrome).

[0040] The present invention also provides the use of an LSD1 inhibitor or a pharmaceutically acceptable salt thereof in the preparation of a medicament for the treatment of bone marrow cancer (preferably selected from acute myeloid leukemia and myelodysplastic syndrome), wherein the medicament is prepared for use in combination (or in combination with) giretinib or a pharmaceutically acceptable salt thereof.

[0041] The present invention also provides the use of giretinib or a pharmaceutically acceptable salt thereof in the preparation of a medicament for the treatment of bone marrow cancer (preferably selected from acute myeloid leukemia and myelodysplastic syndrome) in combination with an LSD1 inhibitor or a pharmaceutically acceptable salt thereof.

[0042] The present invention also provides the use of giretinib or a pharmaceutically acceptable salt thereof in combination with an LSD1 inhibitor or a pharmaceutically acceptable salt thereof for the preparation of a medicament for the treatment of bone marrow cancer (preferably selected from acute myeloid leukemia and myelodysplastic syndrome).

[0043] The present invention also provides the use of giretinib or a pharmaceutically acceptable salt thereof in the preparation of a medicament for the treatment of bone marrow cancer (preferably selected from acute myeloid leukemia and myelodysplastic syndrome), wherein the medicament is prepared for use in combination (or in combination with) an LSD1 inhibitor or a pharmaceutically acceptable salt thereof.

[0044] The present invention also provides the use of a combination comprising an LSD1 inhibitor or a pharmaceutically acceptable salt thereof and giretinib or a pharmaceutically acceptable salt thereof for the treatment of myeloma, preferably selected from acute myeloid leukemia and myelodysplastic syndrome.

[0045] The present invention also provides the use of an LSD1 inhibitor or a pharmaceutically acceptable salt thereof in combination with giretinib or a pharmaceutically acceptable salt thereof for the treatment of bone marrow cancer (preferably selected from acute myeloid leukemia and myelodysplastic syndrome), wherein the LSD1 inhibitor or a pharmaceutically acceptable salt thereof and the giretinib or a pharmaceutically acceptable salt thereof are provided in the same pharmaceutical formulation or in separate pharmaceutical formulations.

[0046] The present invention also provides the use of an LSD1 inhibitor or a pharmaceutically acceptable salt thereof for the treatment of bone marrow cancer (preferably selected from acute myeloid leukemia and myelodysplastic syndrome), in combination with giretinib or a pharmaceutically acceptable salt thereof.

[0047] The present invention also provides the use of an LSD1 inhibitor or a pharmaceutically acceptable salt thereof in combination with giretinib or a pharmaceutically acceptable salt thereof for the treatment of bone marrow cancer (preferably selected from acute myeloid leukemia and myelodysplastic syndrome).

[0048] The present invention also provides the use of an LSD1 inhibitor or a pharmaceutically acceptable salt thereof for the treatment of bone marrow cancer (preferably selected from acute myeloid leukemia and myelodysplastic syndrome), wherein the LSD1 inhibitor or a pharmaceutically acceptable salt thereof is administered in combination with giretinib or a pharmaceutically acceptable salt thereof.

[0049] The present invention also provides the use of giretinib or a pharmaceutically acceptable salt thereof for the treatment of bone marrow cancer (preferably selected from acute myeloid leukemia and myelodysplastic syndrome), in combination with an LSD1 inhibitor or a pharmaceutically acceptable salt thereof.

[0050] The present invention also provides the use of giretinib or a pharmaceutically acceptable salt thereof in combination with an LSD1 inhibitor or a pharmaceutically acceptable salt thereof for the treatment of bone marrow cancer (preferably selected from acute myeloid leukemia and myelodysplastic syndrome).

[0051] The present invention also provides the use of giretinib or a pharmaceutically acceptable salt thereof for the treatment of bone marrow cancer (preferably selected from acute myeloid leukemia and myelodysplastic syndrome), wherein the giretinib or a pharmaceutically acceptable salt thereof is administered in combination with an LSD1 inhibitor or a pharmaceutically acceptable salt thereof.

[0052] In the methods and uses according to the invention, the patient is a human or an animal (e.g., a non-human mammal), preferably a human.

[0053] In some implementations, LSD1 inhibitors are small molecules.

[0054] In some embodiments, the LSD1 inhibitor is selected from adastat, prorodemstat (CC-90011), bomedstat, seclidemstat, 1-((4-(methoxymethyl)-4-(((1R,2S)-2-phenylcyclopropylamino)methyl)piperidin-1-yl)methyl)cyclobutanecarboxylic acid, 3-(cyanomethyl)-3-(4-{[(1R,2S)-2-phenylcyclopropyl]amino}piperidin-1-yl)azacyclobutane-1-sulfenamide and pharmaceutically acceptable salts thereof (i.e., pharmaceutically acceptable salts of any of the above reagents).

[0055] In some implementations, the LSD1 inhibitor is selected from adastat, pulrodemstat (CC-90011), bondemstat, and pharmaceutically acceptable salts thereof.

[0056] In some implementations, the LSD1 inhibitor is Pulrodemstat (CC-90011) or a pharmaceutically acceptable salt thereof.

[0057] In some implementations, the LSD1 inhibitor is Bomedemstat or a pharmaceutically acceptable salt thereof.

[0058] A preferred LSD1 inhibitor is idastat or a pharmaceutically acceptable salt thereof. In some embodiments, the LSD1 inhibitor is idastat dihydrochloride.

[0059] In some implementation schemes, bone marrow cancer is acute myeloid leukemia.

[0060] In some implementation schemes, acute myeloid leukemia is relapsed or refractory acute myeloid leukemia.

[0061] In some implementation schemes, acute myeloid leukemia is relapsed acute myeloid leukemia.

[0062] In some implementation schemes, acute myeloid leukemia is refractory acute myeloid leukemia.

[0063] In some embodiments, acute myeloid leukemia (AML) is AML with genetic, epigenetic, or post-transcriptional alterations that affect (e.g., increase) FLT3 expression and / or FLT3 activity. Specifically, AML can be AML with FLT3 mutations and / or genetic, epigenetic, or post-transcriptional alterations that affect (e.g., increase) FLT3 expression and / or FLT3 activity. In some embodiments, AML is AML with FLT3 mutations and / or genetic, epigenetic, or post-transcriptional alterations that result in increased FLT3 expression levels or increased FLT3 activity, wherein the increased FLT3 expression level or increased FLT3 activity leads to uncontrolled cell proliferation.

[0064] In some implementations, acute myeloid leukemia is acute myeloid leukemia with an FLT3 mutation.

[0065] In some implementations, acute myeloid leukemia is a relapsed or refractory acute myeloid leukemia with genetic, epigenetic, or post-transcriptional alterations that affect (e.g., increase) FLT3 expression and / or FLT3 activity. For example, acute myeloid leukemia can be a relapsed or refractory acute myeloid leukemia with FLT3 mutations and / or genetic, epigenetic, or post-transcriptional alterations that affect (e.g., increase) FLT3 expression and / or FLT3 activity.

[0066] In some implementations, acute myeloid leukemia is relapsed or refractory acute myeloid leukemia with an FLT3 mutation.

[0067] In some implementations, acute myeloid leukemia is relapsed acute myeloid leukemia with genetic, epigenetic, or post-transcriptional alterations that affect (e.g., increase) FLT3 expression and / or FLT3 activity. For example, acute myeloid leukemia can be relapsed acute myeloid leukemia with FLT3 mutations and / or genetic, epigenetic, or post-transcriptional alterations that affect (e.g., increase) FLT3 expression and / or FLT3 activity.

[0068] In some implementations, acute myeloid leukemia is relapsed acute myeloid leukemia with an FLT3 mutation.

[0069] In some implementations, acute myeloid leukemia is a refractory acute myeloid leukemia with genetic, epigenetic, or post-transcriptional alterations that affect (e.g., increase) FLT3 expression and / or FLT3 activity. For example, acute myeloid leukemia can be a refractory acute myeloid leukemia with FLT3 mutations and / or genetic, epigenetic, or post-transcriptional alterations that affect (e.g., increase) FLT3 expression and / or FLT3 activity.

[0070] In some implementations, acute myeloid leukemia is refractory acute myeloid leukemia with an FLT3 mutation.

[0071] In some implementations, the FLT3 mutation is an activating FLT3 mutation, particularly a mutation that leads to ligand-independent FLT3 dimerization and constitutive activation of FLT3.

[0072] In some embodiments, the FLT3 mutation is an internal tandem repeat mutation in the juxtamembrane domain (FLT3-ITD) or a point mutation or deletion in the tyrosine kinase domain (FLT3-TKD). In some embodiments, the FLT3 mutation is FLT3-ITD. In some embodiments, the FLT3 mutation is FLT3-TKD. In some embodiments, the FLT3 mutation is both FLT3-ITD and FLT3-TKD.

[0073] In some embodiments, the FLT3 mutation is a mutation in the tyrosine kinase domain (FLT3-TKD), particularly a point mutation (e.g., nucleotide substitution) affecting (or involving) the 835th aspartic acid residue (D835) or the deletion of D835 in wild-type FLT3, and / or a point mutation (e.g., nucleotide substitution) affecting (or involving) the 836th isoleucine residue (I836) or the deletion of I836 in wild-type FLT3. Therefore, the FLT3 mutation can be (or can include), for example, a D835 mutation, an I836 mutation, or a D835 / I836 mutation. Specifically, the D835 mutation can be, for example, a D835Y mutation (i.e., an FLT3 mutation in which the 835th aspartic acid (D) residue (D835) is replaced / substituted with a tyrosine (Y) residue), a D835V mutation, a D835H mutation, a D835G mutation, a D835N mutation, or a D835 deletion. In some implementations, the FLT3 mutation is (or includes) the D835Y mutation. Furthermore, the FLT3 mutation may also be (or may include) point mutations affecting / involving the tyrosine residue at position 842 (Y842) or the deletion of Y842 in wild-type FLT3, point mutations affecting / involving the lysine residue at position 663 (K663) or the deletion of K663 in wild-type FLT3, and / or point mutations affecting / involving the valine residue at position 592 (V592) or the deletion of V592 in wild-type FLT3, such as the Y842C mutation, the K663Q mutation, or the V592A mutation, or any combination thereof.

[0074] In some implementations, LSD1 inhibitors (or pharmaceutically acceptable salts thereof) and gidatetinib (or pharmaceutically acceptable salts thereof) are used as second- or third-line treatment for relapsed or refractory acute myeloid leukemia.

[0075] In some embodiments, the myeloma is a myelodysplastic syndrome. In some embodiments, the myeloma is a myelodysplastic syndrome with genetic, epigenetic, or post-transcriptional alterations that affect (e.g., increase) FLT3 expression and / or FLT3 activity. Specifically, the myeloma can be a myelodysplastic syndrome with an FLT3 mutation and / or genetic, epigenetic, or post-transcriptional alterations that affect (e.g., increase) FLT3 expression and / or FLT3 activity. In some embodiments, the myeloma is a myelodysplastic syndrome with an FLT3 mutation (e.g., any of the exemplary FLT3 mutations described above) and / or genetic, epigenetic, or post-transcriptional alterations that result in increased FLT3 expression levels or increased FLT3 activity, wherein the increased FLT3 expression levels or increased FLT3 activity lead to uncontrolled cell proliferation. In some embodiments, the myeloma is a myelodysplastic syndrome with an FLT3 mutation (e.g., any of the exemplary FLT3 mutations described above).

[0076] In some implementations, the LSD1 inhibitor (or a pharmaceutically acceptable salt thereof) and giretinib (or a pharmaceutically acceptable salt thereof) are administered as separate pharmaceutical formulations. Therefore, the LSD1 inhibitor (or a pharmaceutically acceptable salt thereof) and giretinib (or a pharmaceutically acceptable salt thereof) are provided as separate pharmaceutical formulations.

[0077] Preferred LSD1 inhibitors, such as adastat (or a pharmaceutically acceptable salt thereof), are administered orally. Exemplary formulations that can be administered orally are described in further detail below.

[0078] Preferably, giretinib (or a pharmaceutically acceptable salt thereof) is administered orally. Exemplary formulations that can be administered by oral ingestion are described in further detail below.

[0079] As described in the examples, it was unexpectedly discovered, within the context of this invention, that the combination of an LSD1 inhibitor and gipretinib exhibits a strong synergistic effect in inhibiting the growth of myeloma such as AML. As explained in Example 1, treatment with a combination of an LSD1 inhibitor and gipretinib using two structurally unrelated and dissimilar LSD1 inhibitors, namely idastat, an irreversible cyclopropylamine-based LSD1 inhibitor, and Pulrodemstat (CC-90011), a reversible non-cyclopropylamine LSD1 inhibitor, showed a synergistic effect in inhibiting the growth of AML cell lines with different genetic backgrounds. Strong synergistic effects were observed in the FLT3-mutant AML cell lines MOLM-13 and MV(4;11) with the combination of idastat plus gipretinib and the combination of Pulrodemstat (CC-90011) plus gipretinib. Notably, as described in Example 1, a synergistic effect was also observed in the FLT3-wild-type (i.e., without FLT3 mutations) AML cell lines OCI-AML3 and TF-1a, which are resistant or poorly responsive to treatment with giretinib or other current AML therapies such as venetoclax. These findings suggest that the combination of LSD1 inhibitors such as adastat (or a pharmaceutically acceptable salt thereof) and giretinib (or a pharmaceutically acceptable salt thereof) is particularly useful for treating AML and other myeloma such as MDS, with or without FLT3 mutations, even in patients who have not responded to other treatments or have relapsed.

[0080] The efficacy of the combination therapy of LSD1 inhibitors and giretinib for myeloma such as AML can be further confirmed in additional in vitro or in vivo experiments and in human clinical trials, which can be easily established by those skilled in the field of drug development.

[0081] LSD1 inhibitors

[0082] As previously stated, the term "LSD1 inhibitor" as used herein refers to a compound that reduces, diminishes, 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 this invention. Preferred LSD1 inhibitors are small molecules. Irreversible and reversible LSD1 inhibitors have been described and can be used in the context of this invention, as shown in the following examples of using giretinib in combination with irreversible and reversible LSD1 inhibitors. Typical irreversible LSD1 inhibitors are cyclopropylamine-based compounds such as idastat, one of the LSD1 inhibitors used in the examples herein. A representative example of a reversible LSD1 inhibitor is the compound Pulrodemstat (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" means an LSD1 inhibitor whose selectivity for LSD1 is at least 10 times that of other FAD-dependent monoamine oxidases, particularly MAO-A and MAO-B.

[0083] The table below provides an exemplary list of small molecule LSD1 inhibitors:

[0084]

[0085] Therefore, the LSD1 inhibitor used in this invention can be, for example, any of the specific compounds listed in the table above or a pharmaceutically acceptable salt of any of these compounds.

[0086] In some embodiments, the LSD1 inhibitor is an LSD1 inhibitor known in the art, including, for example, those listed in 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, WO 2013 / 057322, WO2014 / 058071, EP2907802A1, WO2014 / 084298, EP2927212A1, WO2014 / 086790, WO2014 / 164867, WO2014 / 194280, WO2014 / 205213, WO2 015 / 021128, WO2015 / 031564, WO2015 / 089192, WO2015 / 120281, WO2015 / 12 3408、WO2015 / 123424、WO2015 / 123437、WO2015 / 123465、WO2015 / 134973、W O2015 / 168466, WO2015 / 181380, WO2015 / 200843, WO2016 / 003917, WO2016 / 004105, WO2016 / 007722, WO2016 / 007727, WO2016 / 007731, WO2016 / 00773 6. WO2016 / 034946, WO2016 / 037005, WO2016 / 123387, WO2016 / 130952, WO2016 / 161282, WO2016 / 172496, WO2016 / 177656, WO2017 / 004519, WO2017 / 027 678、WO2017 / 079476、WO2017 / 079670、WO2017 / 090756、EP3381896A1、WO2017 / 109061、WO2017 / 116558、WO2017 / 149463、WO2017 / 157322、EP3431471A 1. WO2017 / 184934, 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, WO20 20 / 052647、WO2020 / 052649、EP3851440A1、WO2020 / 138398、WO2020 / 159285、EP3907225A1、WO2021 / 058024、WO2021 / 0958 35. WO2021 / 175079, US2017-0283397, US2022-0064126, CN103054869, CN103319466, CN104119280, CN105541806, CN1059 24362, CN105985265, CN106045862, CN106045881, CN106432248, CN106478639, CN106831489, CN106928235, CN107033148 CN107174584, CN107176927, CN107459476, CN107474011, CN107501169, CN107936022, CN108530302, CN10 9265462, CN109293664, CN109535019, CN110204551, CN110478352, CN111072610, CN111454252, CN112110 The LSD1 inhibitor can be any of the compounds disclosed in CN112409310, CN112920130, CN113087712, CN113105479, CN113264903, CN113582906, CN113599380, KR20190040763, or KR20190040783, each of which is incorporated herein by reference in its entirety (including, in particular, the compounds described in the embodiments section of each of these documents). Therefore, an LSD1 inhibitor can be, for example, a compound disclosed in any of the foregoing documents (including, for example, the embodiments section of any of these documents), wherein the compound can be used in a non-salt form or a pharmaceutically acceptable salt form.

[0087] In some embodiments, the LSD1 inhibitor is selected from the following compounds: adastat, pulrodemstat (CC-90011), bomedemstat, seclidemstat, 1-((4-(methoxymethyl)-4-(((1R,2S)-2-phenylcyclopropylamino)methyl)piperidin-1-yl)methyl)cyclobutanecarboxylic acid, 3-(cyanomethyl)-3-(4-{[(1R,2S)-2-phenylcyclopropyl]amino}piperidin-1-yl)azacyclobutane-1-sulfonamide and pharmaceutically acceptable salts thereof.

[0088] Adalactone is a selective and irreversible LSD1 inhibitor. Adalactone is the INN of the following compound:

[0089]

[0090] [CAS Registry No. 1431304-21-0], also known as ORY-1001 or (trans)-N1-((1R,2S)-2-phenylcyclopropyl)cyclohexane-1,4-diamine. Adaldux has been described in, for example, Example 5 of WO2013 / 057322. Pharmaceutically acceptable salts, including hydrochloride salts, are also described therein.

[0091] Pulrodemstat is a reversible LSD1 inhibitor.

[0092]

[0093] [CAS Registry No. 1821307-10-1], also known as CC-90011, has the chemical name 4-[2-(4-aminopiperidin-1-yl)-5-(3-fluoro-4-methoxyphenyl)-1-methyl-6-t-oxy-1,6-dihydropyrimidin-4-yl]-2-fluorobenzyl nitrile. Pulrodemstat (CC-90011) is described, for example, in WO2015 / 168466 and WO2017 / 79670. Pharmaceutically acceptable salts, including benzenesulfonates, are also described therein.

[0094] Bomedemstat is an irreversible LSD1 inhibitor.

[0095]

[0096] [CAS Registry No. 1990504-34-1], also known as IMG-7289, has the chemical name N-[(2S)-5-{[(1R,2S)-2-(4-fluorophenyl)cyclopropyl]amino}-1-(4-methylpiperazin-1-yl)-1-oxopentane-2-yl]-4-(1H-1,2,3-triazol-1-yl)benzylamine. Bomedemstat has been described, for example, in WO2016 / 130952 and WO2018 / 35259. Pharmaceutically acceptable salts, including bis-toluenesulfonate, are also described therein.

[0097] Seclidemstat is an LSD1 inhibitor of the following formula:

[0098]

[0099] [CAS Registry No. 1423715-37-0], also known as SP-2577, chemical name (E)-N'-(1-(5-chloro-2-hydroxyphenyl)ethylene)-3-((4-methylpiperazin-1-yl)sulfonylurea)benzylhydrazine. Seclidemstat has been described, for example, in WO2013 / 025805 and WO2014 / 205213.

[0100] 1-((4-(methoxymethyl)-4-(((1R,2S)-2-phenylcyclopropylamino)methyl)piperidin-1-yl)methyl)cyclobutanecarboxylic acid is an irreversible LSD1 inhibitor, as described, for example, in WO2015 / 123465 and WO2017 / 27678. Pharmaceutically acceptable salts of this compound, including p-toluenesulfonate, are also described therein.

[0101] 3-(cyanomethyl)-3-(4-{[(1R,2S)-2-phenylcyclopropyl]amino}piperidin-1-yl)azacyclobutane-1-sulfonamide is an irreversible LSD1 inhibitor, as described, for example, in WO2020 / 047198. Pharmaceutically acceptable salts of it are also described therein.

[0102] Vafidemstat is an irreversible LSD1 inhibitor of the following formula:

[0103]

[0104] It is also known as ORY-2001, 5-((((1R,2S)-2-(4-(benzyloxy)phenyl)cyclopropyl)amino)methyl)-1,3,4-oxadiazole-2-amine or (-)5-((((trans)-2-(4-(benzyloxy)phenyl)cyclopropyl)amino)methyl)-1,3,4-oxadiazole-2-amine. Vafidemstat has been described, for example, in Example 35 of WO2012 / 13728.

[0105] In some implementations, the LSD1 inhibitor is selected from adastat, pulrodemstat (CC-90011), bondemstat, and pharmaceutically acceptable salts thereof.

[0106] A particularly good LSD1 inhibitor is idastat or a pharmaceutically acceptable salt thereof. In some embodiments, idastat dihydrochloride is used.

[0107] Gefitinib

[0108] Gefitinib is the INN of the following compound:

[0109]

[0110] [CAS Registry 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]pyrazin-2-methylamine. Gefitinib is an FLT3 inhibitor, particularly a type I FLT3 inhibitor, and the corresponding drug is sold under the brand name Xospata®. Gefitinib fumarate is preferred.

[0111] Unless otherwise expressly stated, any reference to LSD1 inhibitors (such as idastat) in this specification and the claims includes such LSD1 inhibitors in non-salt form and any pharmaceutically acceptable salt thereof. When the LSD1 inhibitor is idastat, it is preferably used in the form of a pharmaceutically acceptable salt, preferably hydrochloride, and more preferably dihydrochloride.

[0112] Similarly, any reference to giretinib in this specification and the claims includes giretinib (non-salt form) and any pharmaceutically acceptable salt thereof. Preferably, giretinib is used in the form of a pharmaceutically acceptable salt, preferably fumarate.

[0113] Administration of the combination of LSD1 inhibitor and gipritinib may include administering the components in any useful manner. For example, the combination of the present invention may be administered using separate pharmaceutical formulations of each active ingredient (i.e., separate formulations of the LSD1 inhibitor and gipritinib), or it may be administered using a pharmaceutical formulation containing both the LSD1 inhibitor and gipritinib. When using separate formulations, such as a first formulation containing an LSD1 inhibitor and a second formulation containing gipritinib, the formulations may be administered in any order, whether sequentially or simultaneously, wherein preferably there is a period of time during which both (or all) active agents exert their biological activity simultaneously.

[0114] In some implementations, one or more additional therapeutic agents may be administered to the patient. These additional therapeutic agents may include one or more additional anticancer agents, including any agents used to treat myeloma, particularly AML, including any corresponding agents listed in the FDA Orange Book or other reference works listing drugs approved in other countries. Additional therapeutic agents may also include one or more antiemetics, such as 5-HT3 antagonists (e.g., palonosetron, ramosetron, alosetron, ondansetron, tropisetron, granisetron, or dolasetron), olanzapine, corticosteroids (e.g., methylprednisolone or dexamethasone), or prochlorperazine.

[0115] pharmaceutical preparations

[0116] The LSD1 inhibitor and giretinib used in the combinations described herein, as well as pharmaceutical compositions comprising the combinations of the present invention, can be administered via any route suitable for the condition to be treated. Suitable routes include oral, parenteral (including subcutaneous, intramuscular, intravenous, intra-arterial, inhalation, intradermal, intrathecal, epidural, and infusion techniques), percutaneous, rectal, nasal, local (including sublingual and sublingual), vaginal, intraperitoneal, intrapulmonary, and intranasal administration. Preferably, oral administration is given of the two components (LSD1 inhibitor and giretinib) when formulated separately or when the two active ingredients are formulated in a single formulation.

[0117] The LSD1 inhibitors and giretinib used in the combinations described herein, as well as the pharmaceutical compositions comprising the combinations of the present invention, can be administered in any convenient pharmaceutical composition or formulation form, such as tablets, powders, capsules, solutions, dispersions, suspensions, syrups, sprays, suppositories, gels, emulsions, patches, etc. Such compositions / formulations may contain components conventional to pharmaceutical formulations, such as diluents, carriers, pH adjusters, preservatives, solubilizers, stabilizers, wetting agents, emulsifiers, sweeteners, colorants, flavoring agents, salts for altering osmotic pressure, buffers, masking agents, antioxidants, and / or other active agents. They may also contain other therapeutically active or therapeutically valuable substances.

[0118] Typical formulations are prepared by mixing an LSD1 inhibitor or gigritinib, or a combination thereof as described herein, with one or more pharmaceutically acceptable excipients. Suitable excipients are well known to those skilled in the art and are described in detail in, for example, “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 contain one or more buffers, stabilizers, surfactants, wetting agents, lubricants, emulsifiers, suspending agents, preservatives, antioxidants, opacifiers, flow aids, processing aids, colorants, sweeteners, flavoring agents, diluents, and / or other known additives to provide an elegant presentation of the medicament (i.e., the compound of the present invention or its pharmaceutical composition) or to facilitate the manufacture of the pharmaceutical product (i.e., the pharmaceutical preparation).

[0119] For oral delivery, compounds can be incorporated into dosage forms containing pharmaceutically acceptable carriers such as binders (e.g., gelatin, cellulose, tragacanth), excipients (e.g., starch, lactose), lubricants (e.g., magnesium stearate, silicon dioxide), disintegrants (e.g., alginate, Primogel, and corn starch), and sweeteners or flavoring agents (e.g., glucose, sucrose, saccharin, methyl salicylate, and menthol). The dosage forms can be delivered orally, for example, in the form of closed gelatin capsules or compressed tablets. Capsules and tablets can be prepared using any conventional techniques. Capsules and tablets can also be coated with various coatings known in the art to modify their flavor, taste, salt color, and shape. Furthermore, liquid carriers such as fatty oils can also be included in the capsules.

[0120] Suitable oral formulations can also be in the form of suspensions, sugar tablets, chewing gum, rice paper capsules, elixirs, etc. If desired, conventional agents for improving flavor, taste, color, and shape can also be included. Furthermore, for convenient administration via enteral feeding tubes to patients who cannot swallow, the active compound can be dissolved in an acceptable lipophilic vegetable oil carrier such as olive oil, corn oil, and safflower oil.

[0121] The compound can also be administered parenterally in the form of a solution or suspension, or in a lyophilized form that can be converted into a solution or suspension before use. In such formulations, diluents or pharmaceutically acceptable carriers, such as sterile water and saline buffers, can be used. Other common solvents, pH buffers, stabilizers, antimicrobial agents, surfactants, and antioxidants can also be included. For example, useful components include sodium chloride, acetate, citrate or phosphate buffers, glycerol, glucose, non-volatile oils, methylparaben, polyethylene glycol, propylene glycol, sodium bisulfate, benzyl alcohol, ascorbic acid, etc. Parenteral formulations can be contained in any conventional container, such as vials and ampoules.

[0122] Subcutaneous implantation for sustained-release compounds can also be a suitable route of administration. This requires implanting the active compound, in any suitable dosage form, into a subcutaneous space, such as a surgical procedure under the anterior abdominal wall. See, for example, Wilson et al. (1984) J. Clin. Psych. 45:242-247. Hydrogels can be used as carriers for sustained-release active compounds. Hydrogels are widely known in the art. They are typically prepared by crosslinking a high molecular weight biocompatible polymer into a network, which swells in water to form a gel-like material. Preferably, the hydrogel is biodegradable or bioabsorbable. For the purposes of this invention, hydrogels made of polyethylene glycol, collagen, or poly(glycolic acid-co-L-lactic acid) can be used. See, for example, Phillips et al. (1984) J. Pharmaceut. Sci., 73:1718-1720.

[0123] Compositions of a drug, such as oral and parenteral formulations, can be formulated into unit dosage forms to facilitate administration and ensure uniformity of dosage. As used herein, “unit dosage form” refers to a physically discrete unit suitable for administration as a unit dose to an individual, each unit containing a predetermined amount of active ingredient calculated to produce the desired therapeutic effect, and one or more suitable pharmaceutical carriers.

[0124] Suitable oral dosage forms for adastat are disclosed, for example, in WO2019 / 211491A1.

[0125] Specifically, adastat can be provided in tablet form. Alternatively, adastat can also be provided in the form of an oral aqueous solution (which can be prepared, for example, from a powder for reconstitution). As mentioned above, adastat is preferably used in the form of adastat dihydrochloride.

[0126] Suitable oral dosage forms of giretinib that can be used in this invention include, for example, those marketed under the name Xospata®. Giretinib is commercially available as film-coated tablets containing 40 mg of giretinib (fumarate). Such oral tablets can be prepared using mannitol (E421), hydroxypropyl cellulose, hydroxypropyl cellulose (low substitution), and magnesium stearate as excipients for the tablet core, and hydroxypropyl methylcellulose, talc, polyethylene glycol, titanium dioxide, and iron oxide yellow (E172) as excipients for the film coating, for example, as described in the Xospata® product characteristics summary, the entire contents of which are incorporated herein by reference (particularly the latest version provided April 1, 2021). Thus, in some embodiments, giretinib is provided in tablet form (e.g., tablets containing 40 mg of giretinib, preferably in the fumarate form).

[0127] In therapeutic applications, the combinations and pharmaceutical compositions 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. Appropriate dosages and suitable durations and frequencies of administration can vary widely and will be 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 method of administration, etc. Generally, appropriate dosages and administration regimens provide the active ingredients of the combinations of the present invention in an amount sufficient to provide therapeutic benefit, such as improved clinical outcomes, such as more frequent complete or partial remission, or more disease-free and / or overall survival, or reduction in symptom severity, or any other objectively identifiable improvement noted by a clinician. Therapeuticly effective doses can generally be assessed or inferred using experimental models, such as dose-response curves from in vitro or animal model testing systems or from human clinical trials.

[0128] As an example, a suitable dose of gipretinib could be the dose currently used in clinical practice for the treatment of AML. The current recommended dose of gipretinib as monotherapy for R / R AML is 120 mg daily, which can be increased to 200 mg daily. Therefore, gipretinib can be administered orally, for example, at a dose of approximately 120 mg daily. Other doses are also possible, for example, due to the synergistic effect (combination effect) of newly identified gipretinib with LSD1 inhibitors, which may allow for a reduction in the gipretinib dose. The gipretinib doses reflected in this article refer to the corresponding amounts of gipretinib free base.

[0129] The appropriate dosage and dosing regimen for LSD1 inhibitors will depend on the specific LSD1 inhibitor used, its LSD1 inhibitory potency, its pharmacokinetic properties, and other factors, as is well known to those skilled in the art.

[0130] Adalstatin is a highly potent active pharmaceutical ingredient (HPAPI). Therefore, the expected daily dose is very low, for example, less than 1 mg / day. Consequently, the drug loading in solid form will also be very low, for example, less than 1 mg API per 100 mg tablet. Generally, in the case of oral administration (e.g., as tablets or as an oral aqueous solution), a daily dose of about 50 μg to about 300 μg of adalstatin as described herein, preferably about 75 μg to about 300 μg (e.g., about 75 μg, about 100 μg, about 125 μg, about 150 μg, about 175 μg, about 200 μg, about 225 μg, about 250 μg, about 275 μg, or about 300 μg, or any range between any two of the aforementioned daily doses) should be appropriate, although these limits may be adjusted where necessary. As used herein, the term “μg” refers to micrograms and is used synonymously with the term “μg”.

[0131] In some implementations, the LSD1 inhibitor is idastat (or a pharmaceutically acceptable salt thereof, such as idastat dihydrochloride), and is administered five days a week and stopped for two days (5 / 2).

[0132] In some embodiments, the LSD1 inhibitor is idastat (or a pharmaceutically acceptable salt thereof, such as idastat dihydrochloride), and is administered orally at a daily dose of about 50 μg to about 300 μg, preferably about 75 μg to about 300 μg (e.g., about 100 μg to about 300 μg), five days a week with a two-day break (5 / 2). Dosages of idastat as reflected herein refer to corresponding amounts of idastat free base. In some embodiments, idastat is administered orally at a daily dose of about 75 μg, five days a week with a two-day break (5 / 2). In some embodiments, idastat is administered orally at a daily dose of about 100 μg, five days a week with a two-day break (5 / 2). In some embodiments, idastat is administered orally at a daily dose of about 150 μg, five days a week with a two-day break (5 / 2). In some embodiments, idastat is administered orally at a daily dose of about 200 μg, five days a week with a two-day break (5 / 2). In some implementations, adastat is administered orally at a daily dose of approximately 250 μg, five days a week with a two-day break (5 / 2). In other implementations, adastat is administered orally at a daily dose of approximately 300 μg, five days a week with a two-day break (5 / 2).

[0133] Products

[0134] The combinations and pharmaceutical compositions of the present invention can be included in containers, packages or dispensers together with the instructions for use.

[0135] In another embodiment of the invention, an article or "medicine box" containing the combination described herein is provided.

[0136] In some embodiments, the article or medicine box comprises a container and a combination of the invention as described herein.

[0137] In some embodiments, the article or cassette comprises: a) a container containing an LSD1 inhibitor formulation (or a pharmaceutically acceptable salt thereof), and b) a container containing giretinib (or a pharmaceutically acceptable salt thereof).

[0138] The product or packaging may also include a label or insert. The term "insert" refers to a package insert typically included in the commercial packaging of a therapeutic product, containing information about the indications, usage, dosage, administration, contraindications, and / or warnings for using such a therapeutic product. Suitable containers include, for example, blister packs, bottles, vials, syringes, etc. Containers can be formed from various materials, such as glass or plastic. Containers may contain a combination or formulation effective for treating the condition and may have a sterile access port (e.g., the container may be an intravenous solution bag or a vial with a stopper that can be punctured by a hypodermic needle). The label or insert indicates that the composition is intended to treat the selected condition, such as AML. Alternatively, or additionally, the product may further include a second container containing pharmaceutically acceptable buffers, such as sterile water for injection (BWFI), phosphate-buffered saline, Ringer's solution, and glucose solution. It may also include other materials desired from a commercial and user perspective, including other buffers, diluents, filters, needles, and syringes.

[0139] The kit may further include instructions for use of the combination, and, if present, a second pharmaceutical formulation. For example, if the kit contains a first pharmaceutical composition / formulation containing an LSD1 inhibitor or a pharmaceutically acceptable salt thereof and a second pharmaceutical composition / formulation containing giretinib or a pharmaceutically acceptable salt thereof, the kit may also include instructions for administering the first and second pharmaceutical compositions / formulations simultaneously, sequentially, or separately to a patient in need.

[0140] In another embodiment, the pillbox is adapted to deliver a combination of solid oral forms, such as tablets or capsules. Such a pillbox preferably includes multiple unit doses. This pillbox may include a card with the doses arranged in order of their intended use. An example of such a pillbox is a "blister pack." Blister packs are well-known in the packaging industry and are widely used for packaging unit dosage forms of pharmaceuticals. If desired, memory aids may be provided, such as in the form of numbers, letters, or other markings, or with a calendar insert, indicating the number of days in the treatment regimen in which the dose can be administered.

[0141] According to one embodiment, the kit may comprise (a) a first container containing an LSD1 inhibitor or a pharmaceutically acceptable salt thereof; (b) a second container containing giretinib or a pharmaceutically acceptable salt thereof; and (c) a third container containing a third pharmaceutical preparation comprising another compound having anticancer activity. Alternatively, or additionally, the kit may comprise another container containing a pharmaceutically acceptable buffer, such as sterile water for injection (BWFI), phosphate-buffered saline, Ringer's solution, and glucose solution. It may also include other materials desired from a commercial and user perspective, including other buffers, diluents, filters, needles, and syringes.

[0142] When the kit contains an LSD1 inhibitor or a pharmaceutically acceptable salt thereof and a giretinib or a pharmaceutically acceptable salt thereof, the kit may include containers for holding the separate components, such as separate bottles or separate foil packs; however, the separate components may also be contained in a single, unseparated container. Typically, the kit includes instructions for administering the separate components. The kit format is particularly advantageous when the separate components are preferably administered in different dosage forms (e.g., oral and parenteral), at different dose intervals, or when the prescribing physician needs to titrate a single component of the combination.

[0143] definition

[0144] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention pertains.

[0145] Unless otherwise expressly stated, the following definitions apply throughout this specification and the scope of the patent applications.

[0146] The term "patient" or "individual" used for the purposes of this invention includes humans and other animals, particularly mammals. Therefore, the methods and uses of this invention can be applied to human treatment and veterinary applications. In a preferred aspect, the individual or patient is a mammal; in the most preferred aspect, the individual or patient is a human (e.g., male or female).

[0147] As used herein, the term "treatment" generally refers to achieving the desired pharmacological and / or physiological effect. This includes partially or completely curing or improving a disease (i.e., cancer) and / or symptoms or side effects attributable to the disease, or partially or completely stopping the progression of a disease and / or symptoms or side effects attributable to the disease. As used herein, the term "treatment" encompasses any treatment of a disease (i.e., cancer) in a patient and includes, but is not limited to, inhibiting cancer, i.e., preventing, delaying, or slowing its development / progression; or alleviating cancer, i.e., causing (complete or partial) regression, correction, or reduction of cancer. This invention specifically and explicitly relates to each of these forms of treatment.

[0148] As used herein, the term "therapeutic effective amount" or "effective amount" for the compounds or combinations of the present invention refers to an amount sufficient to produce the desired biological effect (e.g., therapeutic effect or benefit) in an individual. Therefore, a therapeutically effective amount of a compound or combination can be an amount sufficient to treat the disease and / or delay its onset or progression and / or alleviate one or more symptoms when administered to an individual with or susceptible to a disease (i.e., cancer). Therapeutic effective amounts will vary depending on the compound, the state of the disease being treated, the severity of the disease, the individual's age and relative health condition, the route and form of administration, the judgment of the attending physician or veterinarian, and other factors.

[0149] The term "pharmaceutically acceptable" refers to the properties of materials used in the preparation of pharmaceutical compositions that are generally safe, non-toxic, and not biologically or otherwise undesirable, and are acceptable for veterinary and / or human pharmaceutical use.

[0150] As used herein, "pharmaceutically acceptable salt" refers to a salt that retains the biological effectiveness of a particular compound as a free acid and / or base and is not biologically or otherwise undesirable. A compound may have a sufficiently acidic functional group, a sufficiently basic functional group, or both, and thus react with any of a number of inorganic or organic bases and random or organic acids to form a pharmaceutically acceptable salt. Exemplary pharmaceutically acceptable salts include salts prepared by reacting compounds of the present invention, such as adastat, with random or organic acids, such as hydrochloride, hydrobromide, sulfate, pyrosulfate, hydrogen sulfate, sulfite, bisulfite, phosphate, monohydrogen phosphate, dihydrogen phosphate, metaphosphate, pyrophosphate, chloride, bromide, iodide, nitrate, acetate, propionate, decanoate, octanoate, acrylate, formate, isobutyrate, hexanoate, heptaate, propynate, oxalate, malonate, succinate, octanoate, sebate, fumarate, maleate, butyn-1 ,4-Diosyl salt, hexyn-1,6-diosyl salt, benzoate, chlorobenzoate, methylbenzoate, dinitrobenzoate, hydroxybenzoate, methoxybenzoate, phthalate, sulfonate, xylenesulfonate, phenylacetate, phenylpropionate, phenylbutyrate, citrate, lactate, γ-hydroxybutyrate, glycolate, tartrate, methanesulfonate (or methanesulfonate), ethanesulfonate, propanesulfonate, benzenesulfonate, toluenesulfonate, trifluoromethanesulfonate, naphthalene-1-sulfonate, naphthalene-2-sulfonate, mandelate, pyruvate, stearate, ascorbate, or salicylate. When the compound carries an acidic moiety, suitable pharmaceutically acceptable salts may include alkali metal salts, such as sodium or potassium salts; alkaline earth metal salts, such as calcium or magnesium salts; and salts formed with suitable organic ligands such as amines, alkylamines, hydroxyalkylamines, lysine, arginine, N-methylglucosamine, procaine, etc. Pharmaceutically acceptable salts are well known in the field.

[0151] 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 the active pharmaceutical ingredient or combination of the present invention and one or more pharmaceutically acceptable excipients, to be administered to a mammal (e.g., a human) in need.

[0152] The terms "pharmaceutically acceptable excipient" or "pharmaceutically acceptable carrier" are used interchangeably and refer to any pharmaceutically acceptable component in a pharmaceutical composition that is non-therapeutic and non-toxic to the individual receiving the drug. Examples include disintegrants, binders, fillers, solvents, buffers, tension agents, stabilizers, antioxidants, surfactants, carriers, diluents, lubricants, etc., used in the formulation of pharmaceutical products. They are generally considered safe for human administration according to established government standards, including those issued by the U.S. Food and Drug Administration and / or the European Medicines Agency. Pharmaceutically acceptable carriers or excipients are well-known to those skilled in the art.

[0153] As used herein, the term "inhibitor" means a compound that competes with, reduces, blocks, inhibits, eliminates, or interferes with the binding of a particular ligand to a particular receptor or enzyme in any way and / or reduces, blocks, inhibits, eliminates, or interferes with the activity or function of a particular protein, such as a receptor or enzyme.

[0154] As used in this article, "small molecule" refers to an organic compound with a molecular weight equal to or less than 900 Daltons, preferably less than 500 Daltons. Molecular weight is the mass of a molecule, and it is calculated by multiplying the atomic weight of each constituent element in the molecular formula by the number of atoms of that element.

[0155] Unless otherwise explicitly stated or contradicted by the context, the term “comprising” (or “containing”) as used herein means “containing, especially”, i.e., “containing, among other elements as desired”. In addition, the term also includes the narrower meanings of “consistently composed of” and “composed of”. For example, the term “A contains B and C” means “A particularly contains B and C,” where A may contain other elements as desired (e.g., “A contains B, C, and D” would also be included), but the term also includes the meanings of “A is essentially composed of B and C” and “A is composed of B and C” (i.e., A contains no other components besides B and C).

[0156] As used in this article, the indefinite articles “a”, “a kind” and the definite article “the” include both plural and singular indicators, unless the context clearly indicates otherwise.

[0157] The term "about" or "approximately" refers to an acceptable error in a particular value as determined by someone skilled in the art, depending in part on how the value was measured or determined. In some embodiments, the term "about" or "approximately" means within 1, 2, 3, or 4 standard deviations. In some embodiments, the term "about" or "approximately" means within 25%, 20%, 15%, 10%, 9%, 8%, 7%, 6%, 5%, 4%, 3%, 2%, 1%, 0.5%, 0.1%, or 0.05% of a given value or range. References to values ​​or ranges provided in conjunction with the term "about" also include references to the corresponding specific values ​​or ranges.

[0158] All publications, patent applications, patents and other references mentioned in this article are incorporated herein by reference in their entirety.

[0159] [Example]

[0160] The following embodiments are provided to illustrate the present invention. They are merely representative examples and should not be considered as limiting the scope of the invention.

[0161] Example 1 - Matrix assay for determining the synergistic effect between LSD1 inhibitors and gipritinib in AML cell lines

[0162] The aim of this assay was to determine the synergistic effect between the LSD1 inhibitor and gipritinib. As a first step, the compound of interest was evaluated as a single agent before setting up a matrix experiment to determine the synergistic effect.

[0163] 1.1 Experimental Design

[0164] 1.1.1 Cell lines and culture conditions

[0165] Mycoplasma-free AML cell lines were maintained in RPMI 10% FBS medium at 37°C in a humidified incubator with a controlled 5% CO2 atmosphere. Cell freezing and thawing were performed according to ATCC recommendations. The genetic map of the cell lines used is shown in Table 1.

[0166] [Table 1]

[0167] 1.1.2 Single-agent viability assay (96 hours)

[0168] Cells were seeded at optimal density in 96-well plates to ensure linear growth in 50 μL of medium throughout the assay (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 triplicate, including controls for medium and carrier treatments for background correction and normalization, respectively. Following seeding, 50 μL of medium containing 2x concentrations of the compound at nine serial dilutions (1:3) was added to the cells to obtain 100 μL of cells containing 1x concentration of each dilution. Cells were then cultured at 37°C in a controlled 5% CO2 atmosphere for 96 hours, and cell viability was evaluated using the AlamarBlue™ cell viability indicator (ThermoFisher Scientific, Waltham, MA / USA). AlamarBlue™ is a cell viability indicator that utilizes the natural reducing power of living cells to convert resamarazine into the fluorescent molecule halogen. In summary, the alamarBlue™ stock solution was diluted 1:20 in culture medium and incubated for 3 hours. Fluorescence was then measured using a TECAN Infinity 2000 plate reader (Tecan Group GmbH, Männedorf, CH; excitation wavelength 540-570 nm, emission wavelength 580-610 nm). For each condition, the average fluorescence was calculated from three technical replicates; background correction was calculated from the fluorescence of the control (culture medium only). Data were analyzed using GraphPad PRISM version 9.0.1 (GraphPad Software, Inc., La Jolla, CA / USA) to calculate best-fit curves and EC50 values.

[0169] 1.1.3 Survival determination of 9×9 matrix (96 hours)

[0170] Each matrix assay was performed on two plates according to the scheme shown in Figure 1, with one compound added from left to right at an increasing concentration and the other compound added from top to bottom at an increasing concentration.

[0171] For this assay, cells were seeded at the optimal density specified in previous sections in 50 μL of medium in 96-well plates; only 100 μL of medium was added to the wells at the edge of the plate for background correction. Two compounds were added at 25 μL each at a 4-fold concentration, resulting in a final volume of 100 μL and a final concentration of 1 for each dilution. As shown in Figure 1, a matrix was designed so that the concentration of the LSD1 inhibitor increased from left to right, while the concentration of gipritinib increased from top to bottom. The first and last rows of plate 1 were repeated in plate 2 (indicated by the arrows in Figure 1) to confirm reproducibility between the two plates. The tested concentrations of the two compounds covered a range of 6561-fold obtained through a total of nine 1:3 dilutions, designed so that the EC50 of the two compounds was horizontally and vertically centered in the matrix (the EC50 of the LSD1 inhibitor and gipritinib corresponded to the fifth well from the right and the fifth well from the bottom, respectively, as shown in Figure 1). Thus, the holes on the diagonal of the plate (marked by horizontal lines in Figure 1) correspond to a fixed EC50 ratio between the two compounds. The EC50 values ​​of the compounds tested in the matrix assay are determined in advance by single-reagent assays as detailed in Section 1.1.2.

[0172] Viability was then determined in at least two independent biological replicates (N=2) using alamarBlue™ staining as described in Section 1.1.2.

[0173] 1.1.3.1 9×9 Matrix Viability Measurement (Data Analysis)

[0174] For each matrix measurement, the data is compared to the control processed by the carrier (in the upper left corner). Standardize 0.5% DMSO to obtain the percentage value of relative residual activity according to the following formula:

[0175] % Relative Residual Viability = Background-corrected RFU-treated Cells / Background-corrected RFU Vector Control x 100

[0176] The percentage of remaining viability was then analyzed using GraphPad PRISM® version 9.0.1 (GraphPad Software, Inc., La Jolla, CA / USA) to calculate the best-fit curve and the EC50 value for a single agent.

[0177] At this point, use the following formula:

[0178] Fa = 1 - (%relative residual viability / 100)

[0179] Calculate the affected portion (Fa) of the following conditions, also known as the fractional effect.

[0180] ● Cells treated with serially diluted LSD1 inhibitors as a single agent (average of the first row of the first and second plates measured in each matrix).

[0181] ● Cells treated with serially diluted gidatetinib as a single agent (in the first column of the matrix assay)

[0182] ● Cells treated with LSD1 inhibitor and giretinib at a fixed ratio corresponding to EC50 values ​​(% of relative residual viability values ​​in the diagonal of the matrix determination; highlighted in Figure 1).

[0183] CalcuSyn software (http: / / www.biosoft.com / w / calcusyn.htm, Biosoft, Cambridge, UK) is designed to determine the nature of interactions (synergistic, additive, or antagonistic) between two compounds by calculating the combination index (CI). This analysis is based on the median effect principle and combination index theorem described by the Chou-Talalay method (TCChou, Pharmacol Rev. 2006;58(3):621-681), where CI < 1 indicates a synergistic effect, CI = 1 indicates an additive effect, and CI > 1 indicates an antagonistic effect. In the case of a synergistic effect (CI < 1), the smaller the CI value, the stronger the synergistic effect. Furthermore, the strength of drug interactions can be further classified according to the CI range, as shown in Table 2.

[0184] [Table 2]

[0185] To produce consistent and informative results, data processed with Calculusyn (for both single-drug and drug combination) needs to conform to the median effect principle and the combination index theorem. Therefore, removing potential outliers and data points that do not match the median effect principle is crucial (TCChou, Pharmacol Rev. 2006;58(3):621-681). To achieve this, the following data filtering strategy is employed:

[0186] In the first step, data dispersion is reduced by removing points with the following characteristics:

[0187] 1) Fa < 0.1

[0188] 2) Compared to the previous point, the increase in Fa is <0.03 (if Fa>0.9).

[0189] These conditions define the plateau of the dose-response curve, where cells have been treated with very low or very high concentrations of the compound (or combination thereof), resulting in a reduction in viability close to 0% or 100% (corresponding to Fa values ​​close to 0 or 1, respectively). It is important to note that the alamarBlueTM signal exhibits very small variations in these regions of the dose-response curve and is likely due to random noise with very little biological significance.

[0190] Next, for each data point, calculate Log10(concentration) and Log10(Fa / (1-Fa)), and generate a scatter plot, reporting the former on the x-axis and the latter on the y-axis. Then, use Excel to obtain the regression line (corresponding to the median effect equation).

[0191] At this point, the distance between each data point and the regression line is calculated using the following equation:

[0192] Distance (ax+by+c=0;X,Y)=(aX+bY+c) / √(a2+b2)

[0193] The Grubbs test is used to identify outliers based on their distance from the median effect equation. For each data point, the absolute value of the distance is tested using the following formula (note that the variables in the Grubbs test can be interchangeably referred to as G or Z):

[0194] G=(Xn-X average value) / s

[0195] Where Xn represents the absolute distance of each point to the regression line; Xmean represents the average of all Xn values; and s represents the standard deviation. G values ​​higher than Gcrit (calculated as α=0.2, as shown below) identify outliers that do not conform to the median effect equation. These data points have been removed to ensure successful calculation of the combined index using CalcuSyn.

[0196]

[0197] If possible, repeat the check more than once to remove multiple outliers until:

[0198] 1. No further outliers were identified, or

[0199] 2. R² > 0.95. To measure data quality, the R-value is also calculated using CalcuSyn software (good data is characterized by an R-value greater than 0.95).

[0200] 1.1.3.2 CalcuSyn Output

[0201] CalcuSyn results are provided as an experimental effect score (Fa) and the associated combination index (CI). The experimental effect score represents the fraction of cells affected by the combination treatment at its fixed EC50 ratio (in the case of cytotoxic treatment, the effect score corresponds to a reduction in viability compared to the vector control, where Fa=1 equals 100% viability reduction). As shown in Table 2 above, CI values ​​indicate the nature and strength of compound interactions, where values ​​below 1 indicate synergistic interactions (the closer the value is to 0, the stronger the synergistic effect), values ​​equal to 1 indicate additive interactions, and values ​​above 1 indicate antagonistic interactions.

[0202] 1.2 Results

[0203] 1.2.1 Single-agent efficacy: Adalstat, Pulrodemstat (CC-90011), Gefitinib, Bomedemstat

[0204] MV(4;11), OCI-AML3, MOLM-13, and TF1a cell lines were inoculated and incubated with a vector (DMSO 0.05%) or adastat in a series of 1:3 dilutions (0.0014–9 nM) as described in Section 1.1.2. In all cases, adastat induced a greater than 20% reduction in viability in at least two biological replicates (compared to the vector control), with EC50 values ​​in the sub-nanometer range. For CC-90011, MV(4;11) and MOLM-13 cells were treated with a vector (DMSO 0.05%) or a series of 1:3 dilutions (0.045–300 nM) as described in Section 1.1.2. In all cases, CC-90011 induced a greater than 20% reduction in viability in at least two biological replicates (compared to the vector control), with EC50 values ​​in the nanometer range. For the gipritinib EC50 assay, MV(4;11), OCI-AML3, MOLM-13, and TF1a cell lines were incubated with a vector (DMSO 0.45%) or a series of 1:3 dilutions as described in Section 1.1.2 (concentrations ranging from 0.014 to 90 nM for MOLM-13 and MV(4;11), and from 1.4 to 9000 nM for TF1a and OCI-AML3). In the FLT3-ITD-containing cell lines MOLM-13 and MV(4;11), gipritinib showed a significant reduction in viability approaching 100% in both cell lines, with EC50 values ​​in the nanomolar range. In cells without the FLT3 mutation, such as TF1a or OCI-AML3 cells, gipritinib induced a >70% reduction in viability, with EC50 values ​​in the micromolar range for both cell lines. For Bomedemstat, MV(4;11) and MOLM-13 cells were treated with the vector (DMSO 0.05%) or a series of 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% reduction in viability (compared to the vector control), with EC50 values ​​in the nanomolar range. Experiments were performed in at least two biological replicates.

[0205] Table 3 shows the EC50 values ​​determined experimentally after incubation for 96 hours with adastat, CC-90011, giretinib, and bomedemstat in specific cell lines.

[0206] [Table 3]

[0207] 1.2.2 Combination of LSD1 inhibitor idastat and gipretinib

[0208] As described in Section 1.1.3, a matrix was performed using gipretinib (0.014–90 nM for MOLM-13 and MV(4;11), and 1.4–9000 nM for TF1a and OCI-AML3) and the covalently and irreversibly LSD1 inhibitor idastat (0.0014–9 nM for all four cell lines). Data analysis and calculation of the combination index were performed as described in Section 1.1.3.1. Table 4 shows the results of the combination index (CI) and corresponding classifications (as described in Table 2) obtained from the combination of idastat and gipretinib, which are associated with specific effect scores (Fa).

[0209] In summary, the combination of idastat and gipritinib demonstrated a strong synergistic effect across a wide range of effect fractions (Fa) in FLT3-mutant gipritinib-sensitive cell lines (MOLM-13, N=3 and MV(4;11), N=2). Importantly, a strong synergistic effect was also observed in FLT3-mutant-free cell lines (WT FLT3) that were poorly responsive to gipritinib monotherapy (OCI-AML3, N=2, TF1a, N=3). These cell lines were also resistant to other current AML therapies. In particular, OCI-AML3 and TF1a cells were resistant to venetoclax (EC50 > 10 μM, tested as described above). These results open the possibility of successfully combining LSD1 inhibitors such as idastat with gipritinib in AML patients with or without FLT3 mutations, or in refractory / relapsed AML patients.

[0210] [Table 4]

[0211] 1.2.3 Combination of LSD1 inhibitor Pulrodemstat (CC-90011) and giretinib

[0212] The synergistic effect between the LSD1 inhibitor and gipretinib described in Section 1.2.2 was further confirmed using another LSD1 inhibitor, specifically a structurally unrelated reversible LSD1 inhibitor, CC-90011. As described in Section 1.1.3, a matrix was performed using gipretinib (concentrations ranging from 0.014 to 90 nM for MOLM-13 and MV(4;11)) and CC-90011 (concentrations ranging from 0.045 to 300 nM for both cell lines). Data analysis and calculation of the combination index were performed as described in Section 1.1.3.1. Table 5 shows the results of the combination index (CI) and corresponding classifications (as described in Table 2) obtained from the combination of CC-90011 and gipretinib, correlated with specific effect scores (Fa).

[0213] In summary, the CC-90011+giretinib combination also showed strong synergistic effects across a wide range of effect fractions (Fa) in the tested cell lines (MOLM-13, N=2 and MV(4;11), N=2).

[0214] [Table 5]

[0215] 1.2.4 Combination of LSD1 inhibitor Bomedemstat and giretinib

[0216] The synergistic effect between the LSD1 inhibitors and giretinib, as described in Sections 1.2.2 and 1.2.3, was further confirmed using another LSD1 inhibitor, Bomedemstat.

[0217] As described in Section 1.1.3, matrix processing was performed using giretinib (concentration range of 0.014 to 90 nM for MOLM-13 and MV(4;11)) and botemstat (concentration range of 0.045 to 300 nM for both cell lines). Data analysis and calculation of the combination index were performed as described in Section 1.1.3.1. Table 6 shows the results of the combination index (CI) and corresponding classifications (as described in Table 2) obtained from the combination of botemstat and giretinib, associated with specific effect scores (Fa).

[0218] In summary, the combination of Bomedemstat and giretinib showed synergistic effects across a wide range of effect fractions (Fa) in the tested cell lines (MOLM-13, N=2 and MV(4;11), N=2).

[0219] [Table 6]

[0220] Using the method described in Example 1, the superior therapeutic effect of combining other LSD1 inhibitors with giratetinib can be demonstrated.

[0221] Similarly, using a method similar to that described in Example 1, the superior therapeutic effect of the combination of LSD1 inhibitor and giretinib in other myelopathic malignancies such as MDS can be demonstrated.

[0222] Although the invention has been described in conjunction with its specific embodiments, it should be understood that further modifications can be made to the invention. This patent or patent application is intended to cover any variations, applications or modifications of the invention and, as described in the appended claims, such variations, applications or modifications generally follow the principles of the invention and include deviations from the disclosure herein that fall within the scope of known or customary practice in the field to which this invention pertains and can be applied to the basic features set forth above.

Claims

1. A combination product comprising an LSD1 inhibitor or a pharmaceutically acceptable salt thereof and gidatetinib or a pharmaceutically acceptable salt thereof in the same pharmaceutical formulation or separate pharmaceutical formulations, wherein the LSD1 inhibitor is adastat.

2. The combination product as claimed in claim 1, wherein the LSD1 inhibitor is adastat dihydrochloride.

3. The combination product as claimed in claim 1 or 2, wherein the LSD1 inhibitor and gidatetinib or a pharmaceutically acceptable salt thereof are provided in separate pharmaceutical formulations.

4. A pharmaceutical composition comprising an LSD1 inhibitor or a pharmaceutically acceptable salt thereof and giretinib or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable excipients, wherein the LSD1 inhibitor is adastat.

5. The pharmaceutical composition as claimed in claim 4, wherein the LSD1 inhibitor is adastat dihydrochloride.

6. Use of a combination comprising an LSD1 inhibitor or a pharmaceutically acceptable salt thereof and giretinib or a pharmaceutically acceptable salt thereof in the preparation of a medicament for the treatment of myeloma, wherein the LSD1 inhibitor is adastat.

7. Use of an LSD1 inhibitor or a pharmaceutically acceptable salt thereof in the preparation of a medicament for the treatment of myeloma, the medicament being used in combination with giretinib or a pharmaceutically acceptable salt thereof, wherein the LSD1 inhibitor is adastat.

8. Use of a giretinib or a pharmaceutically acceptable salt thereof in the preparation of a medicament for the treatment of myeloma, the medicament being used in combination with an LSD1 inhibitor or a pharmaceutically acceptable salt thereof, wherein the LSD1 inhibitor is adastat.

9. The use as described in claim 6, wherein the LSD1 inhibitor is adastat dihydrochloride.

10. The use as described in claim 7, wherein the LSD1 inhibitor is adastat dihydrochloride.

11. The use as described in claim 8, wherein the LSD1 inhibitor is adastat dihydrochloride.

12. The use as claimed in any one of claims 6 to 11, wherein the bone marrow cancer is selected from acute myeloid leukemia and myelodysplastic syndrome.

13. The use as claimed in any one of claims 6 to 11, wherein the bone marrow cancer is acute myeloid leukemia.

14. The use as described in claim 13, wherein the acute myeloid leukemia is relapsed or refractory acute myeloid leukemia.

15. The use as described in claim 13, wherein the acute myeloid leukemia is an acute myeloid leukemia with an FLT3 mutation.

16. The use as described in claim 13, wherein the acute myeloid leukemia is a relapsed or refractory acute myeloid leukemia with an FLT3 mutation.

17. The use as claimed in any one of claims 6 to 11, wherein the LSD1 inhibitor and gidatetinib or a pharmaceutically acceptable salt thereof are administered orally.

18. The use as described in claim 13, wherein the LSD1 inhibitor and gidatetinib or a pharmaceutically acceptable salt thereof are administered orally.

19. The use as described in claim 16, wherein the LSD1 inhibitor and gidatetinib or a pharmaceutically acceptable salt thereof are administered orally.

20. The use as claimed in any one of claims 6 to 11, wherein the LSD1 inhibitor and giretinib or a pharmaceutically acceptable salt thereof are administered using separate pharmaceutical formulations.

21. The use as described in claim 13, wherein the LSD1 inhibitor and gidatetinib or a pharmaceutically acceptable salt thereof are administered using separate pharmaceutical formulations.

22. The use as described in claim 16, wherein the LSD1 inhibitor and gidatetinib or a pharmaceutically acceptable salt thereof are administered using separate pharmaceutical formulations.

23. The use as described in claim 17, wherein the LSD1 inhibitor and gidatetinib or a pharmaceutically acceptable salt thereof are administered using separate pharmaceutical formulations.

24. The use as described in claim 18, wherein the LSD1 inhibitor and gidatetinib or a pharmaceutically acceptable salt thereof are administered using separate pharmaceutical formulations.

25. The use as described in claim 19, wherein the LSD1 inhibitor and gidatetinib or a pharmaceutically acceptable salt thereof are administered using separate pharmaceutical formulations.

26. The use as described in claim 23, wherein the LSD1 inhibitor and gidatetinib or a pharmaceutically acceptable salt thereof are administered simultaneously in separate pharmaceutical formulations.

27. The use as described in claim 23, wherein the LSD1 inhibitor and gidatetinib or a pharmaceutically acceptable salt thereof are administered sequentially using separate pharmaceutical formulations.

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