Solid oral dosage forms of a combination of decitabine and cedazuridine

Abstract

An embodiment of the present invention is a solid oral dosage form, wherein the solid oral dosage form, upon daily administration to a subject, provides plasma levels of decitabine having a 5-day area under the curve (AUC) of decitabine, the area under the curve (AUC) being equal to or greater than 20 mg / m administered as a one-hour (1 h) infusion. 2 According to an embodiment of the present invention, a solid oral dosage form is provided, wherein the solid oral dosage form is administered daily to a subject at a dose of 20 mg / m administered as a one-hour (1 h) infusion. 2 Also provided is a solid oral dosage form as described above that provides a pharmacodynamic effect that is equivalent to the pharmacodynamic effect for a daily intravenous dose of decitabine. Methods of treatment using solid oral dosage forms according to embodiments of the present invention are also provided.

Description

[Technical Field]

[0001] Declaration of priority This patent application claims the benefit of U.S. Provisional Application No. 62 / 981,304, filed February 25, 2020, the entire contents of which are incorporated herein by reference.

[0002] The present invention relates to a solid oral dosage form comprising cedazuridine and decitabine. In particular, the present invention relates to a solid oral dosage form comprising a fixed-dose combination of cedazuridine and decitabine, which provides a pharmacokinetic, pharmacodynamic, or combination thereof equivalent to that achieved with intravenous decitabine. [Background technology]

[0003] The enzymes adenosine deaminase (ADA, EC 3.5.4.4) and cytidine deaminase (CDA, EC 3.5.4.5) function in humans and other organisms to deaminate naturally occurring aminopurine and aminopyrimidine nucleosides, respectively. They may also convert active nucleoside-based drugs into inactive metabolites. CDA is a component of the pyrimidine salvage pathway, which converts cytidine and deoxycytidine to uridine and deoxyuridine, respectively, by hydrolytic deamination (Arch. Biochem. Biophys. 1991, 290, 285-292; Methods Enzymol. 1978, 51, 401-407; Biochem. J. 1967, 104, 7P). It also deaminates many synthetic cytosine analogs, which are clinically useful drugs (Cancer Chemother. Pharmacol. 1998, 42, 373-378; Cancer Res. 1989, 49, 3015-3019; Antiviral Chem. Chemother. 1990, 1, 255-262). Conversion of cytosine compounds to uridine derivatives usually results in loss of therapeutic activity or additional side effects. It has also been shown that cancers that have acquired resistance to cytosine analog drugs often overexpress CDA (Leuk. Res. 1990, 14, 751-754). Leukemia cells expressing high levels of CDA may exhibit resistance to cytosine antimetabolites, thereby limiting the antitumor activity of such therapeutic agents (Biochem. Pharmacol. 1993, 45, 1857-1861). CDA is highly expressed in the intestine and liver and may therefore affect the bioavailability of therapeutic cytidine analogs.

[0004] The cytidine analog decitabine (5-aza-2'-deoxycytidine) is an antitumor agent and hypomethylating agent (HMA) for the treatment of myelodysplastic syndromes (MDS), and may also be potentially useful for the treatment of acute myeloid leukemia and chronic myeloid leukemia. Decitabine is not readily bioavailable when administered orally due to rapid inactivation by CDA.

[0005] [ka]

[0006] Sedazuridine ((4R)-2'-deoxy-2',2'-difluoro-3,4,5,6-tetrahydrouridine; also known as E7727), shown below, is a recently developed CDA inhibitor. Cedazuridine, and methods for making and / or using it, are further disclosed in U.S. Patent No. 8,268,800 and U.S. Patent No. 9,834,576, the contents of which are incorporated herein by reference in their entireties.

[0007] [ka] Summary of the Invention [Problem to be solved by the invention]

[0008] Because decitabine lacks oral bioavailability, current treatment regimens using decitabine require daily parenteral injections for 5 to 7 days over months or years. An orally bioavailable decitabine dosage form would alleviate the burden of monthly, multiday intravenous infusions or subcutaneous injections, which can involve long-distance travel for clinic visits. [Means for solving the problem]

[0009] The present invention is based in part on the development of a solid oral dosage form of decitabine and cedazuridine, which, upon daily administration to a subject, provides plasma levels of decitabine having a 5-day area under the curve (AUC) for decitabine, the area under the curve (AUC) being greater than that of a 20 mg / m2 dose administered as a 1-hour infusion. 2 is equivalent to the 5-day AUC for a daily intravenous (IV) dose of decitabine of 1. In some embodiments, daily administration of such solid oral dosage forms to a subject results in a ratio of the AUC of decitabine on day 2 to day 1 of about 1.5:1 to about 2:1.

[0010] Another aspect of the invention is a solid oral dosage form comprising decitabine and cedazuridine, wherein the solid oral dosage form is administered to a subject daily at a dose of 20 mg / m administered as a 1 hour infusion. 2 According to a particular embodiment, the pharmacodynamic effect is DNA demethylation.

[0011] An additional aspect of the present invention relates to a method of treating a disorder in a subject in need thereof, comprising administering to the subject a solid oral dosage form according to an embodiment of the present invention, thereby treating cancer in the subject, hi some embodiments, the disorder is cancer.

[0012] A further aspect of the present invention relates to a method of inhibiting the degradation of decitabine in a subject in need thereof, comprising administering to the subject a solid oral dosage form according to an embodiment of the present invention, thereby inhibiting the degradation of decitabine in said subject.

[0013] Another aspect of the present invention relates to a method of reducing DNA methylation (e.g., LINE-1 methylation) in a subject in need thereof, comprising administering to the subject a solid oral dosage form according to an embodiment of the present invention, thereby reducing DNA methylation in the subject.

[0014] Additional aspects of the invention relate to methods of using solid oral dosage forms according to embodiments of the invention in methods of treating disorders, inhibiting the degradation of decitabine, and reducing DNA methylation (e.g., LINE-1 methylation).

[0015] These and other aspects of the present invention are described in more detail in the detailed description of the invention below. [Brief explanation of the drawings]

[0016] [Figure 1] FIG. 1 is a diagram illustrating a Phase 1 dose escalation study designed to establish recommended doses of cedazuridine and decitabine. [Figure 2] FIG. 2 is a graph of the mean decitabine concentration (ng / mL) over time (hours) for several dosing regimens in the Phase 1 study described in FIG. [Figure 3] FIG. 3 is a graph illustrating a Phase 2 randomized crossover study designed to confirm the doses of cedazuridine and decitabine identified in the Phase 1 study of FIG. [Figure 4] Figure 4 shows the mean decitabine AUC (hours·ng / mL) on days 1, 2, and 5 for oral decitabine / cedazuridine and for IV decitabine in the phase 2 study described in Figure 3. [Figure 5A] Figure 5A shows the relative LINE-1 demethylation (%) for sequences of ASTX727 (1 cycle) versus IV decitabine (2 cycles) in the Phase 2 trial described in Figure 3. Figure 5A provides the relative LINE-1 progression over the course of ASTX727. [Figure 5B] Figure 5B shows the relative LINE-1 demethylation (%) for sequences of ASTX727 (1 cycle) versus IV decitabine (2 cycles) in the phase 2 trial described in Figure 3. Figure 5B provides the relative LINE-1 progression over the IV decitabine course. [Figure 6A] Figure 6A shows the relative LINE-1 demethylation (%) for sequences from IV decitabine (1 cycle) to ASTX727 (2 cycles) in the phase 2 trial described in Figure 3. Figure 6A provides the relative LINE-1 progression over the IV decitabine course. [Figure 6B] Figure 6B shows the relative LINE-1 demethylation (%) for sequences from IV decitabine (1 cycle) to ASTX727 (2 cycles) in the phase 2 trial described in Figure 3. Figure 6B provides the relative LINE-1 progression over the ASTX727 course. [Figure 7] FIG. 7 is a graph illustrating a Phase 3 randomized crossover study designed to establish the efficacy, safety, and maximal LINE-1 demethylation for an oral dosage form of ASTX727, comparable to IV decitabine. [Figure 8] Figure 8 shows PK analyses for oral ASTX727 and IV decitabine in the Phase 3 study described in Figure 7. Figure 8 shows plasma decitabine AUC (hours·ng / mL) for oral ASTX727 on Days 1, 2, and 5, and AUC (hours·ng / mL) for IV decitabine on Days 1 and 5. [Figure 9] FIG. 9 provides the maximum LINE-1 demethylation LSM (95% CI) for both oral ASTX727 and IV decitabine between cycles 1 and 2, as described in FIG. DETAILED DESCRIPTION OF THE INVENTION

[0017] The present invention is described in more detail below. This description is not intended to be a detailed catalog of all the different ways in which the invention may be implemented, or a detailed catalog of all the features that may be added to the 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 invention. Thus, the following specification is intended to describe some particular embodiments of the invention, but is not intended to exhaustively specify all permutations, combinations, and variations thereof.

[0018] 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 present 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 present specification describes a composite as comprising components A, B, and C, it is specifically contemplated that any of A, B, or C, or combinations thereof, alone or in any combination, can be omitted or waived.

[0019] 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 for the purpose of describing particular embodiments only and are not intended to be limiting of the present invention.

[0020] All publications, patent applications, patents, nucleotide sequences, amino acid sequences, and other references mentioned herein are incorporated by reference in their entirety.

[0021] definition

[0022] As used in this detailed description 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.

[0023] 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 a combination when interpreted as the alternative ("or").

[0024] Moreover, the present invention also contemplates that in some embodiments of the invention, any feature or combination of features described herein can be excluded or omitted.

[0025] Moreover, as used herein, the term "about," when referring to a measurable value, such as an amount, dose, 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.

[0026] 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 "comprise."

[0027] An "effective amount" refers to the amount necessary to produce a desired effect (e.g., increasing the half-life, bioavailability, or efficacy of a CDA-based drug, treating cancer in a subject, reducing DNA methylation in a subject, inhibiting cytidine deaminase in a subject, or inhibiting degradation of a CDA-based drug by cytidine deaminase).

[0028] "AUC" refers to the area under the concentration time curve of an active agent, e.g., decitabine.

[0029] "Half-life" refers to the period of time required for the concentration or amount of a compound in a subject to decrease to exactly half of a given concentration or amount.

[0030] "Pharmaceutically acceptable" refers to properties and / or substances that are acceptable to a patient from a pharmacological and / or toxicological standpoint, and / or to a pharmaceutical chemist from a physical and / or chemical standpoint with respect to composition, formulation, stability, patient acceptance, bioavailability, and compatibility with other ingredients.

[0031] "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. Such salts may be formed with acids, including, but not limited to, acetate, adipate, alginate, aspartate, benzoate, benzenesulfonate, bisulfate butyrate, butyrate, citrate, camphorate, camphorsulfonate, cyclopentanepropionate, digluconate, dodecyl sulfate, ethanesulfonate, fumarate, glucoheptanoate, glycerophosphate, hemisulfate, heptanoate, hexanoate, hydrochloride, hydrobromide, hydroiodide, 2-hydroxyethanesulfonate, 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, and diamyl sulfate; long-chain halides, such as decyl, lauryl, myristyl, and stearyl chlorides, bromides, and iodides; and aralkyl halides, such as phenethyl bromide.

[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 material (e.g., a compound or composition of the invention, a CDA-based drug, and / or other therapeutic agent) 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 encompasses 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, 1.5-fold, 2-fold, 3-fold, 4-fold, 5-fold, 6-fold, 8-fold, 10-fold, 12-fold, 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, inhibition or reduction results in little or essentially no detectable activity (at most, by an insignificant amount, e.g., less than about 10% or even less than 5%).

[0036] A "subject" refers to a cell or tissue in vitro or in vivo, or to an animal or human. An animal or human subject may also be referred to as a "patient."

[0037] "Animal" means a living organism having sensations and the power of voluntary movement and requiring oxygen and organic food for its existence.

[0038] "Mammal" refers to a warm-blooded vertebrate animal having hair or fur. Examples include, but are not limited to, members of the human, equine, porcine, bovine, murine, canine, or feline species.

[0039] 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, mitigation, or reduction of at least one clinical symptom is achieved. "Treatment" with respect to a disease, disorder, or condition may refer to: (i) inhibiting the disease, disorder, or condition, e.g., arresting its onset; and / or (ii) alleviating the disease, disorder, or condition, e.g., causing regression of clinical symptoms.

[0040] "Preventing," with respect to a disease, disorder, or condition, refers to preventing the disease, disorder, or condition, e.g., not developing clinical symptoms of the disease, disorder, or condition. As used herein, the terms "prevent," "prevents," or "prevention" (and their grammatical equivalents) can also refer to delaying the onset of a disease or disorder, or alleviating symptoms of a disease or disorder once it has occurred. These terms do not imply the complete abolition of the disease, but encompass any type of prophylactic treatment that reduces the incidence of the condition or slows the onset and / or progression of the condition.

[0041] The terms "administering" or "administration" of the compounds and / or compositions of the invention to a subject include routes of introducing or delivering the compound to a subject to perform its intended function. For the solid oral dosage forms of the invention, the method of administration is intended to be oral. The pharmacokinetics and pharmacodynamics of the solid oral dosage forms are comparable to those achieved by intravenous administration of decitabine, which is typically provided by infusion. When the infusion is said to be administered over a period of one hour, it is intended to mean that a solution containing a specified concentration of decitabine is administered over that period. Administration encompasses self-administration and administration by another.

[0042] "Cancer" refers to an abnormal growth of cells that tends to grow in an uncontrolled manner and in some cases metastasize (spread). Specific cancers include, but are not limited to, those identified in U.S. Patent Application Publication No. 2006 / 0014949 and the following: cardiac: sarcoma (e.g., angiosarcoma, fibrosarcoma, rhabdomyosarcoma, liposarcoma, etc.), myxoma, rhabdomyoma, fibroma, lipoma, and teratoma; lung: bronchogenic carcinoma (e.g., squamous cell carcinoma, undifferentiated small cell carcinoma, undifferentiated large cell carcinoma, adenocarcinoma, etc.), alveolar carcinoma (e.g., bronchiolar carcinoma, etc.), bronchial adenoma, sarcoma, lymphoma, chondromatous hamartoma, mesothelioma; gastrointestinal: esophageal (e.g., squamous cell carcinoma, adenocarcinoma, leiomyosarcoma, lymphoma, etc.), stomach (e.g., carcinoma, lymphoma, leiomyosarcoma, etc.), pancreas (e.g., ductal adenocarcinoma, insulinoma, glucagonoma, gastrinoma, carcinoid tumor, vipoma, etc.), small intestine (e.g., adenocarcinoma, lymphoma, carcinoid tumor, Kaposi's sarcoma, leiomyoma, hemangioma, lipoma, neurofibroma, fibroma, etc.), large intestine (e.g., adenocarcinoma, tubular adenoma, villous adenoma, hamartoma, leiomyoma, etc.); urogenital tract: kidney (e.g., adenocarcinoma, Wilms' tumor, nephroblastoma, lymphoma, leukemia, etc.), bladder and and urethra (e.g., squamous cell carcinoma, transitional cell carcinoma, adenocarcinoma, etc.), prostate (e.g., adenocarcinoma, sarcoma, etc.), testis (e.g., seminoma, teratoma, embryonal carcinoma, teratocarcinoma, choriocarcinoma, sarcoma, stromal cell carcinoma, fibroma, fibroadenoma, adenomatous tumor, lipoma, etc.); liver: liver cancer (e.g., hepatocellular carcinoma, etc.), bile duct carcinoma, hepatoblastoma, angiosarcoma, hepatocellular adenoma, hemangioma; bone: osteogenic sarcoma (e.g., osteosarcoma, etc.), fibrosarcoma, malignant fibrous histiocytoma, chondrosarcoma, Ewing's sarcoma, malignant lymphoma (e.g., reticulum cell sarcoma, etc.), multiple myeloma, malignant Giant cell tumors, chordomas, osteochondromas (e.g., osteochondral exostoses, etc.), benign chondroma, chondroblastoma, chondromyxoid fibroma, osteoid osteoma, and giant cell tumor; nervous system: skull (e.g., osteoma, hemangioma, granuloma, xanthomas, osteitis deformans, etc.), meninges (e.g., meningioma, meningeal sarcoma, glioma, etc.), brain (e.g., astrocytoma, medulloblastoma, etc.), glioma, ependymoma, germ cell tumor [pinealoma], glioblastoma multiforme, oligodendroglioma, schwannoma, retinoblastoma, congenital tumors, etc.), spinal cord (e.g., neurofibroma, meningioma, glioma, sarcoma, etc.);Gynecology: uterus (e.g., endometrial cancer, etc.), cervix (e.g., cervical cancer, preneoplastic cervical dysplasia, etc.), ovary (e.g., ovarian cancer [serous cystadenocarcinoma, mucinous cystadenocarcinoma, unclassified carcinoma], granulosa-meningothecal cell tumor, Sertoli-Leydig cell tumor, dysgerminoma, malignant teratoma, etc.), vulva (e.g., squamous cell carcinoma, carcinoma in situ, adenocarcinoma, fibrosarcoma, melanoma, etc.), vagina (e.g., clear cell carcinoma, squamous cell carcinoma, Botryoid sarcoma (embryonal rhabdomyosarcoma), fallopian tube (carcinoma), etc.); hematology: blood (e.g., myeloid leukemia [acute and chronic], acute lymphoblastic leukemia, chronic lymphocytic leukemia, myeloproliferative disorders, multiple myeloma, myelodysplastic syndrome, etc.), Hodgkin's disease, non-Hodgkin's lymphoma; skin: malignant melanoma, basal cell carcinoma, squamous cell carcinoma, Kaposi's sarcoma, dysplastic nevi, lipoma, hemangioma, dermatofibroma, keloid, psoriasis, etc.; and adrenal gland: neuroblastoma.

[0043] Solid Oral Dosage Formulations

[0044] The present invention provides a solid oral dosage form comprising decitabine and cedazuridine, referred to as ASTX727 and marketed as INQOVI for the treatment of myelodysplastic syndromes. (登録商標) It has been marketed as cedazuridine. Previously, it has been shown that administering an oral dose of cedazuridine before administering an oral dose of decitabine increases the exposure of decitabine. However, given the low bioavailability of decitabine and the reduced bioavailability of oral administration compared to intravenous administration, a solid oral dosage form comprising decitabine and cedazuridine was expected to have a significantly lower bioavailability than intravenous decitabine. Surprisingly, the inventors of the present invention have demonstrated that daily administration to a subject (e.g., a human) provides plasma levels of decitabine with a 5-day area under the curve (AUC) for decitabine, which is greater than the area under the curve (AUC) for a 20 mg / m2 dose administered as a 1-hour infusion. 2

[0003] Additionally, the present inventors have discovered a solid oral dosage form of a combination of decitabine and cedazuridine that has equivalent or improved epigenetic effects (e.g., LINE-1 demethylation, e.g., %F cell proliferation) and / or reduced myelosuppressive effects (e.g., neutropenia) compared to those obtained with IV decitabine in IPSS-low and / or IPSS-intermediate-1 myelodysplastic syndrome (MDS) cancer patients. As used herein, the term "equivalent" refers to a value that is less than 10% from the reference value, e.g., less than 10%, less than 9%, less than 8%, less than 7%, less than 6%, less than 5%, less than 4%, less than 5%, less than 4%, less than 3%, less than 2%, or less than 1%.

[0045] Thus, according to embodiments of the present invention, a solid oral dosage form is provided that contains both decitabine and cedazuridine. As used herein, the terms "decitabine" and "cedazuridine" include the compound itself and pharmaceutically acceptable salts thereof. In some embodiments of the present invention, a solid oral dosage form is provided that contains decitabine and cedazuridine, wherein the solid oral dosage form, upon daily administration to a subject, provides a plasma level of decitabine having a 5-day area under the curve (AUC) for decitabine, the area under the curve (AUC) being 20 mg / m administered as a 1-hour infusion. 2 In some embodiments of the invention, the AUC of decitabine on Day 2 versus Day 1 (AUC 0~24 ) is about 1.5:about 1 to about 2:about 1, for example, about 1.5:about 1 to about 1.8:about 1, for example, about 1.7:about 1 to about 2:about 1, for example, about 1.5:about 1, about 1.6:about 1, about 1.7:about 1, about 1.8:about 1, about 1.9:about 1 or about 2:about 1.

[0046] The Primary Endpoint PK Analysis Set was the 5-day cumulative AUC of decitabine after administration of the solid dosage form. 0~t Used to calculate exposure. The following assumptions are used: 1) A steady state is reached on the second day of administration of the solid dosage form; 2) Decitabine AUC on Days 2 and 5 based on achievement of steady state on Day 2 0~t is the daily AUC from days 2 to 5 in an estimated 5-day administration of solid dosage form 0~t Represents.

[0047] Therefore, PK data from 3 days of continuous PK sampling were used to estimate the 5-day oral decitabine AUC 0~t To calculate total exposure, AUC on day 1 0~t (First solid dosage form dose) (AUC on day 2 0~t AUC on day +5 0~t ) × 2 is added. AUC on day 2 0~t If unavailable, AUC on day 5 0~t is replaced by; the converse is also true.

[0048] 5-day AUC after IV decitabine 0~t To calculate exposure, DACOGEN showed no accumulation on day 5 compared to day 1 during a 5-day infusion. (登録商標) Based on the prescribing information, (AUC 0~t AUC on day +5 0~t ) / 2 multiplied by 5. AUC on Day 1 0~t If not available, AUC on day 5 0~t The reverse is also true. Since t=24 hours, AUC 0~t is AUC 0~24 Please note that

[0049] In some embodiments of the present invention, the solid oral dosage form, when administered daily to a subject, has a pharmacodynamic effect equivalent to that of a daily intravenous dose of 20 mg / m2 of decitabine administered as a 1-hour infusion. The type of pharmacodynamic effect includes any effect now known or later discovered. According to certain embodiments, the pharmacodynamic effect is DNA demethylation.

[0050] Pharmaceutical compositions (e.g., compounds, compositions, drugs, and / or therapeutic agents) comprising decitabine and cedazuridine are provided as solid oral dosage forms, meaning that the pharmaceutical compositions are in solid form and are 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., those intended for buccal, sublingual, and systemic absorption), caplets, boluses, powders, granules, pastes for application to the tongue, capsules, including hard gelatin capsules and soft gelatin capsules, mouth sprays, troches, lozenges, and pellets. Pharmaceutical compositions may be formulated for immediate release, sustained release, or controlled release.

[0051] 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 pharmaceutically acceptable excipients.

[0052] In some embodiments of the invention, the solid oral dosage form comprises decitabine and cedazuridine in a weight ratio ranging from about 30:about 100 to about 40:about 100, such as about 35:about 100.

[0053] In some embodiments of the present invention, the solid oral dosage form is a unit dosage form containing about 35 mg of decitabine. In some embodiments of the present invention, the solid oral dosage form is a unit dosage form containing about 100 mg of cedazuridine. Moreover, in some embodiments, the solid oral dosage form is a unit dosage form containing about 35 mg of decitabine and about 100 mg of cedazuridine. In some embodiments of the present invention, the unit dosage form contains about 35 mg of decitabine and about 100 mg of cedazuridine, and at least one pharmaceutically acceptable excipient.

[0054] "Pharmaceutically acceptable excipient" can mean any substance, not itself a therapeutic agent, added to a pharmaceutical composition to serve as a carrier, diluent, adjuvant, binder, and / or vehicle for delivery of a therapeutic agent to a subject, or to improve its handling or storage characteristics, or to improve the ability or facilitation of forming the compound or composition into a unit dosage form for administration. Pharmaceutically acceptable excipients are well known in the pharmaceutical arts and are described, for example, in Remington's Pharmaceutical Sciences, Mack Publishing Co., Easton, Pa. (e.g., 2nd ed., 2000), and Handbook of Pharmaceutical Excipients, American Pharmaceutical Association, Washington, D.C. (e.g., 1 st ,2 ndand 3rd Eds., 1986, 1994, and 2000, respectively). As will be known to those skilled in the art, excipients may serve a variety of functions and may be described, for example, as wetting agents, buffering agents, suspending agents, lubricants, emulsifying agents, disintegrating agents, absorbents, preservatives, surfactants, colorants, flavoring agents, and sweetening agents. Examples of pharmaceutically acceptable excipients include, but are not limited to: (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) excipients, such as cocoa butter and suppository wax; (9) oils, such as peanut oil, cottonseed oil, safflower oil, sesame oil, olive oil, corn oil, etc. coconut oil and soybean oil; (10) glycols, such as propylene glycol; (11) polyols, such as glycerin, sorbitol, mannitol, and polyethylene glycol; (12) esters, such as ethyl oleate and ethyl laurate; (13) agar; (14) buffers, such as magnesium hydroxide, 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 materials used in pharmaceutical formulations.

[0055] Examples of diluents include lactose, lactose monohydrate, cellulose, microcrystalline cellulose, sorbitol, calcium hydrogen 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 flow agents include colloidal silicon dioxide, corn starch, and talc. Examples of lubricants include stearic acid, magnesium stearate, calcium stearate, talc, paraffin, sodium lauryl sulfate, sodium benzoate, and polyethylene glycol.

[0056] In some embodiments, the solid oral dosage form comprises one or more of a diluent, a binder, a disintegrant, a flow agent, and a lubricant. In some embodiments, the solid oral dosage form comprises a diluent, a binder, a disintegrant, a flow agent, and a lubricant. According to certain embodiments of the present invention, the solid oral dosage form comprises the following additives: lactose monohydrate as a diluent; hydroxypropyl methylcellulose as a binder; croscarmellose sodium as a disintegrant; colloidal silicon dioxide as a flow agent; 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, according to certain embodiments, the tablet is coated with a film, which may be colored. While any pharmaceutically acceptable coating may be used, in some embodiments, the tablet is coated with OPADRY. (登録商標) Coated with a coating.

[0057] In some embodiments, cedazuridine is present in the solid oral dosage form in an amount of about 17 to about 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 w / w%, or any value therebetween, e.g., about 19.4 w / w%.

[0058] In some embodiments, decitabine is present in the solid oral dosage form in an amount of about 4 to about 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 7.88, or about 8.0 w / w%, or any value therebetween, e.g., about 6.8 w / w%.

[0059] 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%, e.g., 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 value therebetween, e.g., about 62.62 w / w%.

[0060] In some embodiments, the binder (e.g., hypromellose) is present in the solid oral dosage form in an amount of about 1 to about 3 w / w%, e.g., 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 value therebetween, e.g., about 1.94 w / w%.

[0061] In some embodiments, the disintegrant (e.g., croscarmellose sodium) is present in the solid oral dosage form in an amount of about 3 to about 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 value therebetween, e.g., about 4.85 w / w%.

[0062] In some embodiments, the fluidizing agent (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 value therebetween, e.g., about 0.97 w / w%.

[0063] 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%, e.g., 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, 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 w / w%, or any value therebetween, e.g., about 0.49 w / w%.

[0064] In some embodiments, the solid oral dosage form comprises the ingredients listed in Table 2.

[0065] [Table 1]

[0066] In some embodiments, the solid oral dosage form comprises the ingredients listed in Table 2.

[0067] [Table 2]

[0068] Other aspects of the invention relate to unit dosage forms and kits comprising at least one unit dosage form, wherein the unit dosage form comprises decitabine and cedazuridine. In some embodiments, the kits provide unit dosage forms that, upon daily administration to a subject (e.g., a human), provide plasma levels of decitabine having a 5-day area under the curve (AUC) for decitabine, the area under the curve (AUC) being 20 mg / m administered as a 1-hour infusion. 2 Alternatively or additionally, in some embodiments, a kit is provided that includes unit dosage forms comprising decitabine and cedazuridine, and is administered daily to a subject (e.g., a human) at a dose of 20 mg / m administered as a 1-hour infusion. 2 The kit provides a pharmacodynamic effect equivalent to that of a daily intravenous dose of decitabine. Thus, the kit may comprise one, two, three, four, five, or more solid oral dosage forms according to an embodiment of the invention. In some embodiments, the kit comprises 5, 6, or 7 unit dose tablets comprising about 35 mg of decitabine and about 100 mg of cedazuridine, and at least one pharmaceutically acceptable excipient.

[0069] The kit may further comprise a container and / or packaging suitable for commercial sale. The container may be any conventional shape or form known in the art, made of a pharmaceutically acceptable material, such as a paper or cardboard box, a glass or plastic bottle or jar, or a resealable pack with individual doses to be extruded from the pack according to a treatment schedule. Multiple containers may be used together in one package. For example, tablets may be placed in a blister pack, and the blister pack may be placed in a box. Two or more containers may be used together in one package. In some embodiments, the container is a bottle, such as a 30 cc white high-density polyethylene bottle containing unit dosage forms (e.g., about 5 unit dosage forms). The bottle may further contain a desiccant, such as a silica desiccant canister. In some embodiments, the container is a blister pack, such as a blister pack formed by aluminum foil on a foil lid, containing one tablet per hole. The blister pack may be present in a single carton.

[0070] 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, as described herein. These instructions may be provided in a variety of ways.

[0071] The information may be associated with the container, for example: written on a label affixed to the container (e.g., a prescription label or another label); contained within 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 by tying or taping, such as an instruction card attached to the neck of the bottle via a string, cord or other line, lanyard or tether-type device.

[0072] Methods of Using the Solid Oral Dosage Forms of the Invention

[0073] According to embodiments of the present invention, provided are methods of administering to a subject a solid oral dosage form comprising cedazuridine and decitabine. According to certain embodiments, methods are provided for administering to a subject a solid oral dosage form comprising cedazuridine and decitabine, wherein the solid oral dosage form, upon daily administration to a subject (e.g., a human), provides a plasma level of decitabine having a 5-day area under the curve (AUC) for decitabine, the area under the curve (AUC) being equal to 20 mg / m administered as a 1-hour infusion. 2 The area under the curve for a 5-day period is equivalent to a daily intravenous (IV) dose of decitabine of 20 mg / m 2 administered as a 1-hour infusion. In some embodiments, daily administration to a subject results in a ratio of AUC for decitabine on day 2 to day 1 of about 1.5:1 to about 2:1. In some embodiments of the invention, the method includes administering to a subject a solid oral dosage form comprising decitabine and cedazuridine, wherein the solid oral dosage form is a 20 mg / m 2 dose administered as a 1-hour infusion. 2 The solid oral dosage form used may be any of the solid oral dosage forms described herein.

[0074] Furthermore, there is provided a method of treating a decitabine-treatable disorder in a subject in need thereof, comprising administering to the subject a solid oral dosage form according to an embodiment of the present invention, thereby treating the disorder. In some embodiments, the decitabine-treatable disorder is a hyperproliferative disease, such as cancer. The method can be used to treat any cancer that is known or later discovered to be effective in treating with decitabine. According to certain embodiments, the disorder is a cancer selected from hematological cancers and solid cancers. Examples of hematological cancers include myelodysplastic syndromes (MDS), leukemia (e.g., acute lymphocytic leukemia (ALL), acute myelogenous leukemia (AML), chronic myelogenous leukemia (CML), myeloproliferative neoplasms (MPN), or chronic myelomonocytic leukemia (CMML)), and lymphoma (e.g., Hodgkin's lymphoma, non-Hodgkin's lymphoma, or T-cell lymphoma). In some embodiments, the solid cancer is selected from pancreatic cancer, ovarian cancer, peritoneal cancer, non-small cell lung cancer, breast cancer, neuroectodermal tumor, and / or sarcoma.

[0075] In some embodiments, a method for treating a hyperproliferative disease, such as cancer, is provided, wherein the cancer is MDS. MDS is a group of cancer diseases that share the inappropriate maturation of bone marrow-derived blood cells, and symptoms can vary. The International Prognostic Scoring System (IPSS) scores the severity of MDS into several risk groups based on the patient's hemoglobin level, absolute neutrophil count (ANC), platelet count, and bone marrow blast percentage. Risk groups include "low," "intermediate-1," "intermediate-2," and "high." Other risk group scoring methods exist, such as the revised IPSS (IPSS-R) and the WHO classification-based prognostic scoring system (WPSS), as described in the NCCN Guidelines for Patients, Myelodysplastic Syndromes, 2018. The methods of the invention can be used to treat hyperproliferative diseases, such as cancer, in subjects (e.g., human patients) diagnosed with any risk group for MDS based on any scoring method. In some embodiments, subjects in need of the invention can include subjects diagnosed with low-risk MDS (defined as IPSS low and / or intermediate-1).

[0076] In some embodiments of the invention, a method is provided for inhibiting the degradation of decitabine in a subject in need thereof, the method comprising administering to the subject a solid oral dosage amount according to an embodiment of the invention, thereby inhibiting the degradation of decitabine in the subject.

[0077] In some embodiments, the present invention provides a method for reducing DNA methylation in a subject in need thereof, comprising administering to the subject a solid oral dosage according to one embodiment of the present invention, thereby reducing DNA methylation in the subject (e.g., thereby enabling a reduction in DNA methylation by a CDA substrate agent). The DNA methylation can be reduced compared to the subject's methylation level before treatment. In some embodiments, DNA methylation of LINE-1 is reduced. LINE-1 is a long, interspersed nuclear element found in human DNA (e.g., the subject), as known in the art, and its methylation level can be measured using standard techniques in the art to determine the genetic effect of a hypomethylating agent, such as a CDA substrate agent (e.g., decitabine).

[0078] The present inventors have shown that administering a solid oral dosage form according to embodiments of the present invention to a subject in need thereof provides 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, 6, 7, 8, 9, 10, 11, 12, 13, 14, or 15%, or more, or any value or range therein), compared to a control measurement before administration, e.g., compared to DNA methylation in the control (e.g., subject "baseline" DNA methylation). DNA methylation in the subject can be assessed quantitatively and / or qualitatively by any standard technique in the art, e.g., as measured by a marker 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, the administration reduces LINE-1 methylation in the subject by at least 5% (e.g., at least 5%, 6%, 7%, 8%, 9%, 10%, 11%, 12%, 13%, 14%, or 15% or more) compared to a control measurement, e.g., compared to LINE-1 methylation in the subject before administration (e.g., subject baseline LINE-1 methylation). For example, in some embodiments, the 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, the 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%.

[0079] In some embodiments, the administration continues until the absolute neutrophil count (ANC) in the subject reaches or exceeds 0.5x10 per L of blood within two weeks (e.g., not more than 14, 13, 12, 11, 10, 9, 8, 7, 6, 5, 4, 3, or 2 consecutive days, or any value or range therein), followed by a 28-day cycle. 9In some embodiments, the administration may reduce the absolute neutrophil count (ANC) in the subject to less than 0.5 x 10 cells / L of blood for up to 2 weeks (e.g., 2 weeks or more, 3 weeks or more, 4 weeks or more, 5 weeks or more, 6 weeks or more, etc.) during treatment. 9 Reduce to less than cells / L (e.g., over multiple repeated 28-day cycles).

[0080] In some embodiments, the administration increases hemoglobin F-expressing cells (i.e., F cells) by at least 5% (e.g., at least 5% or more, 6% or more, 7% or more, 8% or more, 9% or more, 10% or more, 15% or more) 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 received treatment), optionally as measured by F cells / red blood cells per sample (e.g., in a patient blood sample). , 20% or more, 25% or more, or 30% or more). For example, in some embodiments, the administration may 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, compared to a baseline control. In some embodiments, the administration may expand the % 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.

[0081] In some embodiments, the administration expands F cells to a total amount of at least 10% to at least 30% or more of the total red blood cells per sample (e.g., in a patient's blood sample) (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, or any value or range of F cells / red blood cells therein). For example, in some embodiments, the administration may expand F cells to a total amount of at least 20%, at least 23%, at least 35%, or more of the total red blood cells in the sample. In some embodiments, the administration expands F cells to a total amount of about 15% to about 30%, about 18% to about 25%, or about 15% to about 35% of the total red blood cells in the sample.

[0082] In some embodiments of the methods of the present invention, the subject can be a mammal. In some embodiments of the methods of the present invention, the subject can be a human.

[0083] Any dosage regimen known to those skilled in the art for adjusting the timing and sequence of drug delivery can be used, and treatment can be repeated as needed in the method of the present invention. For example, the solid oral dosage form of the present invention can be administered once, twice, three or four times a day, as a single dose, multiple individual doses, or by continuous infusion. According to a specific embodiment, the solid oral dosage form is administered once a day.

[0084] In some embodiments of the present invention, administration of a solid oral dosage form according to an embodiment of the present invention may occur from about 1 day to about 28 days per 28-day cycle (e.g., about 1 day, about 2 days, about 3 days, about 4 days, about 5 days, about 6 days, about 7 days, about 8 days, about 9 days, about 10 days, about 11 days, about 12 days, about 13 days, about 14 days, about 15 days, about 16 days, about 17 days, about 18 days, about 19 days, about 20 days, about 21 days, about 22 days, about 23 days, about 24 days, about 25 days, about 26 days, about 27 days, or about 28 days per 28-day cycle). According to certain embodiments, administration of a solid oral dosage form may occur once daily for 5 days (e.g., 5 consecutive days) per 28-day cycle. In some embodiments, administration of a solid oral dosage form according to an embodiment of the present invention may occur on consecutive days in a 28-day cycle. For example, solid oral dosage forms according to embodiments of the invention can be administered for five consecutive days. In some embodiments, solid oral dosage forms according to embodiments of the invention can be administered for any three consecutive days (e.g., on Monday, Tuesday, and Wednesday, i.e., "MTW"; on Tuesday, Wednesday, and Thursday, i.e., "TWTh"; on Wednesday, Thursday, and Friday, i.e., "WThF"; on Thursday, Friday, and Saturday, i.e., "ThFS"; on Friday, Saturday, and Sunday, i.e., "FSS"; on Saturday, Sunday, and Monday, i.e., "SSM"; and / or on Sunday, Monday, and Tuesday, i.e., "SMT"). In some embodiments, administration of solid oral dosage forms according to embodiments of the present invention may be carried out for 5 consecutive days (e.g., 5 consecutive days of MTWThF or any other combination), 7 consecutive days (7 consecutive days of MTWThFSS or any other combination), 14 consecutive days (e.g., 2 consecutive weeks); 21 consecutive days (e.g., 3 consecutive weeks), and / or 28 consecutive days (e.g., 4 consecutive weeks) per 28-day cycle.Daily treatment may be repeated, for example, one or more times per 28 day cycle, for example weekly or biweekly.

[0085] In some embodiments, administration of solid oral dosage forms according to embodiments of the present invention can be carried out on non-consecutive days in a 28-day cycle, for example, 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, or 27 or more non-consecutive days. The non-consecutive days can comprise a schedule of every other day (e.g., Monday-Friday), every second day, every third day, every fourth day, every fifth day, every sixth day, every seventh day, etc., within the 28-day cycle. The non-consecutive days can be repeated by administering for several consecutive days (e.g., "on"), followed by not administering for several days (e.g., "off"), followed by administering for several consecutive days, and so on, within the 28-day cycle. For example, in some embodiments, the administration can be carried out on two non-consecutive days (e.g., every Monday and Friday, or any combination of two non-consecutive days). In some embodiments, the administration can be performed on three non-consecutive days (e.g., three non-consecutive days of MWF or any other combination). The non-consecutive treatment can be repeated one or more times per 28-day cycle, e.g., weekly, biweekly.

[0086] In some embodiments, a period of 0 to 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) can pass between multiple 28-day treatment cycles of the invention. Treatment-free periods may be desirable to allow a subject (e.g., a human patient) of the invention to remain healthy enough to continue treatment. The duration of a treatment cycle can be determined by a physician using standard techniques in the art, and can be determined, for example, based on adequate blood counts, e.g., a reasonable lack of neutropenia (e.g., an absolute neutrophil count (ANC) in the subject of at least 0.5x10). 9 cells / L or 0.5x10 9The dose is typically 100 mg / mL or more (cells / L or more) and may be adjusted over the course of treatment based on the administering physician's judgment. In some embodiments, the time period between treatment cycles may be minimal, e.g., no time period, e.g., starting immediately after the next 28-day period. In some embodiments, the time period between treatment cycles may be 1 week, 2 weeks, 3 weeks, 4 weeks, 5 weeks, 6 weeks, or more.

[0087] In some embodiments, the administration can be performed for a total of 10 days per 28-day cycle, for example, where the 10 days of administration include 5 consecutive days of administration (e.g., 5 days "on"), followed by 2 consecutive days without administration (e.g., 2 days "off"), followed by 5 consecutive days of administration (e.g., 5 days "on") per 28-day cycle. In some embodiments, the administration can be performed for a total of 14 days, for example, where the 14 days of administration include 7 days "on", followed by 7 days "off", followed by 7 days "on" per 28-day cycle. In some embodiments, the administration can be performed for a total of 9 days, for example, where the 9 days of administration include 3 consecutive days "on", followed by 4 consecutive days "off", followed by 3 consecutive days "on", followed by 4 consecutive days "off", followed by 3 consecutive days "on" per 28-day cycle. In some embodiments, the administration can be carried out, for example, for a total of 9 days, where the 9 days of administration include 3 non-consecutive days "on" (e.g., MWF), followed by 1 day "off," followed by 3 non-consecutive days "on" (e.g., MWF), followed by 1 day "off," followed by 3 non-consecutive days "on" per 28-day cycle.

[0088] In some embodiments, administering a solid oral dosage form according to embodiments of the present invention can be carried out for one or more weeks per 28 day cycle, for example, one, two, three, or four weeks per 28 day cycle, which weeks can be consecutive and / or non-consecutive.

[0089] The dosing regimen may include pretreatment and / or co-administration with at least one additional therapeutic agent. In such cases, the solid oral dosage form containing 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 within the solid oral dosage form.

[0090] Examples of chemotherapeutic agents include alkylating agents (e.g., the alkylating agents can include doxorubicin, cyclophosphamide, estramustine, carmustine, mitomycin, bleomycin, etc.); antimetabolites (e.g., the antimetabolites can include 5-fluoro-uracil, capecitabine, gemcitabine, nelarabine, fludarabine, methotrexate, etc.); platinizing agents (e.g., the platinizing agents can include cisplatin, oxaliplatin, carboplatin, etc.); topoisomerase inhibitors (e.g., the topoisomerase inhibitors can include topotassium iodide, thiazolinone ... These agents may include, but are not limited to, tubulin agents (e.g., the tubulin agents may include paclitaxel, docetaxel, vinorelbine, vinblastine, vincristine, other taxanes, epothilones, etc.); signaling inhibitors (e.g., which may include kinase inhibitors, antibodies, farnesyltransferase inhibitors, etc.); and other chemotherapeutic agents (e.g., tamoxifen; antimitotic agents, e.g., polo-like kinase inhibitors or aurora kinase inhibitors, etc.).

[0091] In some embodiments, the present invention contemplates a daily dose of about 35 mg of decitabine, thus, for example, a cumulative dose of about 175 mg per 28-day cycle of decitabine treatment for a 5-day dosing schedule. Dose levels, modes of administration, and dosing regimens can be varied by those skilled in the art using known techniques as determined necessary for a subject (e.g., patient).

[0092] In some embodiments, the present invention contemplates a daily dose of about 100 mg of cedazuridine, with a cumulative dose of about 500 mg per 28-day period for a 5-day dosing schedule. Dose levels, modes of administration, and dosing regimens can be varied by those skilled in the art using known techniques as determined necessary for a subject (e.g., patient).

[0093] In some embodiments, the methods of the invention can be carried out by administering cedazuridine and decitabine separately (e.g., in separate dosage forms) in the same amounts and / or ratios as found in the solid oral dosage forms of the invention, and using the same dosing regimens.

[0094] It will be apparent to those skilled in the art that certain embodiments of the present invention may be directed to one, more, or all of the above-identified aspects as well as other aspects, and may include one, more, or all of the above-identified and below-identified aspects as well as other embodiments.

[0095] Other than in the examples, or where otherwise indicated, all numbers expressing quantities of ingredients, reaction conditions, and so forth used in the specification and claims are to be understood as being modified by the term "about." Accordingly, unless otherwise indicated, such numbers are approximations that may vary depending upon the desired properties sought to be obtained by the present invention. 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.

[0096] 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.

[0097] Having described the invention, the invention is described in more detail in the following examples, which are included herein for illustrative purposes only and are not intended to limit the invention.

[0098] Example

[0099] Example 1: ASTX727 Phase 1 Study The ASTX727 Phase 1 trial was conducted with standard doses of IV decitabine (decitabine 20 mg / m 2 Dose escalation was designed to establish recommended doses of cedazuridine and decitabine likely to achieve an AUC equivalent to that of IV decitabine. Figure 1 provides an overview of the study design. In cycle 1, each patient received oral decitabine at a cohort-defined dose on day -3 and decitabine 20 mg / m on day 1. 2Patients were given a 1-hour intravenous infusion of decitabine and cedazuridine, followed by cohort-defined doses of oral decitabine and cedazuridine on days 2–5. In cycle 2 and beyond, oral decitabine and cedazuridine were given on days 1–5. The cedazuridine dose was titrated initially, and decitabine was titrated once CDA inhibition by cedazuridine approached maximum efficacy. Only one drug was titrated per cohort. Fixed doses were given without adjustment for body weight or body surface area. Full-day pharmacokinetic analyses of decitabine were included on days 1, 2, and 5. The starting doses were 20 mg for oral decitabine and 40 mg for cedazuridine (human-equivalent doses with a safety margin approximately 100-fold greater than the level of adverse effects not observed in cynomolgus monkeys). Escalation of each agent occurred if the mean decitabine AUC for the oral agent was less than 90% of the mean decitabine AUC for IV decitabine in the cohort and no dose-limiting toxicity was observed. Dose-limiting toxicity was defined as grade 4 hematologic toxicity or grade 3 lasting ≥14 days and unrelated to the underlying disease. Once the decitabine AUC target range, established as the primary endpoint and with IV decitabine, reached a dose deemed safe, the cohort closest to IV decitabine exposure was expanded to 18 evaluable patients. Dose escalation for patients previously receiving a lower dose was permitted at the investigator's discretion if the patient tolerated the initially assigned dose.

[0100] The pharmacokinetic profile of decitabine was characterized by analysis of EDTA-treated plasma by a validated liquid chromatography-tandem mass spectrometry method using tetrahydrouridine (Santa Cruz Biotechnology, Dallas, TX) for stabilization and a linear assay range of 0.5 to 100 ng / mL of decitabine. Serial plasma samples (pre-dose through 24 hours post-dose) were collected on days -3, 1, 2, and 5 of the first cycle (and immediately prior to dosing on days 3 and 4). Specifically, pharmacokinetic samples were obtained pre-dose and at 0.25, 0.5, 1.0 (IV only, 1.083 hours), 1.5, 2, 3, 4, 6, 8, and 24 hours post-dose.

[0101] Patients could discontinue treatment or be withdrawn from the study at the investigator's discretion due to disease progression, unacceptable toxicity, patient request, withdrawal of consent, or lack of benefit.

[0102] The results of the Phase 1 study are shown in Table 3 below and in FIG.

[0103] [Table 3]

[0104] CED = cedazuridine; DEC = decitabine; gCV% = geometric coefficient of variation a Oral dosing was not adjusted for weight or body surface area. IV doses were 20 mg / m in all cohorts. 2 It was. b One subject in Cohort 1 was excluded as an extreme outlier. c IV data for 18 patients and 1 patient were excluded as extreme outliers. d Total 5-day IV AUC calculated for the total IV population 0~t Geometric mean (N=41)

[0105] In Figure 2, the two highlighted curves show exposures from 100 mg cedazuridine and 30 and 40 mg oral decitabine (cohorts 4 and 5 in Table 3). At these doses, oral decitabine exposure was 81% to 128% of IV decitabine exposure. Based on this, the intermediate dose of decitabine between 30 and 40 mg, i.e., 35 mg, was predicted to be closest to IV.

[0106] Example 2: Dose Confirmation for ASTX727 Phase 2 Study A phase 2 trial of ASTX727 was conducted in a single cycle with decitabine at 20 mg / m 2 The study consisted of a randomized crossover design of IV daily (5 days) vs. oral decitabine / cedazuridine once daily (5 days), where patients were crossed over to the other agent after two cycles (see Figure 3). From cycle 3 onwards, all patients continued oral decitabine / cedazuridine once daily (5 days) every 28-day cycle until progression.

[0107] Baseline characteristics for patients in Phase 2 are shown in Table 4.

[0108] [Table 4]

[0109] Decitabine and cedazuridine will be given as individual capsules of decitabine (35 mg) and CED (100 mg) in the dose-escalation and dose-expansion phases of Phase 1 and the initial dose-confirmation phase of Phase 2, and then combined as a single fixed-dose combination (FDC) tablet (ASTX727) of both decitabine (35 mg) and cedazuridine (100 mg) in the second phase of Phase 2 and in Phase 3. The composition of the ASTX727 FDC tablet used in the Phase 3 clinical trial is shown in Table 5.

[0110] [Table 5]

[0111] Five-day plasma decitabine AUC of individual capsules of decitabine (35 mg) and cedazuridine (100 mg) 0~t is shown in Table 6A, and the plasma decitabine AUC on day 5 for a single ASTX727 tablet 0~t is shown in Table 6B.

[0112] [Table 6A]

[0113] IV = decitabine 20 mg / m 2 IV infusion (1 hour). Oral = 100 mg cedazuridine and 35 mg decitabine capsules CI = Confidence Interval; IV = Intravenous; Geo.LSM = Geometric Least Squares Means; CV = Coefficient of Variation

[0114] [Table 6B]

[0115] IV = decitabine 20 mg / m 2 IV infusion (1 hour). Oral = ASTX727 FDC tablets (100 / 35 mg cedazuridine / decitabine) CI = Confidence Interval; IV = Intravenous; Geo.LSM = Geometric Least Squares Means; CV = Coefficient of Variation

[0116] Figure 4 shows the effect of oral 100 mg cedazuridine and 35 mg decitabine versus decitabine 20 mg / m 2Individual and geometric mean plasma decitabine AUC after a single infusion of 0~24 to provide. The 5-day oral decitabine exposure was approximately 98% of that of IV decitabine, confirming that the doses selected for cedazuridine and decitabine in the tablets closely matched those of IV decitabine.

[0117] Hematology and global DNA methylation were assessed with a long interspersed nuclear element-1 (LINE-1) methylation bisulfite sequencing assay on days 1, 8, 15, 22, and 29 of the first cycle (Yang, AS, Koshi KD, Choi SW, et al. DNA methylation changes after 5-aza-2-deoxycytidine therapy in patients with leukemia. Can. Res. 2006;66;5495-503). Changes in DNA methylation after treatment were expressed as relative change (%) and calculated as follows: 100 x ([methylation after a given treatment day - treatment day] - [baseline methylation]. Adverse events were assessed through physical examination and laboratory monitoring (hematology, metabolic profile, and liver enzymes) before treatment on day 1 of each cycle (weekly for hematology in the first two cycles). During treatment, patients were evaluated for adverse events and clinical response, including hematology, metabolic profile, liver enzymes, indicated physical examinations, vital signs, transfusion records, and medication records. Once treatment was discontinued, patients were followed for survival and progression to acute myeloid leukemia. Dose reductions or delays were permitted at the investigator's discretion to allow recovery from drug-related myelosuppression.

[0118] The results of the LINE-1 study are shown in Figures 5A-5B and 6A-6B. Phase 2 efficacy and safety dates for the study are shown in Tables 7 and 8, respectively.

[0119] [Table 7]

[0120] a IWG 2006 criteria; b Transfusion independence for at least 8 weeks in patients who were dependent at baseline

[0121] [Table 8]

[0122] Example 3: Phase 3 study Phase 3 was a randomized crossover design in which MDS and CMML patients eligible for decitabine were randomized to either Sequence A, in which they received ASTX727 for one cycle and then IV decitabine for two cycles, or Sequence B, in the reverse order. All patients received ASTX727 from cycle 3 onward to evaluate long-term efficacy and safety. To demonstrate equivalence of AUC between oral and IV administration, 118 evaluable patients were required (see Figure 7). Key inclusion criteria for subjects were: 1) candidacy for IV decitabine; 2) ECOG PS 0-2; 3) life expectancy of at least 3 months; 4) adequate organ function; and 5) one prior cycle of HMA permitted. The primary endpoint included 5-day total plasma levels of decitabine AUC (oral / IV 90% CI 80%-125%). Secondary endpoints were efficacy, including response rate, transfusion independence, duration of response, leukemia-free, overall survival, and safety of ASTX727; and efficacy including Max LINE-1 demethylation.

[0123] Of 133 patients treated in phase 3, 123 completed both IV and 5-day oral cycles, and both decitabine AUCs were assessed. The ratio of 5-day plasma decitabine AUCs to oral / IV was approximately 99%, with a 90% confidence interval of approximately 93% to 106%. Sensitivity and secondary analyses of all patients treated with PK evaluation all confirmed the results of the primary analysis (see Table 9).

[0124] [Table 9]

[0125] 1 Paired patient population: Patients who received both ASTX727 and IV decitabine in the first two randomized cycles and had adequate PK samples

[0126] The study achieved its primary endpoint with high confidence: a 5-day oral / IV plasma decitabine AUC of approximately 99% (with a 90% CI of approximately 93-106%). All sensitivity and secondary PK AUC analyses confirmed the findings from the primary analysis.

[0127] Figure 8 shows individual patient exposures for both ASTX727 on days 1, 2, and 5 and IV decitabine on days 1 and 5. As can be seen, the individual exposures for patients treated with either oral or IV decitabine largely overlap with each other, even though oral decitabine is given at a fixed dose while IV is administered based on body surface area. The AUC for decitabine on day 1 is slightly lower than the AUC for days 2 through 5 and the AUC for IV administration. The ratio of AUC for decitabine on day 2 to day 1 is about 1.5:1 to about 2:1.

[0128] Figure 9 shows that the pharmacodynamic effects of global DNA demethylation, as measured by the LINE-1 assay, were also nearly identical when oral was compared to IV in cycles 1 and 2. The difference in DNA methylation between oral and IV administration was less than 1% and not significant.

[0129] In summary, oral ASTX727 fixed dose tablets (cedazuridine / decitabine 100 / 35 mg) were administered in combination with IV decitabine 20 mg / m 2Compared with the primary endpoint, oral ASTX727 achieved approximately 99% of the 5-day plasma decitabine AUC systemic exposure. Furthermore, robust results were confirmed in all AUC sensitivity and secondary analyses. Furthermore, oral ASTX727 achieved nearly identical pharmacodynamic effects to IV decitabine (less than 1% difference in LINE-1% DNA demethylation). Additionally, the durable clinical responses, 50% transfusion independence, and median survival of 18.3 months observed in a phase 2 study with long-term follow-up are consistent with IV decitabine. Furthermore, there were no significant differences in adverse events, including GI adverse events, between oral ASTX727 and IV decitabine in the first two randomized cycles.

[0130] The foregoing is illustrative of the present invention and is not to be construed as limiting thereof. The present invention is defined by the following claims, with equivalents of the claims to be included therein.

Claims

1. 1. A solid oral formulation comprising cedazuridine and decitabine, wherein the solid oral formulation comprises The solid oral formulation comprises 100 mg of cedazuridine, 35 mg of decitabine, lactose monohydrate, hydroxypropyl methylcellulose, croscarmellose sodium, colloidal silicon dioxide, and magnesium stearate.

2. A solid oral formulation comprising cedazuridine and decitabine, wherein the solid oral formulation, upon daily administration to a human, provides plasma levels of decitabine having a 5-day area under the curve (AUC) for decitabine that is equivalent to the 5-day area under the curve for a daily intravenous dose of 20 mg / m2 of decitabine administered as a 1-hour infusion; 10. The solid oral formulation of claim 1, comprising 100 mg of cedazuridine, 35 mg of decitabine, lactose monohydrate, hydroxypropyl methylcellulose, croscarmellose sodium, colloidal silicon dioxide, and magnesium stearate.

3. 3. The solid oral formulation of claim 1, wherein daily administration to a human results in a ratio of AUC for decitabine on day 1 to day 2 of 1.5:1 to 2:

1.

4. 4. The solid oral formulation of any one of claims 1 to 3, wherein the solid oral formulation, upon daily administration to humans, provides a pharmacodynamic effect that is equivalent to the pharmacodynamic effect of a daily intravenous dose of 20 mg / m2 of decitabine administered as a 1-hour infusion.

5. 5. The solid oral formulation of claim 4, wherein the pharmacodynamic effect is DNA demethylation.

6. A solid oral formulation described in any one of claims 1 to 5, comprising 100 mg of cedazuridine, 35 mg of decitabine, 322.5 mg of lactose monohydrate, 10 mg of hypromellose, 25 mg of croscarmellose sodium, 5 mg of colloidal silicon dioxide, and 2.5 mg of magnesium stearate per 500 mg of the solid oral formulation.

7. The solid oral formulation according to any one of claims 1 to 6, wherein the solid oral formulation is a tablet or a capsule.

8. The solid oral dosage form of any one of claims 1 to 7, further comprising a coating.

9. 9. The solid oral dosage form of claim 8, wherein the coating is a color coating.

10. The solid oral formulation of any one of claims 1 to 9, for use in treating a disorder treatable with decitabine in a subject in need thereof.

11. 11. The solid oral formulation of claim 10, wherein the disorder treatable with decitabine is a hyperproliferative disease.

12. 11. The solid oral formulation of claim 10, wherein the disorder treatable with decitabine is cancer.

13. 13. The solid oral formulation of claim 12, wherein the cancer is selected from hematological cancers and solid cancers.

14. 14. The solid oral formulation of claim 13, wherein the hematological cancer is selected from myelodysplastic syndrome (MDS), leukemia, and lymphoma.

15. the leukemia is acute lymphocytic leukemia, acute myeloid leukemia, chronic myelogenous leukemia, myeloproliferative disease or chronic myelomonocytic leukemia, and / or the lymphoma is Hodgkin's lymphoma, non-Hodgkin's lymphoma or T-cell lymphoma; and / or 15. The solid oral formulation of claim 14, wherein the myelodysplastic syndrome (MDS) is lower-risk MDS.

16. 14. The solid oral formulation of claim 13, wherein the solid cancer is selected from pancreatic cancer, ovarian cancer, peritoneal cancer, non-small cell lung cancer, breast cancer, neuroectodermal tumors, and sarcoma.

17. 17. The solid oral formulation of any one of claims 10 to 16, wherein the solid oral formulation is administered from 1 to 28 days per 28-day cycle.

18. 18. The solid oral formulation of any one of claims 10 to 17, wherein the solid oral formulation is administered on consecutive days in a 28 day cycle or on non-consecutive days in a 28 day cycle.

19. 19. The solid oral formulation of any one of claims 10 to 18, wherein the solid oral formulation is administered 1 week, 2 weeks, 3 weeks, or 4 weeks per 28 day cycle.

20. The solid oral formulation according to any one of claims 1 to 9, for use in reducing DNA methylation in a subject in need thereof.

21. 10. The solid oral formulation of claim 1, for use in inhibiting the degradation of decitabine in a subject in need thereof.

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