EP4734995A1 - Quinoline carboxamides for use in the treatment of mpn - Google Patents

Abstract

Described herein is certain quinoline carboxamides for use in the treatment of a myeloproliferative neoplasm (MPN). The quinoline carboxamides may more specifically be used in the treatment of advanced stages of MPN, including accelerated-phase MPN and secondary acute myeloid leukemia, i.e., acute myeloid leukemia evolving from an antecedent myeloproliferative neoplasm (post-MPN AML), optionally in combination with a further compound selected from a Janus kinase (JAK) inhibitor, a bromodomain and extra-terminal motif protein (BET) inhibitor, a B-cell lymphoma 2 (Bcl-2) inhibitor, and combinations thereof. Also included are pharmaceutical combinations of the quinoline carboxamides and second agents such as a BET inhibitor or a Bcl-2 inhibitor. Further included are certain quinoline carboxamides for use in combination with a BET inhibitor or a Bcl-2 inhibitor, in the treatment of a myeloproliferative neoplasm (MPN).

Description

QUINOLINE CARBOXAMIDES FOR USE IN THE TREATMENT OF MPN

CROSS-REFERENCE TO RELATED APPLICATIONS

[0001 ] The present application claims priority to, and the benefit of, U.S. Provisional Patent Application No. 63/510,726, filed 28 June 2023 and titled QUINOLINE CARBOXAMIDES FOR USE IN THE TREATMENT OF MPN, U.S. Provisional Patent Application No. 63/514,844, filed 21 July 2023 and titled QUINOLINE CARBOXAMIDES FOR USE IN THE TREATMENT OF MPN, and U.S. Provisional Patent Application No. 63/594,235, filed 30 October 2023 and titled QUINOLINE CARBOXAMIDES FOR USE IN THE TREATMENT OF MPN, each of which is incorporated by reference herein in its entirety for all purposes.

FIELD OF THE INVENTION

[0002] The present invention relates to the treatment of a myeloproliferative neoplasm (MPN) with certain quinoline carboxamides. The quinoline carboxamides may more specifically be used in the treatment of advanced stages of MPN, including accelerated-phase MPN and secondary acute myeloid leukemia, i.e., acute myeloid leukemia evolving from an antecedent myeloproliferative neoplasm (post-MPN AML), optionally in combination with a further compound selected from a JAK (Janus kinase) inhibitor, a BET (Bromodomain and Extra-Terminal motif protein) inhibitor, a Bcl-2 (B-cell lymphoma 2) inhibitor, and combinations thereof. Also included are pharmaceutical combinations of the quinoline carboxamides and second agents such as a BET inhibitor or a Bcl-2 inhibitor. The invention further relates to certain quinoline carboxamides for use in combination with at least one of a BET inhibitor and a Bcl-2 inhibitor, in the treatment of a myeloproliferative neoplasm (MPN).

BACKGROUND

[0003] Tasquinimod and a method for its preparation were described in WO 99/55678 and WO 00/03991, which publications also disclosed the utility of tasquinimod and other quinoline carboxamides for the treatment of diseases resulting from autoimmunity, such as multiple sclerosis, insulin-dependent diabetes mellitus, systemic lupus erythematosus, rheumatoid arthritis, inflammatory bowel disease and psoriasis and, furthermore, diseases where pathologic inflammation plays a major role, such as asthma, atherosclerosis, stroke, and Alzheimer’s disease. [0004] Processes for preparing tasquinimod also have been described in WO 03/106424 and in WO 2012/004338. A deuterated form of tasquinimod was described in WO 2012/175541. WO 2022/248401 discloses particles of tasquinimod in free base form or as a pharmaceutically acceptable salt, and the use of such particles, said particles having a D(v,0.9) of at most 30 pm and a D(v,0.5) of at most 15 pm. In WO/2023/275248, degradation products of tasquinimod in a pharmaceutical formulation are identified and used in methods for assessing the suitability for use of such a formulation.

[0005] The use of various quinoline carboxamides for the treatment of cancer, more particularly solid cancers, such as prostate cancer and breast cancer, was disclosed in WO 01/30758. It has been found that these compounds bind to and inhibit the interactions of an immunomodulatory protein (S 100A9), which protein promotes tumor development, influences suppressive and pro-angiogenic cells in the tumor microenvironment and participates in the establishment of pre- metastatic niches.

[0006] WO 2016/078921 discloses tasquinimod for use in the treatment of leukemia including acute lymphoblastic leukemia, acute myeloid leukemia, chronic lymphocytic leukemia, and chronic myeloid leukemia. WO 2016/042112 discloses tasquinimod for use in the treatment of multiple myeloma. WO 2022/018240 discloses tasquinimod for use in the prevention or treatment of a myeloproliferative neoplasm associated with a fibrotic phase, such as primary myelofibrosis, essential thrombocythemia or polycythemia vera.

WO2022/152902 discloses tasquinimod or a pharmaceutically acceptable salt thereof for use in the treatment of myelodysplastic syndrome.

[0007] WO 2016/146329 discloses tasquinimod for use in combination with a PD-1 and/or PD-L1 inhibitor in the treatment of cancer, in particular bladder cancer. WO 2021/175924 discloses tasquinimod for use in combination with and at least one further compound selected from a proteasome inhibitor, an immunomodulatory imide, and an antibody for use in the treatment of multiple myeloma.

[0008] What is needed are novel uses and methods of treatment including tasquinimod.

SUMMARY OF THE INVENTION

[0009] A first aspect relates to a pharmaceutical combination comprising a compound of formula (I) wherein R is selected from hydrogen and methyl, or a pharmaceutically acceptable salt thereof, and a bromodomain and extra-terminal motif protein (BET) inhibitor, a B-cell lymphoma 2 (Bcl-2) inhibitor, or a combination thereof.

[0010] A further aspect relates to a pharmaceutical combination comprising a compound of formula (I) as defined herein or a pharmaceutically acceptable salt thereof, and a BET inhibitor, a Bcl-2 inhibitor, or a combination thereof.

[0011] A further aspect relates to the pharmaceutical combination as defined herein for use in the treatment of a myeloproliferative neoplasm (MPN).

[0012] A further aspect relates to a compound of formula (I) as defined herein or a pharmaceutically acceptable salt thereof, for use in the treatment of a MPN, wherein the treatment further comprises administration of a BET inhibitor, a Bcl-2 inhibitor, or a combination thereof.

[0013] A further aspect relates to a kit comprising (i) a compound of formula (I) as defined herein or a pharmaceutically acceptable salt thereof, (ii) a BET inhibitor, a Bcl-2 inhibitor, or a combination thereof, and (hi) instructions for use thereof.

[0014] A further aspect relates to the use of a compound of formula (I) as defined herein or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for combination with a BET inhibitor, a Bcl-2 inhibitor, or a combination thereof, in the treatment of a MPN.

[0015] A further aspect relates to the use of (i) a compound of formula (I) as defined herein or a pharmaceutically acceptable salt thereof, and (ii) a BET inhibitor, a Bcl-2 inhibitor, or a combination thereof, in the manufacture of a medicament or a pharmaceutical kit for the treatment of a MPN.

[0016] A further aspect relates to a method for the treatment of a MPN by administration of (i) a compound of formula (I) as defined herein or a pharmaceutically acceptable salt thereof, and (ii) a BET inhibitor, a Bcl-2 inhibitor, or a combination thereof, to a mammalian subject in need of such treatment. [0017] The MPN may be selected from chronic myelogenous leukemia (CML), polycythemia vera, primary myelofibrosis, essential thrombocythemia, chronic neutrophilic leukemia, chronic eosinophilic leukemia. Philadelphia chromosome-negative MPN (e.g., polycythemia vera, essential thrombocythemia, the prefibrotic form of primary myelofibrosis, or a combination thereof), frequently progress to more overt forms of myelofibrosis and advanced stages of MPN (e.g., accelerated-phase MPN, post-MPN AML, or a combination thereof).

[0018] A further aspect relates to a compound of formula (I) as defined herein, for use in the treatment of MPN, such as advanced stages of MPN.

[0019] According to this aspect, the compound of formula (I), or the pharmaceutically acceptable salt thereof, may be administered as a monotherapy or in combination with a further therapeutically active agent, such as a BET inhibitor, a JAK inhibitor, a Bcl-2 inhibitor, or a combination thereof.

[0020] Therefore, a further aspect relates to a compound of formula (I) as defined herein, or a pharmaceutically acceptable salt thereof, for use in the treatment of advanced stages of MPN, wherein the treatment further comprises administration of a therapeutically active agent selected from a JAK inhibitor, a BET inhibitor, a Bcl-2 inhibitor, and a combination thereof.

[0021] A further aspect relates to a pharmaceutical combination comprising a compound of formula (I) as defined herein, or a pharmaceutically acceptable salt thereof; and a therapeutically active agent selected from a JAK inhibitor, a BET inhibitor, a Bcl-2 inhibitor, and combinations thereof, for use in the treatment of advanced stages of MPN.

[0022] A further aspect relates to a pharmaceutical composition for use in the treatment of advanced stages of MPN, comprising a compound of formula (I) as defined herein, or a pharmaceutically acceptable salt thereof; and optionally a therapeutically active agent selected from a JAK inhibitor, a BET inhibitor, a Bcl-2 inhibitor, and combinations thereof, and optionally a pharmaceutically acceptable excipient.

[0023] A further aspect relates to a kit for use in the treatment of advanced stages of MPN, comprising a compound of formula (I) as defined herein, or a pharmaceutically acceptable salt thereof; and a therapeutically active agent selected from a JAK inhibitor, a BET inhibitor, a Bcl-2 inhibitor, and combinations thereof, and a package insert with instructions for use of said kit. [0024] A further aspect relates to the use of a compound of formula (I) as defined herein above, or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for the treatment of advanced stages of MPN.

[0025] A further aspect relates to a method for the treatment of advanced stages of MPN by administration of a compound of formula (I) as defined herein above, or a pharmaceutically acceptable salt thereof, to a mammalian subject in need of such treatment.

[0026] A further aspect relates to the use of a compound of formula (I) as defined herein above, or a pharmaceutically acceptable salt thereof, and a therapeutically active agent selected from a JAK inhibitor, a BET inhibitor, a Bcl-2 inhibitor, and combinations thereof, in the manufacture of a medicament or a pharmaceutical kit for the treatment of advanced stages of MPN.

[0027] A further aspect relates to a method for the treatment of advanced stages of MPN by administration of a compound of formula (I) as defined herein above, or a pharmaceutically acceptable salt thereof, and a therapeutically active agent selected from a JAK inhibitor, a BET inhibitor, a Bcl-2 inhibitor, and combinations thereof, to a mammalian subject in need of such treatment.

[0028] Further aspects and embodiments thereof are described herein below.

BRIEF DESCRIPTION OF THE DRAWINGS

[0029] FIGs. 1A to 1C show bar charts for (FIG. 1 A) % apoptosis of the human MPN cell lines SET-2 and HEL92.1.7, (FIG. IB) % non-viable post-MPN AML cells, and (FIG. 1C) % non-viable normal CD34+ cord blood progenitor cells, after treatment with different concentrations of tasquinimod for 48 hours in vitro.

[0030] FIGs. 2A and 2B show bar charts for the relative mRNA expression, compared to untreated cells, of different genes in (FIG. 2A) the human MPN cell line SET-2, and (FIG. 2B) patient-derived CD34+ MF-MPN cells, after treatment with 50 pM tasquinimod in vitro for 16 hours.

[0031] FIGs. 3 A and 3B are Kaplan-Meier plots showing the percent survival of mice in a patient derived xenograft (PDX) model for advanced MPN after treatment with tasquinimod, ruxolitining, birabresib (OTX015), or a vehicle, in two independent studies. Irradiated NOD scid gamma (NSG) mice were engrafted with mutant calreticulin (CALR) and telomerase reverse transcriptase (TERT) expressing post-MPN-AML cells derived from a patient. Treatment started day 15 post-infusion of post-MPN-AML cells, with (FIG. 3 A) vehicle, 10 mg/kg of tasquinimod, or 30 mg/kg of tasquinimod, or with (FIG. 3B) vehicle, 30 mg/kg tasquinimod, 30 mg/kg ruxolitinib or 30 mg/kg birabresib (OTX015).

[0032] FIGs. 4A to 4D show (FIG. 4A) the % apoptosis of human MPN cell line SET- 2, and (FIG. 4B) the Delta Synergy scores for the same cell line, after combination treatment with different concentrations of tasquinimod and the JAK inhibitor ruxolitinib for 48 hours, and (FIG. 4C) the % non-viable post-MPN AML cells derived from a patient and (FIG. 4D) the Delta Synergy scores for the same cell line, after combination treatment with different concentrations of tasquinimod and the JAK inhibitor ruxolitinib for 48 hours.

[0033] FIGs. 5A to 5F show (FIGs. 5A, 5C, and 5E) the percentage of non-viable cells of post-MPN AML cells derived from three different patients, and (FIGs. 5B, 5D, and 5F) the Delta Synergy scores obtained for these cells, after combination treatment of the cells with different concentrations of tasquinimod and the BET inhibitor CPI-0610 for 48 hours.

[0034] FIGs. 6A to 6F show the percentage of non-viable cells of (FIG. 6A) human MPN cell line SET-2 and (FIGs. 6C and 6E) post-MPN AML cells derived from two different patients, after combination treatment with different concentrations of tasquinimod and the BET-inhibitor birabresib (OTX015) for 72 hours, and (FIGs. 6B, 6D, and 6F) show the Delta Synergy scores for the same cell lines.

[0035] FIGs. 7A to 7C show (FIG. 7A) the survival and (FIGs. 7B and 7C) spleen size in a patient derived xenograft (PDX) model for advanced MPN after treatment with vehicle, tasquinimod, ruxolitinib, or birabresib (OTX015), or tasquinimod (TQ) in combination with ruxolitinib, or birabresib (OTX015). FIG. 7A is a Kaplan-Meier plot showing the percent survival of mice in the different treatment groups, FIG. 7B is a Kaplan-Meier plot showing the spleen length (in mm) of treated mice, and FIG. 7C shows representative spleen images from each treatment group.

[0036] FIGs. 8A to 8D show (FIG. 8A) the % apoptosis of human MPN cell line SET- 2, and (FIG. 8B) the Delta Synergy scores for the same cell line, after combination treatment with different concentrations of tasquinimod and the Bcl-2 inhibitor navitoclax for 72 hours, and (FIG. 8C) the % non-viable post-MPN AML cells derived from a patient and (FIG. 8D) the Delta Synergy scores for the same cell line, after combination treatment with different concentrations of tasquinimod and the Bcl-2 inhibitor navitoclax for 72 hours.

[0037] FIGs. 9A to 9F show the percentage of non-viable cells of (FIG. 9A) human MPN cell line SET-2 and (FIGs. 9C and 9E) post-MPN AML cells derived from two different patients, after combination treatment with different concentrations of tasquinimod and the BCL-2-inhibitor venetoclax for 72 hours, and (FIGs. 9B, 9D, and 9F) show the Delta Synergy scores for the same cell lines.

DETAILED DESCRIPTION OF THE INVENTION

DEFINITIONS

[0038] Unless defined otherwise or clearly indicated by context, all technical and scientific terms and abbreviations used herein have the same meaning as commonly understood by one of ordinary skill in the field of art to which this disclosure belongs. However, definitions of some of the terms used herein will be given herein below.

[0039] The terms “a,” “an,” and “the” include plural referents unless otherwise specified or clearly apparent from the context. The indefinite article “a” or “an” thus usually means “at least one”.

[0040] The term “about” when referring to a measurable value such as an amount, a temporal duration etc., is intended to cover variations of ±20%, ±15%, ±10%, ±5%, ±2%, ±1%, ±0.5% or ±0.1% from the specified value.

[0041] As used herein, “administration”, “administering”, and the like, means the giving of, dispensing of, or application of medicines, drugs, or remedies to a subject (e.g., a mammal subject, preferably a human) to relieve or cure a pathological condition. Oral administration is one way of administering the instant compounds to the subject.

[0042] For the purpose of the present description, the term TASQ may be used to refer to a compound of formula (I).

[0043] By “combination” as used herein is meant that TASQ and a further therapeutically active agent, e.g., a BET inhibitor, a JAK inhibitor, a Bcl-2 inhibitor, or a combination thereof, may be administered simultaneously in one and the same formulation, or in separate formulations, administered concurrently or separately. The combination of TASQ and the further therapeutically active agent includes administration of each compound separately, e.g., sequentially or at different time points. In some embodiments, TASQ and the further therapeutically active agent are administered essentially at the same time, e.g., simultaneously (concomitantly) or sequentially. In some embodiments, TASQ is administered over a first treatment period, followed by administration of the further therapeutically active agent over a second treatment period, and optionally followed by combined administration of TASQ and the further therapeutically active agent over a third treatment period. In some embodiments, the further therapeutically active agent is administered over a first treatment period, followed by administration of TASQ over a second treatment period, and optionally followed by combined administration of TASQ and the further therapeutically active agent over a third treatment period. In some embodiments, the further therapeutically active agent is a BET inhibitor or a Bcl-2 inhibitor. In some embodiments, the further therapeutically active agent is a BET inhibitor. In some embodiments, the further therapeutically active agent is a Bcl-2 inhibitor.

[0044] As used herein, “effective” when referring to an amount of a therapeutically active agent or a combination of therapeutically active agents, refers to the amount that is sufficient to yield a desired therapeutic response without undue adverse side effects (such as toxicity, irritation, or allergic response), commensurate with a reasonable benefit/risk ratio when used in the manner of this invention.

[0045] As used herein, “excipient” refers to a substance formulated alongside the active ingredient(s) of a medication included for such purposes as long-term stabilization, to provide bulk to a solid formulation, to act as a carrier and/or diluent, to confer a therapeutic enhancement on the active ingredient in the final dosage form, e.g., by facilitating absorption, reducing viscosity, or enhancing solubility. An excipient can also be useful in the manufacturing process, e.g., by facilitating powder flowability or providing non-stick properties. Examples of excipients are antiadherents, binders, coatings, colours, disintegrants, flavours, glidants, lubricants, preservatives, sorbents, sweeteners, vehicles (carriers), and combinations thereof.

[0046] The terms “comprising”, “containing”, and “including” (or other forms thereof, e.g., “comprises”, “contains”, “includes”, and the like) are construed as being inclusive and open ended. Specifically, the terms and variations thereof mean that the specified features, steps, or components are included, but do not mean that other features, steps, or components are excluded, unless so specified or apparent from the context.

[0047] A “mammal” as referred to herein may be an animal, such as a dog, a horse, a cat, a monkey, a rat, a sheep, a cow, a goat, a rabbit, etc., or a human. Preferably, the mammal is a human.

[0048] The term “neoplasm” refers to an abnormal mass of tissue that forms when cells grow and divide more than they should or do not die when they should.

[0049] The term “myeloproliferative neoplasm” (MPN) refers to a type of disease in which the bone marrow makes too many red blood cells, platelets, or certain white blood cells. Examples of MPNs are mentioned herein. [0050] The term “advanced stages of MPN”, refers to stages of the MPN where the peripheral blood or bone marrow myeloblast count is at least 10 %. For example, the term “advanced-stage MPN” refers to a MPN in (having progressed to) advanced stage, i.e., wherein the peripheral blood or bone marrow myeloblast count is at least 10 %.

[0051] The term “accelerated-phase MPN”, refers to a stage of the MPN where the peripheral blood or bone marrow myeloblast count is at least 10 % but lower than 20 %.

[0052] The term “secondary acute myeloid leukemia arising from MPN” (or “post- MPN AML”), refers to a stage of the MPN where the myeloblast count is at least 20% in the peripheral blood or bone marrow. Post-MPN AML may also be referred to as blast phase MPN.

[0053] The term “Philadelphia chromosome” refers to a genetically abnormal chromosome 22 that comprises a reciprocal translocation, t(9;22)(q34;ql 1 ), of genetic material between said chromosome and chromosome 9, and contains the fusion gene BCR- ABL1.

[0054] The term “Philadelphia chromosome-negative” indicates the absence of the genetically abnormal Philadelphia chromosome.

[0055] The term “Philadelphia chromosome-negative MPN” refers to a MPN wherein no Philadelphia chromosome is present in the cells of the MPN patient.

[0056] “Optional” or “optionally” means that the subsequently described event or circumstance may but need not occur, and that the description includes instances where the event or circumstance occurs and instances in which it does not.

[0057] “Pharmaceutically acceptable” means that which is useful in preparing a pharmaceutical composition that is generally safe, non-toxic, and neither biologically nor otherwise undesirable and includes that which is acceptable for veterinary use as well as human pharmaceutical use.

[0058] Examples of pharmaceutically acceptable salts include salts with (as counter ion) an alkali metal ion, e.g., Li⁺, Na⁺ or K⁺, or with an alkaline earth metal ion, e.g., Mg²⁺ or Ca²⁺, or with any other pharmaceutically acceptable metal ion, e.g., Zn²⁺ or Al³⁺; or pharmaceutically acceptable salts formed with organic bases, such as diethanolamine, ethanolamine, N-methylglucamine, triethanolamine or tromethamine. Further examples of pharmaceutically acceptable salts include acid addition salts, e.g., with a strong mineral acid, such as a hydrohalic acid, e.g., hydrochloric acid.

[0059] The terms “simultaneous” or “concurrent” (or “simultaneously” or “concurrently”), in connection with administration of more than one active ingredient to a subject, implies that the active ingredients are administered essentially at the same time, whether via the same or different routes of administration.

[0060] The term “separate” (or “separately”), in connection with administration of more than one active ingredient to a subject, refers to administration of active ingredients in separate form and/or at separate moments in time, whether via the same or different routes of administration.

[0061] The term “sequential” (or “sequentially”), in connection with administration of more than one active ingredient to a subject, indicates that the administration of a first active ingredient is followed by the administration of the second active ingredient, whether immediately or after a period of time.

[0062] Reference to TASQ or to any other active ingredient (e.g., any specific BET inhibitor, JAK inhibitor, or Bcl-2 inhibitor) as made herein should be construed as a reference to the free base or non-salt form thereof, as well as to a pharmaceutically acceptable salt or solvate (e.g., hydrate) thereof, unless otherwise specified or apparent from the context.

[0063] “Therapeutically effective amount” means an amount of a therapeutically active ingredient, e.g., TASQ or a pharmaceutically salt thereof, that, when administered in combination with a further compound as defined herein, for treating a disease state of a subject, is sufficient to effect such treatment for the disease state. The “therapeutically effective amount” will vary depending on, for example, the age and relative health of the treated subject, the state of progression of the disease, the route and form of administration, the particular combination of TASQ and the further compound(s), etc.

[0064] As used herein the terms “treatment” or “treating” is an approach for obtaining beneficial or desired results including clinical results. Beneficial or desired clinical results can include, but are not limited to, alleviation or amelioration of one or more symptoms of the treated disease, diminishment of extent of the disease, stabilization (i.e., not worsening) of the state of the disease, preventing, delaying, or slowing of progression of the disease, amelioration or palliation of the disease state, and remission (whether partial or total), whether detectable or undetectable. The term can also mean prolonging survival as compared to expected survival without the treatment.

[0065] Myeloproliferative neoplasms include chronic myelogenous leukemia, chronic neutrophilic leukemia, polycythemia vera (PV) with predominant erythrocytosis, primary and idiopathic myelofibrosis (MF) with megakaryocyte expansion and progressive bone marrow fibrosis, essential thrombocythemia (ET) with pronounced thrombocytosis, chronic eosinophilic leukemia, and mastocytosis. MPN also includes advanced stages of MPN, i.e., accelerated-phase MPN, defined as a peripheral blood or bone marrow myeloblast count of >10% to less than 20% and secondary acute myeloid leukemia arising from MPN (post-MPN AML), defined as >20% myeloblasts in the peripheral blood or bone marrow of a patient with an antecedent Philadelphia chromosome-negative MPN.

THE COMPOUND OF FORMULA (I)

[0066] In some embodiments, in the compound of formula (I), R is methyl, i.e., the compound is 4-hydroxy-5-methoxy-N, l-dimethyl-2-oxo-N-[4-(trifluoromethyl)phenyl]-l,2- dihydroquinoline-3-carboxamide (tasquinimod), having the structural formula

[0067] As mentioned herein above, tasquinimod, pharmaceutically acceptable salts thereof, deuterated forms thereof, crystalline salts thereof, and pharmaceutical compositions containing tasquinimod or its salt, as well as methods for preparing tasquinimod, its salts, deuterated forms and pharmaceutical compositions containing tasquinimod and tasquinimod salts have been described in WO 99/55678, WO 00/03991, WO 03/106424, WO 2012/004338 and WO 2012/175541 as described above, which documents are hereby incorporated by reference in their entireties into the present application.

[0068] In some embodiments, any reference to a compound of formula (I) also encompasses a deuterated form of thereof. As mentioned herein above, a deuterated form of tasquinimod is described in WO 2012/175541. In some embodiments, thus, tasquinimod has a deuterium enrichment in the amide-N methyl of at least 70%, more preferably at least 90%. In some other embodiments, the compound of formula (I) is non-deuterated, having a deuterium content corresponding to the natural abundance of deuterium.

[0069] In some embodiments, in the compound of formula (I), R is hydrogen, i.e., the compound is 4-hydroxy-5-methoxy-l-methyl-2-oxo-N-[4-(trifluoromethyl)phenyl]-l,2- dihydroquinoline-3-carboxamide, having the structural formula [0070] As used herein, the term TASQ refers generally to a compound of formula (I). In some preferred embodiments, TASQ refers to 4-hydroxy-5-methoxy-N,l-dimethyl-2-oxo- N-[4-(trifluoromethyl)phenyl]-l,2-dihydroquinoline-3-carboxamide (tasquinimod). In some other embodiments, TASQ refers to 4-hydroxy-5-methoxy-l-methyl-2-oxo-N-[4- (trifluoromethyl)phenyl]-l,2-dihydroquinoline-3-carboxamide.

[0071] In some embodiments, TASQ refers to a pharmaceutically acceptable salt of a compound of formula (I), e.g., a salt with a monovalent metal cation, such as a sodium or potassium salt.

THE BET INHIBITOR

[0072] The bromodomain and extra terminal (BET) protein family, including the ubiquitously expressed BRD2, BRD3, and BRD4 proteins and the testis -limited BRDT protein, plays a crucial role in regulating gene transcription through epigenetic interactions between bromodomains and acetylated histones during cellular proliferation and differentiation processes. BET proteins however have also been reported to be involved in oncogenesis and, therefore, compounds capable of inhibiting BET proteins have been developed for use as anti-cancer agents. Thus, BET inhibitors have been disclosed in, for example, WO 1998/011111, WO 2006/129623, WO 2008/092231, WO 2009/158404, WO 2009/084693, WO 2010/123975, WO 2011/143669, WO 2011/143660, WO 2011/143651, WO 2011/054845, WO 2011/054844, WO 2011/161031, WO 2011/054848, WO 2011/054846, WO 2011/054843, WO 2012/174487, WO 2012/075383, WO 2012/151512, WO 2012/116170, WO 2013/030150, WO 2013/027168, WO 2013/024104, WO 2013/097601, and WO 2013/033268, each of which are incorporated herein by reference.

[0073] Some specific examples of BET inhibitors are listed herein below, with alternative names in brackets, and with CAS numbers and IUPAC names: pelabresib (CPI-0610), CAS No. 1380087-89-7, IUPAC name: 2-[(45)-6-(4- chlorophenyl)-l-methyl-477-[l,2]oxazolo[5,4-d][2]benzazepin-4-yl]acetamide; birabresib (OTX-015, MK-8628), CAS No. 202590-98-5, IUPAC name: 2-[(9S)-7-(4- chlorophenyl)-4,5,13-trimethyl-3-thia-l,8,l l,12-tetrazatricyclo[8.3.0.0²-⁶]trideca- 2(6),4,7,10, 12-pentaen-9-yl]-A-(4-hydroxyphenyl)acetamide; molibresib (I-BET 762, GSK525762; GSK525762A), CAS No. 1260907-17-2, IUPAC name: 2-[(4S)-6-(4-chlorophenyl)-8-methoxy-l-methyl-4H-[l,2,4]triazolo[4,3- a][l,4]benzodiazepin-4-yl]-A-ethylacetamide; I-BET 151 (GSK1210151A), CAS No. 1300031-49-5, IUPAC name: 7-(3,5-dimethyl- l,2-oxazol-4-yl)-8-methoxy-l-[(lR)-l-pyridin-2-ylethyl]-3/Z-imidazo[4,5-c]quinolin-2-one);

TEN-010 ((S)-JQ-35), CAS No. 1446144-04-2, IUPAC name: 2-[(9S)-7-(4- chlorophenyl)-4,5,13-trimethyl-3-thia- 1 ,8, 1 l ,12-tetrazatricyclo[8.3.0.0²’⁶]trideca- 2(6),4,7,10,12-pentaen-9-yl]-/V-[3-(4-methylpiperazin-l-yl)propyl]acetamide;

JQ1 ((+)-JQ-l), CAS No. 1268524-70-4, IUPAC name: tert-butyl 2-[(95)-7-(4- chlorophenyl)-4,5,13-trimethyl-3-thia-l,8,l l,12-tetrazatricyclo[8.3.0.0²’⁶]trideca- 2(6),4,7,10, 12-pentaen-9-yl]acetate;

ABBV-744 (ABBV744, ABBV 744), CAS No. 2138861-99-9, IUPAC name: A-ethyl- 4-[2-(4-fluoro-2,6-dimethylphenoxy)-5-(2-hydroxypropan-2-yl)phenyl]-6-methyl-7-oxo-177- pyrrolo[2,3-c]pyridine-2-carboxamide; mivebresib (ABBV-075, ABBV075), CAS No. 1445993-26-9, IUPAC name: A-[4- (2,4-difluorophenoxy)-3-(6-methyl-7-oxo-177-pyrrolo[2,3-c]pyridin-4- yl)phenyl]ethanesulfonamide; apabetalone (RVX-208, RVX-000222), CAS No. 1044870-39-4, IUPAC name: 2-[4- (2-hydroxyethoxy)-3,5-dimethylphenyl]-5,7-dimethoxy-3H-quinazolin-4-one;

BMS-986158 (BMS986158), CAS No. 1800340-40-2, IUPAC name: 2-[3-(3,5- dimethyltriazol-4-yl)-5-[(S)-oxan-4-yl(phenyl)methyl]pyrido[3,2-b]indol-7-yl]propan-2-ol;

MS417 (GTPL7512), CAS No. 916489-36-6, IUPAC name: methyl 2-[(95)-7-(4- chlorophenyl)-4,5,13-trimethyl-3-thia-l,8,l l,12-tetrazatricyclo[8.3.0.0²’⁶]trideca- 2(6),4,7,10,12-pentaen-9-ylJacetate;

AZD-5153 (AZD5153), CAS No. 1869912-39-9, IUPAC name: (3R)-4-[2-[4-[l-(3- methoxy-[l,2,4]triazolo[4,3-b]pyridazin-6-yl)piperidin-4-yl]phenoxy]ethyl]-l,3- dimethylpiperazin-2-one; and

INCB054329 (INCB54329), CAS No. 1628607-64-6, IUPAC name: (115)-7-(3,5- dimethyl-l,2-oxazol-4-yl)-l l-pyridin-2-yl-9-oxa-l,3-diazatricyclo[6.3.1.0^{4 12}]dodeca- 4(12),5,7-trien-2-one.

[0074] The BET inhibitor used herein may be a bromodomain-containing protein 2 (BRD2) inhibitor, a bromodomain-containing protein 3 (BRD3) inhibitor, and/or a bromodomain-containing protein 4 (BRD4) inhibitor. In some embodiments, the BET inhibitor is a BRD2 inhibitor. In some embodiments, the BET inhibitor is a BRD3 inhibitor. In some embodiments, the BET inhibitor is a BRD4 inhibitor.

[0075] In some embodiments, the BET inhibitor is selected from BET inhibitors as disclosed in any one of the WO pamphlets referred to herein above. [0076] In some embodiments, the BET inhibitor is selected from pelabresib, birabresib, molibresib, I-BET 151, TEN-010, JQ1, ABBV-744, mivebresib, apabetalone, BMS-986158, MS417, AZD-5153, and INCB054329, and pharmaceutically acceptable salts thereof.

[0077] In some embodiments, the BET inhibitor is selected from pelabresib or a pharmaceutically acceptable salt thereof, birabresib or a pharmaceutically acceptable salt thereof, and a combination thereof.

[0078] In some embodiments, the BET inhibitor is birabresib or a pharmaceutically acceptable salt thereof. In some embodiments, the BET inhibitor is pelabresib or a pharmaceutically acceptable salt thereof. In some embodiments, the BET inhibitor is molibresib or a pharmaceutically acceptable salt thereof. In some embodiments, the BET inhibitor is I-BET 15 lor a pharmaceutically acceptable salt thereof. In some embodiments, the BET inhibitor is TEN-010 or a pharmaceutically acceptable salt thereof. In some embodiments, the BET inhibitor is JQ1 or a pharmaceutically acceptable salt thereof. In some embodiments, the BET inhibitor is ABBV-744 or a pharmaceutically acceptable salt thereof. In some embodiments, the BET inhibitor is mivebresib or a pharmaceutically acceptable salt thereof. In some embodiments, the BET inhibitor is apabetalone or a pharmaceutically acceptable salt thereof. In some embodiments, the BET inhibitor is BMS-986158 or a pharmaceutically acceptable salt thereof. In some embodiments, the BET inhibitor is MS417or a pharmaceutically acceptable salt thereof. In some embodiments, the BET inhibitor is AZD-5153 or a pharmaceutically acceptable salt thereof. In some embodiments, the BET inhibitor is INCB054329 or a pharmaceutically acceptable salt thereof.

THE BCL-2 INHIBITOR

[0079] The Bcl-2 family of proteins comprises several family members, including Bcl-2 (B-cell lymphoma 2), Bcl-xL (B-cell lymphoma-extra large), Bcl-w (Bcl-2-like protein 2 or BCL2L2), Mcl-1 (induced myeloid leukemia cell differentiation protein), and Al (Bcl-2- related protein Al or BCL2A1). The family is involved in the regulation of apoptosis at the mitochondrion and has been found to play an important role in various diseases, including cancers, immune diseases, and autoimmune diseases.

[0080] As used herein, the term Bcl-2 inhibitor refers to an inhibitor of one or more of the Bcl-2 family of proteins, such as Bcl-2, Bcl-xL, Bcl-w, Mcl-1, Al, or combinations thereof. Thus, as referred to herein, a Bcl-2 inhibitor may be, but not limited to, an inhibitor of, for example, Bcl-2, Bcl-xL, and Bcl-w; or an inhibitor of Bcl-2 and Bcl-xL. [0081] Some specific examples of Bcl-2 inhibitors are listed herein below, with alternative names in brackets, and with CAS numbers and IUPAC names: navitoclax (ABT263, ABT-263), CAS No. 923564-51-6, IUPAC name: 4-(4-{ [2-(4- Chlorophenyl)-5 ,5 -dimethylcyclohex- 1 -en- 1 -yl]methyl } piperazin- 1 -yl)-N-(4- { [(2R)-4- (morpholin-4-yl)-l-(phenylsulfanyl)butan-2-yl]amino}-3-(trifluoromethanesulfonyl)benzene- 1 - sulfony l)benzamide ; lisaftoclax, (APG2575, APG-2575), CAS No. 2180923-05-9, IUPAC name: 4-[4-[[8- (4-chlorophenyl)spiro[3.5]non-7-en-7-yl]methyl]piperazin-l-yl]-N-[4-[[(2S)-l,4-dioxan-2- yl]methylamino]-3-nitrophenyl]sulfonyl-2-(lH-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide; obatoclax, (GX15-070), CAS No. 803712-67-6, IUPAC name: 2-(2-((3,5-Dimethyl- lH-pyrrol-2-yl)methylene)-3-methoxy-2H-pyrrol-5-yl)-lH-indole; and venetoclax (ABT- 199, GDC-0199, G-7601), CAS No. 1257044-40-8, IUPAC name: 4-(4-{ [2-(4-Chlorophenyl)-4,4-dimethyl-l-cyclohexen-l-yl]methyl}-l-piperazinyl)-N-({3- nitro-4-[(tetrahydro-2H-pyran-4-ylmethyl)amino]phenyl]sulfonyl)-2-(lH-pyrrolo[2,3- b]pyridin-5-yloxy)benzamide.

[0082] In some embodiments, the Bcl-2 inhibitor is navitoclax or a pharmaceutically acceptable salt thereof. In some embodiments, the Bcl-2 inhibitor is lisaftoclax or a pharmaceutically acceptable salt thereof. In some embodiments, the Bcl-2 inhibitor is obatoclax or a pharmaceutically acceptable salt thereof. In some embodiments, the Bcl-2 inhibitor is obatoclax mesylate or a pharmaceutically acceptable salt thereof. In some embodiments, the Bcl-2 inhibitor is navitoclax or a pharmaceutically acceptable salt thereof.

THE COMBINATION OF TASQ AND THE FURTHER THERAPEUTICALLY ACTIVE AGENT OR AGENTS

[0083] Also provided herein is a combination of TASQ and a further therapeutically active agent that is a BET inhibitor, a Bcl-2 inhibitor, or a combination thereof. In some embodiments, the further therapeutically active agent is or comprises a BET inhibitor. In some embodiments, the further therapeutically active agent is or comprises a Bcl-2 inhibitor (e.g., navitoclax or a pharmaceutically acceptable salt thereof, or venetoclax or a pharmaceutically acceptable salt thereof). In some embodiments, the BET inhibitor may be selected from, for example, pelabresib, birabresib, molibresib, I-BET-151, TEN-010, IQ1, apabetalone, and INCB054329, or a pharmaceutically acceptable salts thereof (e.g., pelabresib or a pharmaceutically acceptable salt thereof, birabresib or a pharmaceutically acceptable salt thereof, or a combination thereof). In some embodiment, the Bcl-2 inhibitor may be selected from, for example, navitoclax, lisaftoclax, obatoclax, and venetoclax, or pharmaceutically acceptable salts thereof. In some embodiments, the Bcl-2 inhibitor is navitoclax or a pharmaceutically acceptable salt thereof. In some embodiments, the Bcl-2 inhibitor is navitoclax. In some embodiments, the Bcl-2 inhibitor is venetoclax or a pharmaceutically acceptable salt thereof. In some embodiments, the Bcl-2 inhibitor is venetoclax.

[0084] TASQ and the further therapeutically active agent may be administered simultaneously in one and the same formulation, or in separate formulations, administered concurrently or separately. The combination of TASQ and the further therapeutically active agent includes administration of each agent sequentially or at different time points. In some embodiments, TASQ and the further agent are administered essentially at the same time, simultaneously or sequentially.

[0085] In some embodiments, TASQ is administered over a first treatment period, followed by administration of the further therapeutically active agent or agents over a second treatment period, and optionally followed by combined administration of TASQ and the further therapeutically active agent or agents over a third treatment period. In some embodiments, the further therapeutically active agent or agents is/are administered over a first treatment period, followed by administration of TASQ over a second treatment period, and optionally followed by combined administration of TASQ and the further therapeutically active agent or agents over a third treatment period. In some embodiments, TASQ is administered over a first treatment period, optionally followed by administration of the further therapeutically active agent or agents over a second treatment period, and followed by combined administration of TASQ and the further therapeutically active agent or agents over a third treatment period. In some embodiments, the further therapeutically active agent or agents is administered over a first treatment period, optionally followed by administration of TASQ over a second treatment period and followed by combined administration of TASQ and the further therapeutically active agent or agents over a third treatment period. Further modalities are contemplated as may be determined by the treating physician. For example, additional and/or different treatment periods may be required depending on the number and type of further therapeutically active agents.

[0086] In some of these embodiments, each treatment period may extend over 1-8 weeks, or over 1-6 weeks, or over 1-4 weeks, e.g., from 2 to 4 weeks, whereby the length of each subsequent period may be the same or different.

[0087] In some embodiments, the treatment is chronic, i.e., it is continued for several years, or without a foreseeable endpoint, i.e., as long as necessary in view of the condition of the treated patient. In some embodiments, the treatment is intermittent, i.e., it is performed for a period of time, then discontinued and optionally re-started again, either in case of need or on a pre-scheduled basis, as may be decided by the treating physician.

[0088] In some embodiments, TASQ and the further therapeutically active agent or agents are administered concurrently, either at the same time or at different time points during the day.

[0089] TASQ is preferably orally administered, e.g., as a capsule or tablet. Likewise, the further therapeutically active agent or agents is preferably orally administered, e.g., as a capsule or tablet.

[0090] However, it should be realized that the invention is not limited to oral administration, and if necessary, either TASQ or the further therapeutically active agent or agents, or both, may also be administered by another route, for example by injection.

[0091] In general, the active ingredients used in the combinations of the invention will be administered in a therapeutically effective amount by any of the accepted modes of administration for agents that serve similar utilities.

[0092] In some preferred advantageous embodiments, the combination provided herein will give rise to a synergistic effect, which may provide for a possibility of reduced dosage. However, as is usual when determining a proper treatment regimen, the proper dosage will normally have to be determined by the treating physician, having regard to factors such as age, weight, condition, etc. of the treated patient.

[0093] In some embodiments, the combination comprises administration of a further therapeutically active agent, given on an outpatient basis, e.g., on days 1, 4, 8, 11 of a 3-week cycle, for a total of up to 8 cycles. While injection or rectal administration of the active ingredient may be contemplated, if necessary, oral administration generally is considered the most convenient.

[0094] In some embodiments, TASQ and the further therapeutically active agent or agents will be administered in separate formulations, e.g., each is administered as oral preparations, in the form of capsules or tablets. In such case, the above description of suitable pharmaceutical preparations may apply to each such formulation independently. For example, in some embodiments, TASQ is administered orally to an individual, and simultaneously, sequentially, or separately, further therapeutically active agent or agents, is/are administered, either orally or by some other mode of administration (when multiple therapeutically active agents are used, they may be administered simultaneously, sequentially, or separately). [0095] In some embodiments, TASQ is administered orally to an individual, e.g., as a capsule or tablet, preceded by, followed by, or during injection or intravenous administration of further therapeutically active agent or agents.

[0096] In some embodiments, administration of TASQ and administration of the further therapeutically active agent or agents take place during the same 24-hour period, more preferably during the same 12-hour period, during the same 10-hour period, during the same 8-hour period, during the same 6-hour period, during the same 3-hour period, during the same 2-hour period, or during the same 1-hour period, e.g., one directly following the other.

[0097] In some embodiments, administration of TASQ is performed daily, whereas administration of the further therapeutically active agent or agents is performed at a treatment schedule that may be the same as that of TASQ, or different, e.g., daily, or weekly, or at any other suitable interval.

[0098] Generally, a daily dosage of TASQ ranging from a minimum of 0.001 mg/kg body weight, or 0.002 mg/kg body weight or 0.005 mg/kg body weight or 0.008 mg/kg body weight, to a maximum of 0.2 mg/kg body weight, or 0.1 mg/kg body weight, or 0.05 mg/kg body weight, or 0.02 mg/kg body weight, or 0.01 mg/kg body weight is contemplated.

[0099] In some embodiments, TASQ is administered in an amount of 0.1 to 0.3 mg/day, or 0.15 to 0.3 mg/day, e.g., 0.2 to 0.3 mg/day (or in a corresponding amount of pharmaceutically acceptable salt of TASQ).

[0100] In some embodiments, TASQ is administered in an amount of 0. 1 to 6 mg/day, or 0.2 to 6 mg/day, or 0.5 to 6 mg/day (or in a corresponding amount of pharmaceutically acceptable salt of TASQ).

[0101] In some embodiments, TASQ is administered in an amount of 0.1 to 1 mg/day, or 0.2 to 1 mg/day, or 0.5 to 1 mg/day (or in a corresponding amount of pharmaceutically acceptable salt of TASQ).

[0102] In some embodiments, TASQ is administered in an amount of 0.2 to 1.5 mg/day, or 0.4 to 1.5 mg/day, or 0.8 to 1.5 mg/day (or in a corresponding amount of pharmaceutically acceptable salt of TASQ).

[0103] In some embodiments, TASQ is administered in an amount of 0.5 to 2 mg/day, or 0.8 to 2 mg/day, e.g., 1 to 2 mg/day (or in a corresponding amount of pharmaceutically acceptable salt of TASQ).

[0104] In some embodiments, TASQ is administered in an amount of 0.8 to 3 mg/day, or 1 to 3 mg/day, e.g., 1.5 to 3 mg/day (or in a corresponding amount of pharmaceutically acceptable salt of TASQ). [0105] In some embodiments, TASQ is administered in an amount of 1 to 6 mg/day, or 2 to 6 mg/day, e.g., 3 to 6 mg/day (or in a corresponding amount of pharmaceutically acceptable salt of TASQ).

[0106] In some embodiments, the dosage of either or both active ingredients may be gradually adjusted to reach optimal results, so-called dosage titration. For example, dosage titration may comprise starting with a low daily dosage of e.g., 0.25 mg of the active ingredient as defined herein and maintaining this dose level for a period of 1 or 2 weeks. In case no significant side effects are encountered that may contraindicate raising the dose, the level may then be increased, for example, to 0.5 mg/day for 1 or 2 weeks, after which period another increase may be contemplated, to reach a daily dosage of 1 mg, and so on. In such a method, if any significant side effects occur after an incremental increase of the dosage, the dosage may again be reduced to a previous level.

[0107] In some embodiments, each of the further therapeutically active agent may be administered to a mammalian patient, such as a human, at a dosage of, for example, 0.005 to 50 mg/kg body weight, 0.01 to 50 mg/kg body weight, 0.05 to 50 mg/kg body weight, 0. 1 to 50 mg/kg body weight, 0.2 to 50 mg/kg body weight, 0.5 to 50 mg/kg body weight, 1 to 50 mg/kg body weight, 2 to 50 mg/kg body weight, 5 to 50 mg/kg body weight, 10 to 50 mg/kg body weight, 15 to 50 mg/kg body weight, 20 to 50 mg/kg body weight, or 25 to 50 mg/kg body weight, for example every second day, once a day, or twice a day, during a treatment period.

[0108] In some embodiments, each of the further therapeutically active agent may be administered to a mammalian patient, such as a human, at a dosage of, for example, 0.005 to 30 mg/kg body weight, 0.01 to 30 mg/kg body weight, 0.05 to 30 mg/kg body weight, 0.1 to 30 mg/kg body weight, 0.2 to 30 mg/kg body weight, 0.5 to 30 mg/kg body weight, 1 to 30 mg/kg body weight, 2 to 30 mg/kg body weight, 5 to 30 mg/kg body weight, 10 to 30 mg/kg body weight, 15 to 30 mg/kg body weight, 20 to 30 mg/kg body weight, or 25 to 30 mg/kg body weight, for example every second day, once a day, or twice a day, during a treatment period.

[0109] In some embodiments, each of the further therapeutically active agent may be administered to a mammalian patient, such as a human, at a dosage of, for example, 0.005 to 20 mg/kg body weight, 0.01 to 20 mg/kg body weight, 0.05 to 20 mg/kg body weight, 0.1 to 20 mg/kg body weight, 0.2 to 20 mg/kg body weight, 0.5 to 20 mg/kg body weight, 1 to 20 mg/kg body weight, 2 to 20 mg/kg body weight, 5 to 20 mg/kg body weight, 10 to 20 mg/kg body weight, or 15 to 20 mg/kg body weight, for example every second day, once a day, or twice a day, during a treatment period.

[0110] In some embodiments, each of the further therapeutically active agent may be administered to a mammalian patient, such as a human, at a dosage of, for example, 0.005 to 10 mg/kg body weight, 0.01 to 10 mg/kg body weight, 0.05 to 10 mg/kg body weight, 0.1 to 10 mg/kg body weight, 0.2 to 10 mg/kg body weight, 0.5 to 10 mg/kg body weight, 1 to 10 mg/kg body weight, 2 to 10 mg/kg body weight, or 5 to 10 mg/kg body weight, for example every second day, once a day, or twice a day, during a treatment period.

[0111] In some embodiments, each of the further therapeutically active agent may be administered to a mammalian patient, such as a human, at a dosage of, for example, 0.005 to 5 mg/kg body weight, 0.01 to 5 mg/kg body weight, 0.05 to 5 mg/kg body weight, 0.1 to 5 mg/kg body weight, 0.2 to 5 mg/kg body weight, 0.5 to 5 mg/kg body weight, 1 to 5 mg/kg body weight, or 2 to 5 mg/kg body weight, for example every second day, once a day, or twice a day, during a treatment period.

[0112] In some embodiments, each of the further therapeutically active agent may be administered to a mammalian patient, such as a human, at a dosage of, for example, 0.005 to 3 mg/kg body weight, 0.01 to 3 mg/kg body weight, 0.05 to 3 mg/kg body weight, 0. 1 to 3 mg/kg body weight, 0.2 to 3 mg/kg body weight, 0.5 to 3 mg/kg body weight, 1 to 3 mg/kg body weight, or 2 to 3 mg/kg body weight, for example every second day, once a day, or twice a day, during a treatment period.

[0113] In some embodiments, each of the further therapeutically active agent may be administered to a mammalian patient, such as a human, at a dosage of, for example, 0.005 to 2 mg/kg body weight, 0.01 to 2 mg/kg body weight, 0.05 to 2 mg/kg body weight, 0.1 to 2 mg/kg body weight, 0.2 to 2 mg/kg body weight, 0.5 to 2 mg/kg body weight, or 1 to 2 mg/kg body weight, for example every second day, once a day, or twice a day, during a treatment period.

[0114] In some embodiments, the further therapeutically active agent is or comprises a BET inhibitor, which is selected from pelabresib, birabresib, molibresib, I-BET-151, TEN- 010, JQ1, apabetalone, and INCB054329, and from pharmaceutically acceptable salts thereof (e.g., from pelabresib and birabresib), and is administered over a treatment period at a dosage of from 5 mg to 300 mg, or from 10 mg to 300 mg, from 25 mg to 300 mg, from 50 mg to 300 mg, or from 100 mg to 300 mg. [0115] In some of these embodiments, each of the further therapeutically active agents is administered over a treatment period, at a dosage of from 5 mg to 200 mg, or from 10 mg to 200 mg, from 25 mg to 200 mg, from 50 mg to 200 mg, or from 100 mg to 200 mg.

[0116] In some of these embodiments, each of the further therapeutically active agents is administered over a treatment period, at a dosage of from 5 mg to 150 mg, or from 10 mg to 150 mg, from 25 mg to 150 mg, or from 50 mg to 150 mg.

[0117] In some of these embodiments, each of the further therapeutically active agents is administered over a treatment period, at a dosage of from 5 mg to 100 mg, or from 10 mg to 100 mg, from 25 mg to 100 mg, or from 50 mg to 100 mg.

[0118] In some of these embodiments, each of the further therapeutically active agents is administered over a treatment period, at a dosage of from 5 mg to 80 mg, from 10 mg to 80 mg, from 25 mg to 80 mg, or from 50 mg to 80 mg.

[0119] In some of these embodiments, each of the further therapeutically active agents is administered over a treatment period, at a dosage of from 5 mg to 50 mg, from 10 mg to 50 mg, or from 25 mg to 50 mg.

[0120] In some embodiments, each of the further therapeutically active compounds may be administered over a treatment period, at a dosage of from 0. 1 mg to 100 mg, from 0.1 mg to 50 mg, from 0.1 mg to 25 mg, from 0.1 mg to 20 mg, from 0.1 to 15 mg, from 0.1 to 10 mg, or from 0.1 to 5 mg.

[0121] In some of these embodiments, each of the further therapeutically active agent may be administered over a treatment period, at a dosage of from 1 mg to 100 mg, from 1 mg to 50 mg, from 1 mg to 25 mg, from 1 mg to 20 mg, from 1 to 15 mg, from 1 to 10 mg, or from 1 to 5 mg.

[0122] In still some further of these embodiments, each of the further therapeutically active agent may be administered over a treatment period, at a dosage of from 2 mg to 100 mg, from 2 mg to 50 mg, from 2 mg to 25 mg, from 2 mg to 20 mg, from 2 to 15 mg, from 2 to 10 mg, or from 1 to 5 mg.

[0123] In still some further of these embodiments, each of the further therapeutically active agent may be administered over a treatment period, at a dosage of from 5 mg to 100 mg, from 5 mg to 50 mg, from 5 mg to 25 mg, from 5 mg to 20 mg, from 5 to 15 mg, or from 5 to 10 mg.

[0124] In still some further of these embodiments, each of the further therapeutically active agent may be administered over a treatment period, at a dosage of from 10 mg to 100 mg, from 10 mg to 50 mg, from 10 mg to 25 mg, from 10 mg to 20 mg, or from 10 to 15 mg. [0125] In the above embodiments, the dosage may be administered, for example, every second day, daily, or twice a day. In some embodiments, administration is daily. Preferably, the administration is by the oral route.

[0126] The treatment period may be determined by the treating physician, and may range from, for example, 1 week to 6 months, 1 week to 2 months, or 2 weeks to 2 months, e.g., 2-4 weeks. The treatment period may also be longer, for example, one year or even several years. Treatment may also be pursued during the patient's lifetime, i.e., chronically, or as determined by the treating physician.

[0127] In some embodiments, TASQ is administered concurrently with the further therapeutically active agent or agents during the entire further therapeutically active agent or agents’ treatment period or during part of the further therapeutically active agent or agents treatment period. In some embodiments, the further therapeutically active agent or agents and TASQ are administered in separate (non-overlapping) treatment periods, optionally with intermediate periods without administration of either TASQ or the further therapeutically active agent or agents.

[0128] Generally, each one of the active ingredients may be administrated on a daily basis, e.g., 1-3 times a day, or 1-2 times a day, such as once daily. In some embodiments, administration occurs on a less frequent basis, e.g., every two days, once a week etc. Administration may follow established treatment cycles, over e.g., 3-6 weeks.

[0129] In some embodiments, TASQ and the further therapeutically active agent or agents (e.g., the BET inhibitor, the Bcl-2 inhibitor, or a combination thereof) are administered following different administration schedules and possibly also different modes of administration. However, preferably, both TASQ and the further therapeutically active agent or agents are administered orally (e.g., as capsule or tablet preparations). In some embodiments, both TASQ and the further therapeutically active agent or agents are provided as capsule preparations suitable for oral administration.

[0130] In some embodiments, the combined use of TASQ and a further therapeutically active agent, selected from a BET inhibitor, a Bcl-2 inhibitor, and a combination thereof, very advantageously may provide a synergistic therapeutic effect (i.e., a more than additive effect).

[0131] One aspect of the invention is a pharmaceutical composition comprising TASQ or a pharmaceutically acceptable salt thereof for use in the treatment of a MPN, wherein the treatment also comprises administration of a pharmaceutical composition comprising a further

T1 therapeutically active agent that is a BET inhibitor, a Bcl-2 inhibitor, or a combination thereof.

[0132] In an aspect, a method of treating a myeloproliferative neoplasm (MPN) in a subject in need thereof comprises administering to the subject TASQ and a further therapeutically active agent that is a BET inhibitor, a Bcl-2 inhibitor, or a combination thereof.

THE PHARMACEUTICAL COMPOSITION

[0133] Whether TASQ and the further therapeutically active agent or agents (e.g., a BET inhibitor, a JAK inhibitor, a Bcl-2 inhibitor, or a combination thereof, such as a BET inhibitor and a Bcl-2 inhibitor) are provided in one and the same pharmaceutical composition, or separately, in different compositions for combined use, each pharmaceutical composition may be suitable for enteral administration, such as rectal or oral administration, or for parenteral administration, to a mammal (especially a human), and comprises the active ingredient(s), in a therapeutically effective amount, optionally in association with a pharmaceutically acceptable excipient, e.g., a pharmaceutically acceptable carrier. The therapeutically effective amount of each active ingredient is as defined herein above and depends, for example, on the species of mammal, the body weight, the age, the individual condition, individual pharmacokinetic data, and the mode of administration.

[0134] For enteral, for example, oral, administration, each active ingredient may be formulated in a wide variety of dosage forms. The pharmaceutically acceptable carriers may be either solid or liquid. Solid form preparations include powders, tablets, pills, lozenges, capsules, cachets, suppositories, and dispersible granules. A solid carrier may be one or more substances which may also act as diluents, flavoring agents, solubilizers, lubricants, suspending agents, binders, preservatives, tablet disintegrating agents, or an encapsulating material. In powders, the carrier generally is a finely divided solid which is a mixture with the finely divided active component. In tablets, the active ingredient generally is mixed with the carrier having the necessary binding capacity in suitable proportions and compacted in the shape and size desired. Suitable carriers include but are not limited to magnesium carbonate, magnesium stearate, talc, sugar, lactose, pectin, dextrin, starch, gelatine, tragacanth, methylcellulose, sodium carboxymethylcellulose, a low melting wax, cocoa butter, and the like.

[0135] Other forms suitable for oral administration include liquid form preparations including emulsions, syrups, elixirs, aqueous solutions, aqueous suspensions, or solid form preparations which are intended to be converted shortly before use to liquid form preparations. Emulsions may be prepared in solutions, for example, in aqueous propylene glycol solutions, or may contain emulsifying agents, for example, such as lecithin, sorbitan monooleate, or acacia. Aqueous solutions can be prepared by dissolving the active ingredient in water and adding suitable colorants, flavoring agents, stabilizers, and thickening agents. Aqueous suspensions can be prepared by dispersing the finely divided active component in water with viscous material, such as natural or synthetic gums, resins, methylcellulose, sodium carboxymethylcellulose, and other well-known suspending agents. Solid form preparations include solutions, suspensions, and emulsions, and may contain, in addition to the active component, colorants, flavors, stabilizers, buffers, artificial and natural sweeteners, dispersants, thickeners, solubilizing agents, and the like.

[0136] Exemplary compositions for rectal administration include suppositories which can contain, for example, a suitable non-irritating excipient, such as cocoa butter, synthetic glyceride esters or polyethylene glycols, which are solid at ordinary temperatures, but liquefy and/or dissolve in the rectal cavity to release the drug.

[0137] The active ingredients also may be administered parenterally, for example, by injection or infusion, for example, by intravenous, intraarterial, intraosseous, intramuscular, intracerebral, intracerebroventricular, intrasynovial, intrasternal, intrathecal, intralesional, intracranial, intratumoral, intracutaneous and subcutaneous injection or infusion. Thus, for parenteral administration, the pharmaceutical compositions may be in the form of a sterile injectable or infusible preparation, for example, as a sterile aqueous or oleaginous suspension. This suspension may be formulated according to techniques known in the art using suitable dispersing or wetting agents (e.g., Tween® 80), and suspending agents. The sterile injectable or infusible preparation may also be a sterile injectable or infusible solution or suspension in a non-toxic parenterally acceptable diluent or solvent. For example, the pharmaceutical composition may be a solution in 1,3-butanediol. Other examples of acceptable vehicles and solvents that may be employed in the compositions of the present invention include, but are not limited to, mannitol, water, Ringer’s solution and isotonic sodium chloride solution. In addition, sterile, fixed oils are conventionally employed as a solvent or suspending medium. For this purpose, any fixed oil may be employed including synthetic mono- or diglycerides. Fatty acids, such as oleic acid and its glyceride derivatives are useful in the preparation of injectables, as are natural pharmaceutically acceptable oils, such as olive oil or castor oil, especially in their polyoxyethylated versions. These oil solutions or suspensions may also contain a long-chain alcohol diluent or dispersant. [0138] Solutions for parenteral use also may contain suitable stabilizing agents, and if necessary, buffer substances. Suitable stabilizing agents include antioxidizing agents, such as sodium bisulfate, sodium sulfite or ascorbic acid, either alone or combined, citric acid and its salts and sodium EDTA. Parenteral solutions may also contain preservatives, such as benzalkonium chloride, methyl- or propyl-paraben, and chlorobutanol.

[0139] Conventional procedures for the selection and preparation of suitable pharmaceutical formulations are described, for example, in “Pharmaceutics - The Science of Dosage Form Design”, M.B. Aulton, Churchill Livingstone, 2nd ed. 2002 (ISBN 0443055173, 9780443055171). Pharmaceutical excipients, e.g., carriers, and methods of preparing pharmaceutical dosage forms also are described in Remington’s Pharmaceutical Sciences, Mack Publishing Company, a standard reference text in art of drug formulation.

[0140] The pharmaceutical composition may comprise in total from about 1% to about 95% active ingredient(s), by weight of the composition, wherein the remainder is comprised of at least one pharmaceutically acceptable excipient. In some embodiments, pharmaceutical composition comprises at least 5%, at least 10%, at least 15%, or at least 20% of active ingredient(s). In some embodiments, the pharmaceutical composition comprises at most 90%, at most 85%, or at most 80%, of active ingredient(s). For example, in some embodiments, the pharmaceutical composition comprises from about 20% to about 90% of active ingredient(s), and at least one pharmaceutically acceptable excipient.

[0141] Also disclosed herein is a pharmaceutical composition (or formulation) comprising, as active ingredients, TASQ or a pharmaceutically acceptable salt thereof and at least one further therapeutically active agent as described herein (e.g., a BET inhibitor, JAK inhibitor, and a Bcl-2 inhibitor, or a combination thereof, such as a BET inhibitor, a Bcl-2 inhibitor, or a combination of a BET inhibitor and a Bcl-2 inhibitor), together with a pharmaceutically acceptable excipient, e.g., a carrier.

THE KIT

[0142] A further aspect disclosed herein is a kit comprising TASQ or a pharmaceutically acceptable salt thereof, a further therapeutically active agent described herein (e.g., a BET inhibitor, a JAK inhibitor, a Bcl-2 inhibitor, or a combination thereof, such as a BET inhibitor, a Bcl-2 inhibitor, or a combination of a BET inhibitor and a Bcl-2 inhibitor), and a package insert with instructions for their use. [0143] In the kit, TASQ and the further therapeutically active agent or agents may be present in forms allowing for separate administration or for administration of the components together.

[0144] In some embodiments, the kit comprises a pharmaceutical formulation containing TASQ or a pharmaceutically acceptable salt thereof, a pharmaceutical formulation containing the further therapeutically active agent or agents, and a package insert with instructions for their use.

[0145] In some embodiments, the kit comprises a pharmaceutical formulation for oral administration, containing TASQ or a pharmaceutically acceptable salt thereof, a pharmaceutical formulation for oral administration containing the further therapeutically active agent or agents, and a package insert with instructions for their use.

[0146] The particular embodiments of any such kit include features as defined in connection with the particular combinations, uses and pharmaceutical formulations (or compositions) described herein.

METHOD OF TREATMENT

[0147] A further aspect disclosed herein is a method of treatment of a MPN, comprising administering TASQ or a pharmaceutically acceptable salt thereof to an individual in need of such treatment, in combination with a further therapeutically active agent as described here (e.g., a BET inhibitor, a JAK inhibitor, a Bcl-2 inhibitor, or a combination thereof, such as a BET inhibitor, a Bcl-2 inhibitor, or a combination of a BET inhibitor and a Bcl-2 inhibitor). The particular embodiments of such a method include features as defined in connection with the particular combinations, pharmaceutical compositions (or formulations), uses and kits as described herein.

THE TREATED INDICATION

[0148] The combination provided herein is useful in therapy, in particular, for the treatment of a myeloproliferative neoplasm (MPN).

[0149] In some embodiments, the combination as disclosed herein is provided for use in the treatment of a MPN, including myelofibrosis (including primary myelofibrosis and myelofibrosis developed from essential thrombocythemia or polycythemia vera), essential thrombocythemia, polycythemia vera, chronic neutrophilic leukemia, chronic myelogenous leukemia, chronic eosinophilic leukemia, and advanced stage MPN, such as accelerated-phase MPN or post-MPN AML. In some embodiments, the MPN is a Philadelphia chromosome- negative MPN (e.g., an advanced stage, Philadelphia chromosome-negative MPN). In some embodiments, the Philadelphia chromosome-negative MPN is selected from myelofibrosis, essential thrombocythemia, and polycythemia vera. In some embodiments, the MPN is myelofibrosis. In some embodiments, the myelofibrosis is primary myelofibrosis.

[0150] Essential thrombocythemia (ET) is characterised by the overproduction of platelets (thrombocytes) by megakaryocytes in the bone marrow. Essential thrombocythemia may develop into myelofibrosis.

[0151] In polycythemia vera, the bone marrow makes too many red blood cells, and the disorder may also result in the overproduction of white blood cells and platelets. Polycythemia vera may develop into myelofibrosis.

[0152] In some embodiments, the MPN is myelofibrosis. Myelofibrosis is a disorder in which normal bone marrow tissue is gradually replaced with a fibrous scar-like material. Over time, this may lead to progressive bone marrow failure. Around one third of people with myelofibrosis have been previously diagnosed with polycythemia (post-polycythaemic myelofibrosis) or essential thrombocythaemia (post-ET myelofibrosis).

[0153] In some embodiments, the MPN is selected from advanced stages of MPN, with an antecedent Philadelphia chromosome-negative MPN. In some of these embodiments, the MPN is accelerated-phase MPN. In some of these embodiments, the MPN is post-MPN AML.

THE COMPOUND OF FORMULA (I) FOR USE IN POST-MPN AML

[0154] In a further aspect, a compound of formula (I) (e.g., TASQ) as defined herein is provided for use in the treatment of secondary acute myeloid leukemia (AMLs) evolving from an antecedent myeloproliferative neoplasm (MPN), e.g., post-MPN AML.

[0155] In this aspect, the compound of formula (I) (e.g., TASQ) may be administered as a monotherapy using dosages and pharmaceutical compositions as described herein above for TASQ in connection with the combination therapy with a BET inhibitor, a Bcl-2 inhibitor, or a combination thereof. Thus, particular embodiments of this aspect include the same features as discussed herein in connection with TASQ in embodiments of the combination therapy aspects, unless otherwise specified or apparent from the context.

THE COMBINATION OF TASQ WITH A FURTHER THERAPEUTIC AGENT SELECTED

FROM A JAK INHIBITOR, A BET INHIBITOR AND A BCL-2 INHIBITOR [0156] A further aspect relates to a combination of TASQ and a therapeutically active agent selected from a JAK inhibitor, a BET inhibitor, and a Bcl-2 inhibitor for use in the treatment of post-MPN AML, or a combination of TASQ and more than one such inhibitor. In this aspect, TASQ may be administered as a combination therapy using dosages and pharmaceutical compositions as described herein above for TASQ in connection with the combination therapy with a BET inhibitor, a Bcl-2 inhibitor, or a combination thereof, for the treatment of a MPN. Thus, particular embodiments of this aspect include the same features as defined in connection with TASQ in embodiments of the above-mentioned previous combination therapy aspects, unless otherwise specified or apparent from the context.

[0157] In some embodiments, the further therapeutic agent is a BET inhibitor, a Bcl-2 inhibitor, or a combination thereof. In some embodiments, the further therapeutic agent is a BET inhibitor or a Bcl-2 inhibitor. In some embodiments, the further therapeutic agent comprises or is a BET inhibitor. In some embodiments, the further therapeutic agent comprises a Bcl-2 inhibitor.

[0158] In some embodiments, the BET inhibitor may be selected from any BET inhibitor, such as any of the BET inhibitors mentioned herein. In some embodiments, the BET inhibitor is pelabresib or a pharmaceutically acceptable salt thereof, or birabresib or a pharmaceutically acceptable salt thereof. In some embodiments, the BET inhibitor is pelabresib or a pharmaceutically acceptable salt thereof. In some embodiments, the BET inhibitor is birabresib or a pharmaceutically acceptable salt thereof.

[0159] In some embodiments, the Bcl-2 inhibitor may be selected from any Bcl-2 inhibitor, such as any of the Bcl-2 inhibitors mentioned herein. In some embodiments, the Bcl-2 inhibitor is selected from navitoclax or a pharmaceutically acceptable salt thereof, lisaftoclax or a pharmaceutically acceptable salt thereof, obatoclax or a pharmaceutically acceptable salt thereof (e.g., obatoclax mesylate), or venetoclax or a pharmaceutically acceptable salt thereof. In some embodiments, the Bcl-2 inhibitor is selected from navitoclax, lisaftoclax, obatoclax (or obatoclax mesylate), and venetoclax.

[0160] In some embodiments, the Bcl-2 inhibitor is navitoclax or a pharmaceutically acceptable salt thereof. In some embodiments, the Bcl-2 inhibitor is lisaftoclax or a pharmaceutically acceptable salt thereof. In some embodiments, the Bcl-2 inhibitor is obatoclax or a pharmaceutically acceptable salt thereof. In some embodiments, the Bcl-2 inhibitor is navitoclax or a pharmaceutically acceptable salt thereof. In some embodiments, the Bcl-2 inhibitor is venetoclax or a pharmaceutically acceptable salt thereof. In some embodiments the Bcl-2 inhibitor is a pharmaceutically acceptable salt of any of the Bcl-2 inhibitors mentioned herein (for example, obatoclax mesylate).

[0161] Janus kinases (JAKs) are protein tyrosine kinases which phosphorylate a group of proteins called Signal Transduction and Activators of Transcription or STATs. When phosphorylated, STATs dimerize, translocate to the nucleus, and activate expression of genes which lead to, amongst other things, cellular proliferation. Due to the central role played by the JAK family in the cytokine dependent regulation of both proliferation and end function of several important cell types, agents capable of inhibiting the JAK kinases have been developed for use in the prevention and chemotherapeutic treatment of disease states dependent on these enzymes, including various myeloproliferative neoplasms (MPN), a group of diseases of the bone marrow in which excess cells are produced. Some examples of JAK inhibitors are ruxolitinib (CAS No. 941678-49-5, IUPAC name: (3R)-3-cyclopentyl-3-[4-(7H- pyrrolo[2,3-d]pyrimidin-4-yl)pyrazol-l-yl]propanenitrile), fedratinib (CAS No. 936091-26-8, IUPAC name: N-tert-Butyl-3-{5-methyl-2-[4-(2-pyrrolidin-l-yl-ethoxy)-phenylamino]- pyrimidin-4-ylamino } -benzenesulfonamide), and pacritinib, (CAS No. 937272-79-2, IUPAC name: (16E)-1 l-[2-(l-pyrrolidinyl)ethoxy]-14,19-dioxa-5,7,26- triazatetracyclo[19.3.1.12,6.18,12]heptacosa-l(25),2(26),3 ,5 ,8, 10, 12(27), 16, 21 ,23-decaene).

[0162] In some embodiments, the further therapeutic agent is a BET inhibitor, a JAK inhibitor, or a combination thereof (e.g., a BET inhibitor or a JAK inhibitor). In some embodiments, the further therapeutic agent is a Bcl-2 inhibitor, a JAK inhibitor, or combination thereof (a Bcl-2 inhibitor or a JAK inhibitor). In some embodiments, the further therapeutic agent is a JAK inhibitor. In some embodiments, the JAK inhibitor preferably is selected from JAK1 inhibitors and JAK2 inhibitors. In some embodiments, the JAK inhibitor is an inhibitor of JAK1 and JAK2. In some embodiments, the JAK inhibitor is ruxolitinib or a pharmaceutically acceptable salt thereof. In some embodiments, the JAK inhibitor is an inhibitor of JAK2. In some embodiments, the JAK inhibitor is fedratinib or a pharmaceutically acceptable salt thereof. In some embodiments, the JAK inhibitor is pacritinib or a pharmaceutically acceptable salt thereof.

[0163] In some embodiments, the JAK inhibitor is selected from ruxolitinib, fedratinib, pacritinib, and from pharmaceutically acceptable salts thereof.

[0164] In some embodiments, the JAK inhibitor may be administered to a mammalian patient, such as a human, at a dosage of, for example, 0.005 to 50 mg/kg body weight, 0.01 to 50 mg/kg body weight, 0.05 to 50 mg/kg body weight, 0.1 to 50 mg/kg body weight, 0.2 to 50 mg/kg body weight, 0.5 to 50 mg/kg body weight, 1 to 50 mg/kg body weight, 2 to 50 mg/kg body weight, 5 to 50 mg/kg body weight, 10 to 50 mg/kg body weight, 15 to 50 mg/kg body weight, 20 to 50 mg/kg body weight, or 25 to 50 mg/kg body weight, for example every second day, once a day, or twice a day, during a treatment period.

[0165] In some embodiments, the JAK inhibitor may be administered to a mammalian patient, such as a human, at a dosage of, for example, 0.005 to 30 mg/kg body weight, 0.01 to 30 mg/kg body weight, 0.05 to 30 mg/kg body weight, 0.1 to 30 mg/kg body weight, 0.2 to 30 mg/kg body weight, 0.5 to 30 mg/kg body weight, 1 to 30 mg/kg body weight, 2 to 30 mg/kg body weight, 5 to 30 mg/kg body weight, 10 to 30 mg/kg body weight, 15 to 30 mg/kg body weight, 20 to 30 mg/kg body weight, or 25 to 30 mg/kg body weight, for example every second day, once a day, or twice a day, during a treatment period.

[0166] In some embodiments, the JAK inhibitor may be administered to a mammalian patient, such as a human, at a dosage of, for example, 0.005 to 20 mg/kg body weight, 0.01 to 20 mg/kg body weight, 0.05 to 20 mg/kg body weight, 0.1 to 20 mg/kg body weight, 0.2 to 20 mg/kg body weight, 0.5 to 20 mg/kg body weight, 1 to 20 mg/kg body weight, 2 to 20 mg/kg body weight, 5 to 20 mg/kg body weight, 10 to 20 mg/kg body weight, or 15 to 20 mg/kg body weight, for example every second day, once a day, or twice a day, during a treatment period.

[0167] In some embodiments, the JAK inhibitor may be administered to a mammalian patient, such as a human, at a dosage of, for example, 0.005 to 10 mg/kg body weight, 0.01 to 10 mg/kg body weight, 0.05 to 10 mg/kg body weight, 0.1 to 10 mg/kg body weight, 0.2 to 10 mg/kg body weight, 0.5 to 10 mg/kg body weight, 1 to 10 mg/kg body weight, 2 to 10 mg/kg body weight, or 5 to 10 mg/kg body weight, for example every second day, once a day, or twice a day, during a treatment period.

[0168] In some embodiments, the JAK inhibitor may be administered to a mammalian patient, such as a human, at a dosage of, for example, 0.005 to 5 mg/kg body weight, 0.01 to 5 mg/kg body weight, 0.05 to 5 mg/kg body weight, 0.1 to 5 mg/kg body weight, 0.2 to 5 mg/kg body weight, 0.5 to 5 mg/kg body weight, 1 to 5 mg/kg body weight, or 2 to 5 mg/kg body weight, for example every second day, once a day, or twice a day, during a treatment period.

[0169] In some embodiments, the JAK inhibitor may be administered to a mammalian patient, such as a human, at a dosage of, for example, 0.005 to 3 mg/kg body weight, 0.01 to 3 mg/kg body weight, 0.05 to 3 mg/kg body weight, 0.1 to 3 mg/kg body weight, 0.2 to 3 mg/kg body weight, 0.5 to 3 mg/kg body weight, 1 to 3 mg/kg body weight, or 2 to 3 mg/kg body weight, for example every second day, once a day, or twice a day, during a treatment period. [0170] In some embodiments, the JAK inhibitor may be administered to a mammalian patient, such as a human, at a dosage of, for example, 0.005 to 2 mg/kg body weight, 0.01 to 2 mg/kg body weight, 0.05 to 2 mg/kg body weight, 0. 1 to 2 mg/kg body weight, 0.2 to 2 mg/kg body weight, 0.5 to 2 mg/kg body weight, or 1 to 2 mg/kg body weight, for example every second day, once a day, or twice a day, during a treatment period.

[0171] In some embodiments, the JAK inhibitor, for example a JAK inhibitor selected from ruxolitinib, fedratinib, pacritinib, and from pharmaceutically acceptable salts thereof, in particular ruxolitinib, is administered over a treatment period at a dosage of from 5 mg to 300 mg, or from 10 mg to 300 mg, from 25 mg to 300 mg, from 50 mg to 300 mg, or from 100 mg to 300 mg.

[0172] In some of these embodiments, the JAK inhibitor is administered over a treatment period, at a dosage of from 5 mg to 200 mg, or from 10 mg to 200 mg, from 25 mg to 200 mg, from 50 mg to 200 mg, or from 100 mg to 200 mg.

[0173] In some of these embodiments, the JAK inhibitor is administered over a treatment period, at a dosage of from 5 mg to 150 mg, or from 10 mg to 150 mg, from 25 mg to 150 mg, or from 50 mg to 150 mg.

[0174] In some of these embodiments, the JAK inhibitor is administered over a treatment period, at a dosage of from 5 mg to 100 mg, or from 10 mg to 100 mg, from 25 mg to 100 mg, or from 50 mg to 100 mg.

[0175] In some of these embodiments, the JAK inhibitor is administered over a treatment period, at a dosage of from 5 mg to 80 mg, from 10 mg to 80 mg, from 25 mg to 80 mg, or from 50 mg to 80 mg.

[0176] In some of these embodiments, the JAK inhibitor is administered over a treatment period, at a dosage of from 5 mg to 50 mg, from 10 mg to 50 mg, or from 25 mg to 50 mg.

[0177] In some of these embodiments, the JAK inhibitor is administered over a treatment period, at a dosage of from 1 mg to 100 mg, from 1 mg to 50 mg, from 1 mg to 25 mg, from 1 mg to 20 mg, from 1 to 15 mg, from 1 to 10 mg, or from 1 to 5 mg.

[0178] In still some further of these embodiments, the JAK inhibitor is administered over a treatment period, at a dosage of from 2 mg to 100 mg, from 2 mg to 50 mg, from 2 mg to 25 mg, from 2 mg to 20 mg, from 2 to 15 mg, from 2 to 10 mg, or from 1 to 5 mg.

[0179] In still some further of these embodiments, the JAK inhibitor is administered over a treatment period, at a dosage of from 5 mg to 100 mg, from 5 mg to 50 mg, from 5 mg to 25 mg, from 5 mg to 20 mg, from 5 to 15 mg, or from 5 to 10 mg. [0180] In still some further of these embodiments, the JAK inhibitor is administered over a treatment period, at a dosage of from 10 mg to 100 mg, from 10 mg to 50 mg, from 10 mg to 25 mg, from 10 mg to 20 mg, or from 10 to 15 mg.

[0181 ] In the above embodiments, the dosage may be administered, for example, every second day, daily, or twice a day. In some embodiments, administration is daily. Preferably, the administration is by the oral route.

[0182] The treatment period may be determined by the treating physician, and may range from, for example, 1 week to 6 months, 1 week to 2 months, or 2 weeks to 2 months, e.g., 2-4 weeks. The treatment period may also be longer, for example, one year or even several years. Treatment may also be pursued during the patient’s lifetime, i.e., chronically, or as determined by the treating physician.

[0183] In some embodiments, TASQ is administered concurrently with the JAK inhibitor during the entire JAK inhibitor treatment period or during part of the JAK inhibitor treatment period. In some embodiments, JAK inhibitor and TASQ are administered in separate (non-overlapping) treatment periods, optionally with intermediate periods without administration of either agent.

[0184] Generally, each one of the active ingredients may be administrated on a daily basis, e.g., 1-3 times a day, or 1-2 times a day, such as once daily. In some embodiments, administration occurs on a less frequent basis, e.g., every two days, once a week etc. Administration may follow established treatment cycles, over e.g., 3-6 weeks.

[0185] In some embodiments, TASQ and the JAK inhibitor are administered following different administration schedules and possibly also different modes of administration. However, preferably, both TASQ and the JAK inhibitor are administered orally, e.g., as capsule or tablet preparations. In some embodiments, both TASQ and the JAK inhibitor are provided as capsule preparations suitable for oral administration.

[0186] In some embodiments, the combined use of TASQ and a JAK inhibitor very advantageously may provide a synergistic therapeutic effect, i.e., a more than additive effect.

[0187] One aspect of the invention is a pharmaceutical composition comprising TASQ or a pharmaceutically acceptable salt thereof for use in the treatment of post-MPN AML, wherein the treatment also comprises administration of a pharmaceutical composition comprising a JAK inhibitor, a BET inhibitor, or a Bcl-2 inhibitor, or a combination thereof.

[0188] A combination, as mentioned herein, of at least two inhibitors selected from a JAK inhibitor, a BET inhibitor, and a Bcl-2 inhibitor may be, for example, a combination of BET inhibitor and one further inhibitor selected from a JAK inhibitor and a Bcl-2 inhibitor. In some embodiments, the combination of inhibitors comprises a Bcl-2 inhibitor. In some embodiments, the combination of inhibitors comprises a JAK inhibitor.

[0189] Further aspects of the present invention are a pharmaceutical composition and a kit for use in the treatment of post-MPN AML, comprising TASQ and a JAK inhibitor, a BET inhibitor, or a Bcl-2 inhibitor. Features of embodiments of these aspects are as generally described herein in relation to the treatment of other indications, such as a MPN.

[0190] A method of treating advanced stages of MPN in a subject, such as a mammalian subject, in need thereof comprises administering to the subject compound of formula (I) or a pharmaceutically acceptable salt thereof, wherein R is selected from hydrogen and methyl, and a JAK inhibitor, a BET inhibitor, a Bcl-2 inhibitor, or a combination thereof.

[0191] In an aspect, a treatment regimen comprises administering a JAK inhibitor, a BET inhibitor, or a Bcl-2 inhibitor to a patient in need of treatment for MEN, a pre-leukemic condition, or myeloproliferative neoplasm, upon resistance to the JAK inhibitor, the BET inhibitor, or the Bcl-2 inhibitor, progression to advanced MPN, MPN with excessive blasts, or accelerated phase or secondary acute myeloid leukemia, administering to the subject TASQ, and optionally continuing administering the JAK inhibitor, BET inhibitor, Bcl-2 inhibitor, or a combination thereof with the TASQ.

EXAMPLES

[0192] The invention is further illustrated in the following non-limiting Examples.

EXAMPLE 1 : USE OF TASQUINIMOD

[0193] The human MPN cell lines SET-2 (DSMZ Cat# ACC 608 (Braunschweig, Germany); RRID:CVCL_2187) and HEL92.1.7, human post-MPN AML cells, isolated from whole blood by density centrifugation (Ficoll®) from four different patients with advanced- MPN (with JAK2V617F or calreticulin mutations), and human normal CD34⁺ progenitor cells from cord blood were cultured in RPMI-1640 medium supplemented with 20% fetal bovine serum (FBS) and treated with different concentrations of tasquinimod for 48 hours. At the end of treatment, cells were washed in 1 X PBS and stained with annexin-V-FTTC (BD Bioscience) and/or TO-PRO™-3 iodide (Invitrogen). The percentage of apoptotic cells (annexin- V-positive) or the percentage of non- viable cells (TO-PRO™-3 iodide positive) were determined by flow cytometry. The results illustrated in FIGs. lA-to 1C show that treatment with tasquinimod induced apoptosis and reduced cell viability of human MPN and post-MPN AML cells. However, tasquinimod had no effect on the survival of normal CD34+ hematopoietic progenitor cells.

[0194] Total RNA was isolated, using an RNA isolation Kit from Ambion, Inc. (catalog # AM1914) according to manufacturer’s instructions, from the human MPN cell line SET-2 (in triplicates) and CD34⁺ MF-MPN cells from a patient with advanced-MPN with myelofibrosis (in duplicates) after 16 hours of treatment with 50 pM tasquinimod. The RNA was reverse transcribed utilizing a kit purchased from Invitrogen (Catalog # 4368814) and the resulting cDNA was used for quantitative real-time PCR using utilizing StepOne™ Plus QPCR instrument and Taqman® reagents purchased from ThermoFisher and primers specific for the different genes. Expression of each gene was normalized to the expression of GAPDH and compared to corresponding untreated control cells. The result illustrated in FIGs. 2A and 2B showed that tasquinimod induced a reduction of gene expression of the cell proliferation and survival including MYCgene in both SET-2 and MF-MPN cells. Also, an increase of p21 expression, which is known to induce cell cycle arrest, was observed for both cell types. These data support that tasquinimod has a direct effect on cell proliferation and survival of MPN cells, while sparing normal hematopoietic progenitor cells. This is associated with induction of gene expression cell cycle inhibitory protein and reduction of gene-expressions that promote cell growth and survival.

[0195] Tasquinimod’s effect on the advanced stages of MPN was further supported by survival data in an in vivo xenograft PDX model, from two independent studies, illustrated in FIGs. 3 A and 3B. Disease specific mutations in IAK2, myeloproliferative leukemia virus (MPL), telomerase reverse transcriptase (TERT), or calreticulin (CALR) genes in hematopoietic stem/progenitor cells (HSCs) cause the chronic phase of Philadelphia chromosome-negative myeloproliferative neoplasms. The HSCs with any of these mutations have increased JAK-STAT 3/5 and NFkB signaling that results in myeloproliferation and extramedullary hematopoiesis, splenomegaly, constitutional symptoms, and myelofibrosis. All these can be partially ameliorated by JAK inhibitors (JAKi), including ruxolitinib, pacritinib and fedaritinib. However, JAKi treatment does not prevent the accumulation of additional “epimutations” in HSCs, resulting in the progression of the chronic MPNs to the advanced MPN with arrested differentiation, resulting in MPN with excess blasts (5 to 9% blasts, EB), MPN in Accelerated Phase (10 to 19% blasts, MPN-AP) and MPN in blastic phase or secondary AML (20% or more blasts, MPN-secondary acute myeloid leukemia (sAML)). Patients with MPN-EB/AP/sAML have a poor prognosis, lose response to JAKi, and exhibit poor survival following standard AML therapy-a median survival of less than 6 months. This highlights the glaring need to develop and test novel effective agents, e.g., tasquinimod, that administered alone or in combination with JAKi or other active agents would yield superior clinical outcomes.

[0196] Briefly, female NOD.Cg-Prkdcscid I12rgtmlWjl/SzJ (NSG™) mice (stock number: 005557; 4-6 weeks of age) [Jackson Labs, Bar Harbor, Maine; RRID: IMSR_JAX:005557] (n=6) that had received a pre-conditioning dose (2.5 Gy) from a cesium- 137 irradiator were infused with 2.5-3.0 x 10⁶ of sAML patient derived xenograft (PDX) cells, having mutations in its CALR and TERT genes, via the lateral tail vein. Mice were monitored for two weeks. Upon confirmation of engraftment, mice were randomized and treatment was started, whereby mice were treated with vehicle (3:1 Labrasol®: ethanol) or tasquinimod (10 or 30 mg/kg, PO, daily x 5 days per week) for eight weeks, whereafter treatment was stopped. Separately, mice were treated with vehicle (3: 1 Labrasol®: ethanol), tasquinimod (10 mg/kg (FIG. 3A) or 30 mg/kg (FIGs. 3A and 3B), PO, daily x 5 days per week), ruxolitinib (30 mg/kg, by oral gavage, daily x 5 days per week), or birabresib (OTX015) (30 mg/kg, by oral gavage, daily x 5 days per week), for 10 weeks. Survival of the mice is illustrated with Kaplan-Meier plots (FIGs. 3A and 3B). The results show a significant improved survival of mice treated with 10 mg/kg and 30 mg/kg tasquinimod as compared to vehicle treated mice. Furthermore, mice treated with 30 mg/kg tasquinimod showed an improved survival compared to mice treated with ruxolitinib or OTX015. Significance was determined by a Mantel-Cox log rank test. P- values of less than 0.05 were assigned significance. *=p< 0.05; **=p< 0.01; ***=p< 0.005; ***=p< 0.001.

EXAMPLE 2: USE OF TASQUINIMOD IN COMBINATION WITH RUXOLITINIB

[0197] The human SET-2 MPN cell line and human post-MPN AML cells from isolated from one patient were cultured in RPMI-1640 medium supplemented with 20% fetal bovine serum (FBS) and treated with tasquinimod and ruxolitinib at different concentrations for 48 hours in vitro, then washed with 1 x phosphate-buffered saline, stained with annexin-V- FITC and/or T0-PR0™-3 iodide as described above, and analyzed by flow cytometry on a BD Accuri™ CFlow-6 flow cytometer (BD Biosciences, San Jose, CA). Drug synergy was assessed by use of the SynergyFinder V2 online web application tool. Delta synergy scores were determined according to the Zero interaction potency (ZIP) model (Bhagwan Y adav et al., Comput Struct Biotechnol J. 2015; 13: 504-513). Delta synergy scores greater than 1.0 indicate a synergistic interaction of the two drugs in the combination. The results illustrated in FIGs. 4A-D show that co-treatment of tasquinimod and the JAK inhibitor ruxolitinib induced synergistic lethal activity in human MPN and post-MPN AML cells.

EXAMPLE 3: USE OF TASQUINIMOD IN COMBINATION WITH PELABRESIB [0198] The Protocol of Example 2 was repeated with tasquinimod and the BET inhibitor pelabresib (CPI-0610). The results illustrated in FIGs. 5A to5F show that cotreatment with tasquinimod and pelabresib induced synergistic lethal activity in human MPN and post-MPN AML cells.

EXAMPLE 4: USE OF TASQUINIMOD IN COMBINATION WITH BIRABRESIB [0199] The Protocol of Example 2 was repeated with tasquinimod and the BET inhibitor birabresib (OTX015). The results illustrated in FIGs. 6A to 6F show that cotreatment with tasquinimod and the BET inhibitor birabresib induced synergistic lethal activity in human MPN and post-MPN AML cells.

EXAMPLE 5: USE OF TASQUINIMOD ALONE OR IN COMBINATION WITH RUXOLITINIB OR BIRABRESIB

[0200] A synergistic interaction of tasquinimod with JAK inhibitor ruxolitinib or with BET inhibitor birabresib in advanced stages of MPN was further supported by combination studies in the in vivo xenograft MPN PDX model as described in Example 1. Briefly, mice were randomized into different treatment groups (n=6-7) and treatment started 2 weeks after injection of the PDX cells with vehicle (3:1 Labrasol®: ethanol), tasquinimod (30 mg/kg, PO, daily x 5 days per week), ruxolitinib (30 mg/kg, by oral gavage, daily x 5 days per week), birabresib (OTX015) (30 mg/kg, by oral gavage, daily x 5 days per week), or the combination of tasquinimod (30 mg/kg) and either ruxolitinib (30 mg/kg) or birabresib (OTX015) (30 mg/kg). [0201] The results show an improved survival of mice treated with the combination of tasquinimod and either ruxolitinib or birabresib compared to mice treated with monotherapy or vehicle, as illustrated in FIG. 7 A.

[0202] Since enlargement of the spleen is a common finding in MPN, the size of the spleens in each treatment group was analyzed in this PDX model. FIGs. 7B and 7C show the effect on spleen size after 6 weeks of treatment with vehicle, tasquinimod, ruxolitinib, birabresib, or the combination of tasquinimod and either ruxolitinib or birabresib.

[0203] The results show that tasquinimod and birabresib as monotherapies reduced the spleen size significantly, compared to vehicle, while ruxolitinib had no effect. However, the combination of tasquinimod with either ruxolitinib or birabresib was superior to vehicle and monotherapy with either agent in reducing the spleen size in this MPN model. Significance was determined by a Mantel-Cox log rank test. P-values of less than 0.05 were assigned significance. *=p< 0.05; **=p<0.01 ***=p<0.005; ****=p<0.001.

EXAMPLE 6: USE OF TASQUINIMOD IN COMBINATION WITH NAVITOCLAX [0204] The Protocol of Example 2 was repeated with tasquinimod and the Bcl-2 inhibitor navitoclax. The results illustrated in FIGs. 8A to 8D show that co-treatment with tasquinimod and navitoclax for 72 hours induces synergistic lethal activity in human MPN and post-MPN AML cells.

EXAMPLE 7: USE OF TASQUINIMOD IN COMBINATION WITH VENETOCLAX [0205] The Protocol of Example 2 was repeated with tasquinimod and the BCL-2 inhibitor venetoclax. Venetoclax was obtained from MedChem Express (Monmouth Junction, NJ). For the in vitro studies, venetoclax was prepared as a 10 mM stock in 100% DMSO and frozen in 5-10 pL aliquots at -80°C to allow for single use. Hiis avoids multiple freeze-thaw cycles that could result in compound decomposition and loss of activity. The results illustrated in FIGs. 9A-9F show that co-treatment with tasquinimod and the BCL-2 inhibitor venetoclax induced synergistic lethal activity in human MPN and post-MPN AML cells.

Claims

CLAIMS What Is Claimed Is:

1. A pharmaceutical combination comprising: a compound of formula (I) wherein R is selected from hydrogen and methyl, or a pharmaceutically acceptable salt thereof; and a further therapeutically active agent comprising a bromodomain and extra-terminal motif protein (BET) inhibitor, a B-cell lymphoma 2 (Bcl-2) inhibitor, or a combination thereof.

2. The pharmaceutical combination according to claim 1 , wherein the further therapeutically active agent comprises the BET inhibitor pelabresib or a pharmaceutically acceptable salt thereof, or birabresib or a pharmaceutically acceptable salt thereof, or the Bcl-2 inhibitor navitoclax or a pharmaceutically acceptable salt thereof, or venetoclax or a pharmaceutically acceptable salt thereof, or a combination thereof.

3. The pharmaceutical combination according to claim 1 or 2, wherein the further therapeutically active agent comprises a BET inhibitor.

4. The pharmaceutical combination according to claim 1 or 2, wherein the further therapeutically active agent comprises a Bcl-2 inhibitor.

5. A pharmaceutical composition comprising: a compound of formula (I) wherein R is selected from hydrogen and methyl, or a pharmaceutically acceptable salt thereof; a further therapeutically active agent comprising a bromodomain and extra-terminal motif protein (BET) inhibitor, a B-cell lymphoma 2 (Bcl-2) inhibitor, or a combination thereof; and a pharmaceutically acceptable excipient.

6. The pharmaceutical composition according to claim 5, wherein the further therapeutically active agent comprises the BET inhibitor pelabresib or a pharmaceutically acceptable salt thereof, or birabresib or a pharmaceutically acceptable salt thereof, or the Bcl-2 inhibitor navitoclax or a pharmaceutically acceptable salt thereof, or venetoclax or a pharmaceutically acceptable salt thereof, or a combination thereof.

7. The pharmaceutical composition according to claim 5 or 6, wherein the further therapeutically active agent comprises a BET inhibitor.

8. The pharmaceutical composition according to claim 5 or 6, wherein the further therapeutically active agent comprises a Bcl-2 inhibitor.

9. A kit comprising a compound of formula (I) wherein R is selected from hydrogen and methyl, or a pharmaceutically acceptable salt thereof; a further therapeutically active agent comprising a bromodomain and extra-terminal motif protein (BET) inhibitor, a B-cell lymphoma 2 (Bcl-2) inhibitor, or a combination thereof; and a package insert with instructions for use of said kit.

10. The kit according to claim 9, wherein the further therapeutically active agent comprises the BET inhibitor pelabresib or a pharmaceutically acceptable salt thereof, or birabresib or a pharmaceutically acceptable salt thereof, or the Bcl-2 inhibitor navitoclax or a pharmaceutically acceptable salt thereof, or venetoclax or a pharmaceutically acceptable salt thereof, or a combination thereof.

11. The kit according to claim 9 or 10, wherein the further therapeutically active agent comprises a BET inhibitor.

12. The kit according to claim 9 or 10, wherein the further therapeutically active agent comprises a Bcl-2 inhibitor.

13. The pharmaceutical combination according to any one of claims 1 to 4, or the pharmaceutical composition according to any one of claims 5 to 8, or the kit according to any one of claims 9 to 12, for use in the treatment of a myeloproliferative neoplasm (MPN).

14. A compound of formula (I) wherein R is selected from hydrogen and methyl, or a pharmaceutically acceptable salt thereof, for use in the treatment of a myeloproliferative neoplasm (MPN), wherein the treatment comprises administration of a further therapeutically active agent comprising a bromodomain and extra-terminal motif protein (BET) inhibitor, a B-cell lymphoma 2 (Bcl-2) inhibitor, or a combination thereof.

15. The compound or pharmaceutically acceptable salt thereof for use according to claim 14, wherein the further therapeutically active agent comprises the BET inhibitor pelabresib or a pharmaceutically acceptable salt thereof, or birabresib or a pharmaceutically acceptable salt thereof, or the Bcl-2 inhibitor navitoclax or a pharmaceutically acceptable salt thereof, venetoclax or a pharmaceutically acceptable salt thereof; or a combination thereof.

16. The compound or pharmaceutically acceptable salt thereof for use according to claim 14 or 15, wherein the further therapeutically active agent comprises a BET inhibitor.

17. The compound or pharmaceutically acceptable salt thereof for use according to claim 14 or 15, wherein the further therapeutically active agent comprises a Bcl-2 inhibitor.

18. Use of a compound of formula (I) wherein R is selected from hydrogen and methyl, or a pharmaceutically acceptable salt thereof, in the manufacture of a combination medicament for the treatment of a myeloproliferative neoplasm (MPN), wherein the combination comprises a further therapeutically active agent comprising a bromodomain and extra-terminal motif protein (BET) inhibitor, a B-cell lymphoma 2 (Bcl-2) inhibitor, or a combination thereof.

19. The use according to claim 18, wherein the further therapeutically active agent comprises the BET inhibitor pelabresib or a pharmaceutically acceptable salt thereof, or birabresib or a pharmaceutically acceptable salt thereof, or the Bcl-2 inhibitor navitoclax or a pharmaceutically acceptable salt thereof, or venetoclax or a pharmaceutically acceptable salt thereof, or a combination thereof.

20. The use according to claim 18 or 19, wherein the further therapeutically active agent comprises a BET inhibitor.

21. The use according to claim 18 or 19, wherein the further therapeutically active agent comprises a Bcl-2 inhibitor.

22. The pharmaceutical combination, the pharmaceutical composition, or the kit, for use according to claim 13, or the compound or pharmaceutically acceptable salt thereof for use according to any one of claims 14 to 17, or the use according to any one of claims 18 to 21 , wherein the MPN is selected from chronic myelogenous leukemia (CML), polycythemia vera, myelofibrosis, essential thrombocythemia, chronic neutrophilic leukemia, chronic eosinophilic leukemia, Philadelphia chromosome-negative MPN, progress to more overt forms of myelofibrosis and advanced stages of MPN.

23. A compound of formula (I) wherein R is selected from hydrogen and methyl, or a pharmaceutically acceptable salt thereof, for use in the treatment of advanced stage myeloproliferative neoplasm (MPN).

24. The compound for use according to claim 23, wherein the treatment comprises administration of a further therapeutically active agent comprising a Janus kinase (JAK) inhibitor, a bromodomain and extra-terminal motif protein (BET) inhibitor, a B-cell lymphoma 2 (Bcl-2) inhibitor, or a combination thereof.

25. The compound for use according to claim 24, wherein the further therapeutically active agent comprises the JAK inhibitor ruxolitinib or a pharmaceutically acceptable salt thereof, or the BET inhibitor pelabresib or a pharmaceutically acceptable salt thereof, or birabresib or a pharmaceutically acceptable salt thereof, or the Bcl-2 inhibitor navitoclax or a pharmaceutically acceptable salt thereof, or venetoclax or a pharmaceutically acceptable salt thereof, or a combination thereof.

26. The compound for use according to claim 24 or 25, wherein the further therapeutically active agent comprises a JAK inhibitor.

27. The compound for use according to claim 24 or 25, wherein the further therapeutically active agent comprises a BET inhibitor.

28. The compound for use according to claim 24 or 25, wherein the further therapeutically active agent comprises a Bcl-2 inhibitor.

29. A pharmaceutical combination comprising a compound of formula (I) wherein R is selected from hydrogen and methyl, or a pharmaceutically acceptable salt thereof; and a further therapeutically active agent comprising a Janus kinase (JAK) inhibitor, a bromodomain and extra-terminal motif protein (BET) inhibitor, a B-cell lymphoma 2 (Bcl-2) inhibitor, or a combination thereof, for use in the treatment of advanced stage myeloproliferative neoplasm (MPN).

30. The pharmaceutical combination for use according to claim 29, wherein the further therapeutically active agent comprises the JAK inhibitor ruxolitinib or a pharmaceutically acceptable salt thereof, or the BET inhibitor pelabresib or a pharmaceutically acceptable salt thereof, or birabresib or a pharmaceutically acceptable salt thereof, or the Bcl-2 inhibitor navitoclax or a pharmaceutically acceptable salt thereof, or venetoclax or a pharmaceutically acceptable salt thereof, or a combination thereof.

31. The pharmaceutical combination for use according to claim 29 or 30, wherein the further therapeutically active agent comprises a JAK inhibitor.

32. The pharmaceutical combination for use according to claim 29 or 30, wherein the further therapeutically active agent comprises a BET inhibitor.

33. The pharmaceutical combination for use according to claim 29 or 30, wherein the further therapeutically active agent comprises a Bcl-2 inhibitor.

34. A pharmaceutical composition for use in the treatment of advanced stage myeloproliferative neoplasm (MPN), the pharmaceutical composition comprising a compound of formula (I) wherein R is selected from hydrogen and methyl, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.

35. The pharmaceutical composition for use according to claim 34, further comprising a further therapeutically active agent comprising a Janus kinase (JAK) inhibitor, a bromodomain and extra-terminal motif protein (BET) inhibitor, a B-cell lymphoma 2 (Bcl-2) inhibitor, or a combination thereof.

36. A kit for use in the treatment of advanced stage myeloproliferative neoplasm (MPN), comprising a compound of formula (I) wherein R is selected from hydrogen and methyl, or a pharmaceutically acceptable salt thereof; a further therapeutically active agent comprising a Janus kinase (JAK) inhibitor, a bromodomain and extra-terminal motif protein (BET) inhibitor, a B-cell lymphoma 2 (Bcl-2) inhibitor, or a combination thereof; and a package insert with instructions for use of said kit.

37. Use of a compound of formula (I) wherein R is selected from hydrogen and methyl, or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for the treatment of advanced stage myeloproliferative neoplasm (MPN).

38. The use according to claim 37, wherein the treatment is in combination with a further therapeutically active agent comprising a Janus kinase (JAK) inhibitor, a bromodomain and extra-terminal motif protein (BET) inhibitor, a B-cell lymphoma 2 (Bcl-2) inhibitor, or a combination thereof.

39. A method of treating a myeloproliferative neoplasm (MPN) in a subject in need thereof, the method comprising administering to the subject (such as a mammal) a compound of formula (I) wherein R is selected from hydrogen and methyl, or a pharmaceutically acceptable salt thereof, and a further therapeutically active agent comprising a bromodomain and extra-terminal motif protein (BET) inhibitor, a B-cell lymphoma 2 (Bcl-2) inhibitor, or a combination thereof.

40. A method of treating advanced stage myeloproliferative neoplasm (MPN) in a subject in need thereof, the method comprising administering a compound of formula (I) wherein R is selected from hydrogen and methyl, or a pharmaceutically acceptable salt thereof, to a mammal in need of such treatment.

41. The method according to claim 40, comprising administering to said mammal a further therapeutically active agent comprising a Janus kinase (JAK) inhibitor, a bromodomain and extra-terminal motif protein (BET) inhibitor, a B-cell lymphoma 2 (Bcl-2) inhibitor, or a combination thereof.