Methods of treating myelodysplastic syndromes with decitabine and cedazuridine

Abstract

Provided herein is a method of treating myelodysplastic syndrome (MDS) in a subject in need of such treatment. Also provided herein is a method of treating low-risk MDS and chronic myelomonocytic leukemia (CMML) in a subject in need of such treatment. Also provided herein is a method of treating low-risk MDS and chronic myelomonocytic leukemia (CMML) in a subject having low-risk MDS and chronic myelomonocytic leukemia (CMML) and having a TP53 mutation. Such a method includes administering to the subject an effective amount of cedazuridine and an effective amount of decitabine, thereby treating the myelodysplastic syndrome. Such a method may increase the survival time of the subject by about 130% to about 400% relative to the survival time obtained by treatment with a hypomethylating agent alone.

Description

[Technical field]

[0001] Declaration of priority This application claims the benefit of U.S. Provisional Application No. 63 / 246,547, filed September 21, 2021, the entire contents of which are incorporated herein by reference.

[0002] [Technical field] The present invention relates to methods for the treatment of cancer, in particular to methods for the treatment of myelodysplastic syndromes. [Background technology]

[0003] Myelodysplastic syndromes (MDS) are a group of bone marrow disorders characterized by a lack of healthy blood cells. Patients with MDS typically have low blood counts, which can lead to infections, anemia, spontaneous bleeding, and / or purpura. In addition, in patients with MDS, mature blood cells may be dysplastic and therefore not function properly. Scoring systems have been developed to determine prognosis and treatment plans for various MDS stages. In the original International Prognostic Scoring System (IPSS), a patient's score is determined based on the percentage of leukemic blast cells in the patient's bone marrow, the type of chromosomal alteration (if any) in the patient's bone marrow cells, and the presence of one or more cytopenias. In the revised International Prognostic Scoring System (IPSS-R), a patient's score is determined based on the percentage of blast cells in the patient's bone marrow, the type and number of chromosomal abnormalities in the patient's cells, and the levels of red blood cells, platelets, and / or neutrophils in the patient's blood. In the World Health Organization (WHO) Prognostic Scoring System (WPSS), a patient's score is determined based on the type of MDS the patient has (based on the WHO classification system), the type of chromosomal abnormality, and whether the patient requires regular blood transfusions.

[0004] Decitabine (5-aza-2'-deoxycytidine), below, a cytidine analog, is an antineoplastic agent and a hypomethylating agent (HMA) that has been used for the treatment of MDS. [ka]

[0005] Cedazuridine ((4R)-2'-deoxy-2',2'-difluoro-3,4,5,6-tetrahydrouridine; also known as E7727) is a cytidine deaminase (CDA) inhibitor. Cedazuridine and methods of making and / or using it are further disclosed in U.S. Patent Nos. 8,268,800 and 9,834,576, the contents of which are incorporated herein by reference in their entireties. [ka]

[0006] Astex Pharmaceuticals, Inc. has announced that it has developed a fixed dose combination of decitabine and cedazuridine (marketed INQOVI by Taiho Pharmaceutical Co., Ltd.) for the treatment of adults with MDS. (登録商標) The company received FDA approval for the treatment of rheumatoid arthritis (sold under the trade name rheumatoid arthritis).

[0007] MDS has also been treated with the administration of hypomethylating agents alone. In one randomized clinical trial, patients were treated with decitabine (15 mg / m 2Patients were treated with decitabine (intravenously administered over 3 hours, every 8 hours for 3 days) or given best supportive care (BSC) alone. An intention-to-treat analysis showed no significant difference in median survival between patients treated with decitabine and those who received supportive care measures alone (14.0 vs. 14.9 months). See Kantarjian H, et al., Decitabine improves patient outcomes in myelodysplastic syndromes, Cancer, April 15, 2006, 106 (8). In another clinical trial by the European Organisation for Research and Treatment of Cancer (EORTC), patients with intermediate- or high-risk MDS aged 60 years or older were treated with low-dose decitabine (intravenously administered over 4 hours, three times a day, for 3 days in 6-week cycles) or received BCS measures alone. The extension of overall survival (OS) with decitabine was not determined to be statistically significant compared to treatment with BSC (OS=10.1 months vs. 8.5 months, respectively). See Lubbert M, et al., Low-dose decitabine versus best supportive care in elderly patients with intermediate- or high-risk myelodysplastic syndrome (MDS) ineligibe for intensive chemotherapy: final results of the randomized phase III study of the European Organisation for Research and Treatment of Cancer Leukemia Group and the German MDS Study Group, J Clin Oncol, 2011 May 20;29 (15):1987-96.

[0008] Azacitidine (or 5-azacitidine) is another hypomethylating agent that has been used to treat MDS. In a randomized, multicenter clinical trial (CALB 9221), patients with MDS were randomly assigned to receive azacitidine or best supportive care (BSC) alone. The median time to leukemic transformation or death was 21 months in patients treated with azacitidine compared with 12 months in the BSC group. See Silverman LR, et al., Randomized controlled trial of azacitidine in patients with the Myelodysplastic Syndrome: A study of the Cancer and Leukemia Group B, J Clin Oncol 2002:20(10):2429-2440. A randomized trial in the IPPS Int-1 population with CC-486, an oral formulation of azacitidine, showed a median overall survival of approximately 17 months in both placebo and treated patients. See Garcia-Manero, et al, Phase III, Randomized, Placebo-Controlled Trial of CC-486 (Oral Azacitidine) in Patients with Lower-Risk Myelodysplastic Syndromes, J. Clin.Onc. (2021) 39:13,1426-1436.

[0009] Low-risk (IPSS low-risk and Int-1 subgroups) MDS patients are typically treated supportively to address cytopenias. DNA methyltransferase inhibitors, such as azacitidine and decitabine, are FDA approved for higher-risk MDS patients, and decitabine's labeling includes IPSS Int-1 patients, although decitabine is not widely used in this population.

[0010] Chronic myelomonocytic leukemia (CMML) is a rare MDS / MPN overlap syndrome that has historically been subsumed under the umbrella of myelodysplastic syndromes (MDS) in clinical trials and treatment. As a result, DNA methyltransferase inhibitors (DNMTi), such as decitabine or azacitidine, have become the established standard of care for the treatment of CMML.

[0011] The approved intravenous or subcutaneous administration requires 5-7 days of treatment every month, which may burden elderly cancer patients due to daily travel and treatment time, and may increase the potential risk of pandemic SARS-CoV-2 infection. In the context of pandemic SARS-CoV-2, parenteral therapy also increases contact with healthcare facilities and increases the risk of infection. DNA methyltransferase inhibitors are rapidly degraded by cytidine deaminase in the intestine and liver, so oral intake has only recently become possible. Summary of the Invention [Means for solving the problem]

[0012] Methods of treating myelodysplastic syndrome (MDS), including high-risk MDS or low-risk MDS, in a subject in need thereof are provided according to embodiments of the present invention. In some embodiments, such methods include administering to the subject an effective amount of cedazuridine and an effective amount of decitabine, thereby treating the MDS. In some embodiments, administering an effective amount of cedazuridine and an effective amount of decitabine increases the survival time (e.g., median overall survival time) of the subject by about 130% to about 400% relative to the survival time obtained by treatment with a hypomethylating agent alone. In some embodiments, the MDS is low-risk MDS. In some embodiments, the MDS is chronic myelomonocytic leukemia (CMML).

[0013] In some embodiments, by administering an effective amount of cedazuridine and an effective amount of decitabine, the survival of the MDS subject is increased by about 200% to about 400% relative to the survival that would be achieved by providing the subject with best supportive care (BSC) alone.

[0014] In some embodiments, administering an effective amount of cedazuridine and an effective amount of decitabine to a subject with MDS provides the subject with a survival time of at least about 28 months, at least about 30 months, at least about 32 months, at least about 34 months, or at least about 36 months. In some embodiments, administering an effective amount of cedazuridine and an effective amount of decitabine to a subject with MDS provides the subject with a leukemia-free survival time of at least about 26 months, at least about 28 months, at least about 30 months, at least about 32 months, or at least about 34 months.

[0015] In some method embodiments of the invention, treating low-risk MDS includes treating low-risk MDS subjects as determined by the International Prognostic Scoring System (IPPS), including Low and Intermediate-1 subgroups. In some method embodiments of the invention, treating low-risk MDS includes treating low-risk MDS subjects as determined by the International Prognostic Scoring System-Revised (IPPS-R), including Very Low, Low, and Intermediate subgroups. In some method embodiments of the invention, treating low-risk MDS includes treating low-risk MDS subjects as determined by the WHO Classification-based Prognostic Scoring System (WPSS), including Very Low, Low, and Intermediate subgroups. In some method embodiments of the invention, treating low-risk MDS includes treating subjects with low-risk MDS as determined by the French-American-British (FAB) criteria.

[0016] In some embodiments of the invention, administering an effective amount of cedazuridine and an effective amount of decitabine to the subject comprises administering the cedazuridine and decitabine to the subject in one or more oral dosage forms. In some embodiments, administering an effective amount of cedazuridine and an effective amount of decitabine to the subject comprises administering a single solid oral dosage form comprising cedazuridine and decitabine. [Brief description of the drawings]

[0017] [Figure 1]Figure 1 shows the randomization and placement of patients. CMML, chronic myelomonocytic leukemia; MDS, myelodysplastic syndrome. [Figure 2A] Figure 2A shows mean plasma decitabine concentration-time profiles after single and multiple doses of intravenous (IV) decitabine and oral decitabine / cedazuridine on days 1, 2, and 5. Linear and semi-logarithmic scales. Figure 2A: Mean plasma decitabine concentration-time profiles on days 1, 2, and 5. [Figure 2B] FIG. 2B shows mean plasma decitabine concentration-time profiles after single and multiple doses of intravenous (IV) decitabine and oral decitabine / cedazuridine on days 1, 2, and 5. Linear and semi-logarithmic scales. FIG. 2B: Lower limit of quantification (LLOQ) of plasma decitabine concentration-time profiles on days 1, 2, and 5. [Diagram 3] Figure 3 is a Kaplan-Meier plot of leukemia-free survival for subjects in a phase 3 trial of oral decitabine / cedazuridine to treat MDS. [Figure 4] Figure 4 is a Kaplan-Meier plot of overall survival for subjects in a phase 3 trial of oral decitabine / cedazuridine to treat MDS. [Diagram 5] FIG. 5 is a Kaplan-Meier plot of leukemia-free survival for subjects with CMML or Int-1 or low-risk MDS in a Phase 3 trial using oral decitabine / cedazuridine to treat MDS. [Figure 6]FIG. 6 is a Kaplan-Meier plot of overall survival for subjects with CMML or Int-1 or low-risk MDS in a Phase 3 trial using oral decitabine / cedazuridine to treat MDS. [Figure 7] Figure 7 shows a Kaplan-Meier plot of the TP53 mutation population compared to the wild-type population. [Figure 8] Figure 8 shows Kaplan-Meier plots for the monoallelic TP53 mutant population compared to the biallelic TP53 population. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0018] The present invention will be described in more detail below. This description is not intended to be a detailed catalog of all the different ways in which the present invention can be implemented, or a detailed catalog of all the features that can be added to the present invention. For example, features shown with respect to one embodiment may be incorporated into other embodiments, and features shown with respect to a particular embodiment may be omitted from that embodiment. In addition, numerous modifications and additions to the various embodiments proposed herein will be apparent to those skilled in the art in light of this disclosure without departing from the present invention. Thus, the following specification is intended to describe some specific embodiments of the present invention, and is not intended to exhaustively specify all permutations, combinations and modifications thereof.

[0019] Unless the context dictates otherwise, it is specifically contemplated that the various features of the invention described herein can be used in any combination. Moreover, the invention also contemplates that in some embodiments of the invention, any feature or combination of features described herein can be excluded or omitted. For example, if the specification describes a complex as comprising components A, B, and C, it is specifically contemplated that any of A, B, or C, or combinations thereof, can be omitted or discarded, either alone or in any combination.

[0020] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs. The terms used in the detailed description of the present invention herein are intended to describe specific embodiments only and are not intended to limit the present invention.

[0021] All publications, patent applications, patents, nucleotide sequences, amino acid sequences, and other references mentioned herein are incorporated by reference in their entirety.

[0022] definition

[0023] As used in the detailed description of the invention and the appended claims, the singular forms "a," "an," and "the" are intended to include the plural forms as well, unless the context clearly dictates otherwise.

[0024] As used herein, "and / or" refers to and includes any and all possible combinations of one or more of the associated listed items, as well as the absence of combinations when interpreted in the alternative ("or").

[0025] Moreover, the present invention also contemplates that in some embodiments of the invention, any feature or combination of features described herein may be excluded or omitted.

[0026] Moreover, as used herein, the term "about" when referring to a measurable value, such as an amount, dosage, time, temperature, etc., of a compound or agent of the invention, is meant to encompass variations of ±10%, ±5%, ±1%, ±0.5% or even ±0.1% of the specified amount.

[0027] As used herein, the transitional phrase "consisting essentially of" should be construed to include recited materials or steps that do not materially affect one or more of the basic and novel characteristics of the claimed invention. Thus, as used herein, the term "consisting essentially of" should not be construed as equivalent to "comprising."

[0028] An "effective amount" refers to the amount necessary to produce a desired effect (e.g., increasing the half-life, bioavailability or efficacy of a therapeutic agent to treat cancer in a subject, or decreasing DNA methylation in a subject).

[0029] "Pharmaceutically acceptable" refers to properties and / or substances that are acceptable to a patient from a pharmacological and / or toxicological standpoint, and / or properties and / or substances that are acceptable to a pharmaceutical chemist from a physical and / or chemical standpoint with regard to composition, formulation, stability, patient acceptability, bioavailability, and compatibility with other ingredients.

[0030] "Pharmaceutically acceptable salt" refers to an acid or base salt of a compound of the present invention, which salt possesses the desired pharmacological activity and is not biologically or otherwise undesirable. The salt may be formed with acids, including, but not limited to, acetate, adipate, alginate, aspartate, benzoate, benzenesulfonate, bisulfate butyrate, butyrate, citrate, camphorate, camphorsulfonate, cyclopentanepropionate, digluconate, dodecylsulfate, ethanesulfonate, fumarate, glucoheptanoate, glycerophosphate, hemisulfate, heptanoate, hexanoate, hydrochloride, hydrobromide, hydroiodide, 2-hydroxyethanesulfate, lactate, maleate, methanesulfonate, 2-naphthalenesulfonate, nicotinate, oxalate, thiocyanate, tosylate, and undecanoate. Examples of base salts include, but are not limited to, ammonium salts; alkali metal salts, such as sodium salts and potassium salts; alkaline earth metal salts, such as calcium salts and magnesium salts; salts with organic bases, such as dicyclohexylamine salts, N-methyl-D-glucamine, and salts with amino acids, such as arginine and lysine. In some embodiments, basic nitrogen-containing groups can be quaternized with agents including lower alkyl halides, such as methyl, ethyl, propyl, and butyl chlorides, bromides, and iodides; dialkyl sulfates, such as dimethyl sulfate, diethyl sulfate, dibutyl sulfate, diamyl sulfate; long chain halides, such as decyl, lauryl, myristyl, stearyl chlorides, bromides, and iodides; and aralkyl halides, such as phenethyl bromide.

[0031] A "pharmaceutical acceptable excipient" can mean any substance that is not itself a therapeutic agent, but is used as a carrier, diluent, adjuvant, binder, and / or vehicle for delivering a therapeutic agent to a subject, or any substance added to a pharmaceutical composition to improve its handling or storage characteristics, or to allow or facilitate the formation of a compound or composition into a unit dosage form for administration.

[0032] "Unit dosage form" refers to a physically discrete unit suitable as a unitary dosage for human or other animal subjects. Each unit dosage form may contain a predetermined amount of active substance (e.g., cedazuridine and / or decitabine) calculated to produce a desired effect.

[0033] "Optional" or "optionally" means that the subsequently described event or circumstance may or may not occur. For example, "optionally substituted" alkyl includes both unsubstituted and substituted alkyl.

[0034] The terms "enhance" or "increase" refer to an increase in a particular parameter of at least about 1.25-fold, about 1.5-fold, about 2-fold, about 3-fold, about 4-fold, about 5-fold, about 6-fold, about 8-fold, about 10-fold, about 12-fold, about 15-fold, etc.

[0035] As used herein, the terms "inhibit" or "reduce" or grammatical variations thereof refer to a decrease or diminishment in a particular level or activity of at least about 15% or more, about 25% or more, about 35% or more, about 40% or more, about 50% or more, about 60% or more, about 75% or more, about 80% or more, about 90% or more, about 95% or more. According to certain embodiments, the inhibition or reduction results in little or essentially no detectable activity (at most, only a small amount, e.g., less than about 10% or even less than 5%).

[0036] As used herein, a "subject" refers to a human. A subject may also be referred to as a patient.

[0037] The terms "treat," "treating," or "treatment of" (or their grammatical equivalents) mean that the severity of a subject's condition is lessened or at least partially improved or ameliorated, and / or some alleviation, palliation, or reduction in at least one clinical symptom is achieved. "Treatment" in reference to a disease, disorder, or condition may refer to: (i) inhibiting the disease, disorder, or condition, e.g., arresting its onset; and / or (ii) relieving the disease, disorder, or condition, e.g., causing regression of clinical symptoms; and / or (ii) stabilizing or controlling the progression of the disease, disorder, or condition, e.g., delaying progression to AML or preventing recurrence or progression of disease after detectable levels of disease have been reduced or are absent. A subject is "in need of" treatment for MDS, high-risk MDS, or low-risk MDS if the subject has MDS, high-risk MDS, or low-risk MDS, respectively, as determined by the IPSS, IPSS-R, WPSS, and / or FAB. A subject is "in need of" treatment for chronic myelomonocytic leukemia (CMML) if the subject meets the French-American-British (FAB) classification for CMML, or any other known criteria for identifying CMML.

[0038] The terms "administering" or "administration" of a compound and / or composition of the invention to a subject include routes of introducing or delivering a compound to a subject to perform its intended function.

[0039] As used herein, "lower-risk MDS" refers to MDS in subjects considered to be at low risk by the International Prognostic Scoring System (IPSS), the International Prognostic Scoring System-Revised (IPSS-R), and / or the WHO-Based Prognostic Scoring System (WPSS). Thus, in some embodiments, a low-risk MDS subject can be classified as Low or Intermediate-1 (also referred to herein as Int-1) as determined by IPSS; Very Low, Low, or Intermediate as determined by IPSS-R; and / or Very Low, Low, or Intermediate as determined by WPSS. Low-risk MDS can also be determined using the French-American-British (FAB) criteria.

[0040] As used herein, a "cycle" refers to a period of 28 consecutive days. In some embodiments, cedazuridine and decitabine are administered on days 1-5 of each 28-day cycle. Multiple cycles or a plurality of cycles may be performed consecutively or with breaks between cycles. Additionally, other cycle lengths and different dosing regimens may also be used.

[0041] As used herein, a "hypomethylating agent" (also known as a DNA methyltransferase or DNMT inhibitor) refers to an agent that inhibits or reduces DNA methylation. Examples of hypomethylating agents include, but are not limited to, decitabine, cytidine, azacytidine (5-azacytidine), and guadecitabine.

[0042] As used herein, the "overall survival time" of a subject is the number of days (or months) from the date of randomization in a clinical trial, or the first date the subject received decitabine and cedazuridine, to the date of the subject's death.

[0043] As used herein, "median overall survival time" is the number of days (or months) from the date of randomization in a clinical trial, or the first date a subject received decitabine and cedazuridine, or the first date a subject received treatment, until half of the patients remain alive, as determined by Kaplan-Meier estimation.

[0044] As used herein, a subject's "leukemia-free survival" is the number of days (or months) from the date of randomization to the date when bone marrow or peripheral blood blasts reach 20% or more or the date of death.

[0045] As used herein, a subject's "median leukemia-free survival" is the number of days (or months) from the date of randomization to the date when half of the patients have bone marrow blasts or peripheral blood blasts ≥ 20% or die, as determined by Kaplan-Meier estimation.

[0046] As used herein, "best supportive care" or "BSC" refers to care or treatment required for a subject that improves or optimizes the subject's quality of life, but is not a chemotherapeutic agent (e.g., hypomethylating agents) for the treatment of MDS. Examples of BSC include administration of narcotic or non-narcotic analgesics, corticosteroids, and gastrointestinal medications.

[0047] How to Treat MDS

[0048] Methods for treating myelodysplastic syndrome (MDS), including high-risk or low-risk MDS, in a subject in need thereof are provided according to embodiments of the present invention. In some embodiments, such methods include administering to the subject an effective amount of cedazuridine and an effective amount of decitabine, thereby treating the MDS. In some embodiments, administering an effective amount of cedazuridine and an effective amount of decitabine increases the survival time (e.g., median overall survival time) of the subject by about 130% to about 400% relative to the survival time achieved by treatment with a hypomethylating agent alone. Thus, in some embodiments, administration of an effective amount of cedazuridine and an effective amount of decitabine increases the survival time of the subject by about 130%, about 135%, about 140%, about 145%, about 150%, about 155%, about 160%, about 165%, about 170%, about 175%, about 180%, about 185%, about 190%, about 195%, about 200%, about 205%, about 210%, about 215%, about 220%, about 225%, about 230%, about 235%, about 240%, about 245%, about 250%, about 255%, about 260%, about 265%, about 270%, about 275%, about 280%, about 285%, about 290%, about 295%, about 300%, about 305%, about 310%, about 315%, about 320%, about 325%, about 330%, about 335%, about 340%, about 345%, about 350%, about 355%, about 360%, about 365%, about 370%, about 375%, about 380%, about 385%, about 390%, about 400%, about 405%, about 410%, about 415%, about 420%, about 425%, about 430%, about 435%, about 440%, about 445%, about 450%, about 455%, about 460%, about 470%, about 475%, about 480%, about 485%, about 490%, about 500%, about 505%, about 500%, about 505%, about 505%, about 505%, about 505%, about 505%, about 5 245%, about 250%, about 255%, about 260%, about 265%, about 270%, about 275%, about 280%, about 285%, about 290%, about 295%, about 300%, about 305%, about 310%, about 315%, about 320%, about 325%, about 330%, about 335%, about 340%, about 345%, about 350%, about 355%, about 360%, about 365%, about 370%, about 375%, about 380%, about 385%, about 390%, about 395%, or about 400% or more, or any range defined therebetween. In some embodiments, administering an effective amount of cedazuridine and an effective amount of decitabine increases the subject's survival (e.g., median overall survival) by at least about 130%, at least about 200%, at least about 250%, at least about 300%, at least about 320%, and / or at least about 330% relative to the survival achieved by treatment with the hypomethylating agent alone.

[0049] In some embodiments, administration of an effective amount of cedazuridine and an effective amount of decitabine increases the subject's leukemia-free survival (e.g., median leukemia-free survival) by about 130% to about 400%, relative to the leukemia-free survival achieved by treatment with the hypomethylating agent alone. Thus, in some embodiments, administration of an effective amount of cedazuridine and an effective amount of decitabine increases the leukemia-free survival of the subject by about 130%, about 135%, about 140%, about 145%, about 150%, about 155%, about 160%, about 165%, about 170%, about 175%, about 180%, about 185%, about 190%, about 195%, about 200%, about 205%, about 210%, about 215%, about 220%, about 225%, about 230%, about 235%, about 240%, about 245%, about 245%, about 250%, about 255%, about 260%, about 265%, about 270%, about 275%, about 280%, about 285%, about 290%, about 295%, about 300%, about 305%, about 310%, about 315%, about 320%, about 325%, about 330%, about 335%, about 340%, about 345%, about 350%, about 355%, about 360%, about 365%, about 370%, about 375%, about 380%, about 385%, about 390%, about 400%, about 405%, about 405%, about 410%, about 415%, about 420%, about 425%, about 430%, about 435%, about 440%, about 445%, about 450%, about 455%, about 460%, about 465%, about 470%, about 475%, about 480%, about 485%, about 490%, about 500%, about 500%, about 505%, about 500%, about 50 The increased amount may be increased by 40%, about 245%, about 250%, about 255%, about 260%, about 265%, about 270%, about 275%, about 280%, about 285%, about 290%, about 295%, about 300%, about 305%, about 310%, about 315%, about 320%, about 325%, about 330%, about 335%, about 340%, about 345%, about 350%, about 355%, about 360%, about 365%, about 370%, about 375%, about 380%, about 385%, about 390%, about 395%, or about 400% or more, or any range defined therebetween. In some embodiments, administering an effective amount of cedazuridine and an effective amount of decitabine increases the subject's leukemia-free survival (e.g., median leukemia-free survival) by at least about 130%, at least about 200%, at least about 250%, at least about 300%, at least about 320%, and / or at least about 330%, relative to the leukemia-free survival achieved by treatment with a hypomethylating agent alone.

[0050] In some embodiments, administration of an effective amount of cedazuridine and an effective amount of decitabine increases the survival time (e.g., median overall survival) of an MDS subject by about 200% to about 400% relative to the survival time that would be achieved if the subject received best supportive care (BSC) alone. Thus, in some embodiments, administration of an effective amount of cedazuridine and an effective amount of decitabine increases the survival time of the subject by about 200%, about 205%, about 210%, about 215%, about 220%, about 225%, about 230%, about 235%, about 240%, about 245%, about 250%, about 255%, about 260%, about 265%, about 270%, about 280%, about 290%, about 300%, about 310%, about 320%, about 330%, about 340%, about 350%, about 360%, about 370%, about 380%, about 390%, about 400%, about 410%, about 420%, about 430%, about 440%, about 450%, about 460%, about 470%, about 480%, about 490%, about 500%, about 510%, about 520%, about 530%, about 540%, about 550%, about 555%, about 560%, about 570%, about 580%, about 590%, about 600%, about 610%, about 620%, about 630%, about 640%, about 650%, about 660%, about 670%, about 680%, about 690%, about 700%, about 710%, about 720%, about 750%, about 760%, about 770%, about 780%, about 790%, 0%, about 275%, about 280%, about 285%, about 290%, about 295%, about 300%, about 305%, about 310%, about 315%, about 320%, about 325%, about 330%, about 335%, about 340%, about 345%, about 350%, about 355%, about 360%, about 365%, about 370%, about 375%, about 380%, about 385%, about 390%, about 395%, or about 400%.

[0051] In some embodiments, administration of an effective amount of cedazuridine and an effective amount of decitabine increases the leukemia-free survival (e.g., median leukemia-free survival) of the MDS subject by about 200% to about 400% relative to the survival achieved if the subject received best supportive care (BSC) alone. Thus, in some embodiments, administration of an effective amount of cedazuridine and an effective amount of decitabine increases the survival of the MDS subject by about 200%, about 205%, about 210%, about 215%, about 220%, about 225%, about 230%, about 235%, about 240%, about 245%, about 250%, about 255%, about 260%, about 265%, about 270%, about 275%, about 276%, about 278%, about 279%, about 280%, about 281%, about 282%, about 283%, about 284%, about 285%, about 286%, about 287%, about 288%, about 289%, about 290%, about 300%, about 301%, about 302%, about 303%, about 304%, about 305%, about 306%, about 307%, about 308%, about 309%, about 310%, about 311%, about 312%, about 313%, about 314%, about 315%, about 316%, about 317%, about 318%, about 319%, about 320%, about 321%, about 322%, about 323%, about 324%, about 325%, about 326%, about 327%, about 328%, about 329%, about 330%, about 335%, about 336%, about 337%, about 338 The increase may be increased to about 75%, about 280%, about 285%, about 290%, about 295%, about 300%, about 305%, about 310%, about 315%, about 320%, about 325%, about 330%, about 335%, about 340%, about 345%, about 350%, about 355%, about 360%, about 365%, about 370%, about 375%, about 380%, about 385%, about 390%, about 395%, or about 400%.

[0052] In some embodiments, administering an effective amount of cedazuridine and an effective amount of decitabine to a subject with MDS provides the subject with a survival time (e.g., median overall survival) of at least about 28 months, at least about 30 months, at least about 32 months, at least about 34 months, or at least about 36 months (including, e.g., at least about 28 months, at least about 30 months, at least about 31 months, at least about 32 months, at least about 33 months, at least about 34 months, at least about 35 months, or at least about 36 months).

[0053] In some embodiments, administering an effective amount of cedazuridine and an effective amount of decitabine to a subject with MDS provides the subject with leukemia-free survival (e.g., median leukemia-free survival) of at least about 26 months, at least about 28 months, at least about 30 months, at least about 32 months, or at least about 34 months (including, e.g., at least about 26 months, at least about 28 months, at least about 30 months, at least about 31 months, at least about 32 months, at least about 33 months, or at least 34 months).

[0054] Methods for treating low-risk MDS in a subject in need thereof are provided according to embodiments of the present invention. In some embodiments, such methods include administering an effective amount of cedazuridine and an effective amount of decitabine to the subject, thereby treating the low-risk MDS. In some embodiments, administering an effective amount of cedazuridine and an effective amount of decitabine increases the survival time (e.g., median overall survival time) of the subject by about 130% to about 400% relative to the survival time obtained by treatment with a hypomethylating agent alone. Thus, in some embodiments, administration of an effective amount of cedazuridine and an effective amount of decitabine increases the survival time of the subject by about 130%, about 135%, about 140%, about 145%, about 150%, about 155%, about 160%, about 165%, about 170%, about 175%, about 180%, about 185%, about 190%, about 195%, about 200%, about 205%, about 210%, about 215%, about 220%, about 225%, about 230%, about 235%, about 240%, about 245%, about 250%, about 255%, about 260%, about 265%, about 270%, about 275%, about 280%, about 285%, about 290%, about 295%, about 300%, about 305%, about 310%, about 315%, about 320%, about 325%, about 330%, about 335%, about 340%, about 345%, about 350%, about 355%, about 360%, about 365%, about 370%, about 375%, about 380%, about 385%, about 390%, about 400%, about 405%, about 410%, about 415%, about 420%, about 425%, about 430%, about 435%, about 440%, about 445%, about 450%, about 455%, about 460%, about 470%, about 475%, about 480%, about 485%, about 490%, about 500%, about 500%, about 505%, about 500%, about 505%, about 505%, about 505%, about 505%, about 5 The increased amount may be increased by 45%, about 250%, about 255%, about 260%, about 265%, about 270%, about 275%, about 280%, about 285%, about 290%, about 295%, about 300%, about 305%, about 310%, about 315%, about 320%, about 325%, about 330%, about 335%, about 340%, about 345%, about 350%, about 355%, about 360%, about 365%, about 370%, about 375%, about 380%, about 385%, about 390%, about 395%, or about 400% or more, or any range defined therebetween.

[0055] In some embodiments, administration of an effective amount of cedazuridine and an effective amount of decitabine increases the leukemia-free survival (e.g., median leukemia-free survival) of the low-risk MDS subject by about 130% to about 400%, relative to the survival achieved by treatment with the leukemia-free hypomethylating agent alone. Thus, in some embodiments, administration of an effective amount of cedazuridine and an effective amount of decitabine increases the leukemia-free survival of the subject by about 130%, about 135%, about 140%, about 145%, about 150%, about 155%, about 160%, about 165%, about 170%, about 175%, about 180%, about 185%, about 190%, about 195%, about 200%, about 205%, about 210%, about 215%, about 220%, about 225%, about 230%, about 235%, about 240%, about 245%, about 245%, about 250%, about 255%, about 260%, about 265%, about 270%, about 275%, about 280%, about 285%, about 290%, about 295%, about 300%, about 305%, about 310%, about 315%, about 320%, about 325%, about 330%, about 335%, about 340%, about 345%, about 350%, about 355%, about 360%, about 365%, about 370%, about 375%, about 380%, about 385%, about 390%, about 400%, about 405%, about 405%, about 410%, about 415%, about 420%, about 425%, about 430%, about 435%, about 440%, about 445%, about 450%, about 455%, about 460%, about 465%, about 470%, about 475%, about 480%, about 485%, about 490%, about 500%, about 500%, about 505%, about 500%, about 50 The increased amount may be increased by 40%, about 245%, about 250%, about 255%, about 260%, about 265%, about 270%, about 275%, about 280%, about 285%, about 290%, about 295%, about 300%, about 305%, about 310%, about 315%, about 320%, about 325%, about 330%, about 335%, about 340%, about 345%, about 350%, about 355%, about 360%, about 365%, about 370%, about 375%, about 380%, about 385%, about 390%, about 395%, or about 400% or more, or any range defined therebetween.

[0056] In some embodiments, administering an effective amount of cedazuridine and an effective amount of decitabine increases the survival time of the low-risk MDS subject by about 200% to about 400% relative to the survival time that would have been achieved if the subject had received best supportive care (BSC) alone. Thus, in some embodiments, administering an effective amount of cedazuridine and an effective amount of decitabine increases the survival time of the subject by about 200%, about 205%, about 210%, about 215%, about 220%, about 225%, about 230%, about 235%, about 240%, about 245%, about 250%, about 255%, about 260%, about 265%, about 270%, about 275%, about 280%, or about 290% relative to the survival time that would have been achieved if the subject had received BSC alone. , about 285%, about 290%, about 295%, about 300%, about 305%, about 310%, about 315%, about 320%, about 325%, about 330%, about 335%, about 340%, about 345%, about 350%, about 355%, about 360%, about 365%, about 370%, about 375%, about 380%, about 385%, about 390%, about 395%, or about 400% or more, or any range defined therebetween.

[0057] In some embodiments, administering an effective amount of cedazuridine and an effective amount of decitabine increases the leukemia-free survival of the low-risk MDS subject (e.g., median leukemia-free survival) by about 200% to about 400% relative to the survival that would be achieved if the leukemia-free subject received best supportive care (BSC) alone. Thus, in some embodiments, administering an effective amount of cedazuridine and an effective amount of decitabine increases the leukemia-free survival of the subject by about 200%, about 205%, about 210%, about 215%, about 220%, about 225%, about 230%, about 235%, about 240%, about 245%, about 250%, about 255%, about 260%, about 265%, about 270%, about 275%, about 276%, about 278%, about 279%, about 280%, about 281%, about 282%, about 283%, about 284%, about 285%, about 286%, about 287%, about 288%, about 289%, about 290%, about 291%, about 292%, about 293%, about 294%, about 295%, about 295%, about 296%, about 297%, about 298%, about 299%, about 300%, about 300%, about 305%, about 305%, about 305%, about 306%, about 307%, about 308%, about 309%, about 309%, about 310%, about 311%, about 312%, about 313%, about 314%, about 315%, about 316%, about 317%, about 318%, about 319%, about 320%, about 325%, about The increased amount may be about 280%, about 285%, about 290%, about 295%, about 300%, about 305%, about 310%, about 315%, about 320%, about 325%, about 330%, about 335%, about 340%, about 345%, about 350%, about 355%, about 360%, about 365%, about 370%, about 375%, about 380%, about 385%, about 390%, about 395%, or about 400% or more, or any range defined therebetween.

[0058] In some embodiments, administering an effective amount of cedazuridine and an effective amount of decitabine to a subject with low-risk MDS provides the subject with a survival time (e.g., median overall survival) of at least about 28 months, at least about 30 months, at least about 32 months, at least about 34 months, or at least about 36 months (including, e.g., at least about 28 months, at least about 30 months, at least about 31 months, at least about 32 months, at least about 33 months, at least about 34 months, at least about 35 months, or at least about 36 months).

[0059] In some embodiments, administering an effective amount of cedazuridine and an effective amount of decitabine to a subject with low-risk MDS provides the subject with leukemia-free survival (e.g., median leukemia-free survival) of at least about 26 months, at least about 28 months, at least about 30 months, at least about 32 months, or at least about 34 months (including, e.g., at least about 26 months, at least about 28 months, at least about 30 months, at least about 31 months, at least about 32 months, at least about 33 months, or at least about 34 months).

[0060] In some method embodiments of the invention, treating MDS includes treating low-risk MDS subjects as determined by the International Prognostic Scoring System (IPPS), which includes Low and Int-1 subgroups. In some method embodiments of the invention, treating MDS includes treating low-risk MDS subjects as determined by the International Prognostic Scoring System-Revised (IPPS-R), which includes Intermediate, Low, and Very Low subgroups. In some method embodiments of the invention, treating MDS includes treating low-risk MDS subjects as determined by the WHO Classification-Based Prognostic Scoring System (WPSS), which includes Intermediate, Low, and Very Low subgroups. In some method embodiments of the invention, treating MDS includes treating low-risk MDS subjects as determined by the French-American-British (FAB) classification.

[0061] Methods of treating chronic myelomonocytic leukemia (CMML) in a subject in need thereof are provided according to embodiments of the present invention. In some embodiments, such methods include administering to the subject an effective amount of cedazuridine and an effective amount of decitabine, thereby treating the CMML. In some embodiments, administering an effective amount of cedazuridine and an effective amount of decitabine increases the survival time (e.g., median overall survival time) of the subject by about 130% to about 400% relative to the survival time achieved by treatment with a hypomethylating agent alone. Thus, in some embodiments, administration of an effective amount of cedazuridine and an effective amount of decitabine increases the survival time of the subject by about 130%, about 135%, about 140%, about 145%, about 150%, about 155%, about 160%, about 165%, about 170%, about 175%, about 180%, about 185%, about 190%, about 195%, about 200%, about 205%, about 210%, about 215%, about 220%, about 225%, about 230%, about 235%, about 240%, about 245%, about 250%, about 255%, about 260%, about 265%, about 270%, about 275%, about 280%, about 285%, about 290%, about 295%, about 300%, about 305%, about 310%, about 315%, about 320%, about 325%, about 330%, about 335%, about 340%, about 345%, about 350%, about 355%, about 360%, about 365%, about 370%, about 375%, about 380%, about 385%, about 390%, about 400%, about 405%, about 410%, about 415%, about 420%, about 425%, about 430%, about 435%, about 440%, about 445%, about 450%, about 455%, about 460%, about 470%, about 475%, about 480%, about 485%, about 490%, about 500%, about 505%, about 500%, about 505%, about 505%, about 505%, about 505%, about 505%, about 5 245%, about 250%, about 255%, about 260%, about 265%, about 270%, about 275%, about 280%, about 285%, about 290%, about 295%, about 300%, about 305%, about 310%, about 315%, about 320%, about 325%, about 330%, about 335%, about 340%, about 345%, about 350%, about 355%, about 360%, about 365%, about 370%, about 375%, about 380%, about 385%, about 390%, about 395%, or about 400% or more, or any range defined therebetween.

[0062] In some embodiments, administration of an effective amount of cedazuridine and an effective amount of decitabine increases the subject's leukemia-free survival (e.g., median leukemia-free survival) by about 130% to about 400%, relative to the survival achieved by treatment with the leukemia-free hypomethylating agent alone. Thus, in some embodiments, administration of an effective amount of cedazuridine and an effective amount of decitabine increases the leukemia-free survival of the subject by about 130%, about 135%, about 140%, about 145%, about 150%, about 155%, about 160%, about 165%, about 170%, about 175%, about 180%, about 185%, about 190%, about 195%, about 200%, about 205%, about 210%, about 215%, about 220%, about 225%, about 230%, about 235%, about 240%, about 245%, about 245%, about 250%, about 255%, about 260%, about 265%, about 270%, about 275%, about 280%, about 285%, about 290%, about 295%, about 300%, about 305%, about 310%, about 315%, about 320%, about 325%, about 330%, about 335%, about 340%, about 345%, about 350%, about 355%, about 360%, about 365%, about 370%, about 375%, about 380%, about 385%, about 390%, about 400%, about 405%, about 405%, about 410%, about 415%, about 420%, about 425%, about 430%, about 435%, about 440%, about 445%, about 450%, about 455%, about 460%, about 465%, about 470%, about 475%, about 480%, about 485%, about 490%, about 500%, about 500%, about 505%, about 500%, about 50 The increased amount may be increased by 40%, about 245%, about 250%, about 255%, about 260%, about 265%, about 270%, about 275%, about 280%, about 285%, about 290%, about 295%, about 300%, about 305%, about 310%, about 315%, about 320%, about 325%, about 330%, about 335%, about 340%, about 345%, about 350%, about 355%, about 360%, about 365%, about 370%, about 375%, about 380%, about 385%, about 390%, about 395%, or about 400% or more, or any range defined therebetween.

[0063] In some embodiments, administering an effective amount of cedazuridine and an effective amount of decitabine increases the survival of the CMML subject by about 200% to about 400% relative to the survival that would have been achieved if the subject had received best supportive care (BSC) alone. Thus, in some embodiments, administering an effective amount of cedazuridine and an effective amount of decitabine increases the survival of the subject by about 200%, about 205%, about 210%, about 215%, about 220%, about 225%, about 230%, about 235%, about 240%, about 245%, about 250%, about 255%, about 260%, about 265%, about 270%, about 275 ... The increase may be increased to about 270%, about 275%, about 280%, about 285%, about 290%, about 295%, about 300%, about 305%, about 310%, about 315%, about 320%, about 325%, about 330%, about 335%, about 340%, about 345%, about 350%, about 355%, about 360%, about 365%, about 370%, about 375%, about 380%, about 385%, about 390%, or about 400%.

[0064] In some embodiments, administration of an effective amount of cedazuridine and an effective amount of decitabine increases the leukemia-free survival of the CMML subject by about 200% to about 400% relative to the survival that would have been achieved if the leukemia-free subject had received best supportive care (BSC) alone. Thus, in some embodiments, administration of an effective amount of cedazuridine and an effective amount of decitabine increases the leukemia-free survival of the subject by about 200%, about 205%, about 210%, about 215%, about 220%, about 225%, about 230%, about 235%, about 240%, about 245%, about 250%, about 255%, about 260%, about 270%, about 275%, about 276%, about 277%, about 278%, about 279%, about 280%, about 281%, about 282%, about 283%, about 284%, about 285%, about 286%, about 287%, about 288%, about 289%, about 290%, about 300%, about 305%, about 306%, about 307%, about 308%, about 309%, about 310%, about 311%, about 312%, about 313%, about 314%, about 315%, about 316%, about 317%, about 318%, about 319%, about 320%, about 325%, about 326%, about 327%, about 328%, about 329%, about 330%, about 335%, about 336%, about 337%, about 338%, about 340%, about 345%, about 346%, about 347%, about 348%, about 350%, about 355%, about 350 265%, about 270%, about 275%, about 280%, about 285%, about 290%, about 295%, about 300%, about 305%, about 310%, about 315%, about 320%, about 325%, about 330%, about 335%, about 340%, about 345%, about 350%, about 355%, about 360%, about 365%, about 370%, about 375%, about 380%, about 385%, about 390%, or about 400%.

[0065] In some embodiments, administering an effective amount of cedazuridine and an effective amount of decitabine to a subject with CMML provides the subject with a survival time (e.g., median overall survival) of at least about 28 months, about 30 months, about 31 months, about 32 months, about 33 months, about 34 months, about 35 months, or about 36 months.

[0066] In some embodiments, administering an effective amount of cedazuridine and an effective amount of decitabine to a subject with CMML provides the subject with leukemia-free survival (e.g., median leukemia-free survival) of at least about 26 months, at least about 28 months, at least about 30 months, at least about 32 months, or at least about 34 months (including, e.g., at least about 26 months, at least about 28 months, at least about 30 months, at least about 31 months, at least about 32 months, at least about 33 months, or at least about 34 months).

[0067] In some method embodiments of the invention, treatment of CMML includes treatment of CMML subjects who meet the French-American-British (FAB) criteria.

[0068] Mutations in the TP53 gene (TP53mut), which encodes the p53 protein, in MDS and CMML patients have been characterized as an independent prognostic factor for poor prognosis. The present invention has been demonstrated to provide improved outcomes in overall survival and leukemia-free survival for patients with either mono-allelic or bi-allelic TP53 mutations. The TP53 mutation can be any mutation in the gene that results in a decrease in TP53 mRNA and / or p53 protein levels or results in a decrease in p53 activity.

[0069] Methods of treating MDS or CMML in a TP53mut subject in need thereof are provided according to embodiments of the present invention. In some embodiments, such methods comprise administering to the subject an effective amount of cedazuridine and an effective amount of decitabine, thereby treating the MDS or CMML. In some embodiments, administering an effective amount of cedazuridine and an effective amount of decitabine increases the survival time (e.g., median overall survival time) of the subject by about 130% to about 400% relative to the survival time achieved by treatment with a hypomethylating agent alone. Thus, in some embodiments, administration of an effective amount of cedazuridine and an effective amount of decitabine increases the survival time of the subject by about 130%, about 135%, about 140%, about 145%, about 150%, about 155%, about 160%, about 165%, about 170%, about 175%, about 180%, about 185%, about 190%, about 195%, about 200%, about 205%, about 210%, about 215%, about 220%, about 225%, about 230%, about 235%, about 240%, about 245%, about 250%, about 255%, about 260%, about 265%, about 270%, about 275%, about 280%, about 285%, about 290%, about 295%, about 300%, about 305%, about 310%, about 315%, about 320%, about 325%, about 330%, about 335%, about 340%, about 345%, about 350%, about 355%, about 360%, about 365%, about 370%, about 375%, about 380%, about 385%, about 390%, about 400%, about 405%, about 410%, about 415%, about 420%, about 425%, about 430%, about 435%, about 440%, about 445%, about 450%, about 455%, about 460%, about 470%, about 475%, about 480%, about 485%, about 490%, about 500%, about 505%, about 500%, about 505%, about 505%, about 505%, about 505%, about 505%, about 5 245%, about 250%, about 255%, about 260%, about 265%, about 270%, about 275%, about 280%, about 285%, about 290%, about 295%, about 300%, about 305%, about 310%, about 315%, about 320%, about 325%, about 330%, about 335%, about 340%, about 345%, about 350%, about 355%, about 360%, about 365%, about 370%, about 375%, about 380%, about 385%, about 390%, about 395%, or about 400% or more, or any range defined therebetween.

[0070] In some embodiments, administration of an effective amount of cedazuridine and an effective amount of decitabine increases leukemia-free survival (e.g., median leukemia-free survival) of TP53mut subjects by about 130% to about 400%, relative to the survival achieved by treatment with the leukemia-free hypomethylating agent alone. Thus, in some embodiments, administration of an effective amount of cedazuridine and an effective amount of decitabine increases the leukemia-free survival of the subject by about 130%, about 135%, about 140%, about 145%, about 150%, about 155%, about 160%, about 165%, about 170%, about 175%, about 180%, about 185%, about 190%, about 195%, about 200%, about 205%, about 210%, about 215%, about 220%, about 225%, about 230%, about 235%, about 240%, about 245%, about 245%, about 250%, about 255%, about 260%, about 265%, about 270%, about 275%, about 280%, about 285%, about 290%, about 295%, about 300%, about 305%, about 310%, about 315%, about 320%, about 325%, about 330%, about 335%, about 340%, about 345%, about 350%, about 355%, about 360%, about 365%, about 370%, about 375%, about 380%, about 385%, about 390%, about 400%, about 405%, about 405%, about 410%, about 415%, about 420%, about 425%, about 430%, about 435%, about 440%, about 445%, about 450%, about 455%, about 460%, about 465%, about 470%, about 475%, about 480%, about 485%, about 490%, about 500%, about 500%, about 505%, about 500%, about 50 The increased amount may be increased by 40%, about 245%, about 250%, about 255%, about 260%, about 265%, about 270%, about 275%, about 280%, about 285%, about 290%, about 295%, about 300%, about 305%, about 310%, about 315%, about 320%, about 325%, about 330%, about 335%, about 340%, about 345%, about 350%, about 355%, about 360%, about 365%, about 370%, about 375%, about 380%, about 385%, about 390%, about 395%, or about 400% or more, or any range defined therebetween.

[0071] In some embodiments, administration of an effective amount of cedazuridine and an effective amount of decitabine increases the survival of a TP53mut subject by about 200% to about 400% relative to the survival that would have been achieved if the subject had received best supportive care (BSC) alone. Thus, in some embodiments, administration of an effective amount of cedazuridine and an effective amount of decitabine increases the survival of the subject by about 200%, about 205%, about 210%, about 215%, about 220%, about 225%, about 230%, about 235%, about 240%, about 245%, about 250%, about 255%, about 260%, about 265%, about 270%, about 275%, about 280%, or about 290% relative to the survival that would have been achieved if the subject had received BSC alone. , about 285%, about 290%, about 295%, about 300%, about 305%, about 310%, about 315%, about 320%, about 325%, about 330%, about 335%, about 340%, about 345%, about 350%, about 355%, about 360%, about 365%, about 370%, about 375%, about 380%, about 385%, about 390%, about 395%, or about 400% or more, or any range defined therebetween.

[0072] In some embodiments, administration of an effective amount of cedazuridine and an effective amount of decitabine increases the leukemia-free survival of a TP53mut subject (e.g., median leukemia-free survival) by about 200% to about 400% relative to the survival that would be achieved if the leukemia-free subject received best supportive care (BSC) alone. Thus, in some embodiments, administration of an effective amount of cedazuridine and an effective amount of decitabine increases the leukemia-free survival of the subject by about 200%, about 205%, about 210%, about 215%, about 220%, about 225%, about 230%, about 235%, about 240%, about 245%, about 250%, about 255%, about 260%, about 265%, about 270%, about 275%, about 276%, about 278%, about 279%, about 280%, about 281%, about 282%, about 283%, about 284%, about 285%, about 286%, about 287%, about 288%, about 289%, about 290%, about 291%, about 292%, about 293%, about 294%, about 295%, about 295%, about 296%, about 297%, about 298%, about 299%, about 300%, about 300%, about 305%, about 305%, about 306%, about 307%, about 308%, about 309%, about 310%, about 311%, about 312%, about 313%, about 314%, about 315%, about 316%, about 317%, about 318%, about 319%, about 320%, about 325%, about 326%, about 327%, about The increased amount may be about 280%, about 285%, about 290%, about 295%, about 300%, about 305%, about 310%, about 315%, about 320%, about 325%, about 330%, about 335%, about 340%, about 345%, about 350%, about 355%, about 360%, about 365%, about 370%, about 375%, about 380%, about 385%, about 390%, about 395%, or about 400% or more, or any range defined therebetween.

[0073] In some embodiments, administering an effective amount of cedazuridine and an effective amount of decitabine provides a subject with MDS or CMML who has a monoallelic TP53mut a survival (e.g., median overall survival) or leukemia-free survival of at least about 20 months, at least about 22 months, at least about 24 months, at least about 26 months, at least about 28 months, at least about 30 months, at least about 32 months, at least about 34 months, or at least about 36 months.

[0074] In some embodiments, administering an effective amount of cedazuridine and an effective amount of decitabine provides a subject with MDS or CMML who has biallelic TP53mut with at least about 10 months, at least about 12 months, at least about 14 months, at least about 16 months, at least about 18 months, or at least about 20 months of survival (e.g., median overall survival) or leukemia-free survival.

[0075] In some embodiments of the present invention, the method comprises administering cedazuridine and decitabine to a subject in one or more oral dosage forms of the present invention by administering an effective amount of cedazuridine and an effective amount of decitabine to a subject.In some embodiments, each oral dosage form is a solid oral dosage form.In some embodiments, a single solid oral dosage form comprising cedazuridine and decitabine is administered.In certain embodiments, a method is provided for administering to a subject an oral dosage form comprising cedazuridine (e.g., 100 mg) and decitabine (e.g., 35 mg) and a pharmacologic acceptable excipient.

[0076] Any dosing regimen known to those skilled in the art to adjust the timing and sequence of drug delivery can be used, and can be repeated as necessary to effectively perform the treatment in the method of the present invention. For example, the oral dosage form can be administered once, twice, three or four times a day, as a single dose, multiple discrete doses, or by continuous infusion. In certain embodiments, at least one solid oral dosage form is administered once a day. In some embodiments, administration of at least one solid oral dosage form according to the embodiments of the present invention can be performed for one or more weeks per 28-day cycle, for example, one week, two weeks, three weeks or four weeks per 28-day cycle. The weeks can be consecutive and / or non-consecutive. In certain embodiments, cedazuridine and decitabine are administered daily for five days (days 1-5) of a 28-day cycle.

[0077] In some embodiments of the invention, the solid oral dosage form comprising cedazuridine and decitabine is administered to the subject once daily for 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, or more days. In some embodiments, the solid oral dosage form comprising cedazuridine and decitabine is administered to the subject once daily on days 1-5 of a 28-day cycle. In some embodiments, on days 1-5 of the cycle, cedazuridine and decitabine are each administered daily to the subject, and on days 6-28 of the cycle, neither cedazuridine nor decitabine is administered. Such solid oral dosage forms can be administered simultaneously, sequentially, or at different times during the same day. In certain embodiments, all solid oral dosage forms are administered simultaneously or at about the same time (e.g., within 5 minutes, within 10 minutes, within 15 minutes, within 20 minutes, within 25 minutes, or within 30 minutes).

[0078] In some embodiments, a unit dosage form containing 35 mg of decitabine and 100 mg of cedazuridine may be administered daily on each of days 1-5 of the cycle. However, in some embodiments, the doses of cedazuridine and decitabine may be varied. This may be appropriate, for example, if this is the second or subsequent cycle for the subject. More information regarding possible dosing schedules and administration for cedazuridine and decitabine is available from Inqovi. (登録商標) can be found in the Prescribing Information and at www.inqovi.com.

[0079] In some embodiments, a period of 0-31 days or more (e.g., 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, or more) may elapse between multiple cycles of the present invention. A treatment-free period may be desirable to allow the subject (e.g., human patient) of the present invention to have sufficient health to continue treatment. The period between treatment cycles can be determined by a physician using standard techniques in the art, for example, based on adequate blood counts, e.g., adequate lack of neutropenia (e.g., absolute neutrophil count (ANC) in the subject is 0.5×10 9 The dose may be determined individually for each subject based on the number of cells / L or more, and may be adjusted over the course of treatment based on the administering physician's judgment. In some embodiments, the period between treatment cycles may be minimal, e.g., there may be no period, e.g., immediately starting the next 28-day period. In some embodiments, the period between treatment cycles may be 1 week, 2 weeks, 3 weeks, 4 weeks, 5 weeks, 6 weeks, or more.

[0080] In some embodiments, the administration regimen may include pretreatment and / or co-administration with at least one additional therapeutic agent. In such cases, decitabine and cedazuridine may be administered simultaneously, separately, or sequentially with at least one additional therapeutic agent. The additional therapeutic agent may also be included in one or more solid oral dosage forms. As used herein, the term "additional therapeutic agent" includes, but is not limited to, chemotherapeutic agents and immunomodulatory agents.

[0081] Examples of chemotherapeutic agents include, but are not limited to, alkylating agents (which may include, for example, doxorubicin, cyclophosphamide, estramustine, carmustine, mitomycin, bleomycin, and the like); antimetabolites (which may include, for example, 5-fluorouracil, capecitabine, gemcitabine, nelarabine, fludarabine, methotrexate, and the like); platinating agents (which may include, for example, cisplatin, oxaliplatin, carboplatin, and the like); topoisomers. enzyme inhibitors (which may include, for example, topotecan, irinotecan, etoposide, etc.); tubulin agents (which may include, for example, paclitaxel, docetaxel, vinorelbine, vinblastine, vincristine, other taxanes, epothilones, etc.); signal transduction inhibitors (e.g., kinase inhibitors, antibodies, farnesyltransferase inhibitors, etc.); and other hormonal or chemotherapeutic agents (e.g., tamoxifen, antimitotic agents (e.g., polo-like kinase inhibitors or aurora kinase inhibitors), etc.). Examples of immunomodulatory agents include, but are not limited to, CTLA-4, PD-1 and PDL-1 antibodies or inhibitors, lenalidomide, etc.

[0082] According to an embodiment of the present invention, administering a combination of decitabine and cedazuridine (e.g., solid oral dosage form) to a subject in need thereof can provide the subject with multiple beneficial responses. For example, in some embodiments, the administration reduces DNA methylation in the subject by at least 5% (e.g., at least 5%, at least 6%, at least 7%, at least 8%, at least 9%, at least 10%, at least 11%, at least 12%, at least 13%, at least 14%, or at least 15%, or more, or any value or range therebetween) compared to a control measurement, e.g., compared to DNA methylation in the subject before administration (e.g., subject "baseline" DNA methylation). DNA methylation in the subject can be quantitatively and / or qualitatively assessed by any standard technique in the art, e.g., as measured by markers of relative global methylation compared to a control, e.g., as measured by LINE-1 methylation compared to a control. For example, in some embodiments, administration reduces LINE-1 methylation in the subject by at least 5% (e.g., at least 5%, at least 6%, at least 7%, at least 8%, at least 9%, at least 10%, at least 11%, at least 12%, at least 13%, at least 14%, or at least 15%, or more) compared to a control measurement, e.g., compared to LINE-1 methylation in the subject prior to administration (e.g., subject baseline LINE-1 methylation). For example, in some embodiments, administration may reduce LINE-1 methylation in the subject by at least 5%, at least 8%, at least 10%, or at least 15% or more. In some embodiments, administration may reduce LINE-1 methylation in the subject by about 5% to about 20%, about 6% to about 15%, or about 8% to about 10%.

[0083] In some embodiments, administration of decitabine and cedazuridine to the subject results in a 28-day cycle within 2 weeks, 3 weeks, or 4 weeks (e.g., 28 or fewer consecutive days, 27 or fewer consecutive days, 26 or fewer consecutive days, 25 or fewer consecutive days, 24 or fewer consecutive days, 23 or fewer consecutive days, 22 or fewer consecutive days, 21 or fewer consecutive days, 20 or fewer consecutive days, 19 or fewer consecutive days, 18 or fewer consecutive days, 17 or fewer consecutive days, 16 or fewer consecutive days, or less than 10 consecutive days, 15 consecutive days, 14 consecutive days, 13 consecutive days, 12 consecutive days, 11 consecutive days, 10 consecutive days, 9 consecutive days, 8 consecutive days, 7 consecutive days, 6 consecutive days, 5 consecutive days, 4 consecutive days, 3 consecutive days, 2 consecutive days, 1 consecutive day, or any value or range therein) in the subject 9 In some embodiments, administration of decitabine and cedazuridine to the subject reduces the absolute neutrophil count (ANC) in the subject to less than 0.5×10 cells / L of blood for a period of 2 weeks or less, 3 weeks or less, or 4 weeks or less during treatment (e.g., during multiple repeated 28-day cycles). 9 Reduced to less than cells / L.

[0084] In some embodiments, administering decitabine and cedazuridine to the subject optionally expands hemoglobin F expressing cells (i.e., F cells) by at least 5% (e.g., at least 5%, at least 6%, at least 7%, at least 8%, at least 9%, at least 10%, at least 15%, at least 20%, at least 25%, or at least 30%, or more) as measured by %F cells / red blood cells per sample (e.g., in the patient's healthy samples), when compared to a "baseline" control %F cells / red blood cells (e.g., when compared to the patient's %F cells / red blood cells before treatment, e.g., when compared to the average %F cells / red blood cells of a patient population (e.g., a healthy patient population) that has not been treated). For example, in some embodiments, administering decitabine and cedazuridine to the subject can expand the %F cells in the subject by at least 5%, at least 8%, at least 10%, at least 15%, or at least 23%, or more, when compared to a baseline control. In some embodiments, the administration may expand %F cells in the subject by about 5% to about 30%, about 6% to about 24%, or about 8% to about 20% compared to a baseline control. In some embodiments, the administration may expand %F cells in the subject by about 5% to about 30%, about 6% to about 24%, or about 8% to about 20% compared to a baseline control.

[0085] In some embodiments, the administration of decitabine and cedazuridine increases F cells to a total of at least 10% to at least 30% of total red blood cells, or more (e.g., at least 15%, at least 16%, at least 17%, at least 18%, at least 19%, at least 20%, at least 21%, at least 22%, at least 23%, at least 24%, at least 25%, at least 26%, at least 27%, at least 28%, at least 29%, or at least 30% or more F cells / red blood cells per sample (e.g., a patient's blood sample), or any value or range thereof). For example, in some embodiments, administration of decitabine and cedazuridine to a subject can expand F cells to a total of at least 15%, at least 20%, at least 23%, at least 35%, or more of total red blood cells in a sample. In some embodiments, administration of decitabine and cedazuridine to a subject can expand F cells to a total amount of about 15% to about 30%, about 18% to about 25%, or about 15% to about 35% of all red blood cells in a sample.

[0086] In some embodiments of the invention, the subject is over 75 years of age. In certain embodiments, the subject is over 18 years of age and is ineligible for induction chemotherapy due to one or more comorbidities. Such comorbidities include, for example, (i) baseline Eastern Cooperative Oncology Group (ECOG) performance status of 2 or 3, (ii) severe cardiac impairment (e.g., congestive heart failure requiring treatment, ejection fraction ≦50%, or chronic stable angina), (iii) severe pulmonary impairment (e.g., diffusing lung capacity for carbon monoxide DLCO ≦65%, or forced expiratory volume in 1 second (FEV1) ≦65%), (iv) creatinine clearance ≧30 mL / min and ≦45 mL / min, and / or (v) moderate hepatic impairment with total bilirubin >1.5 and ≦3.0 times the upper limit of normal (ULN).

[0087] Dosage levels, modes of administration, and dosing regimens can be modified by one of skill in the art using known techniques as determined necessary for a subject (eg, patient).

[0088] Oral dosage form

[0089] The methods described herein may use any form of decitabine and cedazuridine and / or pharmaceutically acceptable salts of either compound. As used herein, decitabine and cedazuridine and their pharmaceutically acceptable salts may be collectively referred to as "therapeutic agents". In addition, when a therapeutic agent is mentioned, it should be understood that the pharmaceutically acceptable salts of the therapeutic agent are also included in this reference. In some embodiments, the therapeutic agent is administered in an oral dosage form, such as a solid oral dosage form. Such oral dosage forms may contain each therapeutic agent separately or may contain a combined dosage form. In certain embodiments, the subject is administered a solid oral dosage form that contains decitabine and cedazuridine.

[0090] In some embodiments, one or more oral dosage forms are solid oral dosage forms, such as solid oral unit dosage forms. The term "solid oral dosage form" means that the pharmaceutical composition is in solid form and is formulated for oral administration. Any suitable solid oral dosage form may be used. Examples of solid oral dosage forms according to embodiments of the present invention include tablets (e.g., intended for buccal, sublingual, and systemic absorption), caplets, boluses, powders, granules, pastes for application to the tongue, capsules, such as those described above, including hard gelatin capsules and soft gelatin capsules, mouth sprays, troches, lozenges, and pellets. The pharmaceutical composition may be formulated for immediate release, sustained release, or controlled release.

[0091] Many possible oral dosage forms can be used in the methods of the invention. For example, decitabine can be present in an oral dosage form ranging from about 10 mg to about 100 mg, about 20 mg to about 45 mg, or about 30 mg to about 40 mg (e.g., about 10 mg, about 20 mg, about 25 mg, about 30 mg, about 35 mg, about 40 mg, about 45 mg, about 50 mg, about 55 mg, about 60 mg, about 65 mg, about 70 mg, about 75 mg, about 80 mg, about 90 mg, or about 100 mg). As another example, cedazuridine may be present in the oral dosage form in a range of about 10 mg to about 150 mg, about 70 mg to about 120 mg, or about 90 mg to about 110 mg (e.g., about 50 mg, about 60 mg, about 70 mg, about 80 mg, about 85 mg, about 90 mg, about 95 mg, about 100 mg, about 105 mg, about 110 mg, about 115 mg, about 120 mg, about 125 mg, about 130 mg, about 140 mg, or about 150 mg). However, in some embodiments of the present invention, one solid oral dosage form is a unit dosage form containing about 35 mg of decitabine. In some embodiments of the present invention, one solid oral dosage form is a unit dosage form containing about 100 mg of cedazuridine. Moreover, in some embodiments, one solid oral dosage form is a unit dosage form (e.g., a fixed-dose combination) comprising about 35 mg of decitabine and about 100 mg of cedazuridine. In some embodiments of the present invention, one unit dosage form comprises about 35 mg of decitabine and about 100 mg of cedazuridine and at least one pharma- ceutically acceptable excipient.

[0092] Pharmaceutically acceptable excipients are well known in the pharmaceutical art and are described, for example, in Remington's Pharmaceutical Sciences, Mack Publishing Co., Easton, Pa (e.g., 20th ed., 2000), and Handbook of Pharmaceutical Excipients, American Pharmaceutical Association, Washington, DC, (e.g., 1st ed., 2nd ed., and 3rd ed., 1986, 1994, and 2000, respectively). As is well known to those skilled in the art, excipients may serve a variety of functions and may be described, for example, as wetting agents, buffers, suspending agents, diluents, binders, lubricating agents, glidants, emulsifiers, disintegrants, absorbents, preservatives, surfactants, coloring agents, flavoring agents, and sweetening agents. Examples of pharma- ceutical acceptable excipients include: (1) sugars, such as lactose, glucose and sucrose; (2) starches, such as corn starch and potato starch; (3) cellulose and its derivatives, such as sodium carboxymethylcellulose, ethylcellulose, cellulose acetate, hydroxypropylmethylcellulose (hypromellose) and hydroxypropylcellulose; (4) powdered tragacanth; (5) malt; (6) gelatin; (7) talc; (8) additives, such as cocoa butter and suppository wax; (9) oils, such as peanut oil, cottonseed oil, safflower oil, sesame oil, olive oil, corn oil and soybean oil; (10) glycosaminoglycans, glyceryl stearate ... (11) polyols, such as propylene glycol; (12) esters, such as ethyl oleate and ethyl laurate; (13) agar; (14) buffers, such as magnesium hydroxide and aluminum hydroxide; (15) alginic acid; (16) pyrogen-free water; (17) isotonic saline; (18) Ringer's solution; (19) ethyl alcohol; (20) pH buffer solutions, (21) polyesters, polycarbonates, and / or polyanhydrides, and (22) other non-toxic compatible substances used in pharmaceutical formulations.

[0093] Examples of diluents include lactose, lactose monohydrate, cellulose, microcrystalline cellulose, sorbitol, dibasic calcium phosphate dehydrate and calcium sulfate dehydrate. Examples of binders include gelatin, glucose, lactose, cellulose, methylcellulose, ethylcellulose, hydroxypropylmethylcellulose (hypromellose), hydroxypropylcellulose, starch, polyvinylpyrrolidone, sodium alginate, carboxymethylcellulose and acacia. Examples of disintegrants include croscarmellose sodium, crospovidone, sodium starch glycolate and starch. Examples of lubricants include colloidal silicon dioxide, corn starch and talc. Examples of glidants include stearic acid, magnesium stearate, calcium stearate, talc, paraffin, sodium lauryl sulfate, sodium benzoate and polyethylene glycol.

[0094] In some embodiments, the solid oral dosage form comprises one or more of a diluent, a binder, a disintegrant, a glidant, and a lubricant. In some embodiments, the solid oral dosage form comprises a diluent, a binder, a disintegrant, a glidant, and a lubricant. In certain embodiments of the present invention, the solid oral dosage form comprises decitabine and / or cedazuridine, and the following additives: lactose monohydrate as a diluent; hydroxypropyl methylcellulose as a binder; croscarmellose sodium as a disintegrant; colloidal silicon dioxide as a glidant; and magnesium stearate as a lubricant. In some embodiments of the present invention, such ingredients are formed into a tablet. In some embodiments, the tablet is an immediate release tablet. Additionally, in certain embodiments, the tablet is coated with a film, which may be colored. Although any pharma- ceutically acceptable coating may be used, in some embodiments, the tablet is coated with Opadry. (登録商標) It is coated with a coating.

[0095] In some embodiments, cedazuridine is present in the solid oral dosage form in an amount of about 17-22 w / w%, e.g., about 17.0, about 17.2, about 17.4, about 17.6, about 17.8, about 18.0, about 18.2, about 18.4, about 18.6, about 18.8, about 19.0, about 19.2, about 19.4, about 19.6, about 19.8, about 20.0, about 20.2, about 20.4, about 20.6, about 20.8, about 21.0, about 21.2, about 21.4, about 21.6, about 21.8, or about 22.0 w / w%, or any range therebetween, e.g., about 19.42 w / w%. In some embodiments, decitabine is present in the solid oral dosage form in an amount of about 4-8% w / w, e.g., about 4.0, about 4.2, about 4.4, about 4.6, about 4.8, about 5.0, about 5.2, about 5.4, about 5.6, about 5.8, about 6.0, about 6.2, about 6.4, about 6.6, about 6.8, about 7.0, about 7.2, about 7.4, about 7.6, about 7.8, or about 8.0 w / w%, or any range therebetween, e.g., about 6.8 w / w%. In some embodiments, the diluent (e.g., lactose monohydrate) is present in the solid oral dosage form in an amount of about 55-70 w / w%, for example, about 55, about 56, about 57, about 58, about 59, about 60, about 61, about 62, about 63, about 64, about 65, about 66, about 67, about 68, about 69, or about 70 w / w%, or any range therebetween, for example, about 62.62 w / w%. In some embodiments, the binder (e.g., hypromellose) is present in the solid oral dosage form in an amount of about 1-3 w / w%, such as about 1.0, about 1.2, about 1.4, about 1.6, about 1.8, about 2.0, about 2.2, about 2.4, about 2.6, about 2.8, or about 3.0 w / w%, or any range therebetween, such as about 1.94 w / w%. In some embodiments, the disintegrant (e.g., croscarmellose sodium) is present in the solid oral dosage form in an amount of about 3-7 w / w%, e.g., about 3.0, about 3.2, about 3.4, about 3.6, about 3.8, about 4.0, about 4.2, about 4.4, about 4.6, about 4.8, about 5.0, about 5.2, about 5.4, about 5.6, about 5.8, about 6.0, about 6.2, about 6.4, about 6.6, about 6.8, or about 7.0 w / w%, or any range therebetween, e.g., about 4.85 w / w%.In some embodiments, the glidant (e.g., colloidal silicon dioxide) is present in the solid oral dosage form in an amount of about 0.5 to 2 w / w%, e.g., about 0.5, about 0.6, about 0.7, about 0.8, about 0.9, about 1.0, about 1.1, about 1.2, about 1.3, about 1.4, about 1.5, about 1.6, about 1.7, about 1.8, about 1.9, or about 2.0 w / w%, or any range therebetween, e.g., about 0.97 w / w%. In some embodiments, the lubricant (e.g., magnesium stearate) is present in the solid oral dosage form in an amount of about 0.1 to 2 w / w%, for example, about 0.1, about 0.2, about 0.3, about 0.4, about 0.5, about 0.6, about 0.7, about 0.8, about 0.9, about 1.0, 1.1, about 1.2, about 1.3, about 1.4, about 1.5, about 1.6, about 1.7, about 1.8, about 1.9, or about 2.0 w / w%, or any range therebetween, for example, about 0.49 w / w%.

[0096] In some embodiments, the solid oral dosage form comprises the ingredients listed in Table 1 below.

[0097] [Table 1]

[0098] In some embodiments, the solid oral dosage form comprises the ingredients listed in Table 2 below.

[0099] [Table 2]

[0100] Further information regarding the compositions and formulations of cedazuridine and decitabine is available from Inqovi. (登録商標) Prescribing information can be found at www.inqovi.com.

[0101] The pharmaceutical compositions of the present invention can be prepared using known materials and techniques, which may include, but are not limited to, mixing and / or blending decitabine and cedazuridine with the pharma- ceutical acceptable excipients.

[0102] In some embodiments of the present invention, the method of the present invention is carried out using a kit comprising at least one unit dosage form comprising decitabine and at least one unit dosage form comprising cedazuridine. In certain embodiments, the kit comprises at least one unit dosage form comprising decitabine and cedazuridine. In some embodiments, the kit provides one unit dosage form comprising about 35 mg of decitabine and about 100 mg of cedazuridine and at least one pharma- ceutically acceptable excipient. Other unit dosage forms may be used, and may vary depending on availability. Daily doses for cedazuridine and / or decitabine may require more than one unit dosage form per day.

[0103] The kit may include the solid oral dosage form for the daily dose for each therapeutic agent (e.g., one tablet containing 35 mg of decitabine and 100 mg of cedazuridine). The kit may also include unit dosage forms for more than one day (e.g., one week) of the cycle or for the entire cycle. Thus, in some embodiments of the invention, the kit may include 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28 or more solid oral dosage forms containing cedazuridine and decitabine according to embodiments of the invention. In some embodiments, the kit may include five solid oral dosage forms (for days 1-5 of the cycle) comprising cedazuridine and decitabine.

[0104] The kit may further comprise a container and / or package suitable for commercial sale. The container may be any conventional shape or form known in the art, made of medicamentously acceptable material, such as a paper or cardboard box, a glass or plastic bottle or jar, a reclosable bag, or a blister pack containing individual doses for pushing out of the pack according to a treatment schedule. Two or more containers may be used together in a single package. For example, tablets are placed in a blister pack, which is then placed in a box. In some embodiments, the container is a bottle, such as a 30cc white high density polyethylene bottle, containing unit dosage forms (e.g., about 5 unit dosage forms). The bottle may further contain a canister of desiccant, such as a silica desiccant. In some embodiments, the container is a blister pack, such as a blister pack formed by aluminum foil or a foil lid, with one tablet per cavity. The blister pack may be in a carton.

[0105] The kit may further include information. The information may be provided on a readable medium. The readable medium may include a label. The information may be directed to a physician, a pharmacist, or a patient. The information may indicate that the unit dosage form may cause one or more adverse effects. The information may include instructions for administering the unit dosage form, for example, in a manner described herein. These instructions may be provided in a variety of ways.

[0106] The information can be associated with the container, for example, by being written on a label adhesively affixed to the container (e.g., a prescription label or a separate label); included inside the container as a written package insert; applied directly to the container, for example printed on the wall of a box or blister pack; or attached, for example by being tied or taped as an instruction card attached to the neck of the bottle via a string, cord or other line, strap, or tether-type device.

[0107] It will be apparent to those skilled in the art that specific embodiments of the present invention may be directed to one, some or all of the above-mentioned aspects as well as other aspects and may include one, some or all of the above-mentioned and below-mentioned embodiments as well as other embodiments.

[0108] Other than in the examples, or unless otherwise indicated, all numbers expressing quantities of ingredients, reaction conditions, and so forth used in the specification and claims should be understood to be modified by the word "about." Accordingly, such numbers are approximations that may vary depending upon the desired properties sought to be obtained by the present invention, unless otherwise indicated. At the very least, and not as an attempt to limit the application of the doctrine of equivalents to the scope of the claims, each numerical parameter should be construed in light of the number of significant digits and ordinary rounding techniques.

[0109] Notwithstanding that the numerical ranges and parameters setting forth the broad scope of the invention are approximations, the numerical values ​​set forth in the examples are reported as precisely as possible, however, any numerical value inherently contains certain errors necessarily resulting from the standard deviation found in their respective testing measurements.

[0110] Having described the invention, the invention is explained in more detail in the following examples, which are included herein for illustrative purposes only and are not intended to limit the invention.

[0111] Example 1 Oral decitabine / cedazuridine versus intravenous (IV) decitabine in MDS, including lower-risk MDS and CMML (Phase 3 clinical trial)

[0112] Myelodysplastic syndromes (MDS) comprise a spectrum of myeloid malignancies characterized by the acquisition of somatic mutations, ineffective hematopoiesis, peripheral blood cytopenias, and a high risk of progression to acute myeloid leukemia (AML). 1 The only known curative treatment is allogeneic hematopoietic stem cell transplantation (HSCT), but many patients are unable to undergo HSCT and the DNA methyltransferase inhibitors (DNMTi) azacitidine and decitabine are the standard of care as disease-modifying therapy for patients with high-risk MDS and for some patients with low-risk MDS. 2 Until recently, both DNMTi approved for use in MDS were administered parenterally and required patients to visit a treatment center daily for 5 or 7 days of a 28-day treatment cycle. Continuous treatment was necessary to maintain efficacy. 3 These parenteral regimens pose a significant burden for the elderly population affected by MDS (median age at diagnosis 73 years). 2 Patients may need transportation and support to appointments during and after treatment. 4~6 , and during the SARS-CoV-2 pandemic, existing infection risks were exacerbated 7,8 .

[0113] The oral bioavailability of both DNMTis is low due to first-pass excretion by the enzyme cytidine deaminase present in the intestine and liver, and the development of orally available DNMTis has been a goal since the introduction of this drug class. 9,10Inhibition of cytidine deaminase is one strategy to increase the oral systemic exposure of decitabine to therapeutic plasma concentrations. Cedazuridine is a synthetic nucleoside analog derived from a competitive cytidine deaminase inhibitor. A phase 1 dose-finding study identified doses of oral decitabine and cedazuridine (30-40 mg and 100 mg, respectively) that provided systemic exposures closest to those achieved with the standard 5-day regimen of intravenous (IV) decitabine in MDS. 11 A phase 2, randomized crossover study confirmed that oral decitabine 35 mg and oral cedazuridine 100 mg administered simultaneously as separate capsules and then as a fixed-dose resulted in decitabine exposure, DNA demethylation, and safety comparable to those of intravenous (IV) decitabine, with clinical responses comparable to those reported for IV decitabine. 12,13 Here, results of a phase 3 study comparing in-patient systemic exposure of oral decitabine / cedazuridine and intravenous (IV) decitabine over a 5-day period are presented. Pharmacodynamics (DNA demethylation), clinical response, survival, and safety were also evaluated.

[0114] method

[0115] Study Design and Oversight: Eligible patients were randomly assigned in a 1:1 ratio to one of two dosing sequences for the first two 28-day treatment cycles: oral decitabine / cedazuridine (one tablet once daily, containing 35 mg decitabine and 100 mg cedazuridine) in cycle 1 and intravenous (IV) decitabine (20 mg / m 2 / day, 1 hour continuous IV infusion) 14(Sequence A), or vice versa (Sequence B). Each treatment was given for the first 5 consecutive days of a 28-day cycle. From the second cycle onwards, patients received treatment with oral decitabine / cedazuridine for the first 5 days of a 28-day cycle until disease progression, unacceptable toxicity, or treatment discontinuation for other reasons. Consistent with standard clinical treatment with parenteral DNMTi, cycles could be delayed or doses reduced if deemed necessary for hematologic or non-hematologic recovery.

[0116] The protocol is available at NEJM.org. Patients who benefit from oral decitabine / cedazuridine will be offered the option to participate in an extension study evaluating survival and long-term safety, which is described in the paper (ClinicalTrials.gov Identifier: NCT04093570).

[0117] An institutional review board or independent ethics committee approved the protocol and amendments at each of the 37 participating study sites in Canada (7 sites) and the United States (30 sites). The study was conducted in accordance with the protocol, International Council for Harmonisation Good Clinical Practice guidelines, and applicable local requirements. Each patient provided informed consent. Clinical response was assessed by an independent review committee.

[0118] Eligibility: Patients aged 18 years or older who are candidates to receive intravenous (IV) decitabine, with an Eastern Cooperative Oncology Group performance status of 0 or 1 and a life expectancy of 3 months or more (pretreated or untreated MDS, chronic myelomonocytic leukemia scored as intermediate-1 or intermediate-2 on the International Prognostic Scoring System, or high-risk). 14 Patients were eligible to participate in the study. One cycle of conditioning with decitabine or azacitidine was permitted. Patients who had received ≥2 cycles of DNMTi prior to the study were excluded.

[0119] Response criteria and endpoints: The primary endpoint was a comparison of total decitabine exposure over 5 days between oral decitabine / cedazuridine and oral IV decitabine for cycles 1 and 2, measured as the area under the curve (AUC). Secondary parameters included other pharmacokinetic measures; pharmacodynamic measures (DNA demethylation of oral decitabine / cedazuridine vs. IV decitabine, measured by long interspersed nuclear element-1 [LINE-1] methylation analysis). 15 Clinical response based on the International Working Group 2006 MDS response criteria (complete response [CR], bone marrow CR, partial response, and hematologic improvement) 16 transfusion independence of red blood cells (RBCs) or platelets (defined as transfusion independence for ≥56 consecutive days after the first study treatment dose among patients who were transfusion-dependent at baseline); leukemia-free survival and overall survival (LFS and OS, respectively); and safety.

[0120] Pharmacokinetic and pharmacodynamic endpoints were assessed based only on data from cycles 1 and 2 after all evaluable patients had completed both cycles. Efficacy and safety endpoints were calculated using all data through a final data cutoff, which occurred after all patients had completed at least 6 months of follow-up or had permanently discontinued treatment, whichever occurred first.

[0121] Statistical Analysis: The primary analysis was the 0-24 hour 5-day area under the curve for decitabine (AUC 0~24 The analysis consisted of two one-sided equivalence tests on the geometric least-squares mean (LSM) ratio for the 0.05-level of statistical significance. A total of 118 patients were planned to provide 90% power at the 0.05 level of statistical significance, with an estimated true ratio of geometric means of 1.0, a within-patient coefficient of variation (CV) on the unlog scale of 0.55, and equivalence limits for the 90% confidence interval (CI) of the ratio of geometric means of 0.8 and 1.25. Assuming that 10% of patients were unevaluable, 132 patients were planned to be randomly assigned. A CV of 0.55 was chosen as a conservative value based on previous studies that estimated a within-patient CV of 0.5. 12 Treatments were considered equivalent if the two-sided 90% CI of the geometric LSM ratios were within a prespecified range of 80% to 125%.

[0122] All statistical tests and CIs were two-sided, with α of 0.05. SAS (登録商標) The statistical package 9.4 (SAS Institute Inc., Cary, NC) was used for the analyses. Pharmacokinetic analyses were performed using Phoenix (登録商標) WinNonlin (登録商標) 7.0 (or higher; Certara, LP, Princeton, NJ).

[0123] The primary endpoint analysis was the AUC 0~24 Based on data from patients for whom ≥ 100 mg / kg / day was available (i.e., paired cycles). For oral therapy, treatment had to be administered within 3 hours of the scheduled time of administration without vomiting within 6 hours after administration. For intravenous (IV) decitabine cycles, decitabine AUC on days 1 or 5 0~24 The plasma concentrations of decitabine were peaked 1 hour after both oral and intravenous (IV) administration, but peaked 30 minutes after IV treatment on the 5th day. Descriptive statistics were calculated for the pharmacokinetic values.

[0124] Natural log-transformed 5-day AUC of oral decitabine / cedazuridine 0~24 An analysis of variance was performed on versus intravenous (IV) decitabine.

[0125] result

[0126] Patients and Treatment: In total, 173 patients were screened, and 138 were randomly assigned 1:1 between the two treatment sequences (Figure 1). Five patients did not receive treatment, and 133 were included in the efficacy and safety analyses. Most treated patients (n=110) were enrolled from US-based centers, with the remaining 23 enrolled from a center in Canada. Median follow-up was 966 days (approximately 2.6 years, range 868-1208 days).

[0127] Most patients (88%) had MDS (Table 1 below). Baseline characteristics were generally balanced between treatment sequences. Sequence A (oral therapy first) had a lower proportion of patients with CMML, a higher proportion of patients with high-risk MDS, a higher proportion of patients with low baseline neutrophils, and a lower proportion of patients with high baseline neutrophils.

[0128] [Table 3] JPEG2024531799000007.jpg116170

[0129] *Body weight SI conversion factor: conventional units x 0.453592; hemoglobin SI conversion factor, conventional units x 0.1; neutrophil conversion factor, conventional units x 0.001; platelet conversion factor, conventional units x 1. †n=6. ‡n=132. Patients with low-risk myelodysplastic syndromes (MDS) were eligible according to the French-American-British classification criteria in accordance with the decitabine label. 14 . BSA (body surface area); CMML (chronic myelomonocytic leukemia); ECOG (Eastern Cooperative Oncology Group); DNMTi (DNA methyltransferase inhibitor); IPSS (International Prognostic Scoring System); RBC (red blood cells); SD (standard deviation).

[0130] Most patients (n = 129 [97%]) received at least 2 cycles of treatment. Patients received a median of 9 cycles (range 1-28). Most patients (n = 100 [75%]) had at least the first dose delayed; more than half (n = 72 [54%]) received at least one dose-reduced cycle. Median treatment duration was 8.18 months (range 0.2-30.9), with 59% of patients treated for 6 months or more and 39% treated for >12 months. The single most common reason for treatment discontinuation was receiving hematopoietic cell transplantation (20%; Figure 1). In total, 123 of 133 treated patients had paired PK samples and were included in the primary endpoint analysis. Reasons for exclusion included sample completeness or data quality issues (n=2 and n=5, respectively; e.g., samples taken from the second lumen of an IV line) and administration of only one treatment cycle (IV, n=3).

[0131] Pharmacokinetics and Pharmacodynamics: Five-Day AUC of Decitabine Between Oral Decitabine / Cedazuridine and Intravenous (IV) Decitabine 0~24 The geometric LSM ratio was 98.9% (90% CI 92.7%, 105.6%), which was within the prespecified range of 80% to 125% (Table 2 below). Secondary pharmacokinetic parameters supported these findings (Table S2). Peak concentrations were higher after intravenous (IV) administration compared with oral administration (Figure 2A). Plasma concentrations remained above the lower limit of quantification for up to 4 hours after intravenous (IV) administration in most patients and for up to 6 hours after oral administration in most patients (Figure 2B).

[0132] [Table 4]

[0133] *Ratio of oral / intravenous geometric least-squares means (LSMs) (%). †Data from some patients were excluded due to data reliability / quality issues. ‡Includes data excluded from the primary endpoint due to data reliability / quality issues. AUC0-24, area under the curve during the most recent 24-hour dosing interval; D / C, oral decitabine / cedazuridine; CI (confidence interval), confidence interval; CV (coefficient of variation), coefficient of variation.

[0134] The difference in maximum demethylation rates between oral decitabine / cedazuridine and intravenous (IV) decitabine in cycles 1 and 2 was less than 1%, with narrow CIs including 0 (Table 3 below). The %LINE-1 maximum demethylation rates were numerically lower in cycle 2 than in cycle 1 for both treatments, but no statistical comparisons were made between these values.

[0135] [Table 5]

[0136] D / C, decitabine / cedazuridine; CI (confidence interval), confidence interval; LINE-1 (long interspersed nuclear element-1), long interspersed nuclear element; LSM (least squares means), least squares mean.

[0137] Efficacy: Overall, 88% (117 / 133) of all patients were evaluable for efficacy. Reasons for not being able to assess efficacy included lack of follow-up bone marrow results or other data required for a complete evaluation.

[0138] The overall response rate was 62% in the total population, including indeterminable response cases (133 / 133). Of the 117 evaluable patients, 70% had a clinical response and 25% achieved a CR (Table 4 below). The median time to first response and median time to best response were approximately 2 months (58 days [range 7-340 days]) and approximately 3.3 months (100 days [range 28-570 days]), respectively. The median duration of best response and median duration of CR were approximately 1 year (371 days [95% CI 289, 439]) and approximately 14 months (430 days [95% CI 355, 568]), respectively.

[0139] [Table 6]

[0140] FIG. 3 is a Kaplan-Meier plot for leukemia-free survival of subjects. FIG. 4 is a Kaplan-Meier plot for overall survival of subjects. FIG. 5 is a Kaplan-Meier plot for leukemia-free survival of subjects with CMML or Int-1 or low-risk MDS. FIG. 6 is a Kaplan-Meier plot for overall survival of subjects with CMML or Int-1 or low-risk MDS. For FIGS. 3-4, sequence A refers to subjects who received oral decitabine / cedazuridine in cycle 1 and intravenous (IV) decitabine in cycle 2. Sequence B refers to subjects who received intravenous (IV) decitabine in cycle 1 and oral decitabine / cedazuridine in cycle 2.

[0141] The median overall survival for all MDS subjects (total population) is 966 days, or approximately 32 months. This is significantly higher than the median overall survival observed with treatment of MDS with azacitidine. This is also significantly higher than the median overall survival observed with treatment of MDS with decitabine alone. Thus, administration of oral cedazuridine and decitabine to treat MDS patients provides an unexpectedly significant improvement in median overall survival.

[0142] Of treated patients, 41% (54 / 133 patients) were RBC transfusion dependent at baseline. More than half of these 54 patients (n=28 [52%]) no longer required RBC transfusions during the study period. Similarly, half of the patients (6 / 12 patients) who required platelet transfusions at baseline became independent of platelet transfusions. Approximately one-third of patients in each transfusion category were transfusion independent for 112 or more consecutive days.

[0143] Fewer than half of treated patients (47%; 62 / 133 patients) progressed to AML or died. Median LFS and OS were approximately 29 months (889 days) and approximately 32 months (966 days), respectively. 44% of patients (n=58) died during the study.

[0144] Safety: The proportion of patients with any adverse events (AEs) during the first two treatment cycles was similar for oral and intravenous IV therapy (98% and 96%, respectively; Table 5 below). Most serious adverse events were considered unrelated to study treatment. However, 8% of patients (11 / 133 patients) had fatal treatment-related serious adverse events during the study. Five of these deaths (5 / 11 patients) were considered related to study medication, two to oral treatment (sepsis and pneumonia), and three to intravenous IV treatment (septic shock [n=2] and pneumonia [n=1]). Discontinuation rates due to adverse events during the first two treatment cycles were low (1 patient each) and similar in each group. No increase in clinically meaningful adverse events attributable to oral treatment was observed.

[0145] [Table 7]

[0146] *Treatment-emergent adverse events (TEAEs) were coded using the Medical Dictionary for Regulatory Activities Version 22.0 and listed in order of decreasing incidence for oral decitabine / cedazuridine (D / C). *>10% of oral decitabine / cedazuridine population. † ≥ 5% of oral decitabine / cedazuridine population.

[0147] The most common treatment-emergent adverse events considered to be related to treatment with oral decitabine / cedazuridine were neutropenia, thrombocytopenia, anemia, leukopenia, fatigue, and nausea. Decreased appetite and nausea occurred in a higher proportion of patients receiving oral decitabine / cedazuridine than intravenous (IV) decitabine during the first two treatment cycles.

[0148] Discussion

[0149] This is the first phase 3 study to demonstrate equivalence in systemic exposure between oral and intravenous (IV) formulations of a DNMTi. Systemic AUC exposure was comparable between oral and intravenous (IV) doses (geometric LSM ratio 99% [90% CI 93%, 106%; Table 2). Demethylation rates were less than 1%, demonstrating pharmacodynamic equivalence (Table 3). Little difference was observed between sequences (i.e., whether oral or IV dose was administered first). Efficacy was similar to that reported in a phase 2 study comparing oral decitabine / cedazuridine with intravenous (IV) decitabine therapy 12 These findings support the conclusion that the biological effects of oral decitabine / cedazuridine and intravenous (IV) decitabine are similar.

[0150] The dosing frequency is the same for both formulations, once daily for the first 5 days of each 28-day treatment cycle. Based on these findings, the US Food and Drug Administration approved oral decitabine / cedazuridine for the same indications as intravenous (IV) decitabine in July 2020. 14,17 .

[0151] The safety profile of oral decitabine / cedazuridine was comparable to that of intravenous (IV) decitabine 13 Treatment-emergent adverse events and deaths were similar in both arms of the study, but the proportion of patients who reported one or more treatment-related serious adverse events in the first two treatment cycles was higher in patients treated with oral therapy (9% vs. 3%). One patient developed a treatment-related serious adverse event while receiving oral therapy in the second cycle, but the investigator considered the adverse event to be related to the intravenous (IV) decitabine given in the first cycle. Recalculation to account for this difference gave serious adverse event rates of 8% and 4% for oral and intravenous (IV) therapy, respectively.

[0152] In a high proportion of patients (7 / 11 patients), the treatment-related serious adverse event with oral therapy was febrile neutropenia. Patients receiving oral therapy first (cycle 1) had a higher rate of baseline neutropenia, consistent with cases of febrile neutropenia. Patients receiving oral therapy first also had a higher rate of high-risk MDS and a higher rate of patients with prior decitabine treatment than patients receiving intravenous (IV) therapy first. However, it is unclear whether these factors influenced the safety findings. Further analysis suggested that the higher incidence of treatment-related serious adverse events among patients receiving oral therapy in the first two cycles may be due to random variability.

[0153] Although caution should be used when comparing response duration and survival rates across studies, the overall response duration rate of 62% in this study compares favorably with overall response duration rates reported in clinical trials of intravenous (IV) decitabine (32%) and other DNMTi parenteral azacitidine (44%-60%). 13,18~20 Similarly, the median survival time of 32 months in this study exceeds previously reported outcomes for intravenous (IV) decitabine (14.0-19.4 months) and parenteral azacitidine (12.0-24.5 months) in clinical trials. 13,18~21 However, actual survival times are lower than those observed in clinical trials. Median OS rates in two SEER-Medicare analyses among patients receiving DNMTi therapy were 12.3 and 13.1 months. 22,23 .

[0154] The proportion of patients progressing to transplant in the study reached 20%, exceeding historical transplant rates in patients receiving DNMTi for MDS and CMML 18,24 , and have suggested that oral decitabine / cedazuridine may be used as a bridge to transplant.

[0155] Oral formulations of cancer therapies are important for patients' health-related quality of life. The majority of patients receiving parenteral DNMTi therapies reported in an online survey that intravenous (IV) and subcutaneous treatments interfere with their social activities (72% and 81%, respectively) and daily living (70% and 87%, respectively) and cause pain (66% and 92%, respectively). 4 A literature review reported that patients generally prefer oral cancer therapy over intravenous (IV) cancer therapy, as well as the convenience of receiving treatment at home. 25These findings may explain, at least in part, the apparent underuse of DNMTi in patients with higher-risk MDS (N=1190; high rates of not initiating DNMTi therapy [44%] and not maintaining DNMTi therapy [25%; defined as <4 cycles or ≥90 days apart]) in a real-world clinical trial using the SEER-Medicare linked data resource. 22 Older age (>80 years), being unmarried, having more comorbidities, and poor performance status were associated with a lower likelihood of using DNMTi therapy. It is estimated that 45% of patients with MDS who initiate DNMTi therapy receive fewer than the recommended four cycles of each agent, despite evidence that early discontinuation is associated with relapse and poor prognosis. 23 These findings highlight the need to reduce the treatment burden for patients and improve their health-related quality of life during treatment.

[0156] CC-486, an oral form of the DNMTi azacitidine, has demonstrated improved OS compared with placebo in patients over 55 years of age who received an average of one cycle of consolidation chemotherapy during CR and is currently available as a maintenance therapy for AML after CR. CC-486 is not approved for the treatment of MDS or CMML, but has been tested in extended dosing schemes (e.g., 14-21 days of a 28-day cycle for AML or MDS). 26,27 and is also being studied in a Phase 3 trial in lower-risk MDS. 28 In the latter trial, there was improvement in RBS transfusion independence but was associated with increased early mortality. CC-486 / oral azacitidine is active but not bioequivalent or interchangeable with the injectable azacitidine used for MDS and CMML. Oral combination cedazuridine / azacitidine therapy in patients with MDS, CMML, or AML is ongoing (ClinicalTrials.gov NCT04256317).

[0157] A strength of this study is its crossover design, in which patients served as their own controls, facilitating within-patient comparisons between the oral and intravenous (IV) formulations during the first two treatment cycles. All patients received oral decitabine / cedazuridine from the second cycle onwards, and therefore the safety and efficacy of the oral and intravenous (IV) formulations were not compared throughout the study period. Given the bioequivalence of oral decitabine / cedazuridine and parenteral decitabine, and the clinical profile consistent with that of IV decitabine, a non-inferiority assessment was deemed unnecessary by the regulatory authorities.

[0158] In summary, this is the first phase 3 study to demonstrate the pharmacological equivalence of oral and intravenous DNMTi in the treatment of patients with MDS or CMML. Currently, data are being prepared from a pharmacokinetic study of oral decitabine / cedazuridine in patients with refractory anemia with excess transformed blasts or AML with less than 30% blasts. The availability of oral DNMTi may reduce the treatment burden for patients, increase initiation and continuation of this treatment regimen, and improve OS and health-related quality of life for patients. It may also facilitate the development of all-oral combination therapies for MDS. Venetoclax, an oral B-cell lymphoma-2 protein, is being tested in combination with oral decitabine / cedazuridine in MDS (ClinicalTrials.gov NCT04655755).

[0159] References JPEG2024531799000012.jpg43170JPEG2024531799000013.jpg219170JPEG2024531799000014.jpg229170JPEG2024531799000015.jpg99170

[0160] Example 2: Prolonged survival in subjects with biallelic TP53-mutated MDS treated with oral decitabine / cedazuridine

[0161] TP53 mutations (TP53mut) in MDS patients have been characterized as an independent prognostic factor for poor outcome. These patients may have similar response rates to hypomethylating agents (HMAs) but may experience a significantly reduced overall survival (OS) compared to patients with wild-type (WT) TP53 (9.4 vs. 20.7 months; see Takahashi et al., Oncotarget, 2016, 7:14172-14187). Further analysis defined monoallelic (MA) and biallelic (BA) / multi-hit TP53mut populations with very different survival outcomes (8.4 vs. 30 months; see Bernard et al., Nat. Med., 2020 Oct;26(10):1549-1556). Oral decitabine / cedazuridine (ASTX727) is a fixed dose combination of decitabine (35 mg) and the cytidine deaminase inhibitor cedazuridine (100 mg) with pharmacokinetic (PK) exposure of 20 mg / m2 daily on a 28-day cycle, consistent with the standard intravenous (IV) decitabine regimen. 2The ASCERTAIN study enrolled subjects with MDS and chronic myelomonocytic leukemia (CMML) and met its primary endpoint of equivalent PK (AUC) of oral decitabine / cedazuridine compared to intravenous (IV) decitabine (Garcia-Manero et al., “Pharmacokinetic Exposure Equivalence and Preliminary Efficacy and Safety from a Randomized Cross Over Phase 3 Study (ASCERTAIN study) of an Oral Hypomethylating Agent ASTX727 (cedazuridine / decitabine) Compared to IV Decitabine,” ASH 2019)); median overall survival (mOS) was 31.7 months (Savona et al., “Prolonged Survival Observed in 133 MDS Patients Treated with Oral Decitabine / Cedazuridine,” 2021 Virtual 16 th (See MDS Conference.) A preliminary analysis of the mutational profiles of subjects enrolled in ASCERTAIN was performed and the impact on overall survival and leukemia-free survival was evaluated based on the NCCN MDS Panel focused on the TP53 mutant population.

[0162] One hundred and thirty-three patients with MDS / CMML were enrolled in ASCERTAIN and randomly assigned to receive either intravenous (IV) decitabine in cycle 1 and oral decitabine / cedazuridine in cycle 2, or the reverse treatment sequence. All subjects continuing beyond cycle 2 received oral decitabine / cedazuridine for all subsequent cycles until disease progression, toxicity, patient decision, or treatment discontinuation with hematopoietic stem cell transplantation. Whole blood drawn before treatment was used for DNA isolation, and molecular abnormalities were identified using a 179-gene next generation sequencing (NGS) hematological malignancies panel, including 30 genes from the NCCN MDS panel.

[0163] Of 133 treated subjects, NGS analysis was available for 125 subjects. The percentage of subjects with mutations in the following genes was as follows: TET2 (36.8%), TP53 (35.2%), ASXL1 (28%), DNMT3A (25.6%), SRSF2_MFSD11 (17.6%), SF3B1 (15.2%), STAG2 (12.8%), EZH2 (11.2%), RUNX1 (11.2%), U2AF1 (10.4%), BCOR (10.4%), and CBL (8.8%). TP53, EZH2, RUNX1, CBL, DNMT3A, SF3B1, and ASXL1 were selected for further analysis based on their reported negative impact on OS and leukemia-free survival (LFS). TP53 and CBL mutations were significantly associated with worse OS (HR and 95% CI: 1.70 (1.00, 2.87) and 2.54 (1.19, 5.43), respectively) and LFS (HR and 95% CI: 1.63 (0.98, 2.72) and 2.01 (0.95, 4.26), respectively) compared with WT genotype, whereas subjects with DNMT3A mutations showed a trend towards a more favorable association with OS and LFS than WT genotype. The TP53mut population (N=44) had a median age of 70.5 years, 63.6% male: 36.4% female, 91% MDS: 9% CMML, IPSS categories: HR 20%, Int-2 30%, Int-1 39%, LR 2%, NA 9%, cytogenetic features: better-risk 27%, intermediate risk 18%, poor risk 48%, N / A 5%, ECOG 0: 39%, 1: 61%, MA 68%, BA / multi-hit 32%. The median OS and LFS of the TP53mut population were 25.5 and 22.1 months, respectively, and the estimated OS and LFS were 33.7 and 31.7 months, respectively, compared with the TP53WT group (Figure 7). The TP53 mutation population was further characterized by allelic status and found to have 14 subjects with BA mutations and 30 subjects with MA TP53 mutations without other chromosomal deletions.The individual estimated mOS and 95% CI in BA vs MA were 13.0 (5.3, 29.1) vs 29.2 (19.8, NE) months (Figure 8).

[0164] In conclusion, the NGS mutation profile of MDS and CMML subjects in the ASCERTAIN study included TP53mut in 35% and this group had a worse survival than the group with WT TP53, which is apparently due to the poor prognosis of the group with BA TP53mut. Conservatively, the estimated survival of BA TP53mut in the ASCERTAIN study with oral decitabine / cedazuridine was 13 months, which compares favorably with previous results.

[0165] It will be understood by those skilled in the art that numerous and various modifications can be made without departing from the spirit of the present invention. Therefore, it should be clearly understood that the forms of the present invention are illustrative only and are not intended to limit the scope of the present invention.

[0166] All publications, patent applications, patents, GenBank, and related references cited herein are incorporated by reference in their entirety. (登録商標) Sequences identified by database accession numbers, and other references are incorporated by reference in their entirety for the teachings relevant to the sentence and / or paragraph presented by reference.

[0167] The foregoing examples are illustrative of the present invention and are not to be construed as limiting the present invention, which is defined by the following claims, with equivalents of the claims to be included therein.

Claims

1. 1. A pharmaceutical combination for treating myelodysplastic syndrome (MDS) in a subject in need thereof, comprising an effective amount of cedazuridine and an effective amount of decitabine, wherein administering said effective amount of cedazuridine and said effective amount of decitabine increases the subject's survival and / or leukemia-free survival by about 130% to about 400% relative to the survival or leukemia-free survival, respectively, achieved by treatment with a hypomethylating agent alone.

2. 10. The pharmaceutical combination of claim 1, wherein the subject is at least 75 years old.

3. 2. The pharmaceutical combination of claim 1, wherein the effective amount of cedazuridine and the effective amount of decitabine are each administered as a solid oral dosage form.

4. 4. The pharmaceutical combination of claim 3, wherein the effective amount of cedazuridine and the effective amount of decitabine are administered together as a combined solid oral dosage form.

5. 2. The pharmaceutical combination of claim 1, wherein the effective amount of cedazuridine and the effective amount of decitabine are administered on days 1 to 5 of a 28-day cycle.

6. 2. The pharmaceutical combination of claim 1, wherein the effective amount of cedazuridine and the effective amount of decitabine are administered multiple times in a 28-day cycle.

7. 2. The pharmaceutical combination of claim 1, wherein the effective amount of cedazuridine and the effective amount of decitabine are present in a solid oral dosage form comprising 100 mg of cedazuridine, 35 mg of decitabine, and at least one pharmaceutically acceptable excipient.

8. 2. The pharmaceutical combination of claim 1, wherein administering to the subject the effective amount of cedazuridine and the effective amount of decitabine provides the subject with survival and / or leukemia-free survival of at least about 28 months, at least about 30 months, at least about 32 months, or at least about 34 months.

9. 1. A pharmaceutical combination for treating myelodysplastic syndrome (MDS) in a subject in need thereof, comprising an effective amount of cedazuridine and an effective amount of decitabine, wherein administering said effective amount of cedazuridine and said effective amount of decitabine to said subject provides survival and / or leukemia-free survival of at least about 28 months, at least about 30 months, at least about 32 months, or at least about 34 months in said subject.

10. 10. The pharmaceutical combination of claim 9, wherein the subject is at least 75 years old.

11. 10. The pharmaceutical combination of claim 9, wherein the effective amount of cedazuridine and the effective amount of decitabine are each administered as a solid oral dosage form.

12. 12. The pharmaceutical combination of claim 11, wherein the effective amount of cedazuridine and the effective amount of decitabine are administered together as a combined solid oral dosage form.

13. 10. The pharmaceutical combination of claim 9, wherein the effective amount of cedazuridine and the effective amount of decitabine are administered on days 1 to 5 of a 28-day cycle.

14. 10. The pharmaceutical combination of claim 9, wherein the effective amount of cedazuridine and the effective amount of decitabine are administered multiple times in a 28-day cycle.

15. 10. The pharmaceutical combination of claim 9, wherein the effective amount of cedazuridine and the effective amount of decitabine are present in a solid oral dosage form comprising 100 mg of cedazuridine, 35 mg of decitabine, and at least one pharmaceutically acceptable excipient.

16. 1. A pharmaceutical combination for treating myelodysplastic syndrome (MDS) in a subject in need thereof, comprising an effective amount of cedazuridine and an effective amount of decitabine, wherein administering said effective amount of cedazuridine and said effective amount of decitabine increases the subject's survival and / or leukemia-free survival by about 200% to about 400% relative to the survival or leukemia-free survival, respectively, achieved by providing best supportive care alone.

17. 1. A pharmaceutical combination for increasing median overall survival and / or median leukemia-free survival in a group of subjects having myelodysplastic syndromes (MDS), comprising an effective amount of cedazuridine and an effective amount of decitabine, wherein administering said effective amount of cedazuridine and said effective amount of decitabine increases median overall survival and / or median leukemia-free survival in said group of subjects by about 130% to about 400% relative to the median survival and / or median leukemia-free survival, respectively, achieved by treatment with a hypomethylating agent alone.

18. 1. A pharmaceutical combination for increasing median overall survival and / or median leukemia-free survival in a group of subjects having myelodysplastic syndromes (MDS), comprising an effective amount of cedazuridine and an effective amount of decitabine, wherein administering said effective amount of cedazuridine and said effective amount of decitabine to said group of subjects provides said group of subjects with a median overall survival and / or median leukemia-free survival of at least about 28 months, at least about 30 months, at least about 32 months, or at least about 34 months.

19. 1. A pharmaceutical combination for treating lower-risk myelodysplastic syndrome (MDS) in a subject in need thereof, comprising an effective amount of cedazuridine and an effective amount of decitabine, wherein administering said effective amount of cedazuridine and said effective amount of decitabine to said subject increases survival and / or leukemia-free survival of said subject by about 130% to about 400% relative to the survival or leukemia-free survival, respectively, achieved by treatment with a hypomethylating agent alone.

20. 20. The pharmaceutical combination of claim 19, wherein the subject is at least 75 years old.

21. 20. The pharmaceutical combination of claim 19, wherein the effective amount of cedazuridine and the effective amount of decitabine are each administered as a solid oral dosage form.

22. 22. The pharmaceutical combination of claim 21, wherein the effective amount of cedazuridine and the effective amount of decitabine are administered together as a combined solid oral dosage form.

23. 20. The pharmaceutical combination of claim 19, wherein the effective amount of cedazuridine and the effective amount of decitabine are administered on days 1 to 5 of a 28-day cycle.

24. 20. The pharmaceutical combination of claim 19, wherein the effective amount of cedazuridine and the effective amount of decitabine are administered multiple times in a 28-day cycle.

25. 20. The pharmaceutical combination of claim 19, wherein the effective amount of cedazuridine and the effective amount of decitabine are present in a solid oral dosage form comprising 100 mg of cedazuridine, 35 mg of decitabine, and at least one pharmaceutically acceptable excipient.

26. 20. The pharmaceutical combination of claim 19, wherein administering to the subject the effective amount of cedazuridine and the effective amount of decitabine provides the subject with survival and / or leukemia-free survival of at least about 28 months, at least about 30 months, at least about 32 months, or at least about 34 months.

27. 1. A pharmaceutical combination for treating lower-risk myelodysplastic syndrome (MDS) in a subject in need thereof, the pharmaceutical combination comprising administering to the subject an effective amount of cedazuridine and an effective amount of decitabine, thereby treating the lower-risk MDS, wherein administering to the subject an effective amount of cedazuridine and an effective amount of decitabine provides the subject with survival and / or leukemia-free survival of at least about 28 months, at least about 30 months, at least about 32 months, or at least about 34 months.

28. 28. The pharmaceutical combination of claim 27, wherein the subject is at least 75 years old.

29. 28. The pharmaceutical combination of claim 27, wherein the effective amount of cedazuridine and the effective amount of decitabine are each administered as a solid oral dosage form.

30. 30. The pharmaceutical combination of claim 29, wherein the effective amount of cedazuridine and the effective amount of decitabine are administered together as a combined solid oral dosage form.

31. 28. The pharmaceutical combination of claim 27, wherein the effective amount of cedazuridine and the effective amount of decitabine are administered on days 1 to 5 of a 28-day cycle.

32. 28. The pharmaceutical combination of claim 27, wherein the effective amount of cedazuridine and the effective amount of decitabine are administered multiple times in a 28-day cycle.

33. 28. The pharmaceutical combination of claim 27, wherein the effective amount of cedazuridine and the effective amount of decitabine are present in a solid oral dosage form comprising 100 mg of cedazuridine, 35 mg of decitabine, and at least one pharmaceutically acceptable excipient.

34. 1. A pharmaceutical combination for treating lower-risk myelodysplastic syndrome (MDS) in a subject in need thereof, comprising an effective amount of cedazuridine and an effective amount of decitabine, wherein administering said effective amount of cedazuridine and said effective amount of decitabine increases the subject's survival and / or leukemia-free survival by about 200% to about 400% relative to the survival or leukemia-free survival, respectively, achieved by providing best supportive care alone.

35. 1. A pharmaceutical combination for increasing median overall survival and / or median leukemia-free survival in a group of subjects having low-risk myelodysplastic syndromes (MDS), comprising an effective amount of cedazuridine and an effective amount of decitabine, wherein administering said effective amount of cedazuridine and said effective amount of decitabine increases the median overall survival and / or median leukemia-free survival of said group of subjects by about 130% to about 400% relative to the median overall survival or median leukemia-free survival, respectively, achieved by treatment with a hypomethylating agent alone.

36. 1. A pharmaceutical combination for increasing median overall survival and / or median leukemia-free survival in a group of subjects with low-risk myelodysplastic syndromes (MDS), comprising an effective amount of cedazuridine and an effective amount of decitabine, wherein administering said effective amount of cedazuridine and said effective amount of decitabine to said group of subjects provides said group of subjects with a median overall survival and / or median leukemia-free survival of at least about 28 months, at least about 30 months, at least about 32 months, or at least about 34 months.

37. 1. A pharmaceutical combination for treating chronic myelomonocytic leukemia (CMML) in a subject in need thereof, comprising an effective amount of cedazuridine and an effective amount of decitabine, wherein administering said effective amount of cedazuridine and said effective amount of decitabine increases the subject's survival and / or leukemia-free survival by about 130% to about 400% relative to the survival or leukemia-free survival, respectively, achieved by treatment with a hypomethylating agent alone.

38. 38. The pharmaceutical combination of claim 37, wherein the subject is at least 75 years old.

39. 38. The pharmaceutical combination of claim 37, wherein the effective amount of cedazuridine and the effective amount of decitabine are each administered as a solid oral dosage form.

40. 40. The pharmaceutical combination of claim 39, wherein the effective amount of cedazuridine and the effective amount of decitabine are administered together as a combined solid oral dosage form.

41. 38. The pharmaceutical combination of claim 37, wherein the effective amount of cedazuridine and the effective amount of decitabine are administered on days 1 to 5 of a 28-day cycle.

42. 38. The pharmaceutical combination of claim 37, wherein the effective amount of cedazuridine and the effective amount of decitabine are administered multiple times in a 28-day cycle.

43. 38. The pharmaceutical combination of claim 37, wherein the effective amount of cedazuridine and the effective amount of decitabine are present in a solid oral dosage form comprising 100 mg of cedazuridine, 35 mg of decitabine, and at least one pharmaceutically acceptable excipient.

44. 38. The pharmaceutical combination of claim 37, wherein administering to the subject the effective amount of cedazuridine and the effective amount of decitabine provides the subject with survival and / or leukemia-free survival of at least about 28 months, about 30 months, about 32 months, or about 34 months.

45. 1. A pharmaceutical combination for treating chronic myelomonocytic leukemia (CMML) in a subject in need thereof, comprising an effective amount of cedazuridine and an effective amount of decitabine, wherein administering said effective amount of cedazuridine and said effective amount of decitabine to said subject provides survival and / or leukemia-free survival of at least about 28 months, at least about 30 months, at least about 32 months, or at least about 34 months in said subject.

46. 46. ​​The pharmaceutical combination of claim 45, wherein the subject is at least 75 years old.

47. 46. ​​The pharmaceutical combination of claim 45, wherein the effective amount of cedazuridine and the effective amount of decitabine are each administered as a solid oral dosage form.

48. 48. The pharmaceutical combination of claim 47, wherein the effective amount of cedazuridine and the effective amount of decitabine are administered together as a combined solid oral dosage form.

49. 46. ​​The pharmaceutical combination of claim 45, wherein the effective amount of cedazuridine and the effective amount of decitabine are administered on days 1 to 5 of a 28-day cycle.

50. 46. ​​The pharmaceutical combination of claim 45, wherein the effective amount of cedazuridine and the effective amount of decitabine are administered multiple times in a 28-day cycle.

51. 46. ​​The pharmaceutical combination of claim 45, wherein the effective amount of cedazuridine and the effective amount of decitabine are present in a solid oral dosage form comprising 100 mg of cedazuridine, 35 mg of decitabine, and at least one pharmaceutically acceptable excipient.

52. 1. A pharmaceutical combination for treating chronic myelomonocytic leukemia (CMML) in a subject in need thereof, comprising an effective amount of cedazuridine and an effective amount of decitabine, wherein administering said effective amount of cedazuridine and said effective amount of decitabine to said subject increases the subject's survival and / or leukemia-free survival by about 200% to about 375% relative to the survival or leukemia-free survival, respectively, achieved by providing best supportive care alone.

53. 1. A pharmaceutical combination for increasing median overall survival and / or median leukemia-free survival in a group of subjects having chronic myelomonocytic leukemia (CMML), comprising an effective amount of cedazuridine and an effective amount of decitabine, wherein administering said effective amount of cedazuridine and said effective amount of decitabine increases the median overall survival and / or median leukemia-free survival of said group of subjects by about 130% to about 400% relative to the median overall survival or median leukemia-free survival, respectively, achieved by treatment with a hypomethylating agent alone.

54. 1. A pharmaceutical combination for increasing median overall survival and / or median leukemia-free survival in a group of subjects having chronic myelomonocytic leukemia (CMML), comprising an effective amount of cedazuridine and an effective amount of decitabine, wherein administering said effective amount of cedazuridine and said effective amount of decitabine to said group of subjects provides said group of subjects with a median overall survival and / or median leukemia-free survival of at least about 28 months, at least about 30 months, at least about 32 months, or at least about 34 months.

55. 1. A pharmaceutical combination for treating myelodysplastic syndrome (MDS) or chronic myelomonocytic leukemia (CMML) in a subject in need of treatment and who has a TP53 mutation, the pharmaceutical combination comprising an effective amount of cedazuridine and an effective amount of decitabine, wherein administering said effective amount of cedazuridine and said effective amount of decitabine increases the subject's survival and / or leukemia-free survival by about 130% to about 400% relative to the survival or leukemia-free survival, respectively, achieved by treatment with a hypomethylating agent alone.

56. 56. The pharmaceutical combination of claim 55, wherein the subject is at least 75 years old.

57. 56. The pharmaceutical combination of claim 55, wherein the effective amount of cedazuridine and the effective amount of decitabine are each administered as a solid oral dosage form.

58. 58. The pharmaceutical combination of claim 57, wherein the effective amount of cedazuridine and the effective amount of decitabine are administered together as a combined solid oral dosage form.

59. 56. The pharmaceutical combination of claim 55, wherein the effective amount of cedazuridine and the effective amount of decitabine are administered on days 1 to 5 of a 28-day cycle.

60. 56. The pharmaceutical combination of claim 55, wherein the effective amount of cedazuridine and the effective amount of decitabine are administered multiple times in a 28-day cycle.

61. 56. The pharmaceutical combination of claim 55, wherein the effective amount of cedazuridine and the effective amount of decitabine are present in a solid oral dosage form comprising 100 mg of cedazuridine, 35 mg of decitabine, and at least one pharmaceutically acceptable excipient.

62. 56. The pharmaceutical combination of claim 55, wherein administering the effective amount of cedazuridine and the effective amount of decitabine to the subject provides the subject with survival and / or leukemia-free survival of at least about 20 months, at least about 22 months, at least about 24 months, at least about 26 months, at least about 28 months, at least about 30 months, at least about 32 months, at least about 34 months, or at least about 36 months for subjects with monoallelic TP53 mutations, or at least about 10 months, at least about 12 months, at least about 14 months, at least about 16 months, at least about 18 months, or at least about 20 months for subjects with biallelic TP53 mutations.

63. 1. A pharmaceutical combination for treating myelodysplastic syndrome (MDS) or chronic myelomonocytic leukemia (CMML) in a subject in need of such treatment and who has a TP53 mutation, comprising an effective amount of cedazuridine and an effective amount of decitabine, wherein administering said effective amount of cedazuridine and said effective amount of decitabine to said subject provides said subject with survival and / or leukemia-free survival of at least about 20 months, at least about 22 months, at least about 24 months, at least about 26 months, at least about 28 months, at least about 30 months, at least about 32 months, at least about 34 months, or at least about 36 months for a subject with a monoallelic TP53 mutation, or at least about 10 months, at least about 12 months, at least about 14 months, at least about 16 months, at least about 18 months, or at least about 20 months for a subject with a biallelic TP53 mutation.

64. 64. The pharmaceutical combination of claim 63, wherein the subject is at least 75 years of age.

65. 64. The pharmaceutical combination of claim 63, wherein the effective amount of cedazuridine and the effective amount of decitabine are each administered as a solid oral dosage form.

66. 66. The pharmaceutical combination of claim 65, wherein the effective amount of cedazuridine and the effective amount of decitabine are administered together as a combined solid oral dosage form.

67. 64. The pharmaceutical combination of claim 63, wherein the effective amount of cedazuridine and the effective amount of decitabine are administered on days 1 to 5 of a 28-day cycle.

68. 64. The pharmaceutical combination of claim 63, wherein the effective amount of cedazuridine and the effective amount of decitabine are administered multiple times in a 28-day cycle.

69. 64. The pharmaceutical combination of claim 63, wherein the effective amount of cedazuridine and the effective amount of decitabine are present in a solid oral dosage form comprising 100 mg of cedazuridine, 35 mg of decitabine, and at least one pharmaceutically acceptable excipient.

70. 1. A pharmaceutical combination for treating myelodysplastic syndrome (MDS) or chronic myelomonocytic leukemia (CMML) in a subject in need of treatment and who has a TP53 mutation, the pharmaceutical combination comprising an effective amount of cedazuridine and an effective amount of decitabine, wherein administering said effective amount of cedazuridine and said effective amount of decitabine increases the subject's survival and / or leukemia-free survival by about 200% to about 400% relative to the survival or leukemia-free survival, respectively, achieved by providing best supportive care alone.

71. 1. A pharmaceutical combination for increasing median overall survival and / or median leukemia-free survival in subjects with myelodysplastic syndrome (MDS) or chronic myelomonocytic leukemia (CMML) who have a TP53 mutation, comprising an effective amount of cedazuridine and an effective amount of decitabine, wherein administering said effective amount of cedazuridine and said effective amount of decitabine increases the median overall survival and / or median leukemia-free survival of said subject group by about 130% to about 400% relative to the median survival or median leukemia-free survival, respectively, achieved by treatment with a hypomethylating agent alone.

72. 1. A pharmaceutical combination for increasing median overall survival and / or median leukemia-free survival in a group of subjects with myelodysplastic syndrome (MDS) or chronic myelomonocytic leukemia (CMML) and who have a TP53 mutation, comprising an effective amount of cedazuridine and an effective amount of decitabine, wherein administering said effective amount of cedazuridine and said effective amount of decitabine to said group of subjects provides said subjects with a median overall survival and / or median leukemia-free survival of at least about 20 months, at least about 22 months, at least about 24 months, at least about 26 months, at least about 28 months, at least about 30 months, at least about 32 months, at least about 34 months, or at least about 36 months for subjects with a monoallelic TP53 mutation, or at least about 10 months, at least about 12 months, at least about 14 months, at least about 16 months, at least about 18 months, or at least about 20 months for subjects with a biallelic TP53 mutation.

73. 1. Use of a composition comprising an effective amount of cedazuridine and an effective amount of decitabine in the preparation of a medicament for treating myelodysplastic syndrome (MDS), optionally lower-risk MDS, in a subject in need thereof, wherein said effective amount of cedazuridine and said effective amount of decitabine increases survival and / or leukemia-free survival of said subject by about 130% to about 400% relative to the survival or leukemia-free survival, respectively, achieved by treatment with a hypomethylating agent alone.

74. 1. Use of a composition comprising an effective amount of cedazuridine and an effective amount of decitabine in the preparation of a medicament for treating myelodysplastic syndrome (MDS), optionally lower-risk MDS, in a subject in need thereof, wherein said effective amount of cedazuridine and said effective amount of decitabine provides survival and / or leukemia-free survival in said subject of at least about 28 months, at least about 30 months, at least about 32 months, or at least about 34 months.

75. 1. Use of a composition comprising an effective amount of cedazuridine and an effective amount of decitabine in the preparation of a medicament for treating myelodysplastic syndrome (MDS), optionally lower-risk MDS, in a subject in need thereof, wherein said effective amount of cedazuridine and said effective amount of decitabine increases survival and / or leukemia-free survival of said subject by about 200% to about 400% relative to survival or leukemia-free survival, respectively, achieved by providing best supportive care alone.

76. 1. Use of a composition comprising an effective amount of cedazuridine and an effective amount of decitabine in the preparation of a medicament for increasing median overall survival and / or median leukemia-free survival in a group of subjects having myelodysplastic syndromes (MDS), wherein said effective amount of cedazuridine and said effective amount of decitabine increases the median overall survival and / or median leukemia-free survival of said group of subjects by about 130% to about 400% relative to the median survival or median leukemia-free survival, respectively, achieved by treatment with a hypomethylating agent alone.

77. 1. Use of a composition comprising an effective amount of cedazuridine and an effective amount of decitabine in the preparation of a medicament for increasing median overall survival and / or median leukemia-free survival in a group of subjects with myelodysplastic syndromes (MDS), wherein said effective amount of cedazuridine and said effective amount of decitabine provides said group of subjects with a median overall survival and / or median leukemia-free survival of at least about 28 months, at least about 30 months, at least about 32 months, or at least about 34 months.

78. 1. Use of a composition comprising an effective amount of cedazuridine and an effective amount of decitabine in the preparation of a medicament for treating chronic myelomonocytic leukemia (CMML) in a subject in need thereof, wherein said effective amount of cedazuridine and said effective amount of decitabine increases the survival and / or leukemia-free survival of said subject by about 130% to about 400% relative to the survival or leukemia-free survival, respectively, achieved by treatment with a hypomethylating agent alone.

79. Use of a composition comprising an effective amount of cedazuridine and an effective amount of decitabine in the preparation of a medicament for treating chronic myelomonocytic leukemia (CMML) in a subject in need thereof, wherein said effective amount of cedazuridine and said effective amount of decitabine for said subject provides said subject with a survival and / or leukemia-free survival of at least about 28 months, at least about 30 months, at least about 32 months, or at least about 34 months.

80. 1. Use of a composition comprising an effective amount of cedazuridine and an effective amount of decitabine in the preparation of a medicament for treating chronic myelomonocytic leukemia (CMML) in a subject in need thereof, wherein said effective amount of cedazuridine and said effective amount of decitabine increases the survival and / or leukemia-free survival of said subject by about 200% to about 375% relative to the survival or leukemia-free survival, respectively, achieved by providing best supportive care alone.

81. 1. Use of a composition comprising an effective amount of cedazuridine and an effective amount of decitabine in the preparation of a medicament for increasing median overall survival and / or median leukemia-free survival in a group of subjects having chronic myelomonocytic leukemia (CMML), wherein said effective amount of cedazuridine and said effective amount of decitabine increases median survival and / or median leukemia-free survival of said group of subjects by about 130% to about 400% relative to the median overall survival or median leukemia-free survival, respectively, achieved by treatment with a hypomethylating agent alone.

82. 1. Use of a composition comprising an effective amount of cedazuridine and an effective amount of decitabine in the preparation of a medicament for increasing median overall survival and / or median leukemia-free survival in a group of subjects with chronic myelomonocytic leukemia (CMML), wherein said effective amount of cedazuridine and said effective amount of decitabine provides said group of subjects with a median overall survival and / or median leukemia-free survival of at least about 28 months, at least about 30 months, at least about 32 months, or at least about 34 months.

83. 1. Use of a composition comprising an effective amount of cedazuridine and an effective amount of decitabine in the preparation of a medicament for treating myelodysplastic syndrome (MDS) or chronic myelomonocytic leukemia (CMML) in a subject in need of treatment and who has a TP53 mutation, wherein said effective amount of cedazuridine and said effective amount of decitabine increases the survival and / or leukemia-free survival of said subject by about 130% to about 400% relative to the survival or leukemia-free survival, respectively, achieved by treatment with a hypomethylating agent alone.

84. 1. Use of a composition comprising an effective amount of cedazuridine and an effective amount of decitabine in the preparation of a medicament for treating myelodysplastic syndrome (MDS) or chronic myelomonocytic leukemia (CMML) in a subject in need of treatment and who has a TP53 mutation, wherein the effective amount of cedazuridine and the effective amount of decitabine provide the subject with survival and / or leukemia-free survival of at least about 20 months, at least about 22 months, at least about 24 months, at least about 26 months, at least about 28 months, at least about 30 months, at least about 32 months, at least about 34 months, or at least about 36 months for a subject with a monoallelic TP53 mutation, or at least about 10 months, at least about 12 months, at least about 14 months, at least about 16 months, at least about 18 months, or at least about 20 months for a subject with a biallelic TP53 mutation.

85. 1. Use of a composition comprising an effective amount of cedazuridine and an effective amount of decitabine in the preparation of a medicament for treating myelodysplastic syndrome (MDS) or chronic myelomonocytic leukemia (CMML) in a subject in need of treatment and who has a TP53 mutation, wherein said effective amount of cedazuridine and said effective amount of decitabine increases the subject's survival and / or leukemia-free survival by about 200% to about 400% relative to the survival or leukemia-free survival, respectively, achieved by providing best supportive care alone.

86. 1. Use of a composition comprising an effective amount of cedazuridine and an effective amount of decitabine in the preparation of a medicament for increasing median overall survival and / or median leukemia-free survival in subjects with myelodysplastic syndrome (MDS) or chronic myelomonocytic leukemia (CMML) and who have a TP53 mutation, wherein said effective amount of cedazuridine and said effective amount of decitabine increases median overall survival and / or median leukemia-free survival of said group of subjects by about 130% to about 400% relative to the median survival or median leukemia-free survival, respectively, achieved by treatment with a hypomethylating agent alone.

87. 1. Use of a composition comprising an effective amount of cedazuridine and an effective amount of decitabine in the preparation of a medicament for increasing median overall survival and / or median leukemia-free survival in a group of subjects in need of treatment for myelodysplastic syndrome (MDS) or chronic myelomonocytic leukemia (CMML) and who have a TP53 mutation, wherein said effective amount of cedazuridine and said effective amount of decitabine provide said group of subjects with a median overall survival and / or median leukemia-free survival of at least about 20 months, at least about 22 months, at least about 24 months, at least about 26 months, at least about 28 months, at least about 30 months, at least about 32 months, at least about 34 months, or at least about 36 months for subjects with a monoallelic TP53 mutation, or at least about 10 months, at least about 12 months, at least about 14 months, at least about 16 months, at least about 18 months, or at least about 20 months for subjects with a biallelic TP53 mutation.

88. 73. A kit comprising one or more (e.g., 1, 2, 3, 4, or 5) doses of an effective amount of cedazuridine (e.g., 100 mg) and one or more (e.g., 1, 2, 3, 4, or 5) doses of an effective amount of decitabine (e.g., 35 mg) for use in the pharmaceutical combination of any one of claims 1 to 72.

89. 73. A combination comprising one or more (e.g., 1, 2, 3, 4, or 5) doses of an effective amount of cedazuridine (e.g., 100 mg) and one or more (e.g., 1, 2, 3, 4, or 5) doses of an effective amount of decitabine (e.g., 35 mg) for use in a pharmaceutical combination according to any one of claims 1 to 72.

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