Combination of rogenolisib and HDAC inhibitors for treatment of hematological malignancies

Abstract

A PI3K-delta inhibitor, or a pharmaceutically acceptable salt thereof, for use in the treatment of a hematological malignancy in a subject wherein the treatment comprises administering to the subject, alone, sequentially or simultaneously, i) the PI3K-delta inhibitor, or a pharmaceutically acceptable salt thereof, and ii) an HDAC inhibitor, or a pharmaceutically acceptable salt thereof. The treatment may further comprise administering to the subject, alone, sequentially or simultaneously, iii) a further chemotherapeutic agent.

Description

[0001] The present disclosure relates to methods of treating hematological malignancies in a patient in need thereof.

[0002] This application claims priority to GB Application No. 2303191.7 filed March 3, 2023 and GB Application No. 2308112.8 filed May 31, 2023, the entire contents of which are incorporated herein by reference. BACKGROUND

[0003] Hematological malignancies, also known as blood cancers, are malignancies that primarily arise from the myeloid and lymphoid lineages. Lymphomas, lymphocytic leukemias, and myelomas arise from the lymphoid lineage, while acute and chronic myeloid leukemias, myelodysplastic syndromes, and myeloproliferative disorders are of myeloid origin.

[0004] Hematological malignancies are a significant cause of morbidity and mortality globally, with nearly 1,000,000 new cases and over 600,000 deaths each year (Jephcote 2020). Several factors contribute to the development of blood cancers, including occupational, lifestyle, and genetic risk factors. Hematological malignancies are a heterogeneous disease with variable outcomes. Indolent lymphomas and chronic leukemias, such as follicular lymphoma (FL), marginal zone lymphoma (MZL), chronic lymphocytic leukemia (CLL), and small lymphocytic lymphoma (SLL), remain chronic diseases that are incurable, requiring patients to undergo repeated exposure to toxic therapies. For aggressive lymphomas and acute leukemias, modern treatment regimens result in long-term survival rates ranging from >80% for Hodgkin lymphoma to about 60-65% for diffuse large B-cell lymphoma (DLBCL) and acute lymphoblastic leukemia (ALL), and <30% for peripheral T-cell lymphoma (PTCL) and acute myeloid leukemia (AML) (Intlekofer and Younes 2014, Kantarjian 2021). More effective therapies are needed to improve the prognosis of patients with hematological malignancies. Furthermore, even for those patients who are cured by combination chemotherapy, often used in conjunction with radiation therapy, such therapies can result in long-term toxicities that impair health, predispose patients to secondary malignancies, and negatively impact quality of life.

[0005] Targeted therapies including phosphatidylinositol 3-kinase (PI3K) inhibitors and histone deacetylase (HDAC) inhibitors have changed the treatment landscape for patients with hematological malignancies. PI3K plays a central role in the regulation of key intercellular pathways including growth, proliferation, survival, migration, and differentiation, and dysregulation of the PI3K pathway is one of the most common pathogenic events in cancer (Kienle and Stilgenbauer 2021). HDACs modulate cell proliferation and angiogenesis and play an important role in cell growth, and upregulated HDACs are present in many cancer types (Chen 2020). Thus, PI3K and HDACs are rational therapeutic targets for hematological malignancies.

[0006] Despite the impressive clinical results shown by PI3K and HDAC inhibitors in a variety of hematological malignancies, certain subtypes are characterized by significantly higher response rates than others and develop resistance to these inhibitors, ultimately leading to clinical disease progression. In addition, both types of inhibitors have serious side effects that limit their therapeutic applicability, and in the case of PI3K inhibitors, even lead to drug withdrawal from the market (Chen 2020, Richardson 2022).

[0007] While great progress has been made in the treatment of hematological malignancies, the need for targeted therapies for hematological malignancies continues to increase. Many patients with this cancer have incurable disease. Therefore, it is important to continue to find new treatments that are more effective for patients with incurable cancer. SUMMARY

[0008] The present invention relates to a new treatment for patients with hematological malignancies. In some embodiments, a method of treating a hematological malignancy in a subject in need thereof is disclosed, comprising administering to the subject a first amount of a compound of Formula I:

[0009]

[0010] or a pharmaceutically acceptable salt thereof, and a second amount of an HDAC inhibitor or a pharmaceutically acceptable salt thereof. In the method, the first amount and the second amount together comprise a therapeutically effective amount. The compound of Formula I can be referred to herein as “Compound 1”. In some of these embodiments, a third amount of an additional chemotherapeutic agent is administered.

[0011] In some embodiments, Compound 1, or a pharmaceutically acceptable salt thereof, is disclosed for use in treating a hematological malignancy in a subject, wherein the treatment comprises administering to the subject, alone, sequentially or simultaneously, i) the Compound 1, or a pharmaceutically acceptable salt thereof, and ii) an HDAC inhibitor, or a pharmaceutically acceptable salt thereof. In some of these embodiments, the treatment further comprises administering to the subject, alone, sequentially or simultaneously, iii) an additional chemotherapeutic agent.

[0012] In some embodiments, an HDAC inhibitor, or a pharmaceutically acceptable salt thereof, is disclosed for use in treating a hematological malignancy in a subject, wherein the treatment comprises administering to the subject, alone, sequentially or simultaneously, i) the HDAC inhibitor, or a pharmaceutically acceptable salt thereof, and ii) Compound 1, or a pharmaceutically acceptable salt thereof. In some of these embodiments, the treatment further comprises administering to the subject, alone, sequentially or simultaneously, iii) an additional chemotherapeutic agent.

[0013] In some embodiments, Compound 1, or a pharmaceutically acceptable salt thereof, is disclosed for use in the manufacture of a medicament for use in treating a hematological malignancy, wherein the treatment comprises administering to the subject, alone, sequentially or simultaneously, i) the medicament comprising Compound 1, or a pharmaceutically acceptable salt thereof, and ii) an HDAC inhibitor, or a pharmaceutically acceptable salt thereof. In some of these embodiments, the treatment further comprises administering to the subject, alone, sequentially or simultaneously, iii) an additional chemotherapeutic agent.

[0014] In the above embodiments, the hematological malignancy can be a lymphoma, a leukemia, a myeloma, a myelodysplastic syndrome, and a myeloproliferative disorder.

[0015] In some embodiments, a pharmaceutical product is disclosed comprising i) Compound 1, or a pharmaceutically acceptable salt thereof, and ii) an HDAC inhibitor, or a pharmaceutically acceptable salt thereof. In some of these embodiments, the pharmaceutical product further comprises iii) an additional chemotherapeutic agent.

[0016] In some embodiments, a kit is disclosed comprising: a first pharmaceutical composition comprising Compound 1, or a pharmaceutically acceptable salt thereof; a second pharmaceutical composition comprising an HDAC inhibitor, or a pharmaceutically acceptable salt thereof; and instructions for using the first pharmaceutical composition and the second pharmaceutical composition in combination. In some of these embodiments, the kit further comprises a third pharmaceutical composition comprising an additional chemotherapeutic agent, and the instructions are for using the first pharmaceutical composition, the second pharmaceutical composition, and the third pharmaceutical composition in combination.

[0017] The combination of Compound 1 and HDAC inhibitors (and additional chemotherapeutic agents, if present) can be synergistic when compared to current monotherapy or combination therapy, and / or can otherwise result in improved therapeutic outcomes or patient prognosis, such as a reduction in side effects and improved tolerability. This can be due to Compound 1 blocking a survival pathway that is activated upon administration of the HDAC inhibitor, or vice versa. BRIEF DESCRIPTION OF DRAWINGS

[0018] Figure 1 Dose response data for the combination of Compound 1 and Vorinostat in HH cell line (cutaneous T-cell lymphoma cell line) is shown.

[0019] Figure 2 Dose response data for the combination of Compound 1 and Romidepsin in HH cell line (cutaneous T-cell lymphoma cell line) is shown. DETAILED DESCRIPTION

[0020] Compound 1 is Example 339 in WO 2011 / 058149, which is incorporated by reference in its entirety. Its structure is according to Formula I:

[0021]

[0022] In IUPAC nomenclature, the above Compound 1 can be called 6-fluoro-3-(morpholin-4- ylcarbonyl)-l-[4-(morpholin-4-ylmethyl)phenyl]-l,4-dihydrochromeno[4,3-c]pyrazole 5,5- dioxide. Alternatively, the structural formula shown above can be described as [6-fluoro-l-(4- morpholin-4-yl-methylphenyl)-5,5-dioxo-4,5-dihydro-lH-5lambda6-thiochromeno[4,3-C]pyrazol-3- yl]-morpholin-4-yl-methanone.

[0023] Compound 1 can be prepared and characterized as described in published patent application WO 2011 / 058149 Al (see Compound 339 on page 69; Preparation on pages 303-307; and Characterization on page 481 and pages 414-418), the information of which is specifically incorporated by reference.

[0024] Based on the procedure disclosed in WO 2011 / 058149 Al, the authors of Haselmayer 2014 describe a five-step preparation procedure for the compound. This procedure starts with the reaction of 8-fluoro-2,3-dihydro-4H-thiochromen-4-one with diethyl oxalate in the presence of sodium ethoxide. The intermediate is cyclized with 4-(4-hydrazinylbenzyl)morpholine to form the pyrazole ring. The thioether is then oxidized to the corresponding sulfone by reaction with meta-chloroperbenzoic acid, followed by saponification of the ethyl ester to the corresponding acid, followed by coupling with morpholine to give the compound of formula I.

[0025] Alternatively, the intermediate of the reaction of 8-fluoro-2,3-dihydro-4H- thiochromen-4-one with diethyl oxalate in the presence of sodium ethoxide is cyclized with 4-hydrazinylbenzoic acid. The benzoic acid is reduced using borane-THF complex and the thioether is oxidized to the corresponding sulfone by reaction with meta-chloroperbenzoic acid. The ethyl ester is saponified to the corresponding acid and the acid and alcohol are chlorinated with excess thionyl chloride in the presence of dimethylformamide, followed by coupling with morpholine, to give Compound 1.

[0026] Compound 1 can be provided in the form of a pharmaceutically acceptable salt. Suitable pharmaceutically acceptable salts are known in the art. Some pharmaceutically acceptable salts of Compound 1 are described in WO2014 / 121901, which is incorporated by reference in its entirety.

[0027] As used herein, Compound 1 is provided in the form of the anhydrous hemifumarate salt (formula shown). Its synthesis and characterization are described in WO2014 / 121901 (page 4). It is referred to as solid form Al. A hemifumarate hydrate (Hl) has also been identified. The anhydrous hemifumarate salt used is crystalline and has a list of powder X-ray peaks as described in WO2014 / 121901. It will be understood that the findings of the present invention are not limited to the use of this solid form, although it is preferred.

[0028] Thus, in some cases, Compound 1 is administered as the hemifumarate salt (formula la). However, it will be understood that the present invention is not limited to this, and other solid forms (e.g., other pharmaceutically acceptable salts) are contemplated.

[0029]

[0030] Haselmayer 2014 et al. also describe the characterization of the compound as a highly selective PI3K5 inhibitor. Tarantelli 2022 further describes the activity of Compound 1 in lymphoma cell lines, and Carlo-Stella 2022 reports data from the first dose cohort of a clinical study of Compound 1 in FL patients (NCT04328844).

[0031] Histone deacetylases (HDACs) are enzymes that play a key role in epigenetic regulation of gene expression by remodeling chromatin through the removal of acetyl groups from histones (Shanmugam 2022). In humans, 18 HDACs have been identified to date and based on their homology to yeast HDACs, they are classified into different classes. The term HDAC inhibitor includes a targeted and selective inhibitor against one of the HDAC classes or a targeted inhibitor against more than one or all HDAC classes. HDAC inhibitors include, but are not limited to, Abexinostat (PCI-24781), Pracinostat (SB939), Quisinostat (JNJ-26481585), Tefinostat (CHR-2845), Panobinostat (LBH589), Belinostat (PXD101), Givinostat (ITF2357), Tucidinostat (CS-055, HBI-8000), Vorinostat (suberoylanilide hydroxamic acid, SAHA), Mocetinostat (MGCD0103), Valproic acid (VAL), Entinostat (MS275), Romidepsin (depsipeptide, FK228), and Trapoxin (TPX).

[0032] Vorinostat (also known as suberoylanilide hydroxamic acid - SAHA) is an orally bioavailable HDAC inhibitor that was approved by the FDA in 2006 for the treatment of cutaneous T-cell lymphoma (CTCL) (Bondarev 2021). Clinically, vorinostat has been evaluated in patients with several hematologic malignancies including multiple myeloma, AML, ALL, myelodysplastic syndrome, DBCL (diffuse large B-cell lymphoma), CLL, SLL, leukemia, and lymphoma. The most common toxic effects observed with vorinostat include thrombocytopenia, anemia, diarrhea, fatigue, nausea, anorexia, weight loss, and taste disturbance. Thromboembolic events, particularly pulmonary embolism (4%), are the most common life-threatening events.

[0033] Vorinostat has the following structure:

[0034]

[0035] The IUPAC name for vorinostat is N-hydroxy-N'-phenyl octanediamide. Its synthesis and characterization are described in US 2008 / 0194692 Al.

[0036] Belinostat is a HDAC inhibitor that is administered intravenously and was approved by the FDA in 2014 for peripheral T-cell lymphoma (PTCL) (Bondarev 2021). Belinostat was studied in patients with several hematologic malignancies including non-Hodgkin’s lymphoma, DBCL, MCL (mantle cell lymphoma), PTCL, lymphoma, large cell lymphoma, myelodysplastic syndrome, AML, ALL (acute lymphoblastic leukemia), CML (chronic myelogenous leukemia), and MM (multiple myeloma). The most common non-hematologic toxicities observed for belinostat were nausea, fatigue, fever, anemia, and vomiting.

[0037] Belinostat has the following structure:

[0038]

[0039] The IUPAC name for belinostat is (2E)-N-hydroxy-3-[3-(phenylsulfonamido)phenyl]prop-2- eneamide. Belinostat is sold under the trade name Beleodaq and was previously known as PXD101. Belinostat is disclosed in US 2004 / 0077726 Al, the synthesis and characterization of which is described in Example 7.

[0040] Panobinostat (sold under the name Farydak) is an orally bioavailable HDAC inhibitor that was approved by the FDA (2015) and EMA (2015) for MM (Bondarev 2021). Panobinostat was studied in patients with several hematologic malignancies including AML, lymphoma, leukemia, MCL, MM, CTCL, PTCL, NK / T-cell lymphoma, ALL, DBCL, CML, MF (myelofibrosis), and myelodysplastic syndrome. The most common toxicities observed for panobinostat were hypophosphatemia, hypokalemia, hyponatremia, increased creatinine, thrombocytopenia, lymphopenia, leukopenia, neutropenia, anemia, diarrhea, fatigue, nausea, peripheral edema, decreased appetite, fever, and vomiting.

[0041] Panobinostat has the following structure:

[0042]

[0043] The IUPAC name for panobinostat is (2E)-N-hydroxy-3-[4-({[2-(2-methyl-lH-indol-3- yl)ethyl]amino}methyl)phenyl]acrylamide. Methods of synthesizing this compound and its characterization are described in Example 200 of WO 02 / 22577.

[0044] Chidamide (also known as chidamide) is an orally bioavailable HDAC inhibitor that was approved by China's National Medical Products Administration in 2014 for use in PTCL (Bondarev 2021). The most common toxicities observed for chidamide are thrombocytopenia, leukopenia, neutropenia, prolonged QTc interval, fatigue, anorexia, diarrhea, nausea, elevated alanine aminotransferase levels, elevated gamma-glutamyltransferase levels, pulmonary infections, elevated aspartate aminotransferase levels, and vomiting.

[0045] Chidamide has the following structure:

[0046]

[0047] The IUPAC name for chidamide is N-(2-amino-4-fluorophenyl)-4- [[[(E)-3-pyridin-3-ylprop-2-enoyl]amino]methyl]benzamide. Chidamide is sold under the brand names Epidaza and Hiyasta.

[0048] Romidepsin is a cyclic depsipeptide that is administered intravenously and was approved by the FDA in 2009 for use in CTCL and in 2011 for use in PTCL (Bondarev 2021). The most common toxicities observed for romidepsin are nausea, fatigue, infections, vomiting, anorexia, anemia, thrombocytopenia, ECG T wave changes, neutropenia, and lymphopenia.

[0049] Romidepsin has the following structure:

[0050]

[0051] The IUPAC name for romidepsin is (1S,4S,7Z,10S,16E,21R)-7- ethylidene-4,21-diisopropyl-2-oxa-12,13-dithia-5,8,20,23-tetraazabicyclo[8.7.6]trideca- 16-ene-3,6,9,19,22-pentone. Romidepsin is also known as Istodax. The synthesis of romidepsin is disclosed in Li 1996.

[0052] Abexinostat is an orally bioavailable experimental candidate drug for use in cancer and has been used in trials investigating treatment of sarcomas, lymphomas, leukemias, lymphocytes, and Hodgkin's disease, among others. Abexinostat has the following structure:

[0053]

[0054] The IUPAC name of abexinostat is 3-[(dimethylamino)methyl]-N-{2-[4- (hydroxyaminocarbonyl)phenoxy]ethyl}-1-benzofuran-2-carboxamide.

[0055] Pracinostat is an orally bioavailable HDAC inhibitor with potential antitumor activity, which is currently in clinical trials for acute myeloid leukemia. Pracinostat has the following structure:

[0056]

[0057] The IUPAC name of pracinostat is (E)-3-[2-butyl-1-[2-(diethylamino)ethyl]benzoimidazol-5-yl]-N- hydroxyprop-2-enamide. The dosing regimen for pracinostat is 60 mg per day.

[0058] Quinoxyrycin is an experimental candidate drug for the treatment of cancer. Quinoxyrycin has been used in trials investigating lymphoma, neoplasms, myelodysplastic syndrome, and advanced or refractory leukemia treatment. Quinoxyrycin has the following structure:

[0059]

[0060] The IUPAC name of quinoxyrycin is N-hydroxy-2-[4-({[(1-methyl-1H-indol-3-yl)methyl]amino}methyl)-1- piperidinyl]-5-pyrimidinecarboxamide.

[0061] Tenofovir disoproxil fumarate is an HDAC inhibitor with potential antitumor activity, which is being investigated for the treatment of hepatocarcinoma in clinical trial NCT02759601. Tenofovir disoproxil fumarate has the following structure:

[0062]

[0063] The IUPAC name of tenofovir disoproxil fumarate is (2S)-2-[[4-[[8-(hydroxyamino)-8-oxooctanoyl]amino]phenyl]methylamino]-2- phenylacetic acid cyclopentyl ester.

[0064] Givinostat (also known as gavinostat or ITF-2357) is a HDAC inhibitor, which is being used in clinical trials for the treatment of various cancers. Givinostat has the following structure:

[0065]

[0066] The IUPAC name for givinostat is {6-[(diethylamino)methyl]naphthalen-2-yl} methyl [4- (hydroxylaminocarbonyl)phenyl]carbamate.

[0067] Entinostat (also known as SNDX-275 or MS-275) is an HDAC inhibitor that is undergoing clinical trials for various cancers. The structure of entinostat is

[0068]

[0069] The IUPAC name for entinostat is ({4[2-aminophenyl)aminocarbonyl]phenyl}methyl)carbamic acid (pyridin-3-yl)methyl ester.

[0070] Trapoxin ((cyclo-(L-phenylalanyl-L-phenylalanyl-D-piperidyl-L-2-amino-8-oxo-9,10- epoxy-decanoyl)) is a cyclic tetrapeptide isolated from the fungus Helicoma ambiens. Trapoxin is an HDAC inhibitor. Trapoxin has two forms, A and B.

[0071] Trapoxin A has the following structure:

[0072]

[0073] Trapoxin B has the following structure:

[0074]

[0075] Valproic acid (also known as valproate, sodium valproate, and valproate semisodium) is a well-established therapy for treating seizures and bipolar disorder, and has also been shown to be an HDAC inhibitor. Valproic acid first entered medical use in the 1960s and is widely genericized, and is listed on the World Health Organization's List of Essential Medicines.

[0076] Valproic acid has the following structure:

[0077]

[0078] The IUPAC name for valproic acid is 2-propylpentanoic acid.

[0079] Mocetinostat (also known as MDCD0103) is an HDAC inhibitor that is undergoing clinical trials for treating various cancers, including follicular lymphoma, Hodgkin's lymphoma, and acute myeloid leukemia. Clinical and pharmacodynamic data support administration at a fixed dose of 90 mg three times per week. Mocetinostat shows promising antitumor activity in several hematological diseases.

[0080] Mocetinostat has the following structure:

[0081]

[0082] The IUPAC name of moxidomine is N-(2-aminophenyl)-4-({[4-(pyridin-3- yl)pyrimidin-2-yl]amino}methyl)benzamide.

[0083] In some embodiments, the additional chemotherapeutic agent can be a second HDAC inhibitor.

[0084] In other embodiments, the additional chemotherapeutic agent can be a DNA methyltransferase inhibitor. DNA methylation mediated by DNA methyltransferases is an important epigenetic process that regulates gene expression and plays a key role in silencing tumor suppressor genes in cancer. It has therefore become a promising therapeutic target for cancer treatment, particularly for hematological tumors (Zhang 2022), DNMT inhibitors can also enhance the immunogenicity of tumor cells by promoting tumor antigen presentation or enhancing the function of cytotoxic T cells. DNMTs are therefore also reasonable therapeutic targets for hematological malignancies. However, first-generation DNMT inhibitors are characterized by high toxicity, poor selectivity, and low bioavailability.

[0085] DNMT inhibitors include, but are not limited to, 5-azacytosine (azacytosine (AZA)), 5-aza-2'-deoxycytidine (decitabine (DAC)), clofarabine, gaudecitabine, and GSK3685032.

[0086] 5-azacytosine (azacytosine (AZA)) has the following structure:

[0087]

[0088] 5-azacytosine is a cytarabine derivative synthesized in 1964 and was first approved by the FDA in 2004.

[0089] Decitabine has the following structure:

[0090]

[0091] Decitabine was approved by the FDA in 2006. The inhibitory activity of DNMT is 30 times that of azacytosine (Zhang 2022).

[0092] Clofarabine has the following structure:

[0093]

[0094] Clofarabine is a purine nucleoside DNMTi approved by the FDA in 2004.

[0095] High decitabine (SGI-110) has the following structure:

[0096]

[0097] which is a dinucleotide derivative of decitabine.

[0098] GSK3685032 has the following structure:

[0099]

[0100] and is described in Pappalardi 2021. It acts as a competitive inhibitor of DNMT1 via competition with the DNMT1 active site loop and target recognition domain for incorporation into hemimethylated DNA.

[0101] Other DNMT inhibitors include, but are not limited to: RX-3117 (TV-1360), 5-fluoro-2- deoxycytidine, 6-dihydro-5-azacytidine (DHAC), fazarabine, cladribine, fludarabine, procaine, epigallocatechin gallate (EGCG), hydralazine, genistein, equol, curcumin, disulfiram, resveratrol, caffeic acid, CP-4200, zebularine, NPEOC-DAC, T-dCyd, 5-aza-t-dCyd, RG108, DC-05, DC-501, DC-517, SGI-1027, CM-272, CM-579, Psammaplin A, Psammaplin G, and UVI5008.

[0102] Definitions

[0103] The term "pharmaceutical composition" includes compositions comprising an active ingredient, and a pharmaceutically acceptable excipient, carrier, or diluent, wherein the active ingredient is Compound 1 or a pharmaceutically acceptable salt thereof, or an HDAC inhibitor or a pharmaceutically acceptable salt thereof, or an additional chemotherapeutic agent. The term "pharmaceutically acceptable excipient, carrier, or diluent" includes compounds, materials, compositions, and / or dosage forms which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of humans and animals without excessive toxicity, irritation, allergic response, or other problem or complication commensurate with a reasonable benefit / risk ratio as determined by those skilled in the art. In some embodiments, the pharmaceutical composition is in a solid dosage form, such as a capsule, tablet, granule, powder, or sachet. In some embodiments, the pharmaceutical composition is in the form of a sterile injectable solution in one or more aqueous or non-aqueous, non-toxic parenterally acceptable buffers, diluents, solubilizers, co-solvents, or carriers. The sterile injectable preparation can also be a sterile injectable aqueous or oleaginous suspension or a suspension in non-aqueous diluents, carriers, or co-solvents, which can be formulated according to known programs using one or more suitable dispersing or wetting agents and suspending agents. The pharmaceutical composition can be a solution for iv bolus / infusion injection or a lyophilized system for reconstitution with a buffer system with or without other excipients (alone or with excipients). The lyophilized freeze-dried material can be prepared from non-aqueous solvents or aqueous solvents. The dosage form can also be a concentrate for further dilution for subsequent infusion.

[0104] The language "treat / treating / treatment" includes reducing or inhibiting tumor cells of a hematological malignancy in a subject, ameliorating one or more symptoms of a hematological malignancy in a subject, or slowing or delaying the progression of a hematological malignancy in a subject. The language "treat / treating / treatment" also includes reducing or inhibiting the growth of a tumor or the proliferation of cancer cells in a subject.

[0105] The language "inhibit / inhibition / inhibiting" includes a reduction in the baseline activity of a biological activity or process.

[0106] The term "subject" includes warm-blooded mammals, such as primates, dogs, cats, rabbits, rats, and mice. In some embodiments, the subject is a primate, such as a human. In some embodiments, the subject has a hematological malignancy.

[0107] The term "therapeutically effective amount" includes an amount of Compound 1 and an amount of an HDAC inhibitor that together will elicit a biological or medical response in a subject, for example, reducing or inhibiting tumor cells; ameliorating symptoms of a hematological malignancy; or slowing or delaying the progression of a hematological malignancy. In some embodiments, the language "therapeutically effective amount" includes an amount of Compound 1 and an HDAC inhibitor that together are effective to at least partially alleviate, inhibit, and / or ameliorate a hematological malignancy or inhibit tumor cells and / or reduce or inhibit the proliferation of cancer cells in a subject. In some embodiments, the language "therapeutically effective amount" includes an amount of Compound 1, an HDAC inhibitor, and an additional chemotherapeutic agent that together are effective to at least partially alleviate, inhibit, and / or ameliorate a hematological malignancy or inhibit tumor cells and / or reduce or inhibit the proliferation of cancer cells in a subject.

[0108] In some embodiments, a method of treating a hematological malignancy in a subject in need thereof is disclosed, comprising administering to the subject a first amount of Compound 1, or a pharmaceutically acceptable salt thereof, and a second amount of an HDAC inhibitor, or a pharmaceutically acceptable salt thereof. In this method, the first amount and the second amount together comprise a therapeutically effective amount. In some of these embodiments, a third amount of an additional chemotherapeutic agent is administered.

[0109] In some embodiments, Compound 1, or a pharmaceutically acceptable salt thereof, for use in treating a hematological malignancy in a subject is disclosed, wherein the treatment comprises administering to the subject i) the Compound 1, or a pharmaceutically acceptable salt thereof, and ii) an HDAC inhibitor, or a pharmaceutically acceptable salt thereof, alone, sequentially, or simultaneously. In some of these embodiments, the treatment further comprises administering to the subject iii) an additional chemotherapeutic agent, alone, sequentially, or simultaneously.

[0110] In some embodiments, an HDAC inhibitor, or a pharmaceutically acceptable salt thereof, for use in treating a hematological malignancy in a subject is disclosed, wherein the treatment comprises administering to the subject i) the HDAC inhibitor, or a pharmaceutically acceptable salt thereof, and ii) Compound 1, or a pharmaceutically acceptable salt thereof, alone, sequentially, or simultaneously. In some of these embodiments, the treatment further comprises administering to the subject iii) an additional chemotherapeutic agent, alone, sequentially, or simultaneously.

[0111] In some embodiments, the use of Compound 1, or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for use in treating a hematological malignancy in a subject is disclosed, wherein the treatment comprises administering to the subject, either separately, sequentially or simultaneously, i) the medicament comprising Compound 1, or a pharmaceutically acceptable salt thereof, and ii) an HDAC inhibitor or a pharmaceutically acceptable salt thereof. In some of these embodiments, the treatment further comprises administering to the subject, either separately, sequentially or simultaneously, iii) an additional chemotherapeutic agent.

[0112] In some embodiments, Compound 1, or a pharmaceutically acceptable salt thereof, and an HDAC inhibitor, or a pharmaceutically acceptable salt thereof (and an additional chemotherapeutic agent, if present), are administered separately, sequentially or simultaneously in a treatment cycle. In some embodiments, Compound 1, or a pharmaceutically acceptable salt thereof, is administered continuously in a treatment cycle, and an HDAC inhibitor, or a pharmaceutically acceptable salt thereof, is also administered continuously in a treatment cycle. In some of these embodiments, an additional chemotherapeutic agent is also administered continuously in a treatment cycle.

[0113] In some embodiments, the HDAC inhibitor is selected from abexinostat (PCI-24781), pracinostat (SB939), quisinostat (JNJ-26481585), tenovin-6 (CHR-2845), panobinostat (LBH589), belinostat (PXD101), givinostat (ITF2357), tuninostat (CS-055, HBI-8000), vorinostat (suberoylanilide hydroxamic acid, SAHA), mocetinostat (MGCD0103), valproic acid (VAL), entinostat (MS275), romidepsin (depsipeptide, FK228), and trichostatin (TPX).

[0114] In some embodiments, the HDAC inhibitor is selected from vorinostat, belinostat, panobinostat, givinostat, or romidepsin.

[0115] In further embodiments, the HDAC inhibitor is selected from vorinostat or romidepsin.

[0116] The term "continuously" or "continuously" refers to the administration of a therapeutic agent, e.g., Compound 1, at regular intervals without stopping or interruption, i.e., without a gap day. A "gap day" refers to a day in which a therapeutic agent is not administered.

[0117] As used herein, a “cycle,” “treatment cycle,” or “dosing regimen” refers to a period of combination therapy that is repeated on a regular schedule. For example, treatment can be given for one week, two weeks, or three weeks, with Compound 1 and the HDAC inhibitor administered in a coordinated manner. In some embodiments, a treatment cycle is about 1 week to about 3 months. In some embodiments, a treatment cycle is about 5 days to about 1 month. In some embodiments, a treatment cycle is about 1 week to about 3 weeks. In some embodiments, a treatment cycle is about 1 week, about 10 days, about 2 weeks, about 3 weeks, about 4 weeks, about 2 months, or about 3 months.

[0118] In some embodiments, Compound 1, or a pharmaceutically acceptable salt thereof, and the HDAC inhibitor, or a pharmaceutically acceptable salt thereof (and the additional chemotherapeutic agent, if present), are administered to the human subject in one or more treatment cycles (e.g., a course of treatment). A “course of treatment” comprises multiple treatment cycles, which can be repeated on a regular schedule, or adjusted to a gradually decreasing schedule as the patient’s disease progression is monitored. For example, a patient’s treatment cycle can have longer treatment cycles and / or shorter rest cycles at the beginning of the course of treatment (e.g., when the patient is first diagnosed), and as the cancer goes into remission, the rest cycles are lengthened, increasing the length of one treatment cycle. The length of the periods of treatment and rest in a treatment cycle, the number of treatment cycles, and the length of the course of treatment can be determined and adjusted by the skilled person throughout the course of treatment based on the patient’s disease progression, treatment tolerance, and prognosis. In some embodiments, the method comprises 1 to 10 treatment cycles. In some embodiments, the method comprises 2 to 8 treatment cycles.

[0119] In some embodiments, Compound 1, or a pharmaceutically acceptable salt thereof, is administered for 28 days in a 28-day treatment cycle, and the HDAC inhibitor, or a pharmaceutically acceptable salt thereof, is administered for 28 days in a 28-day treatment cycle.

[0120] In some embodiments, Compound 1, or a pharmaceutically acceptable salt thereof, is administered for 28 days in a 28-day treatment cycle, and the HDAC inhibitor, or a pharmaceutically acceptable salt thereof, is administered on days 1, 8, and 15 of a 28-day treatment cycle.

[0121] In some embodiments, Compound 1, or a pharmaceutically acceptable salt thereof, is administered for 28 days in a 28-day treatment cycle, and the HDAC inhibitor, or a pharmaceutically acceptable salt thereof, is administered on days 1, 3, 8, 10, and 12 of a 21-day treatment cycle.

[0122] In some embodiments, Compound 1, or a pharmaceutically acceptable salt thereof, is administered for 28 days in a 28-day treatment cycle, and the HDAC inhibitor, or a pharmaceutically acceptable salt thereof, is administered on days 1 to 5 of a 21-day treatment cycle.

[0123] Dose

[0124] In some embodiments, Compound 1, or a pharmaceutically acceptable salt thereof, is administered orally. In some embodiments, Compound 1, or a pharmaceutically acceptable salt thereof, is in tablet dosage form. In some embodiments, Compound 1 as a hemifumarate is administered at a dose of 40 mg per day. In some embodiments, Compound 1 as a hemifumarate is administered at a dose of 80 mg per day.

[0125] In some embodiments, the HDAC inhibitor, or a pharmaceutically acceptable salt thereof, is administered orally. In some embodiments, the HDAC inhibitor, or a pharmaceutically acceptable salt thereof, is in tablet dosage form. In some embodiments, the HDAC inhibitor, or a pharmaceutically acceptable salt thereof, is in capsule dosage form. In some embodiments, the HDAC inhibitor, or a pharmaceutically acceptable salt thereof, is administered at a dose of 10 mg to 1 g per day.

[0126] In some embodiments, the HDAC inhibitor, or a pharmaceutically acceptable salt thereof, is administered as an intravenous (IV) infusion.

[0127] In some embodiments, the additional chemotherapeutic agent is administered orally. In some embodiments, the additional chemotherapeutic agent is in tablet dosage form. In some embodiments, the additional chemotherapeutic agent is in capsule dosage form. In some embodiments, the additional chemotherapeutic agent is administered by injection. In some embodiments, the additional chemotherapeutic agent is administered by intravenous (IV) infusion. In some embodiments, the additional chemotherapeutic agent is administered at a dose of 10 mg to 1 g per day.

[0128] In some embodiments, Compound 1 and the HDAC inhibitor are taken together on an empty stomach, with no food intake two hours before and one hour after the empty stomach.

[0129] In some embodiments, Compound 1 is taken on an empty stomach, with no food intake two hours before and one hour after Compound 1, and the HDAC inhibitor is taken with food, thus at least two hours before or one hour after Compound 1.

[0130] In some embodiments, the HDAC inhibitor is dosed weekly.

[0131] In some embodiments, a pharmaceutical product comprising i) Compound 1, or a pharmaceutically acceptable salt thereof, and ii) an HDAC inhibitor, or a pharmaceutically acceptable salt thereof, is disclosed. In some embodiments, Compound 1, or a pharmaceutically acceptable salt thereof, and the HDAC inhibitor, or a pharmaceutically acceptable salt thereof, are present in a single dosage form. In some embodiments, Compound 1, or a pharmaceutically acceptable salt thereof, and the HDAC inhibitor, or a pharmaceutically acceptable salt thereof, are present in separate dosage forms. In some of these embodiments, the pharmaceutical product further comprises iii) an additional chemotherapeutic agent.

[0132] In some embodiments, a kit comprising: a first pharmaceutical composition comprising Compound 1, or a pharmaceutically acceptable salt thereof; a second pharmaceutical composition comprising an HDAC inhibitor, or a pharmaceutically acceptable salt thereof; and instructions for using the first pharmaceutical composition and the second pharmaceutical composition in combination is disclosed. In some of these embodiments, the kit further comprises a third pharmaceutical composition comprising an additional chemotherapeutic agent, and the instructions are for using the first pharmaceutical composition, the second pharmaceutical composition, and the third pharmaceutical composition in combination.

[0133] In some embodiments, the HDAC inhibitor is abexinostat (PCI-24781), pracinostat (SB939), quisinostat (JNJ-26481585), tenovinc (CHR-2845), panobinostat (LBH589), belinostat (PXD101), givinostat (ITF2357), tuninostat (CS-055, HBI-8000), vorinostat (suberoylanilide hydroxamic acid, SAHA), mocetinostat (MGCD0103), valproic acid (VAL), entinostat (MS275), romidepsin (depsipeptide, FK228), and trichostatin (TPX).

[0134] In some embodiments, the HDAC inhibitor is vorinostat. Vorinostat as monotherapy is administered orally, for example by tablet or capsule. The dosing regimen for vorinostat is 400 mg or 300 mg once daily, taken with food, and the strength of vorinostat capsules is 100 mg. In some embodiments, vorinostat is administered at a dose of 100 mg-500 mg per day. In some embodiments, vorinostat is administered at a dose of 200 mg, 300 mg, or 400 mg per day. In some embodiments, vorinostat is administered at a dose of 300 mg per day. In some embodiments, vorinostat is administered at a dose of 400 mg per day. In some embodiments, the dose of vorinostat is administered orally as 3 or 4 100 mg capsules per day. In further embodiments, vorinostat is administered with food each day.

[0135] In some embodiments, a pharmaceutical product comprising i) Compound 1, or a pharmaceutically acceptable salt thereof, and ii) vorinostat, or a pharmaceutically acceptable salt thereof, is disclosed. In some embodiments, Compound 1, or a pharmaceutically acceptable salt thereof, and vorinostat, or a pharmaceutically acceptable salt thereof, are present in a single dosage form. In some embodiments, Compound 1, or a pharmaceutically acceptable salt thereof, and vorinostat, or a pharmaceutically acceptable salt thereof, are present as separate dosage forms.

[0136] In some embodiments, the HDAC inhibitor is belinostat. Belinostat is administered intravenously. The recommended dose of belinostat is 1000 mg per square meter of body surface area administered by intravenous infusion over 30 minutes once daily on days 1-5 of a 21-day cycle. Cycles can be repeated until disease progression or unacceptable toxicity occurs. Dose adjustments for thrombocytopenia and neutropenia are common for platelet and absolute neutrophil minimum count counts. Belinostat for injection is supplied in a vial with 500 mg of lyophilized powder for reconstitution. In some embodiments, belinostat is administered by intravenous infusion over 20-40 minutes once daily at a dose of 500-1200 mg per square meter of body surface area. In further embodiments, belinostat is administered by intravenous infusion over 20-40 minutes once daily at a dose of 500-1200 mg per square meter of body surface area on days 1-5 of a 21-day cycle.

[0137] In some embodiments, the HDAC inhibitor is panobinostat. Panobinostat is administered orally, for example, by tablet or capsule. The recommended starting dose of panobinostat is 20 mg taken orally once daily on days 1, 3, 5, 8, 10, and 12 of a 21-day cycle. Panobinostat capsules are available in three strengths (10 mg, 15 mg, and 20 mg). In some embodiments, panobinostat is administered at a dose of 5-40 mg once daily. In some embodiments, panobinostat is administered at a dose of 20 mg once daily. In some embodiments, panobinostat is administered at a dose of 5-40 mg once daily every 2-3 days for 2 weeks. In further embodiments, panobinostat is administered at a dose of 5-40 mg once daily on days 1, 3, 5, 8, 10, and 12 of a 21-day cycle.

[0138] In some embodiments, the HDAC inhibitor is vorinostat. Vorinostat is administered orally, for example, by tablet or capsule. The recommended dose and dosage regimen of vorinostat is 400 mg once daily. In some embodiments, vorinostat is administered at a dose of 200 mg to 600 mg once daily. In some embodiments, vorinostat is administered at a dose of 400 mg once daily. In some embodiments, 400 mg of vorinostat is administered once every 3 days.

[0139] In some embodiments, the HDAC inhibitor is romidepsin. Romidepsin is administered intravenously. The recommended dose and dosage regimen of romidepsin is 14 mg per square meter of body surface area administered over four hours on days 1, 8, and 15 of a 28-day cycle. Treatment can need to be stopped or interrupted, with or without dose reduction to 10 mg per square meter of body surface area, to control adverse drug reactions. Romidepsin for injection is supplied in a vial with 10 mg for reconstitution. In some embodiments, romidepsin is administered at a dose of 5 mg to 30 mg per square meter of body surface area administered over a period of 2 hours to 6 hours. In further embodiments, romidepsin is administered at a dose of 5 mg to 30 mg per square meter of body surface area administered once a week. In further embodiments, romidepsin is administered at a dose of 5 mg to 30 mg per square meter of body surface area administered over a period of 2 hours to 6 hours on days 1, 8, and 15 of a 28-day cycle. In some embodiments, romidepsin is administered at a dose of 10 mg or 14 mg per square meter of body surface area administered over a period of 2 hours to 6 hours. In further embodiments, romidepsin is administered once a week. In further embodiments, romidepsin is administered over a period of about 4 hours.

[0140] In some embodiments, a pharmaceutical product comprising i) Compound 1, or a pharmaceutically acceptable salt thereof, and ii) romidepsin, or a pharmaceutically acceptable salt thereof, is disclosed. In some embodiments, Compound 1, or a pharmaceutically acceptable salt thereof, and romidepsin, or a pharmaceutically acceptable salt thereof, are present as separate dosage forms. In some embodiments, Compound 1 is administered orally as a tablet or capsule, and romidepsin is administered intravenously. In some embodiments, oral and intravenous administration is sequential or simultaneous administration.

[0141] In some embodiments, the hematological malignancy is a lymphoma, including cutaneous B-cell lymphoma, cutaneous T-cell lymphoma, Hodgkin lymphoma, non-Hodgkin lymphoma, FL, mantle cell lymphoma (MCL), MZL, DLBCL, SLL, PTCL, and Waldenstrom macroglobulinemia.

[0142] In some embodiments, the hematological malignancy is leukemia, including ALL, AML, CLL, chronic myelogenous leukemia, hairy cell leukemia, myelodysplastic syndrome, myeloproliferative disorder, and myelofibrosis.

[0143] In some embodiments, the hematological malignancy is myeloma, including multiple myeloma.

[0144] Without wishing to be bound by theory, the combination of Compound 1 and an HDAC inhibitor can benefit patients who are non-responsive or refractory to Compound 1 or the HDAC inhibitor. In addition, the combination of Compound 1 and an HDAC inhibitor can deepen or make more durable the response to Compound 1 or the HDAC inhibitor. Furthermore, the combination of Compound 1 and an HDAC inhibitor can allow for a reduction in the dose of the HDAC inhibitor, thereby improving tolerability and quality of life.

[0145] In addition, where the additional chemotherapeutic agent is a second HDAC inhibitor, the above reasoning can equally apply. Where the additional chemotherapeutic agent is a DNA methyltransferase inhibitor, the combination can benefit patients who are non-responsive or refractory to any of Compound 1, the HDAC inhibitor, and the DNMT inhibitor. In addition, the combination of Compound 1, the HDAC inhibitor, and the DNMT inhibitor can deepen or make more durable the response to Compound 1, the HDAC inhibitor, or the DNMT inhibitor. Furthermore, the combination of Compound 1, the HDAC inhibitor, and the DNMT inhibitor can allow for a reduction in the dose of the HDAC inhibitor or the DNMT inhibitor, thereby improving tolerability and quality of life.

[0146] Methods of the application

[0147] As described in more detail below, the present inventors have surprisingly found that the combination of Compound 1 and an HDAC inhibitor has a synergistic effect on the proliferation of hematological malignancy cell lines. Accordingly, a combination therapy with improved anti-proliferative activity can be provided.

[0148] Secondly, the present inventors have surprisingly found that the synergistic anti-tumor activity of the combination of Compound 1 and an HDAC inhibitor is not limited to a particular hematological malignancy. Accordingly, a combination therapy with improved therapeutic activity against a variety of hematological malignancies can be provided.

[0149] Additionally, the present inventors have surprisingly found that the combination of Compound 1 and an HDAC inhibitor results in tumor cell killing, which is not observed when either inhibitor is used alone. Accordingly, a combination that can reduce tumor burden can be provided.

[0150] Furthermore, the present inventors have surprisingly found that the combination of Compound 1 and an HDAC inhibitor has synergistic effects at sub-therapeutic doses. Accordingly, a combination with improved tolerability can be provided.

[0151] Examples

[0152] The compounds of the application will now be further explained by reference to the following non-limiting examples.

[0153] Example 1. Efficacy of Compound 1 in combination with HDAC inhibitors vorinostat and romidepsin in in vitro assays using the cutaneous T-cell lymphoma (CTCL) cell line HH Figure 1

[0154] HH (CRL-2105) cells were exposed to increasing doses of Compound 1, increasing doses of Volitinostat or Romidepsin and increasing doses of the combination of Compound 1 and Volitinostat or Romidepsin. Compound 1 and Volitinostat were used with a maximum concentration of 10 mM after an eight-fold dose response design based on 1 :3 compound dilutions plus an untreated control. Romidepsin was used with a maximum concentration of 20 mM after an eight-fold dose response design based on 1 :2 compound dilutions plus an untreated control.

[0155] Cells were incubated for 72 hours at 37°C and 5% C02. The anti-proliferative effect of single and combination treatments was determined by adding 20 pL of MTT [3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide] reagent (Sigma Aldrich, Buchs, Switzerland) to each well and incubating the plates for 4 hours at 37°C, followed by the addition of 50 pL of sodium dodecyl sulfate (SDS) (250 mM SDS, 0.21% fuming HC1) lysis buffer. Lysed cells were left overnight and then absorbance was read at 570 nm using a Cytation 3 instrument (BioTek, Winoosku, VT, USA). The effect of the combination was determined according to the Chou-Talalay Combination Index (CI) (Chou 2008, Chou 2010) and calculated with the Synergy R package (Lee 2007). The effect of the combination was defined as strongly synergistic for CI values below <0.3, synergistic for CI values between 0.3 and 0.9, additive for CI values between 0.9 and 1.1 and antagonistic for CI values >1.1.

[0156] Data from two representative experiments are shown in Figure 2 and Example 2. Efficacy of Compound 1 in combination with HDAC inhibitors in in vitro assays using several different hematological cell lines

[0157] The combination of Compound 1 and Volitinostat in HH was synergistic with a median CI value of 0.64. The combination of Compound 1 and Romidepsin in HH was synergistic with a median CI value of 0.89.

[0158] HDAC inhibitor Cell line (origin)

[0159] ​Cell lines from different hematological malignancies were exposed to increasing doses of Compound 1, increasing doses of HDAC inhibitors, and the combination of increasing doses of Compound 1 and HDAC inhibitors. Compound 1 and vorinostat were used at a maximum concentration of 10 mM after an eight-fold dose response design based on a 1:3 compound dilution plus an untreated control. Belinostat was used at a maximum concentration of 10 mM after an eight-fold dose response design based on a 1:4 compound dilution plus an untreated control.

[0160] Cells were incubated for 72 hours at 37°C and 5% C02. The anti-proliferative effect of single and combination treatments was determined by adding 20 pL of MTT [3-(4,5-dimethylthiazolyl-2)-2,5-diphenyltetrazolium bromide] reagent (Sigma Aldrich, Buchs, Switzerland) to each well and incubating the plates for 4 hours at 37°C, followed by the addition of 50 pL of sodium dodecyl sulfate (SDS) (250 pM SDS, 0.21% fuming HC1) lysis buffer. Lysed cells were kept overnight, and then absorbance was read at 570 nm using a Cytation 3 instrument (BioTek, Winoosku, VT, USA). The effect of the combination was determined according to the Chou-Talalay Combination Index (CI) (Chou 2008, Chou 2010) and calculated with the Synergy R package (Lee 2007). The effect of the combination was defined as strongly synergistic for CI values below <0.3, synergistic for CI values between 0.3 and 0.9, additive for CI values between 0.9 and 1.1, and antagonistic for CI values >1.1.

[0161] The CI values of representative experiments are shown in Table 1:

[0162] Table 1. CI values of combinations of Compound 1 and HDAC inhibitors in different hematological cell lines

[0163] CI value (median) 95% CI confidence interval Belinostat Farage (DLBCL) Belinostat JVM2 (MCL) 0.51 0.46-0.65 Belinostat TMD8 (DLBCL) 0.62 0.44-1.1 Belinostat A20 (murine B-cell lymphoma) 0.87 0.62-1.2 Belinostat MEC1 (CLL) 0.87 0.45-1.3 Vorinostat Farage (DLBCL) 0.45 0.36-0.67 Vorinostat JVM2 (MCL) 0.69 0.58-0.92 Vorinostat MEC1 (CLL) 0.71 0.58-0.82 Statement ​ 0.83 0.66-1.49

[0164] References

[0165] To more fully describe and disclose the present application and the state of the art to which the present application pertains, many publications are cited herein. The complete citations for these references are provided below. The entire disclosure of each of these publications is incorporated by reference herein.

[0166]

[0167]

[0168] ​

[0169] 1. A method of treating a hematological malignancy in a subject in need thereof comprising administering to the subject a first amount of a compound of Formula I:

[0170]

[0171] or a pharmaceutically acceptable salt thereof, and a second amount of an HDAC inhibitor or a pharmaceutically acceptable salt thereof, wherein the first amount and the second amount together comprise a therapeutically effective amount.

[0172] 2. The method of statement 1, wherein the hematological malignancy is a lymphoma, a leukemia, a myeloma, a myelodysplastic syndrome, or a myeloproliferative disorder.

[0173] 3. The method of statement 2, wherein the lymphoma is cutaneous B-cell lymphoma, cutaneous T-cell lymphoma, Hodgkin’s lymphoma, non-Hodgkin’s lymphoma, FL, mantle cell lymphoma (MCL), MZL, DLBCL, SLL, PTCL, and Waldenstrom’s macroglobulinemia.

[0174] 4. The method of statement 2, wherein the leukemia is ALL, AML, CLL, chronic myelogenous leukemia, hairy cell leukemia, myelodysplastic syndrome, myeloproliferative disorder, and myelofibrosis.

[0175] 5. The method of any one of statements 1 to 4, wherein the HDAC inhibitor is selected from abexinostat, pracinostat, quinoxyryl, tenovinc, panobinostat, belinostat, givinostat, tusifinostat, vorinostat, mocetinostat, valproic acid, entinostat, romidepsin, and trilostin.

[0176] 6. The method of any one of statements 1 to 5, wherein Compound 1 is administered as a hemifumarate salt at a dose of 40 mg or 80 mg per day.

[0177] 7. The method of any one of statements 1 to 6, wherein the HDAC inhibitor or a pharmaceutically acceptable salt thereof is administered at a dose of 10 mg to 1 g per day.

[0178] 8. The method of any one of statements 1 to 7, wherein the HDAC inhibitor is selected from vorinostat or a pharmaceutically acceptable salt thereof.

[0179] 9. The method of any one of statements 1 to 8, wherein the HDAC inhibitor is vorinostat or a pharmaceutically acceptable salt thereof, and is administered at a dose of 200 mg, 300 mg, or 400 mg per day.

[0180] 10. The method of any one of statements 1 to 7, wherein the HDAC inhibitor is romidepsin.

[0181] 11. The method of any one of statements 1 to 10, wherein a third amount of an additional chemotherapeutic agent is administered.

[0182] 12. The method of statement 11, wherein the additional chemotherapeutic agent is a second HDAC inhibitor.

[0183] 13. The method of statement 11, wherein the additional chemotherapeutic agent is a DNA methyltransferase inhibitor.

[0184] 14. The method of statement 13, wherein the DNA methyltransferase inhibitor is selected from 5-azacitidine, 5-aza-2’-deoxycytidine, clofarabine, decitabine, GSK3685032 RX-3117, 5-fluoro-2-deoxycytidine, 6-dihydro-5-azacytidine, fazadirabine, cladrabine, fludarabine, procain, epigallocatechin gallate, hydralazine, genistein, equol, curcumin, disulfiram, resveratrol, caffeic acid, CP-4200, zebularine, NPEOC-DAC, T-dCyd, 5-aza-t-dCyd, RG108, DC-05, DC-501, DC-517, SGI-1027, CM-272, CM-579, palmarine A, palmarine G, and UVI5008.

[0185] 15. A compound of Formula I:

[0186]

[0187] or a pharmaceutically acceptable salt thereof, for use in treating a hematological malignancy in a subject, wherein the treatment comprises administering to the subject i) the compound 1 or a pharmaceutically acceptable salt thereof, and ii) an HDAC inhibitor or a pharmaceutically acceptable salt thereof, either alone, sequentially, or simultaneously.

[0188] 16. The compound 1 or a pharmaceutically acceptable salt thereof for use according to statement 15, wherein the hematological malignancy is a lymphoma, a leukemia, a myeloma, a myelodysplastic syndrome, or a myeloproliferative disorder.

[0189] 17. The compound 1 or a pharmaceutically acceptable salt thereof for use according to statement 16, wherein the lymphoma is cutaneous B-cell lymphoma, cutaneous T-cell lymphoma, Hodgkin’s lymphoma, non-Hodgkin’s lymphoma, FL, mantle cell lymphoma (MCL), MZL, DLBCL, SLL, PTCL, and Waldenstrom’s macroglobulinemia.

[0190] 18. Compound 1, or a pharmaceutically acceptable salt thereof, for use according to statement 16, wherein the leukemia is ALL, AML, CLL, chronic myelogenous leukemia, hairy cell leukemia, myelodysplastic syndrome, myeloproliferative disorder, and myelofibrosis.

[0191] 19. Compound 1, or a pharmaceutically acceptable salt thereof, for use according to any one of statements 15 to 18, wherein the HDAC inhibitor is selected from abexinostat, pracinostat, quinoxyrycin, tenovinc, panobinostat, belinostat, givinostat, tuninostat, vorinostat, mocetinostat, valproic acid, entinostat, romidepsin, and trichostatin.

[0192] 20. Compound 1, or a pharmaceutically acceptable salt thereof, for use according to any one of statements 15 to 19, wherein Compound 1 is administered as a hemifumarate salt at a dose of 40 mg or 80 mg per day.

[0193] 21. Compound 1, or a pharmaceutically acceptable salt thereof, for use according to any one of statements 15 to 20, wherein the HDAC inhibitor, or a pharmaceutically acceptable salt thereof, is administered at a dose of 10 mg to 1 g per day.

[0194] 22. Compound 1, or a pharmaceutically acceptable salt thereof, for use according to any one of statements 15 to 21, wherein the HDAC inhibitor is selected from vorinostat or a pharmaceutically acceptable salt thereof.

[0195] 23. Compound 1, or a pharmaceutically acceptable salt thereof, for use according to any one of statements 15 to 22, wherein the HDAC inhibitor is vorinostat or a pharmaceutically acceptable salt thereof, and is administered at a dose of 200 mg, 300 mg, or 400 mg per day.

[0196] 24. Compound 1, or a pharmaceutically acceptable salt thereof, for use according to any one of statements 15 to 21, wherein the HDAC inhibitor is romidepsin.

[0197] 25. Compound 1, or a pharmaceutically acceptable salt thereof, for use according to any one of claims 15 to 24, wherein the treatment further comprises administering iii) an additional chemotherapeutic agent to the subject, alone, sequentially, or simultaneously.

[0198] 26. Compound 1, or a pharmaceutically acceptable salt thereof, for use according to statement 25, wherein the additional chemotherapeutic agent is a second HDAC inhibitor.

[0199] 27. Compound 1, or a pharmaceutically acceptable salt thereof, for use according to statement 25, wherein the additional chemotherapeutic agent is a DNA methyltransferase inhibitor.

[0200] 28. Compound 1, or a pharmaceutically acceptable salt thereof, for use according to statement 27, wherein the DNA methyltransferase inhibitor is selected from 5-azacitidine, 5-aza-2'- deoxycytidine, clofarabine, decitabine, GSK3685032 RX-3117, 5-fluoro-2-deoxycytidine, 6-dihydro-5-azacytidine, fazarabine, cladrabine, fludarabine, procain, epigallocatechin gallate, hydralazine, genistein, equol, curcumin, disulfiram, resveratrol, caffeic acid, CP-4200, zebularine, NPEOC-DAC, T-dCyd, 5-aza-t-dCyd, RG108, DC-05, DC-501, DC-517, SGI-1027, CM-272, CM-579, palmarine A, palmarine G, and UVI5008.

[0201] 29. An HDAC inhibitor, or a pharmaceutically acceptable salt thereof, for use in treating a hematological malignancy in a subject, wherein the treatment comprises administering to the subject i) the HDAC inhibitor, or a pharmaceutically acceptable salt thereof, and ii) a compound of Formula I:

[0202]

[0203] or a pharmaceutically acceptable salt thereof, either alone, sequentially, or simultaneously.

[0204] 30. The HDAC inhibitor, or a pharmaceutically acceptable salt thereof, for use according to statement 29, wherein the hematological malignancy is a lymphoma, a leukemia, a myeloma, a myelodysplastic syndrome, or a myeloproliferative disorder.

[0205] 31. The HDAC inhibitor, or a pharmaceutically acceptable salt thereof, for use according to statement 30, wherein the lymphoma is cutaneous B-cell lymphoma, cutaneous T-cell lymphoma, Hodgkin’s lymphoma, non-Hodgkin’s lymphoma, FL, mantle cell lymphoma (MCL), MZL, DLBCL, SLL, PTCL, and Waldenstrom’s macroglobulinemia.

[0206] 32. The HDAC inhibitor, or a pharmaceutically acceptable salt thereof, for use according to statement 30, wherein the leukemia is ALL, AML, CLL, chronic myelogenous leukemia, hairy cell leukemia, myelodysplastic syndrome, myeloproliferative disorder, and myelofibrosis.

[0207] 33. The HDAC inhibitor or pharmaceutically acceptable salt thereof for use according to any one of statements 29 to 32, wherein the HDAC inhibitor is selected from abexinostat, pracinostat, quinozostat, tenovincostat, panobinostat, belinostat, givinostat, tusisetat, vorinostat, mocetinostat, valproic acid, entinostat, romidepsin, and trichostatin.

[0208] 34. The HDAC inhibitor or pharmaceutically acceptable salt thereof for use according to any one of statements 29 to 33, wherein Compound 1 is administered as a hemifumarate salt at a dose of 40 mg or 80 mg per day.

[0209] 35. The HDAC inhibitor or pharmaceutically acceptable salt thereof for use according to any one of statements 29 to 34, wherein the HDAC inhibitor or pharmaceutically acceptable salt thereof is administered at a dose of 10 mg to 1 g per day.

[0210] 36. The HDAC inhibitor or pharmaceutically acceptable salt thereof for use according to any one of statements 29 to 35, wherein the HDAC inhibitor is selected from vorinostat or a pharmaceutically acceptable salt thereof.

[0211] 37. The HDAC inhibitor or pharmaceutically acceptable salt thereof for use according to any one of statements 29 to 36, wherein the HDAC inhibitor is vorinostat or a pharmaceutically acceptable salt thereof, and is administered at a dose of 200 mg, 300 mg, or 400 mg per day.

[0212] 38. The HDAC inhibitor or pharmaceutically acceptable salt thereof for use according to any one of statements 29 to 37, wherein the HDAC inhibitor is romidepsin.

[0213] 39. The HDAC inhibitor or pharmaceutically acceptable salt thereof for use according to any one of claims 29 to 38, wherein the treatment further comprises administering iii) an additional chemotherapeutic agent to the subject, alone, sequentially, or simultaneously.

[0214] 40. The HDAC inhibitor or pharmaceutically acceptable salt thereof for use according to statement 39, wherein the additional chemotherapeutic agent is a second HDAC inhibitor.

[0215] 41. The HDAC inhibitor or pharmaceutically acceptable salt thereof for use according to statement 39, wherein the additional chemotherapeutic agent is a DNA methyltransferase inhibitor.

[0216] 42. The HDAC inhibitor or pharmaceutically acceptable salt thereof for use according to statement 41, wherein the DNA methyltransferase inhibitor is selected from 5-azacytidine, 5-aza-2'- deoxycytidine, clofarabine, decitabine, GSK3685032 RX-3117, 5-fluoro-2-deoxycytidine, 6-dihydro-5-azacytidine, fazarabine, cladrabine, fludarabine, procain, epigallocatechin gallate, hydralazine, genistein, equol, curcumin, disulfiram, resveratrol, caffeic acid, CP-4200, zebularine, NPEOC-DAC, T-dCyd, 5-aza-t-dCyd, RG108, DC-05, DC-501, DC-517, SGI-1027, CM-272, CM-579, palmarine A, palmarine G, and UVI5008.

[0217] 43. A compound of Formula I:

[0218]

[0219] or a pharmaceutically acceptable salt thereof for use in the manufacture of a medicament for use in the treatment of a hematological malignancy, wherein the treatment comprises administering to the subject i) the medicament comprising Compound 1, or a pharmaceutically acceptable salt thereof, and ii) an HDAC inhibitor, or a pharmaceutically acceptable salt thereof, either alone, sequentially, or simultaneously.

[0220] 44. The use of Compound 1, or a pharmaceutically acceptable salt thereof, according to statement 43, wherein the hematological malignancy is a lymphoma, a leukemia, a myeloma, a myelodysplastic syndrome, or a myeloproliferative disorder.

[0221] 45. The use of Compound 1, or a pharmaceutically acceptable salt thereof, according to statement 44, wherein the lymphoma is cutaneous B-cell lymphoma, cutaneous T-cell lymphoma, Hodgkin’s lymphoma, non-Hodgkin’s lymphoma, FL, mantle cell lymphoma (MCL), MZL, DLBCL, SLL, PTCL, and Waldenstrom’s macroglobulinemia.

[0222] 46. The use of Compound 1, or a pharmaceutically acceptable salt thereof, according to statement 44, wherein the leukemia is ALL, AML, CLL, chronic myelogenous leukemia, hairy cell leukemia, myelodysplastic syndrome, myeloproliferative disorder, and myelofibrosis.

[0223] 47. Use of Compound 1, or a pharmaceutically acceptable salt thereof, according to any one of statements 43 to 46, wherein the HDAC inhibitor is selected from abexinostat, pracinostat, quinoxyrycin, tenovinc, panobinostat, belinostat, givinostat, tusironstat, vorinostat, mocetinostat, valproic acid, entinostat, romidepsin, and trichostatin.

[0224] 48. Use of Compound 1, or a pharmaceutically acceptable salt thereof, according to any one of statements 43 to 47, wherein Compound 1 is administered as a hemifumarate salt at a dose of 40 mg or 80 mg per day.

[0225] 49. Use of Compound 1, or a pharmaceutically acceptable salt thereof, according to any one of statements 43 to 48, wherein the HDAC inhibitor, or a pharmaceutically acceptable salt thereof, is administered at a dose of 10 mg to 1 g per day.

[0226] 50. Use of Compound 1, or a pharmaceutically acceptable salt thereof, according to any one of statements 43 to 49, wherein the HDAC inhibitor is selected from vorinostat, or a pharmaceutically acceptable salt thereof.

[0227] 51. Use of Compound 1, or a pharmaceutically acceptable salt thereof, according to any one of statements 43 to 50, wherein the HDAC inhibitor is vorinostat, or a pharmaceutically acceptable salt thereof, and is administered at a dose of 200 mg, 300 mg, or 400 mg per day.

[0228] 52. Use of Compound 1, or a pharmaceutically acceptable salt thereof, according to any one of statements 43 to 51, wherein the HDAC inhibitor is romidepsin.

[0229] 53. Use of Compound 1, or a pharmaceutically acceptable salt thereof, for use according to any one of statements 43 to 52, wherein the treatment further comprises administering iii) an additional chemotherapeutic agent to the subject, alone, sequentially or simultaneously.

[0230] 54. Use of Compound 1, or a pharmaceutically acceptable salt thereof, for use according to statement 53, wherein the additional chemotherapeutic agent is a second HDAC inhibitor.

[0231] 55. Use of Compound 1, or a pharmaceutically acceptable salt thereof, for use according to statement 53, wherein the additional chemotherapeutic agent is a DNA methyltransferase inhibitor.

[0232] 56. The use of Compound 1, or a pharmaceutically acceptable salt thereof, for use according to statement 55, wherein the DNA methyltransferase inhibitor is selected from 5-azacitidine, 5-aza-2'-deoxycytidine, clofarabine, decitabine, GSK3685032 RX-3117, 5-fluoro-2-deoxycytidine, 6-dihydro-5-azacytidine, fazarabine, cladrabine, fludarabine, procain, epigallocatechin gallate, hydralazine, genistein, equol, curcumin, disulfiram, resveratrol, caffeic acid, CP-4200, zebularine, NPEOC-DAC, T-dCyd, 5-aza-t-dCyd, RG108, DC-05, DC-501, DC-517, SGI-1027, CM-272, CM-579, pamaquin A, pamaquin G, and UVI5008.

[0233] 57. A pharmaceutical product comprising i) a compound of Formula I:

[0234]

[0235] or a pharmaceutically acceptable salt thereof, and ii) an HDAC inhibitor or a pharmaceutically acceptable salt thereof.

[0236] 58. The pharmaceutical product according to statement 57, wherein the pharmaceutical product further comprises iii) an additional chemotherapeutic agent.

[0237] 59. A kit comprising: a first pharmaceutical composition comprising a compound of Formula I:

[0238]

[0239] or a pharmaceutically acceptable salt thereof; a second pharmaceutical composition comprising an HDAC inhibitor or a pharmaceutically acceptable salt thereof; and instructions for using the first pharmaceutical composition and the second pharmaceutical composition in combination.

[0240] 60. The kit according to statement 59, wherein the kit further comprises a third pharmaceutical composition comprising an additional chemotherapeutic agent, and the instructions are for using the first pharmaceutical composition, the second pharmaceutical composition, and the third pharmaceutical composition in combination.

Claims

1. A compound of Formula I: Formula I or a pharmaceutically acceptable salt thereof, for use in treating a hematological malignancy in a subject, wherein the treatment comprises administering to the subject i) the compound 1 or a pharmaceutically acceptable salt thereof, and ii) an HDAC inhibitor or a pharmaceutically acceptable salt thereof, alone, sequentially, or simultaneously.

2. The compound 1 or a pharmaceutically acceptable salt thereof for use according to claim 1, wherein the hematological malignancy is a lymphoma, a leukemia, a myeloma, a myelodysplastic syndrome, or a myeloproliferative disorder.

3. The compound 1 or a pharmaceutically acceptable salt thereof for use according to claim 2, wherein the lymphoma is cutaneous B-cell lymphoma, cutaneous T-cell lymphoma, Hodgkin’s lymphoma, non-Hodgkin’s lymphoma, FL, mantle cell lymphoma (MCL), MZL, DLBCL, SLL, PTCL, and Waldenstrom’s macroglobulinemia.

4. The compound 1 or a pharmaceutically acceptable salt thereof for use according to claim 2, wherein the leukemia is ALL, AML, CLL, chronic myelogenous leukemia, hairy cell leukemia, myelodysplastic syndrome, myeloproliferative disorder, and myelofibrosis.

5. The compound 1 or a pharmaceutically acceptable salt thereof for use according to any one of claims 1 to 4, wherein the HDAC inhibitor is selected from abexinostat, pracinostat, quinoxaline, tenovinc, panobinostat, belinostat, givinostat, tusifostat, vorinostat, mocetinostat, valproic acid, entinostat, romidepsin, and trichostatin.

6. The compound 1 or a pharmaceutically acceptable salt thereof for use according to any one of claims 1 to 5, wherein compound 1 is administered as a hemifumarate salt at a dose of 40 mg or 80 mg per day.

7. The compound 1 or a pharmaceutically acceptable salt thereof for use according to any one of claims 1 to 6, wherein the HDAC inhibitor or a pharmaceutically acceptable salt thereof is administered at a dose of 10 mg to 1 g per day.

8. The compound 1 or a pharmaceutically acceptable salt thereof for use according to any one of claims 1 to 7, wherein the HDAC inhibitor is selected from vorinostat or a pharmaceutically acceptable salt thereof.

9. The compound 1 or a pharmaceutically acceptable salt thereof for use according to any one of claims 1 to 8, wherein the HDAC inhibitor is vorinostat or a pharmaceutically acceptable salt thereof, and is administered at a dose of 200 mg, 300 mg, or 400 mg per day.

10. The compound 1 or a pharmaceutically acceptable salt thereof for use according to any one of claims 1 to 7, wherein the HDAC inhibitor is romidepsin.

11. The compound 1 or a pharmaceutically acceptable salt thereof for use according to any one of claims 1 to 10, wherein the treatment further comprises administering to the subject iii) an additional chemotherapeutic agent, wherein the additional chemotherapeutic agent is a second HDAC inhibitor or a DNA methyltransferase inhibitor. ​ 12. An HDAC inhibitor, or a pharmaceutically acceptable salt thereof, for use in treating a hematological malignancy in a subject, wherein the treatment comprises administering to the subject, either alone, sequentially or simultaneously, i) the HDAC inhibitor, or a pharmaceutically acceptable salt thereof, and ii) a compound of Formula I: Formula I or a pharmaceutically acceptable salt thereof.

13. The HDAC inhibitor, or a pharmaceutically acceptable salt thereof, for use according to claim 12, wherein the hematological malignancy is a lymphoma, a leukemia, a myeloma, a myelodysplastic syndrome, or a myeloproliferative disorder.

14. The HDAC inhibitor, or a pharmaceutically acceptable salt thereof, for use according to claim 13, wherein the lymphoma is cutaneous B-cell lymphoma, cutaneous T-cell lymphoma, Hodgkin’s lymphoma, non-Hodgkin’s lymphoma, FL, mantle cell lymphoma (MCL), MZL, DLBCL, SLL, PTCL, and Waldenstrom’s macroglobulinemia.

15. The HDAC inhibitor, or a pharmaceutically acceptable salt thereof, for use according to claim 13, wherein the leukemia is ALL, AML, CLL, chronic myelogenous leukemia, hairy cell leukemia, myelodysplastic syndrome, myeloproliferative disorder, and myelofibrosis.

16. The HDAC inhibitor, or a pharmaceutically acceptable salt thereof, for use according to any one of claims 12 to 15, wherein the HDAC inhibitor is selected from abexinostat, pracinostat, quinoxyryl, terosini, panobinostat, belinostat, givinostat, tusifinostat, vorinostat, mocetinostat, valproic acid, entinostat, romidepsin, and trichostatin.

17. The HDAC inhibitor, or a pharmaceutically acceptable salt thereof, for use according to any one of claims 12 to 16, wherein Compound 1 is administered as a hemifumarate salt at a dose of 40 mg or 80 mg per day.

18. The HDAC inhibitor, or a pharmaceutically acceptable salt thereof, for use according to any one of claims 12 to 17, wherein the HDAC inhibitor, or a pharmaceutically acceptable salt thereof, is administered at a dose of 10 mg to 1 g per day.

19. The HDAC inhibitor, or a pharmaceutically acceptable salt thereof, for use according to any one of claims 12 to 18, wherein the HDAC inhibitor is selected from vorinostat, or a pharmaceutically acceptable salt thereof.

20. The HDAC inhibitor, or a pharmaceutically acceptable salt thereof, for use according to any one of claims 12 to 19, wherein the HDAC inhibitor is vorinostat, or a pharmaceutically acceptable salt thereof, and is administered at a dose of 200 mg, 300 mg, or 400 mg per day.

21. The HDAC inhibitor, or a pharmaceutically acceptable salt thereof, for use according to any one of claims 12 to 20, wherein the HDAC inhibitor is romidepsin. ​ 22. The HDAC inhibitor, or a pharmaceutically acceptable salt thereof, for use according to any one of claims 12 to 21, wherein the treatment further comprises administering iii) an additional chemotherapeutic agent, either alone, sequentially or simultaneously to the subject, wherein the additional chemotherapeutic agent is a second HDAC inhibitor or a DNA methyltransferase inhibitor.

23. A pharmaceutical product comprising i) a compound of Formula I: Formula I or a pharmaceutically acceptable salt thereof, and ii) an HDAC inhibitor or a pharmaceutically acceptable salt thereof.

24. The pharmaceutical product according to claim 23, wherein the pharmaceutical product further comprises iii) an additional chemotherapeutic agent.

25. A kit comprising: a first pharmaceutical composition comprising a compound of Formula I: Formula I a second pharmaceutical composition comprising an HDAC inhibitor or a pharmaceutically acceptable salt thereof; and instructions for using the first pharmaceutical composition and the second pharmaceutical composition in combination.

26. The kit according to claim 25, wherein the kit further comprises a third pharmaceutical composition comprising an additional chemotherapeutic agent, and the instructions are for using the first pharmaceutical composition, the second pharmaceutical composition and the third pharmaceutical composition in combination. or a pharmaceutically acceptable salt thereof; ​ ​ ​

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