Methods of treating chronic myelomonocytic leukemia

Abstract

The present disclosure provides a method of treating chronic myelomonocytic leukemia in a subject in need of such treatment, comprising administrating to the subject a janus kinase (JAK) inhibitor and a hypomethylating agent. In an example the JAK inhibitor is pacritinib and the hypomethylating agent is azacitidine.

Description

METHODS OF TREATING CHRONIC MYELOMONOCYTIC LEUKEMIA RELATED APPLICATIONS

[0001] This application claims the benefit of priority to U.S. Provisional Patent Application No.63 / 595122, filed November 1, 2023. BACKGROUND OF THE INVENTION

[0002] Chronic myelomonocytic leukemia (CMML) is a clonal hematopoietic malignancy that belongs to the WHO category of myelodysplastic syndrome / myeloproliferative neoplasms (MDS / MPN) overlap syndromes. Clinically, CMML is characterized by both monocytosis (both absolute and relative) and bone marrow dysplasia. Other signs and symptoms include splenomegaly, constitutional symptoms, cytopenias, and a propensity towards evolution to acute myeloid leukemia (AML). Patients can be subclassified into dysplastic (CMML-MDS, WBC <13 x 109 / L) or proliferative (CMML-MPN ≥13 x 109 / L) subtypes, with the latter having a worse overall and leukemia-free survival.3 Other risk factors include anemia, thrombocytopenia, stage, adverse cytogenetics, and mutations such as ASXL1, RUNX1, NRAS, and SETBP1. A rare disorder, the estimated prevalence of CMML is 1 to 2 per 100,000.

[0003] Allogeneic hematopoietic stem cell transplantation remains the only curative therapy for patients with CMML. Patients with intermediate or high-risk disease have a dismal survival. In one prognostic scoring system, patients with intermediate-2 and high risk disease had a median overall survival (OS) of 13 and 5 months, respectively. The mainstay of treatment in this population is hypomethylating agents, which have marginally improved survival but do not appear to affect the evolution of disease. Therapies are urgently needed which can provide symptomatic benefit and halt the underlying disease pathobiology.

[0004] At present, hypomethylating agents (HMA) are the only FDA-approved therapy for CMML. Although limited in their ability to control disease evolution, activity of hypomethylating agents has been demonstrated in multiple retrospective and prospective trials. The overall response rate (ORR) of hypomethylating agents by MDS / MPN response criteria is 71%, based on a large retrospective study. The majority of patients only had clinical benefit (CB) in spleen or symptoms, with only 17% of patients achieving a complete response (CR). New therapies are urgently needed, however, to not only improve response rates but also impact theunderlying disease biology. The present disclosure is directed to overcoming these and other deficiencies in the art. SUMMARY OF THE INVENTION

[0005] In certain aspects, the present disclosure provides a method of treating chronic myelomonocytic leukemia in a subject in need of such treatment, comprising administrating to the subject a janus kinase (JAK) inhibitor and a hypomethylating agent. DETAILED DESCRIPTION OF THE INVENTION

[0006] Pacritinib is a JAK inhibitor that has a unique profile and which may be uniquely well suited for the treatment of CMML, including targeting of colony stimulating factor 1 receptor (CSF1R) and interleukin-1 related kinase 1 (IRAK1), both of which are upregulated in CMML and related diseases (Obba Autophagy 2015, Rhyasen Cancer Cell 2013). Additionally, pacritinib was recently shown to be a potent inhibitor of acrosomal vesicle protein 1 (ACVR1) (Oh AJH 2023), potentially allowing for increased iron availability and improvement in anemia.

[0007] Pacritinib ((16E)-11-(2-pyrrolidin-1-ylethoxy)-14,19-dioxa-5,7,27- triazatetracyclo[19.3.1.12,6.18,12]heptacosa-1(24),2(27),3,5,8(26),9,11,16,21(25),22-decaene, marketed as, in a non-limiting example, VONJO®) has been evaluated preclinically in CMML primary samples and mouse models where it demonstrated significant, albeit heterogenous activity (Yoshimi Blood 2017). The molecular formula is C28H32N4O3and the structural formula is:

[0008] Pacritinib is a potent,FLT3 kinase activities (50% inhibitory concentration IC50=23 nM and 22 nM, respectively), as well as JAK2V617F mutant kinase activity (IC50=19 nM).

[0009] In order to identify improved dosage regimens of pacritinib for further clinical development in MF, a phase 2 dose-ranging study (PAC203) was initiated, and enrollment wascompleted in January 2019. Three dosage levels (100 mg QD, 100 mg BID, and 200 mg BID) were selected to allow adequate characterization of dose–response relationships for the efficacy and safety of pacritinib. See Gerds AT, Savona MR, Scott BL, et al. Determining the recommended dose of pacritinib: results from the PAC203 dose-finding trial in advanced myelofibrosis. Blood Adv. Nov 242020;4(22):5825-5835.

[0010] PPK and exposure-response analysis utilizing clinical PK / PD data from all completed clinical studies along with data from 54 patients and 109 patients from Week 24 and Week 12, respectively, in the PAC203 study showed that systemic exposure (area under the curve AUC, Cmax, and minimum concentration observed Cmin) of the 100 mg QD and 100 mg BID regimens is, as originally predicted, well below that of the 400 mg QD and 200 mg BID regimens. Simulation results indicate that AUC and Cminare similar between 200 mg BID and 400 mg QD while the median peak concentration (Cmax) is higher with 200mg QD; however, there is considerable overlap. In addition, the reduction in spleen volume and TSS projected with the 200 mg BID and 400 mg QD regimens is substantially greater than that projected with the 100 mg QD and 100 mg BID regimens, which is consistent with the respective higher systemic exposure. Simulated and observed SVR and TSS endpoints correlated with systemic exposure of pacritinib with substantially lower clinical efficacy evident for the 100 mg QD and 100 mg BID regimens.

[0011] A hypomethylating agent (HMA) is a drug that inhibits the modification of DNA nucleotides by addition of a methyl group. Azacitidine is a hypomethylating agent with the structure:75mg / m2for 7 days out of a 28 day cycle is the approved dose utilized in myelodysplastic syndrome (MDS) and acute myeloid leukemia (AML).

[0012] Another HMA, decitabine is 4-amino-1-(2-deoxy-β-D-erythro-pentofuranosyl)- 1,3,5-triazin-2(1H)-one, and has the structure:

[0013] Non-limiting examples of hypomethylating agents include azacitidine, decitabine (e.g., DACOGEN®), decitabine in combination with cedazuridine (e.g., INVOQI®), and guadecitabine.

[0014] To enhance the activity of pacritinib in CMML, it was also evaluated in combination with azacitidine (4-amino-1-[(2R,3R,4S,5R)-3,4-dihydroxy-5- (hydroxymethyl)oxolan-2-yl]-1,3,5-triazin-2-one, marketed as, in a non-limiting example, VIDAZA®) in GM-CSF hypersensitive cell lines and primary CMML cells (in vitro) (Ma ASH 2015).

[0015] As disclosed herein, a method of treatment of CMML may include administration of a JAK inhibitor, such as pacritinib, in combination with administration of a hypomethylating agent, such as azacitidine. In certain aspects, the present disclosure provides methods of treating chronic myelomonocytic leukemia in a subject in need of such treatment, comprising administrating to the subject a Janus kinase (JAK) inhibitor and a hypomethylating agent.

[0016] In certain embodiments, the JAK inhibitor is pacritinib. In exemplary embodiments, the JAK inhibitor is pacritinib citrate.

[0017] In certain embodiments, the hypomethylating agent is selected from azacitidine, decitabine, and guadecitabine. In certain exemplary embodiments, the hypomethylating agent is azacitidine. In some embodiments, the hypomethylating agent may be decitabine.

[0018] In certain embodiments, the JAK inhibitor is administered once daily, twice daily, or thrice daily.

[0019] In certain embodiments, the hypomethylating agent will be administered once daily, twice daily, or thrice daily.

[0020] In certain embodiments, the JAK inhibitor is administered at a daily dose of about 1,000 mg or less, about 900 mg or less, about 800 mg or less, about 700 mg or less, about 600 mg or less, about 500 mg or less, about 400 mg or less, about 300 mg or less, about 200 mg or less, about 100 mg or less, about 50 mg or less, or about 25 mg or less

[0021] In some embodiments, the JAK inhibitor is administered in a daily dose of from 50 mg to 400 mg. In some embodiments, the daily dose is from 55 mg to 400 mg. In some embodiments, the daily dose is from 60 mg to 400 mg. In some embodiments, the daily dose is from 65 mg to 400 mg. In some embodiments, the daily dose is from 75 mg to 400 mg. In some embodiments, the daily dose is from 100 mg to 400 mg. In some embodiments, the daily dose is from 125 mg to 400 mg. In some embodiments, the daily dose is from 150 mg to 400 mg. In some embodiments, the daily dose is from 200 mg to 400 mg. In some embodiments, the daily dose is from 300 mg to 400 mg. In some embodiments, the daily dose is from 50 mg to 400 mg. In some embodiments, the daily dose is from 50 mg to 300 mg. In some embodiments, the daily dose is from 50 mg to 200 mg. In some embodiments, the daily dose is from 50 mg to 100 mg. In some embodiments, the daily dose is from 50 mg to 125 mg. In some embodiments, the daily dose is from 100 mg to 300 mg. In some embodiments, the daily dose is from 150 mg to 400 mg. In some embodiments, the daily dose is from 175 mg to 325 mg. In some embodiments, the daily dose is from 175 mg to 225 mg.

[0022] In some embodiments, the daily dose of the JAK inhibitor is about 100 mg. In some embodiments, the daily dose is about 150 mg. In some embodiments, the daily dose is about 200 mg. In some embodiments, the daily dose is about 225 mg. In some embodiments, the daily dose is about 250 mg. In some embodiments, the daily dose is about 275 mg. In some embodiments, the daily dose is about 300 mg. In some embodiments, the daily dose is about 325 mg. In some embodiments, the daily dose is about 350 mg. In some embodiments, the daily dose is about 375 mg. In some embodiments, the daily dose is about 400 mg.

[0023] In some embodiments, the daily dose of the JAK inhibitor is administered in one dose per day (QD). In some embodiments, the daily dose is administered in one dose of about 50 mg per day. In some embodiments, the daily dose is administered in one dose of about 75 mg per day. In some embodiments, the daily dose is administered in one dose of about 100 mg per day. In some embodiments, the daily dose is administered in one dose of about 125 mg per day. In some embodiments, the daily dose is administered in one dose of about 150 mg per day. Insome embodiments, the daily dose is administered in one dose of about 175 mg per day. In some embodiments, the daily dose is administered in one dose of about 200 mg per day. In some embodiments, the daily dose is administered in one dose of about 225 mg per day. In some embodiments, the daily dose is administered in one dose of about 250 mg per day. In some embodiments, the daily dose is administered in one dose of about 275 mg per day. In some embodiments, the daily dose is administered in one dose of about 300 mg per day. In some embodiments, the daily dose is administered in one dose of about 350 mg per day. In some embodiments, the daily dose is administered in one dose of about 400 mg per day.

[0024] In some embodiments, the daily dose of the JAK inhibitor is administered in two or more doses per day. In some embodiments, the daily dose is administered in two doses per day (BID). In some embodiments, the daily dose is administered as two doses of about 25 mg each per day. In some embodiments, the daily dose is administered as two doses of about 50 mg each per day. In some embodiments, the daily dose is administered as two doses of about 75 mg each per day. In some embodiments, the daily dose is administered as two doses of about 100 mg each per day. In some embodiments, the daily dose is administered as two doses of about 125 mg each per day. In some embodiments, the daily dose is administered as two doses of about 150 mg each per day. In some embodiments, the daily dose is administered as two doses of about 200 mg each per day.

[0025] In certain embodiments the hypomethylating agent is administered parenterally. In certain embodiments, the hypomethylating agent is administered at a daily dose of about 400 mg / m2of body surface area (BSA) or less, about 300 mg / m2BSA or less, about 200 mg / m2BSA or less, about 150 mg / m2BSA or less, about 100 mg / m2BSA or less, about 75 mg / m2BSA or less, about 50 mg / m2BSA, or less about 25 mg / m2BSA or less, about 20 mg / m2BSA or less, about 15 mg / m2BSA or less, about 10 mg / m2BSA or less, or about 5 mg / m2BSA or less.

[0026] In certain embodiments, the hypomethylating agent is administered at a daily dose of about 25 to about 400 mg / m2of body surface area (BSA), about 40 to about 300 mg / m2BSA, about 50 to about 200 mg / m2BSA, about 60 to about 120 mg / m2BSA, about 70 to about 100 mg / m2BSA, about 75 mg / m2BSA, about 25 to about 50 mg / m2BSA, or about 10 to about 20 mg / m2BSA.

[0027] In certain embodiments, the hypomethylating agent is administered by continuous infusion over about 60 minutes, about 120 minutes, about 140 minutes, about 160 minutes, about 180 minutes, about 200 minutes, about 220 minutes, or about 240 minutes.

[0028] In certain embodiments the hypomethylating agent is administered orally. In certain embodiments the hypomethylating agent is administered at a daily dose of about 500 mg, at a daily dose of about 475 mg, at a daily dose of about 450 mg, at a daily dose of about 425 mg, at a daily dose of about 400 mg, at a daily dose of about 375 mg, at a daily dose of about 350 mg, at a daily dose of about 325 mg, at a daily dose of about 300 mg, at a daily dose of about 275 mg, at a daily dose of about 250 mg, at a daily dose of about 225 mg, at a daily dose of about 200 mg, at a daily dose of about 175 mg, at a daily dose of about 150 mg, at a daily dose of about 125 mg, at a daily dose of about 100 mg, at a daily dose of about 75 mg, at a daily dose of about 50 mg, or at a daily dose of about 25 mg.

[0029] In certain embodiments, the JAK inhibitor is administered at a daily dose of about 50 to about 300 mg and the hypomethylating agent is administered at a daily dose of about 25 to about 150 mg / m2of body surface area (BSA).

[0030] In certain embodiments, the JAK inhibitor is administered at a daily dose of about 75 to about 250 mg and the hypomethylating agent is administered at a daily dose of about 50 to about 100 mg / m2of body surface area (BSA).

[0031] In certain embodiments, the JAK inhibitor is administered at a daily dose of about 100 mg. In alternative embodiments, the JAK inhibitor is administered at a daily dose of about 200 mg.

[0032] In certain embodiments, the JAK inhibitor is administered at a daily dose of about 100 mg and the hypomethylating agent is administered at a daily dose of about 75 mg / m2of body surface area (BSA).

[0033] In certain embodiments, the JAK inhibitor is administered at a daily dose of about 200 mg and the hypomethylating agent is administered at a daily dose of about 75 mg / m2of body surface area (BSA).

[0034] In certain embodiments, the JAK inhibitor is pacritinib and the hypomethylating agent is azacitidine.

[0035] In certain embodiments, the JAK inhibitor is administered twice daily.

[0036] In certain embodiments, the hypomethylating agent is administered once daily.

[0037] In certain embodiments, the JAK inhibitor is administered twice daily and the hypomethylating agent is administered once daily.

[0038] In certain embodiments, the JAK inhibitor is administered orally.

[0039] In certain embodiments, the hypomethylating agent is administered parenterally. In certain embodiments, the hypomethylating agent is administered daily for three days, four days, five days, or six days. In certain embodiments, the hypomethylating agent is administered daily for seven days. In certain embodiments, the hypomethylating agent is administered daily for ten days. In certain embodiments, the hypomethylating agent is administered daily for fourteen days.

[0040] In further embodiments, the hypomethylating agent is administered in a cycle, the cycle comprising daily administration for seven days followed by twenty-one days without administration of the hypomethylating agent. In alternative embodiments, the hypomethylating agent is administered in a cycle, the cycle comprising daily administration for fourteen days followed by fourteen days without administration of the hypomethylating agent. In alternative embodiments, the hypomethylating agent is administered in a cycle, the cycle comprising administration every 8 hours for 3 days followed by six weeks without administration of the hypomethylating agent. In alternative embodiments, the hypomethylating agent is administered in a cycle, the cycle comprising daily administration for 5 days followed by four weeks without administration of the hypomethylating agent.

[0041] In additional embodiments, the hypomethylating agent is administered in a cycle, the cycle comprising a total period of one week, two weeks, three weeks, four weeks, five weeks, six weeks, seven weeks, eight weeks, ten weeks, twelve weeks, fourteen weeks, sixteen weeks, or twenty weeks.

[0042] In some embodiments, the cycle is repeated three or more times. In other embodiments, the cycle is repeated four times. In certain embodiments, the cycle is repeated six times. In certain embodiments, the cycle is repeated more than six times.

[0043] In some embodiments, the subject has received treatment with a previous hypomethylating agent. In some embodiments, the treatment with the previous hypomethylating agent was monotherapy. In some preferred embodiments, the previous hypomethylating agent is azacitidine, decitabine, or guadecitabine. In some embodiments, the CMML is refractory to treatment with the previous hypomethylating agent (e.g. azacitidine, decitabine, orguadecitabine). In some embodiments, the subject has symptoms of CMML following treatment with the previous hypomethylating agent. Such symptoms may include one or more of anemia, fever, weight loss, night sweats, infection, bleeding, synovitis, lymphadenopathy, skin rashes, pleural effusion, pericardial effusion or peritoneal effusion following the initial treatment with the hypomethylating agent.

[0044] In some embodiments, the pacritinib is a free base having a molecular weight of about 472.59 g / mol. In some embodiments, the pacritinib is administered as a pharmaceutically acceptable salt, and the total daily dose of pacritinib is calculated based on the molecular weight of the free base. Thus, the quantity of pacritinib salt to be administered is calculated by multiplying the desired quantity of pacritinib free base by the ratio of the molecular weight of the salt divided by the molecular weight of the free base.

[0045] In some embodiments, the pacritinib is a citrate salt. In some embodiments, the pacritinib citrate has a molecular weight of about 664.7 g / mol. In such embodiments, the total daily dose of pacritinib is calculated based on the molecular weight of the citrate salt. Thus, the quantity of pacritinib citrate salt is calculated by multiplying the desired administration quantity of pacritinib free base by 1.4065, to yield the total mg of pacritinib citrate equivalent.

[0046] In some embodiments, the pacritinib is administered orally in the form of a gelatin capsule. Each capsule can comprise, for example, 100 mg of pacritinib, e.g., as 140.65 mg of pacritinib citrate. In some embodiments, the gelatin capsule also comprises inactive ingredients such as microcrystalline cellulose NF, polyethylene glycol 8000 (PEG 8000) NF, and magnesium stearate NF.

[0047] The term “treat” or “treatment” as used herein refers to a method or process involving the administration of a pharmaceutical composition for the purpose of alleviating, mitigating, managing, preventing, or curing a medical condition, disease, disorder, ailment, or abnormal physiological state in a human or animal subject. Treatment specifically encompasses therapeutic interventions that rely on the use of pharmaceutical agents, including but not limited to drugs, compounds, biologics, or any combination thereof. These pharmaceuticals may be delivered via various routes, such as oral, intravenous, intramuscular, subcutaneous, transdermal, inhalation, or other appropriate means, and can include chemical entities, biotechnological products, small molecules, or large molecules, such as proteins or nucleic acids. “Treatment” within the scope of this disclosure includes pharmaceutical aspects of therapeutic approaches andthe innovative methods, formulations, delivery systems, dosing regimens, and pharmaceutical compositions associated with the effective application of these agents. It may encompass novel and inventive pharmaceutical formulations, delivery methods, or combinations of pharmaceuticals to achieve the intended therapeutic goals in healthcare and wellness for human or animal subjects.

[0048] The term “combination treatment” or administering or administration in “combination” refers to a method or process that involves the concurrent or sequential administration of two or more pharmaceutical compounds to a human or animal subject with the collective intent of alleviating, mitigating, managing, preventing, or curing a medical condition, disease, disorder, ailment, or abnormal physiological state. Combination treatment specifically encompasses therapeutic interventions that rely on the synergistic or additive effects achieved by using multiple pharmaceutical compounds in concert. These pharmaceutical compounds may encompass chemical entities, organic or inorganic molecules, compounds, or any combination thereof, and may be administered via various routes, such as oral, intravenous, intramuscular, subcutaneous, transdermal, inhalation, or other appropriate means. Combination treatment within the scope of this disclosure includes inventive methods, dosing regimens, and compound combinations aimed at enhancing therapeutic efficacy by utilizing the synergistic or additive properties of pharmaceutical compounds when administered together or in an overlapping timeframe of administration or pharmaceutical activity Administration in combination may include but is not limited to simultaneous administration of two pharmaceuticals. It may encompass novel and inventive approaches to optimize the treatment outcomes for medical conditions or diseases in human or animal subjects through the application of multiple pharmaceutical compounds in combination.

[0049] Formulations for administration of a JAK inhibitor or HMA to a subject include those suitable for oral, parenteral (including subcutaneous, intradermal, intramuscular, intravenous and intraarticular), rectal and topical (including dermal, buccal, sublingual and intraocular) administration. The most suitable route may depend upon the condition and disorder of a recipient or intended purpose of the administration. A formulation may conveniently be presented in unit dosage form and may be prepared by any of the methods well known in the art of pharmacy. Methods may include a step of bringing into association a JAK inhibitor or HMA or a pharmaceutically acceptable salt thereof (“active ingredient”) with a carrier whichconstitutes one or more accessory ingredients. In general, formulations may be prepared by uniformly and intimately bringing into association an active ingredient with liquid carriers or finely divided solid carriers or both and then, if necessary, shaping the product into the desired formulation. The amount of active ingredient that can be combined with a carrier material to produce a single dosage form will generally be that amount of the compound that produces a therapeutic effect. Generally, out of 100 percent, this amount will range from about 1 percent to about 99 percent of active ingredient, preferably from about 5 percent to about 70 percent, most preferably from about 10 percent to about 30 percent.

[0050] Formulations of the present disclosure suitable for oral administration may be presented as discrete units such as capsules, cachets or tablets each containing a predetermined amount of an active ingredient; as a powder or granules; as a solution or a suspension in an aqueous liquid or a non-aqueous liquid; or as an oil-in-water liquid emulsion or a water-in-oil liquid emulsion. A JAK inhibitor or HMA may also be presented as a bolus, electuary or paste. For oral or other administration, a JAK inhibitor or HMA may be suspended in a solution, or dissolved in a solvent, such as alcohol, DMSO, water, saline, or other solvent, which may be further diluted or dissolved in another solution or solvent, and may or may contain a carrier or other excipient in some examples. Besides inert diluents, the oral compositions can also include adjuvants such as wetting agents, emulsifying and suspending agents, sweetening, flavoring, coloring, perfuming and preservative agents. Suspensions, in addition to the active compounds, may contain suspending agents as, for example, ethoxylated isostearyl alcohols, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum metahydroxide, bentonite, agar-agar and tragacanth, and mixtures thereof.

[0051] In certain embodiments, a JAK inhibitor or HMA may be incorporated with excipients and used in the form of ingestible tablets, buccal tablets, troches, capsules, elixirs, suspensions, syrups, wafers, and the like. Tablets, troches, pills, capsules and the like may also contain the following: a binder, such as, for example, gum tragacanth, acacia, cornstarch, gelatin or combinations thereof; an excipient, such as, for example, dicalcium phosphate, mannitol, lactose, starch, magnesium stearate, sodium saccharine, cellulose, magnesium carbonate or combinations thereof; a disintegrating agent, such as, for example, corn starch, potato starch, alginic acid or combinations thereof; a lubricant, such as, for example, magnesium stearate; a sweetening agent, such as, for example, sucrose, lactose, saccharin or combinations thereof; aflavoring agent, such as, for example peppermint, oil of wintergreen, cherry flavoring, orange flavoring, etc. When the dosage unit form is a capsule, it may contain, in addition to materials of the above type, a liquid carrier. Various other materials may be present as coatings or to otherwise modify the physical form of the dosage unit. For instance, tablets, pills, or capsules may be coated with shellac, sugar, or both. When the dosage form is a capsule, it may contain, in addition to materials of the above type, carriers such as a liquid carrier. Gelatin capsules, tablets, or pills may be enterically coated. Enteric coatings prevent denaturation of the composition in the stomach or upper bowel where the pH is acidic. Upon reaching the small intestines, the basic pH therein dissolves the coating and permits the composition to be released and absorbed by specialized cells, e.g., epithelial enterocytes and Peyer’s patch M cells. A syrup of elixir may contain the active compound sucrose as a sweetening agent methyl and propylparabens as preservatives, a dye and flavoring, such as cherry or orange flavor. Of course, any material used in preparing any dosage unit form should be pharmaceutically pure and substantially non-toxic in the amounts employed. In addition, the active compounds may be incorporated into sustained- release preparation and formulations.

[0052] A tablet may be made by compression or molding, optionally with one or more accessory ingredients. Compressed tablets may be prepared by compressing in a suitable machine an active ingredient in a free-flowing form such as a powder or granules, optionally mixed with a binder, lubricant, inert diluent, lubricating, surface active or dispersing agent. Molded tablets may be made by molding in a suitable machine a mixture of the powdered compound moistened with an inert liquid diluent. Tablets may optionally be coated or scored and may be formulated so as to provide sustained, delayed or controlled release of an active ingredient therein.

[0053] A JAK inhibitor or HMA may applied to any sample in which binding to or chelation of copper is desirable, or in which inhibition of enzymatic activity as disclosed herein is desired, or in which it may be desirable to test a potential role or importance of copper’s availability. A sample may include, as described above, an abiotic sample. Or it may be a sample of cells, tissue, or bodily fluids taken or harvested from a living organism or previously living organism. A sample could also include a subject meaning an organism, including a human or nonhuman animal. For example, a subject may include a human or nonhuman animal in need of medical treatment. A sample could also include a biological solution, a suspension of biologicalmaterial, or tissue, such as a solution or suspension of components taken from living cells or previously living cells, or from culture or tissue medial in which living cells or tissue were cultured, or may include bodily fluids, such as blood, saliva, cerebrospinal fluid, ascites, lymph, plasma, serum, mucous, or other bodily fluids or secretions. A biological sample could be a solution or suspension of organic molecules or other compounds produced by living cells. A sample that contains organic molecules synthesized other than by living cells, tissue, or organisms, such as by man-made methods, including synthetic copies of otherwise naturally occurring compounds, would not constitute a biological solution or suspension.

[0054] The phrases "parenteral administration" and "administered parenterally" as used herein mean modes of administration other than enteral and topical administration, usually by injection, and includes, without limitation, intravenous, intramuscular, intraarterial, intrathecal, intracapsular, intraorbital, intracardiac, intradermal, intraperitoneal, transtracheal, subcutaneous, subcuticular, intraarticular, subcapsular, subarachnoid, intraspinal and intrasternal injection and infusion.

[0055] Formulations for parenteral or other administration include aqueous and non- aqueous sterile injection solutions which may contain anti-oxidants, buffers, bacteriostats and solutes which render a formulation isotonic with the blood of the intended recipient. Formulations for parenteral or other administration also may include aqueous and non-aqueous sterile suspensions, which may include suspending agents and thickening agents. The formulations may be presented in unit-dose of multi-dose containers, for example sealed ampoules and vials, and may be stored in a freeze-dried (lyophilized) condition requiring only the addition of a sterile liquid carrier, for example saline, phosphate-buffered saline (PBS) or the like, immediately prior to use. Extemporaneous injection solutions and suspensions may be prepared from sterile powders, granules and tablets of the kind previously described.

[0056] As used herein, the term “pharmaceutically acceptable carrier” refers to sterile aqueous or nonaqueous solutions, dispersions, suspensions or emulsions, as well as sterile powders for reconstitution into sterile injectable solutions or dispersions just prior to use. Examples of suitable aqueous and nonaqueous carriers, diluents, solvents or vehicles include water, ethanol, polyols (such as glycerol, propylene glycol, polyethylene glycol and the like), carboxymethylcellulose and suitable mixtures thereof, vegetable oils (such as olive oil) and injectable organic esters such as ethyl oleate. Proper fluidity can be maintained, for example, bythe use of coating materials such as lecithin, by the maintenance of the required particle size in the case of dispersions and by the use of surfactants. These compositions can also contain adjuvants such as preservatives, wetting agents, emulsifying agents and dispersing agents. Prevention of the action of microorganisms can be ensured by the inclusion of various antibacterial and antifungal agents such as paraben, chlorobutanol, phenol, sorbic acid and the like. It can also be desirable to include isotonic agents such as sugars, sodium chloride and the like.

[0057] In some cases, in order to prolong the effect of a drug, it is desirable to slow the absorption of the drug from subcutaneous or intramuscular injection. This may be accomplished by the use of a liquid suspension of crystalline or amorphous material having poor water solubility. The rate of absorption of the drug then depends upon its rate of dissolution, which, in turn, may depend upon crystal size and crystalline form. Alternatively, delayed absorption of a parenterally administered drug form is accomplished by dissolving or suspending the drug in an oil vehicle. Prolonged absorption of the injectable pharmaceutical form can also be brought about by the inclusion of agents, such as aluminum monostearate and gelatin, which delay absorption.

[0058] Injectable depot forms are made by forming microencapsuled matrices of the drug in biodegradable polymers such as polylactide-polyglycolide, poly(orthoesters) and poly(anhydrides). Depending upon the ratio of a JAK inhibitor or HMA to polymer and the nature of the particular polymer employed, the rate of JAK inhibitor or HMA release can be controlled. Depot injectable formulations are also prepared by entrapping the drug in liposomes or microemulsions which are compatible with body tissues. The injectable formulations can be sterilized, for example, by filtration through a bacterial-retaining filter or by incorporating sterilizing agents in the form of sterile solid compositions which can be dissolved or dispersed in sterile water or other sterile injectable media just prior to use. Suitable inert carriers can include sugars such as lactose.

[0059] A JAK inhibitor or HMA formulation may include different types of carriers depending on whether it is to be administered in solid, liquid or aerosol form, and whether it needs to be sterile for such routes of administration as injection. A JAK inhibitor or HMA can be administered intravenously, intradermally, transdermally, intrathecally, intraarterially, intraperitoneally, intranasally, intravaginally, intrarectally, topically, intramuscularly,subcutaneously, mucosally, orally, topically, locally, inhalation (e.g., aerosol inhalation), injection, infusion, continuous infusion, localized perfusion bathing target cells directly, via a catheter, via a lavage, in cremes, in lipid compositions (e.g., liposomes), or by other method or any combination of the forgoing as would be known to one of ordinary skill in the art (see, for example, Remington’s Pharmaceutical Sciences, 18th Ed. Mack Printing Company, 1990.

[0060] The term “pharmaceutically acceptable salt” refers to salts prepared from pharmaceutically acceptable non-toxic acids or bases including inorganic acids and bases and organic acids and bases. Unless otherwise specified, reference herein to a JAK inhibitor or HMA, or to any such compound in particular, includes reference to a pharmaceutically acceptable salt thereof. When the compounds of the present disclosure are basic, salts may be prepared from pharmaceutically acceptable non-toxic acids including inorganic and organic acids. Suitable pharmaceutically acceptable acid addition salts for the compounds of the present disclosure include acetic, adipic, alginic, ascorbic, aspartic, benzenesulfonic (besylate), benzoic, betulinic, boric, butyric, camphoric, camphorsulfonic, carbonic, citric, ethanedisulfonic, ethanesulfonic, ethylenediaminetetraacetic, formic, fumaric, glucoheptonic, gluconic, glutamic, hydrobromic, hydrochloric, hydroiodic, hydroxynaphthoic, isethionic, lactic, lactobionic, laurylsulfonic, maleic, malic, mandelic, methanesulfonic, mucic, naphthylenesulfonic, nitric, oleic, pamoic, pantothenic, phosphoric, pivalic, polygalacturonic, salicylic, stearic, succinic, sulfuric, tannic, tartaric acid, teoclatic, p-toluenesulfonic, ursolic and the like. When the compounds contain an acidic side chain, suitable pharmaceutically acceptable base addition salts for the compounds of the present disclosure include, but are not limited to, metallic salts made from aluminum, calcium, lithium, magnesium, potassium, sodium and zinc or organic salts made from lysine, arginine, N,N'-dibenzylethylenediamine, chloroprocaine, choline, diethanolamine, ethylenediamine, meglumine (N-methylglucamine) and procaine. Further pharmaceutically acceptable salts include, when appropriate, nontoxic ammonium cations and carboxylate, sulfonate and phosphonate anions attached to alkyl having from 1 to 20 carbon atoms.

[0061] A JAK inhibitor or HMA may be formulated into a composition in a free base, neutral or salt form. Pharmaceutically acceptable salts, include the acid addition salts, e.g., those formed with the free amino groups of a proteinaceous composition, or which are formed with inorganic acids such as for example, hydrochloric or phosphoric acids, or such organic acids as acetic, oxalic, tartaric or mandelic acid. Salts formed with the free carboxyl groups can also bederived from inorganic bases such as for example, sodium, potassium, ammonium, calcium or ferric hydroxides; or such organic bases as isopropylamine, trimethylamine, histidine or procaine. Upon formulation, solutions will be administered in a manner compatible with the dosage formulation and in such amount as is therapeutically effective. The formulations are easily administered in a variety of dosage forms such as formulated for parenteral administrations such as injectable solutions, or aerosols for delivery to the lungs, or formulated for alimentary administrations such as drug release capsules and the like.

[0062] As used herein, the term “physiologically functional derivative” refers to any pharmaceutically acceptable derivative of a compound of the present disclosure that, upon administration to a mammal, is capable of providing (directly or indirectly) a compound of the present disclosure or an active metabolite thereof. Such derivatives, for example, esters and amides, will be clear to those skilled in the art, without undue experimentation. Reference may be made to the teaching of Burger’s Medicinal Chemistry and Drug Discovery, 5th Edition, Vol 1: Principles and Practice.

[0063] As used herein, the term “effective amount” means an amount of a JAK inhibitor or HMA pharmaceutical agent that may elicit a biological or medical response of a cell, tissue, system, animal, or human that is being sought, for instance, by a researcher or clinician. The term “therapeutically effective amount” means any amount which, as compared to a corresponding subject who has not received such amount, results in improved treatment, healing, prevention, or amelioration of a disease, disorder, or side effect, or a decrease in the rate of advancement of a disease or disorder. The term also includes within its scope amounts effective to enhance normal physiological function. For use in therapy, therapeutically effective amounts of a JAK inhibitor or HMA, as well as salts, solvates, and physiological functional derivatives thereof, may be administered as the raw chemical. Additionally, the active ingredient may be presented as a pharmaceutical composition.

[0064] Pharmaceutical compositions of the present disclosure include an effective amount of a JAK inhibitor or HMA and optionally one or more additional agents dissolved or dispersed in a pharmaceutically acceptable carrier. The phrases “pharmaceutical or pharmacologically acceptable” refers to molecular entities and compositions that do not produce an adverse, allergic or other untoward reaction when administered to an animal, such as, for example, a human, as appropriate. The preparation of a pharmaceutical composition that containsa JAK inhibitor or HMA and optionally one or more additional active ingredient will be known to those of skill in the art in light of the present disclosure, as exemplified by Remington’s Pharmaceutical Sciences, 18th Ed. Mack Printing Company, 1990. Moreover, for animal (e.g., human) administration, it will be understood that preparations should meet sterility, pyrogenicity, general safety and purity standards as required by FDA Office of Biological Standards.

[0065] Further in accordance with the present disclosure, the composition of the present disclosure suitable for administration may be provided in a pharmaceutically acceptable carrier with or without an inert diluent. The carrier should be assimilable and includes liquid, semi- solid, i.e., pastes, or solid carriers. Except insofar as any conventional media, agent, diluent or carrier is detrimental to the recipient or to the therapeutic effectiveness of the composition contained therein, its use in administrable composition for use in practicing the methods of the present disclosure is appropriate. Examples of carriers or diluents include fats, oils, water, saline solutions, lipids, liposomes, resins, binders, fillers and the like, or combinations thereof. The composition may also comprise various antioxidants to retard oxidation of one or more component. Additionally, the prevention of the action of microorganisms can be brought about by preservatives such as various antibacterial and antifungal agents, including but not limited to parabens (e.g., methylparabens, propylparabens), chlorobutanol, phenol, sorbic acid, thimerosal or combinations thereof.

[0066] In accordance with the present disclosure, a JAK inhibitor or HMA may be combined with a carrier in any convenient and practical manner, i.e., by solution, suspension, emulsification, admixture, encapsulation, absorption and the like. Such procedures are routine for those skilled in the art.

[0067] In various embodiments of the present disclosure, the composition is combined or mixed thoroughly with a semi-solid or solid carrier. The mixing can be carried out in any convenient manner such as grinding. Stabilizing agents can be also added in the mixing process in order to protect the composition from loss of therapeutic activity, i.e., denaturation in the stomach. Examples of stabilizers for use in the composition include buffers, amino acids such as glycine and lysine, carbohydrates such as dextrose, mannose, galactose, fructose, lactose, sucrose, maltose, sorbitol, mannitol, etc.

[0068] In further embodiments, the present disclosure may concern the use of pharmaceutical lipid vehicle compositions that include a JAK inhibitor or HMA and an aqueoussolvent. As used herein, the term “lipid” will be defined to include any of a broad range of substances that is characteristically insoluble in water and extractable with an organic solvent. This broad class of compounds are well known to those of skill in the art, and as the term “lipid” is used herein, it is not limited to any particular structure. Examples include compounds which contain long-chain aliphatic hydrocarbons and their derivatives. A lipid may be naturally occurring or synthetic (i.e., designed or produced by man). However, a lipid is usually a biological substance. Biological lipids are well known in the art, and include for example, neutral fats, phospholipids, phosphoglycerides, steroids, terpenes, lysolipids, glycosphingolipids, glycolipids, sulphatides, lipids with ether and ester-linked fatty acids and polymerizable lipids, and combinations thereof. Of course, compounds other than those specifically described herein that are understood by one of skill in the art as lipids are also encompassed by the compositions and methods of the present disclosure.

[0069] One of ordinary skill in the art would be familiar with the range of techniques that can be employed for dispersing a composition in a lipid vehicle. For example, a JAK inhibitor or HMA may be dispersed in a solution containing a lipid, dissolved with a lipid, emulsified with a lipid, mixed with a lipid, combined with a lipid, covalently bonded to a lipid, contained as a suspension in a lipid, contained or complexed with a micelle or liposome, or otherwise associated with a lipid or lipid structure by any means known to those of ordinary skill in the art. The dispersion may or may not result in the formation of liposomes.

[0070] The actual dosage amount of a composition of the present disclosure administered to a subject (e.g., an animal or human patient) can be determined by physical and physiological factors such as body weight, severity of condition, the type of disease being treated, previous or concurrent therapeutic interventions, idiopathy of the patient and on the route of administration, and purpose of treatment. Depending upon the dosage and the route of administration, the number of administrations of a preferred dosage and / or an effective amount may vary according to the response of the subject or purpose of treatment. The practitioner responsible for administration will, in any event, determine the concentration of active ingredient(s) in a composition and appropriate dose(s) for the individual subject.

[0071] A daily dose refers to a total dosage administered within a 24 hour period. If administered twice per day, about one half of a daily dose may be given twice per day, or any first fraction of a daily dose may be given in a first administration and any amount of a dailydoes remaining after a fist daily administration given as a second fraction of a daily dose in a second daily administration. Similarly, if administered thrice per day, about one third of a daily dose may be given thrice per day, or any first fraction of a daily dose may be given in a first administration and any fraction of an amount of a daily does remaining after a fist daily administration given as a second fraction of a daily dose in a second daily administration and any amount of a daily does remaining after first and second daily administrations given as a third fraction of a daily dose in a third daily administration.

[0072] A daily dose of pacritinib may be about 1,000 mg or less, about 900 mg or less, about 800 mg or less, about 700 mg or less, about 600 mg or less, about 500 mg or less, about 400 mg or less, about 300 mg or less, about 200 mg or less, about 100 mg or less, about 50 mg or less, or about 25 mg or less, about 10 mg or less, about 5 mg or less, or about 1 mg or less. In still a further example, the hypomethylating agent is azacitidine and the azacitidine is administered at a daily dose of about 400 mg / m2of body surface area (BSA) or less, about 500 mg / m2BSA or less, about 400 mg / m2BSA or less, about 300 mg / m2BSA or less, about 200 mg / m2BSA or less, about 150 mg / m2BSA or less, about 100 mg / m2BSA or less, about 50 mg / m2BSA, less or about 25 mg / m2BSA or less, about 10 mg / m2BSA or less, about 5 mg / m2BSA or less, or about 1 mg / m2BSA or less.

[0073] For use in the methods of this invention, active compounds can be given per se or as a pharmaceutical composition containing, for example, 0.1 to 99.5%, more preferably, 0.5 to 90%, of active ingredient in combination with a pharmaceutically acceptable carrier.

[0074] Unless otherwise specified, dose of a composition administered as a basis of BSA is calculated according to a Dubois Formula for BSA Dosing, wherein dose administered = BSA Based Dose * 0.007184 * Height(cm)^0.725 * Weight(kg)^0.425. Alternatively, dose of a composition administered as a basis of BSA may be calculated according to a Monteller Formula for BSA Dosing, wherein dose administered = BSA Based Dose x square root [(Height (cm) x Weight (kg)) / 3600].

[0075] As used herein, the singular forms “a”, “an” and “the” include plural referents unless the content clearly dictates otherwise. Thus, for example, reference to “a protein” includes a mixture of two or more proteins, and the like.

[0076] As used herein, the term “about” or “approximately” means within 10% of a given value or range. For example, where an amount of “about 1,000” is stated, it includes values within a range of from 900 to 1,100.

[0077] “Administering” or “administration of” a substance, a compound or an agent to a subject can be carried out using one of a variety of methods known to those skilled in the art. For example, a compound or an agent can be administered, intravenously, arterially, intradermally, intramuscularly, intraperitoneally, subcutaneously, ocularly, sublingually, orally (by ingestion), intranasally (by inhalation), intraspinally, intracerebrally, and transdermally (by absorption, e.g., through a skin duct). A compound or agent can also appropriately be introduced by rechargeable or biodegradable polymeric devices or other devices, e.g., patches and pumps, or formulations, which provide for the extended, slow or controlled release of the compound or agent. Administering can also be performed, for example, once, a plurality of times, and / or over one or more extended periods.

[0078] The term “agent” is used herein to denote a chemical compound (such as an organic or inorganic compound, a mixture of chemical compounds), a biological macromolecule (such as a nucleic acid, an antibody, including parts thereof as well as humanized, chimeric and human antibodies and monoclonal antibodies, a protein or portion thereof, e.g., a peptide, a lipid, a carbohydrate), or an extract made from biological materials such as bacteria, plants, fungi, or animal (particularly mammalian) cells or tissues. Agents include, for example, agents whose structure is known, and those whose structure is not known. The ability of such agents to inhibit AR or promote AR degradation may render them suitable as “therapeutic agents” in the methods and compositions of this disclosure.

[0079] A “patient,” “subject,” or “individual” are used interchangeably and refer to either a human or a non-human animal. These terms include mammals, such as humans, primates, livestock animals (including bovines, porcines, etc.), companion animals (e.g., canines, felines, etc.) and rodents (e.g., mice and rats). EXAMPLES

[0080] The invention now being generally described will be more readily understood by reference to the following examples, which are included merely for purposes of illustration of certain aspects and embodiments of the present invention and are not intended to limit the invention.

[0081] Example 1: Clinical Study of Pacritinib in combination with azacitidine in patients with chronic myelomonocytic leukemia (CMML)

[0082] This is a phase 1 / 2 trial of pacritinib in combination with azacitidine in patients with CMML. Patients are newly diagnosed or previously treated but cannot have received a prior JAK inhibitor. Patients who have previously been treated with a hypomethylating agent (HMA) must have received ≤ 1 cycle. Phase 1 follows a 3+3 dose de-escalation design to identify the RP2D of pacritinib in combination with fixed dosing of azacitidine therapy. Phase 2 follows a Simon’s two stage design to determine the preliminary efficacy of pacritinib in combination with azacitidine at the RP2D.

[0083] Pacritinib is initially tested at a dose of 200 mg twice daily (dose level 0) in combination with azacitidine 75mg / m2, which can be administered subcutaneously or intravenously, for 7 days in a 28-day cycle. If there are 2 DLTs in the first 6 patients, there will be a dose escalation to pacritinib 100mg twice daily (dose level -1) and an additional 6 patients are enrolled. Based on the phase 1, 3+3 dose de-escalation design, 6-12 patients are enrolled in the phase 1 portion.

[0084] After the completion of phase 1 and identification of the recommended phase 2 dose (RP2D), phase 2 employs a Simon two stage design. This portion includes the 6 patients enrolled during the phase 1 portion at the MTD. An interim analysis for futility will occur. If 3 or fewer patients have had a clinical benefit (CB) or better, as defined by 2015 MDS / MPN IWG criteria, the PI and DSMC will meet to discuss the totality of the evidence and determine if the trial shall proceed. In the second stage, an additional 12 patients are enrolled. INCORPORATION BY REFERENCE

[0085] All publications and patents mentioned herein are hereby incorporated by reference in their entirety as if each individual publication or patent was specifically and individually indicated to be incorporated by reference. In case of conflict, the present application, including any definitions herein, will control. EQUIVALENTS

[0086] Those skilled in the art will recognize, or be able to ascertain using no more than routine experimentation, numerous equivalents to the methods of treatment described herein. Such equivalents are considered to be within the scope of this invention and are covered by thefollowing claims. Those skilled in the art will also recognize that all combinations of embodiments described herein are within the scope of the invention.

Claims

CLAIMS 1. A method of treating chronic myelomonocytic leukemia in a subject in need of such treatment, comprising administrating to the subject a janus kinase (JAK) inhibitor and a hypomethylating agent.

2. The method of claim 1, wherein the JAK inhibitor is pacritinib.

3. The method of claim 1 or 2, wherein the JAK inhibitor is pacritinib citrate.

4. The method of claims 1 to 3, wherein the hypomethylating agent is selected from azacitidine, decitabine, and guadecitabine.

5. The method of any one of claims 1 to 4, wherein the hypomethylating agent is azacitidine.

6. The method of any one of claims 1 to 5, wherein the JAK inhibitor is administered once daily, twice daily, or thrice daily.

7. The method of any one of claims 1 to 6, wherein the hypomethylating agent will be administered once daily, twice daily, or thrice daily.

8. The method of any one of claims 1 to 7, wherein the JAK inhibitor is administered at a daily dose of about 1,000 mg or less, about 900 mg or less, about 800 mg or less, about 700 mg or less, about 600 mg or less, about 500 mg or less, about 400 mg or less, about 300 mg or less, about 200 mg or less, about 100 mg or less, about 50 mg or less, or about 25 mg or less.

9. The method of any one of claims 1 to 8, wherein the hypomethylating agent is administered at a daily dose of about 400 mg / m2of body surface area (BSA) or less, about 300 mg / m2BSA or less, about 200 mg / m2BSA or less, about 150 mg / m2BSA or less, about 100 mg / m2BSA or less, about 75 mg / m2BSA or less, about 50 mg / m2BSA or less, about 25 mg / m2BSA or less, about 20 mg / m2BSA or less, about 15 mg / m2BSA or less, about 10 mg / m2BSA or less, or about 5 mg / m2BSA or less.

10. The method of any one of claims 1 to 9, wherein the JAK inhibitor is administered at a daily dose of about 50 to about 300 mg and the hypomethylating agent is administered at a daily dose of about 25 to about 150 mg / m2of body surface area (BSA).

11. The method of any one of claims 1 to 10, wherein the JAK inhibitor is administered at a daily dose of about 75 to about 250 mg and the hypomethylating agent is administered at a daily dose of about 50 to about 100 mg / m2of body surface area (BSA).

12. The method of any one of claims 1 to 11, wherein the JAK inhibitor is administered at a daily dose of about 100 mg.

13. The method of any one of claims 1 to 11, wherein the JAK inhibitor is administered at a daily dose of about 200 mg.

14. The method of any one of claims 1 to 11, wherein the JAK inhibitor is administered at a daily dose of about 300 mg.

15. The method of any one of claims 1 to 12, wherein the JAK inhibitor is administered at a daily dose of about 100 mg and the hypomethylating agent is administered at a daily dose of about 75 mg / m2of body surface area (BSA).

16. The method of any one of claims 1 to 11 or 13, wherein the JAK inhibitor is administered at a daily dose of about 200 mg and the hypomethylating agent is administered at a daily dose of about 75 mg / m2of body surface area (BSA).

17. The method of any one of claims 1 to 16, wherein the JAK inhibitor is pacritinib and the hypomethylating agent is azacitidine.

18. The method of any one of claims 1 to 17, wherein the JAK inhibitor is administered twice daily.

19. The method of any one of claims 1 to 18, wherein the hypomethylating agent is administered once daily.

20. The method of any one of claims 1 to 19, wherein the JAK inhibitor is administered twice daily and the hypomethylating agent is administered once daily.

21. The method of any one of claims 1 to 20, wherein the JAK inhibitor is administered orally.

22. The method of any one of claims 1 to 21, wherein the hypomethylating agent is administered parenterally.

23. The method of any one of claims 1 to 21, wherein the hypomethylating agent is administered orally.

24. The method of any one of claims 1 to 23, wherein the hypomethylating agent is administered daily for a period of seven days.

25. The method of any one of claims 1 to 23, wherein the hypomethylating agent is administered every 8 hours for three days.

26. The method of any one of claims 1 to 23, wherein the hypomethylating agent is administered daily for a period of five days.

27. The method of any one of claims 1 to 24, wherein the hypomethylating agent is administered in a cycle, the cycle comprising daily administration for a period of seven days followed by twenty-one days without administration of the hypomethylating agent.

28. The method of any one of claims 1 to 23, wherein the hypomethylating agent is administered in a cycle, the cycle comprising daily administration for fourteen days followed by fourteen days without administration of the hypomethylating agent.

29. The method of any one of claims 1 to 23, wherein the hypomethylating agent is administered in a cycle, the cycle comprising administration every 8 hours for 3 days followed by six weeks without administration of the hypomethylating agent.

30. The method of any one of claims 1 to 23, wherein the hypomethylating agent is administered in a cycle, the cycle comprising daily administration for 5 days followed by four weeks without administration of the hypomethylating agent.

31. The method of any one of claims 27 to 30, wherein the cycle is repeated three or more times.

32. The method of any one of claims 27 to 30, wherein the cycle is repeated six times.

33. The method of any one of claims 1-32, wherein the subject has received treatment with a previous hypomethylating agent for chronic myelomonocytic leukemia.

34. The method of claim 33, wherein the chronic myelomonocytic leukemia is refractory to treatment with the previous hypomethylating agent.

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