EA045934B1 - COMBINED SOLID ORAL DOSAGE FORMS OF DECITABINE AND CEDAZURIDINE - Google Patents

Description

Statement of priority

This application claims priority to US Provisional Application Serial No. 62/981304, filed February 25, 2020, the contents of which are incorporated herein by reference in their entirety.

Field of technology to which the invention relates

The present invention relates to solid oral dosage forms that include cedazuridine and decitabine. In particular, the invention relates to solid oral dosage forms that include a fixed dose combination of cedazuridine and decitabine, the dosage forms providing pharmacokinetic and/or pharmacodynamic effects equivalent to those achieved with intravenous administration of decitabine.

Prior Art

The enzymes adenosine deaminase (ADA, EC 3.5.4.4) and cytidine deaminase (CDA, EC 3.5.4.5) function to deaminate natural aminopurine and aminopyrimidine nucleosides, respectively, in humans and other organisms. They can also convert active nucleoside drugs into inactive metabolites. CDA is a component of the pyrimidine recycling pathway. It 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 a number of synthetic cytosine analogs that are clinically useful drugs (Cancer Chemother. Pharmacol. 1998, 42, 373-378; Cancer Res. 1989, 49, 3015-3019; Antiviral Chem. Chemother. 1990, 1, 255262) . 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 become resistant to cytosine analogue drugs often overexpress CDA (Leuk. Res. 1990, 14, 751-754). Leukemia cells expressing high levels of CDA may exhibit resistance to cytosine antimetabolites and thereby limit the antitumor activity of such therapeutics (Biochem. Pharmacol. 1993, 45, 1857-1861). CDA is also expressed at high levels in the intestine and liver and may therefore influence the bioavailability of therapeutic cytidine analogues.

Decitabine (5-aza-2'-deoxycytidine), a cytidine analog, is an antineoplastic and hypomethylating agent (HMA) for the treatment of myelodysplastic syndromes (MDS) with potential utility in the treatment of acute myelogenous leukemia as well as chronic myelogenous leukemia. Decitabine is not readily bioavailable when administered orally due to the rapid inactivation of CDA. nh ₂

N^N A J ¹ ON p ( 'OH OH

5-p1p-2'-de1oxnvntndnn (decvtpbvv)

Cedazuridine ((4R)-2'-deoxy-2',2'-difluoro-3,4,5,6-tetrahydrouridine; also known as E7727) is a recently developed CDA inhibitor. Cedazuridine and methods for its preparation and/or use are further disclosed in US Patent Nos. 8,268,800 and 9,834,576, the contents of which are incorporated herein by reference in their entirety.

He

Cedazuridine

Due to the poor oral bioavailability of decitabine, treatments using decitabine currently require parenteral injections daily for 5-7 days over a period of months or even years. An oral, bioavailable formulation of decitabine would reduce the burden associated with monthly multi-day intravenous infusions or subcutaneous injections, which sometimes involve lengthy travel to clinic visits.

Summary of the invention

The present invention is based in part on the development of solid oral dosage forms of decitabine and cedazuridine, wherein the solid oral dosage form when administered daily

- 1045934 provides the subject with plasma levels of decitabine with a 5-day area under the curve (AUC) for decitabine that is equivalent to the 5-day AUC for a daily intravenous (IV) dose of decitabine 20 mg/m ² administered as a one-hour infusion. In some embodiments, when such a solid oral dosage form is administered daily to a subject, the AUC ratio for decitabine on day 2 compared to day 1 is about 1.5:1 to 2:1.

Another aspect of the invention relates to solid oral dosage forms containing decitabine and cedazuridine, which, when administered daily to a subject, provide a pharmacodynamic effect that is equivalent to the pharmacodynamic effect of a daily intravenous dose of decitabine 20 mg/m ² as a one-hour infusion. In specific embodiments, the pharmacodynamic effect is DNA demethylation.

A further aspect of the invention relates to methods of treating a disorder in a subject in need thereof, comprising administering to the subject a solid oral dosage form in accordance with an embodiment of the invention that provides treatment for cancer in the subject. In some embodiments, the disorder is cancer.

Another aspect of the invention relates to methods of inhibiting the degradation of decitabine in a subject in need thereof, comprising administering to the subject a solid oral dosage form in accordance with an embodiment of the invention that inhibits the degradation of decitabine in the subject.

Another aspect of the invention relates to methods of reducing DNA methylation (eg, LINE-1 methylation) in a subject in need thereof, comprising administering to the subject a solid oral dosage form in accordance with an embodiment of the invention that reduces DNA methylation in the subject.

A further aspect of the invention relates to the use of a solid oral dosage form in accordance with an embodiment of the invention in methods of treating disorders, methods of inhibiting decitabine degradation and methods of reducing DNA methylation (e.g. LINE-1 methylation)

These and other aspects of the invention are set forth in more detail in the description of the invention below.

Brief description of drawings

Fig. 1 is a graph describing a Phase 1 dose-escalation study designed to establish the recommended dose of cedazuridine and decitabine.

Fig. 2 is a plot of mean decitabine concentration (ng/mL) versus time (hours) for several dosing regimens in the Phase 1 study described in FIG. 1.

Fig. 3 is a graph describing a Phase 2 randomized crossover study designed to confirm the dosing of cedazuridine and decitabine determined in the Phase 1 study of FIG. 1.

Fig. 4 shows the mean AUC of _0-24 decitabine (h-ng/mL) on days 1, 2, and 5 for oral decitabine/cedazuridine and for intravenous decitabine in the Phase 2 study described in FIG. 3.

Fig. 5A and 5B show relative LINE-1 demethylation (%) for the sequence from ASTX727 (Cycle 1) and intravenous decitabine (Cycle 2) in the Phase 2 study described in FIG. 3. Fig. 5A represents the relative progression of LINE-1 for the ASTX727 course, and FIG. 5B represents the relative progression of LINE-1 for a course of intravenous decitabine.

Fig. 6A and 6B show relative LINE-1 demethylation (%) for the IV sequence of decitabine (Cycle 1) and ASTX727 (Cycle 2) in the Phase 2 study described in FIG. 3. In FIG. 6A shows the relative progression of LINE-1 for a course of intravenous decitabine, and FIG. Figure 6B shows the relative LINE-1 progression for the ASTX727 course.

Fig. 7 is a graph describing a Phase 3 randomized crossover study designed to establish intravenous decitabine equivalence, efficacy, safety, and maximal LINE-1 demethylation for the oral formulation of ASTX727.

Fig. 8 shows pharmacokinetic analysis of oral ASTX727 and IV decitabine in the Phase 3 study described in FIG. 7. In FIG. Figure 8 shows the plasma decitabine AUC _0-24 (h-ng/mL) for oral ASTX727 on days 1, 2 and 5 and the decitabine AUC _0-24 (h-ng/mL) for intravenous decitabine on days 1 and 5.

Fig. 9 presents the RMSEA of maximum LINE-1 demethylation (95% CI) for both oral ASTX727 and IV decitabine during Cycle 1 and Cycle 2 as described in FIG. 7.

Detailed Description of the Invention

Below, the present invention is explained in more detail. This description is not intended to be a detailed catalog of all the different ways in which the invention may be implemented or all the features that may be added to the present invention. For example, character

- 2045934 The characteristics illustrated with respect to one embodiment may be included in other embodiments, and the characteristics illustrated with respect to a particular embodiment may be excluded from that embodiment. Moreover, numerous changes and additions to the various embodiments proposed herein, which will be apparent to those skilled in the art in light of the present disclosure, do not depart from the scope of the present invention. Accordingly, the following description is intended to illustrate some specific embodiments of the invention and not to comprehensively describe all permutations, combinations and variations thereof.

Unless the context indicates otherwise, it is specifically intended that the various features of the invention described herein may be used in any combination. In addition, the present invention also contemplates that in some embodiments, any feature or combination of features set forth herein may be excluded or omitted. By way of illustration, if the specification states that a complex contains components A, B, and C, it is specifically intended that any one of components A, B, or C, or a combination thereof, may be omitted and omitted from the specification individually or in any combination.

Unless otherwise specified, all technical and scientific terms used in this application have the same meaning as commonly understood by one skilled in the art to which this invention relates. The terminology used in the description of the present invention is intended only for the purpose of describing specific embodiments and is not intended to limit the invention.

All publications, patent applications, patents, nucleotide sequences, amino acid sequences and other references mentioned in this application are incorporated by reference in their entirety.

Definitions

As used in the specification and the accompanying claims, the singular forms are intended to also include the plural forms unless the context clearly indicates otherwise.

As used herein, the term and/or refers to and covers any and all possible combinations of one or more related enumerated items, as well as the absence of combinations when interpreted in the alternative (or).

In addition, the present invention also contemplates that in some embodiments, any feature or combination of features set forth herein may be omitted or omitted.

In addition, the term approximately, as used herein in relation to a measurable value such as an amount of a compound or agent of the present invention, dose, time, temperature, etc., means that it covers variations of ±10%, ±5%, ±1%, ±0.5% or even ±0.1% of the specified amount.

As used herein, the transitional phrase consisting essentially of is to be interpreted as covering the listed materials or steps, as well as those that do not materially affect the essential and novel features of the claimed invention. Thus, the term consisting essentially of, as used in this application, should not be interpreted as equivalent to the term containing.

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

AUC refers to the area under the concentration-time curve for an active agent such as decitabine.

Half-life refers to the period of time required for the concentration or amount of a compound in a subject to decrease to exactly one-half of that concentration or amount.

Pharmaceutically acceptable refers to those properties and/or substances that are acceptable to the patient from a pharmacological and/or toxicological point of view, and/or to the pharmaceutical manufacturing chemist from a physical and/or chemical point of view with respect to composition, formulation, stability, acceptability for patients, bioavailability and compatibility with other ingredients.

A pharmaceutically acceptable salt refers to an acid or base salt of a compound of the invention that has the required pharmacological activity and is not biologically or otherwise undesirable. The salt may be formed by acids which include acetate, adipate, alginate, aspartate, benzoate, benzenesulfonate, bisulfate, butyrate, citrate, camphorate, camphorsulfonate, cyclopentane propionate, digluconate, dodecyl sulfate, ethanesulfonate, fumarate, gluco

- 3 045934 heptanoate, glycerophosphate, hemisulfate, heptanoate, hexanoate, hydrochloride, hydrobromide, hydroiodide, 2-hydroxyethanesulfonate, lactate, maleate, methanesulfonate, 2-naphthalene sulfonate, nicotinate, oxalate, thiocyanate, tosylate and undecanoate. Examples of the basic salt include ammonium salts, alkali metal salts such as sodium and potassium salts, alkaline earth metal salts such as calcium and magnesium salts, salts with organic bases such as dicyclohexylamine salts, N-methyl-E-glucamine and salts with amino acids such as, but not limited to, arginine and lysine. In some embodiments, the 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, diethyl, dibutyl and diamyl sulfates; long chain halides such as decyl, lauryl, myristyl and stearyl chlorides, bromides and iodides; and aralkyl halides such as phenethyl bromides.

A single-dose dosage form refers to a physically discrete unit suitable as a unit dose for humans or other animals. Each single-dose dosage form may contain a predetermined amount of active agent (eg, a compound or composition of the invention, a CDA substrate drug, and/or other therapeutic agent) calculated to produce the desired effect.

Optional or optional means that the subsequently described event or circumstance may or may not occur and that the description includes cases in which the event or circumstance occurs and cases in which it does not occur. For example, alkyl, which is optionally substituted, includes both unsubstituted alkyl and substituted alkyl.

The term amplification or magnification refers to an increase in the specified parameter by at least about 1.25 times, 1.5 times, 2 times, 3 times, 4 times, 5 times, 6 times, 8 times, 10 times, 12 times, 15 times, etc.

The term inhibit or reduce, or grammatical variations thereof, as used herein, refers to reducing or reducing a specified level or activity by at least about 15%, 25%, 35%, 40%, 50%, 60%, 75%, 80 %, 90%, 95% and more. In certain embodiments, inhibition or reduction results in little or virtually no detectable activity (at most a small amount, such as less than about 10% or even 5%).

Subject refers to a cell or tissue in vitro or in vivo, animal or human. The animal or human subject may also be referred to as the patient.

An animal refers to a living organism that has sensitivity and the ability to move voluntarily, and which requires oxygen and organic food for its existence.

Mammal refers to a warm-blooded vertebrate animal with hair or fur. Examples include, but are not limited to, human, equine, porcine, bovine, mouse, dog, or cat species.

By the term treat or treat (or grammatically equivalent terms) it is meant that the severity of a subject's condition is reduced or at least partially alleviated or improved, and/or that some relief, mitigation, or reduction of at least one clinical symptom is achieved. Treatment for a disease, disorder or condition may refer to: (i) suppression of the disease, disorder or condition, such as stopping its progression; and/or (ii) alleviating the disease, disorder or condition, for example inducing regression of clinical symptoms.

Prevention in relation to a disease, disorder or condition refers to preventing the disease, disorder or condition, for example, preventing the development of clinical symptoms of the disease, disorder or condition. As used herein, the term prevent, prevent, or prevent (and their grammatical equivalents) may also refer to delaying the onset of a disease or disorder, or reducing symptoms upon the onset of a disease or disorder. These terms do not imply complete elimination of the disease and cover any type of preventive treatment that reduces the incidence of the condition or delays the onset and/or progression of the condition.

The term administering or using a compound and/or composition of the present invention to a subject includes a method of administering or delivering a compound to a subject to perform its intended function. For the solid oral dosage forms of the invention, the route of administration is intended to be oral. The pharmacokinetics and pharmacodynamics of solid oral dosage forms are compared with those obtained with intravenous decitabine, which is usually administered by infusion. When an infusion is said to be administered over one (1) hour, it means that a solution containing decitabine at the specified concentration is administered over that period of time. Application includes self-administration and administration by another person.

Cancer refers to the abnormal growth of cells that tend to multiply uncontrollably and, in some cases, metastasize (spread). Specific types of cancer include those identified in Publication No. US 2006/0014949 and the following: cardiac tumors:

- 4 045934 sarcoma (for example, such as angiosarcoma, fibrosarcoma, rhabdomyosarcoma, liposarcoma, etc.), myxoma, rhabdomyoma, fibroma, lipoma and teratoma; lung tumors: bronchogenic carcinoma (for example, such as squamous cell, undifferentiated small cell, undifferentiated large cell, adenocarcinoma, etc.), alveolar (for example, such as bronchiolar) carcinoma, bronchial adenoma, sarcoma, lymphoma, chondromatous hamartoma, mesothelioma; tumors of the gastrointestinal tract: esophagus (for example, such as squamous cell carcinoma, adenocarcinoma, leiomyosarcoma, lymphoma, etc.), stomach (for example, such as carcinoma, lymphoma, leiomyosarcoma, etc.), pancreas (for example, such as ductal adenocarcinoma, insulinoma, glucagonoma, gastrinoma, carcinoid tumors, VIPoma, etc.), small intestine (for example, such as adenocarcinoma, lymphoma, carcinoid tumors, Kaposi's sarcoma, leiomyoma, hemangioma, lipoma, neurofibroma, fibroma, etc. etc.), colon (for example, such as adenocarcinoma, tubular adenoma, villous adenoma, hamartoma, leiomyoma, etc.); genitourinary tract: kidney (for example, such as adenocarcinoma, Wilms tumor, nephroblastoma, lymphoma, leukemia, etc.), bladder and urethra (for example, such as squamous cell carcinoma, transitional cell carcinoma, adenocarcinoma, etc.) , prostate (for example, such as adenocarcinoma, sarcoma), testis (for example, such as seminoma, teratoma, embryonal carcinoma, teratocarcinoma, choriocarcinoma, sarcoma, interstitial cell carcinoma, fibroma, fibroadenoma, adenomatoid tumors, lipoma, etc.); liver: hepatoma (for example, hepatocellular carcinoma, etc.), cholangiocarcinoma, hepatoblastoma, angiosarcoma, hepatocellular adenoma, hemangioma; bones: osteogenic sarcoma (for example, such as osteosarcoma, etc.), fibrosarcoma, malignant fibrous histiocytoma, chondrosarcoma, Ewing's sarcoma, malignant lymphoma (for example, such as reticular cell sarcoma), multiple myeloma, malignant giant cell tumor, chordoma, osteochondroma (eg, such as osteochondral exostoses), benign chondroma, chondroblastoma, chondromyxofibroma, osteoid osteoma and giant cell tumors; nervous system: skull (for example, such as osteoma, hemangioma, granuloma, xanthoma, osteitis deformans, etc.), meninges (for example, such as meningioma, meningiosarcoma, gliomatosis, etc.), brain (for example, such as astrocytoma, medulloblastoma, glioma, ependymoma, germinoma [pinealoma], glioblastoma multiforme, oligodendroglioma, schwannoma, retinoblastoma, congenital tumors, etc.), spinal cord (for example, such as neurofibroma, meningioma, glioma, sarcoma, etc.) P.); gynecological tumors: uterus (for example, endometrial carcinoma, etc.), cervix (for example, cervical carcinoma, precancerous cervical dysplasia, etc.), ovarian (for example, ovarian carcinoma [serous cystadenocarcinoma, mucinous cystadenocarcinoma, unclassified carcinoma], granulosa-theca cell tumors, Sertoli-Leydig cell tumors, dysgerminoma, malignant teratoma, etc.), vulva (for example, such as squamous cell carcinoma, intraepithelial carcinoma, adenocarcinoma, fibrosarcoma, melanoma, etc.), vagina (for example, such as clear cell carcinoma, squamous cell carcinoma, botryoid sarcoma (embryonic rhabdomyosarcoma), fallopian tube tumor (carcinoma), etc.); hematological tumors: blood (for example, such as myeloid leukemia [acute and chronic], acute lymphoblastic leukemia, chronic lymphocytic leukemia, myeloproliferative diseases, multiple myeloma, myelodysplastic syndromes, etc.), Hodgkin's disease, non-Hodgkin's lymphoma; skin: malignant melanoma, basal cell carcinoma, squamous cell carcinoma, Kaposi's sarcoma, moles, dysplastic nevi, lipoma, angioma, dermatofibroma, keloids, psoriasis, etc.; and adrenal glands: neuroblastoma; but are not limited to those listed.

Solid oral dosage forms

The present invention relates to solid oral dosage forms containing decitabine and cedazuridine. The solid oral dosage form is designated ASTX727 and marketed as INQOVI® for the treatment of myelodysplastic syndromes. Oral cedazuridine prior to oral decitabine has previously been shown to increase decitabine exposure. However, given the low bioavailability of decitabine and the reduced bioavailability with oral administration compared with intravenous administration in general, a solid oral dosage form containing decitabine and cedazuridine was expected to have significantly lower bioavailability than intravenous decitabine. Surprisingly, the present inventors have discovered solid oral dosage forms that, when administered daily to a subject (e.g., a human), provide plasma decitabine levels with a 5-day area under the curve (AUC) for decitabine that is equivalent to the 5-day AUC for daily intravenous (IV) ) dose of decitabine 20 mg/m ² administered as a one-hour infusion. In addition, the present inventors have discovered combination solid oral dosage forms of decitabine and cedazuridine that have equivalent or improved epigenetic effects (e.g., LINE-1 demethylation, e.g., % F cell proliferation) and/or reduced myelosuppressive effects (e.g., neutropenia) , compared with those obtained with intravenous decitabine in cancer patients with myelodysplastic syndrome (MDS) with low and intermediate-1 IPSS (International Prognostic Scoring System) scores. As used herein, the term equivalent refers to a value that differs by less than 10% from

- 5 045934 reference value, for example less than 10%, 9%, 8%, 7%, 6%, 5%, 4%, 3%, 2% or 1%.

Thus, in accordance with embodiments of the present invention, solid oral dosage forms are provided that include both decitabine and cedazuridine. As used herein, the terms decitabine and cedazuridine include the compounds themselves and any pharmaceutically acceptable salts thereof. In some embodiments, the invention provides solid oral dosage forms containing decitabine and cedazuridine that, when administered daily to a subject, provide decitabine plasma levels with a 5-day AUC for decitabine equivalent to the 5-day AUC for a daily intravenous dose of 20 mg/m ² decitabine. administered as a one-hour (1 hour) infusion. In some embodiments, when administered daily to a subject, the AUC ratio (AUC _0-24 ) for decitabine on day 2 compared to day 1 is about 1.5:1 to 2:1, such as about 1.5 :1 to 1.8:1, eg about 1.7:1 to 2:1, eg about 1.5:1; 1.6:1; 1.7:1; 1.8:1; 1.9:1 or 2:1.

The primary endpoint PK assay kit is used to calculate the 5-day cumulative exposure AUC of _0-t decitabine after administration of the solid dosage form. The following assumptions are used:

1) The equilibrium state is achieved on the 2nd day of taking the solid dosage form;

2) Based on reaching steady state on day 2, the AUC _0-t of decitabine from days 2 to 5 is the daily AUC _0-t from days 2 to 5 for an assumed 5-day use of the solid dosage form .

Therefore, to calculate the total 5-day oral exposure of decitabine, AUC _0-t using pharmacokinetic data from the 3-day sequential pharmacokinetic sampling, day 1 AUC _0-t (first dose of solid dosage form) is added to (AUC _0-t 2 day + AUC _0-t day 5) x 2. If the value of AUC _0-t on day 2 is not available, it is replaced by AUC _0-t on day 5; the reverse is also true.

To calculate the 5-day exposure to decitabine, AUC _0-t after intravenous administration of decitabine (AUC0-t day 1 + AUC0-t day 5)/2 is multiplied by 5, based on the information in the instructions for use of DACOGEN® (Instructions for use DACOGEN® 2014) that there was no accumulation on day 5 compared to day 1 with a 5-day infusion. If AUC0-t data on day 1 are not available, they are replaced with AUC _0-t on day 5; the reverse is also true. Please note that t = 24 hours, so AUC _0-t is equal to AUC _0-24 .

In some embodiments of the present invention, the solid oral dosage form, when administered daily to a subject, provides a pharmacodynamic effect that is equivalent to the pharmacodynamic effect of a daily intravenous dose of decitabine 20 mg/m ² administered over a one-hour (1 hour) infusion. The type of pharmacodynamic effect includes any effect currently known or discovered later. In specific embodiments, the pharmacodynamic effect is DNA demethylation.

Pharmaceutical compositions (eg, compound, composition, drug and/or therapeutic agent) containing decitabine and cedazuridine are presented in the form of a solid oral dosage form, which means that the pharmaceutical compositions are in solid form and formulated for oral administration. Any suitable solid oral dosage form may be used. Examples of solid oral dosage forms in accordance with embodiments of the invention include tablets (eg, those intended for buccal, sublingual and systemic absorption), capsules, boluses, powders, granules, tongue pastes, capsules, including hard gelatin capsules and soft gelatin capsules , mouth sprays, lozenges, lozenges and balls. Pharmaceutical compositions may be formulated for immediate, sustained or controlled release.

The pharmaceutical compositions of the invention can be prepared using known materials and methods, which may include, but are not limited to, mixing and/or combining decitabine and cedazuridine with pharmaceutically acceptable excipients.

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

In some embodiments, the solid oral dosage form is a unit dosage form containing about 35 mg of decitabine. In some embodiments, the oral solid dosage form is a single-dose dosage form containing about 100 mg of cedazuridine. Additionally, in some embodiments, the solid oral dosage form is a single-dose dosage form containing about 35 mg of decitabine and about 100 mg of cedazuridine. In some embodiments, the single-dose dosage form contains about 35 mg of decitabine and about 100 mg of cedazuridine and at least one pharmaceutically acceptable excipient.

- 6 045934

A pharmaceutically acceptable excipient can mean any substance, not itself a therapeutic agent, used as a carrier, diluent, adjuvant, binding agent and/or vehicle for delivering a therapeutic agent to a subject, or added to a pharmaceutical composition for the purpose of improving processing or processing properties. storage, or to facilitate easy preparation of the compound or composition into a single-dose dosage form for administration. Pharmaceutically acceptable excipients are well known in the pharmaceutical field and are described, for example, in Remington's Pharmaceutical Sciences, Mack Publishing Co., Easton, Pa. (eg, 20th ed., 2000) and Handbook of Pharmaceutical Excipients, American Pharmaceutical Association, Washington, DC. DC (e.g., 1st, 2nd, and 3rd ed., 1986, 1994, and 2000, respectively). As is known to those skilled in the art, excipients can perform various functions and can be described, for example, as wetting agents, buffering agents, suspending agents, lubricants, emulsifiers, disintegrants, absorbents, preservatives, surfactants, coloring agents, flavoring agents and sweeteners. Examples of pharmaceutically 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) excipients 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) 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) buffering agents such as magnesium hydroxide and aluminum hydroxide; (15) alginic acid; (16) pyrogen-free water; (17) isotonic solution; (18) Ringer's solution; (19) ethyl alcohol; (20) buffer solutions for pH regulation; (21) polyesters, polycarbonates and/or polyanhydrides and (22) other non-toxic compatible substances used in pharmaceutical formulations, but not limited to them.

Examples of diluents include lactose, lactose monohydrate, cellulose, microcrystalline cellulose, sorbitol, dibasic calcium phosphate dehydrate, and calcium sulfate dehydrate. Examples of binding agents include gelatin, glucose, lactose, cellulose, methylcellulose, ethylcellulose, hydroxypropylmethylcellulose (hypromellose), hydroxypropylcellulose, starch, polyvinylpyrrolidone, sodium alginate, carboxymethylcellulose and gum acacia. Examples of disintegrants include croscarmellose sodium, crospovidone, sodium starch glycolate and starch. Examples of glidants 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.

In some embodiments, the solid oral dosage form includes one or more of a diluent, a binding agent, a disintegrant, a glidant, and a lubricant. In some embodiments, the solid oral dosage form includes a diluent, a binder, a disintegrant, a glidant, and a lubricant. In specific embodiments of the invention, the solid oral dosage form includes the following excipients: lactose monohydrate as a diluent; hydroxypropyl methylcellulose as a binding agent; croscarmellose sodium as a disintegrant; colloidal silicon dioxide as a glidant; and magnesium stearate as a lubricant. In some embodiments of the invention, such components 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 that may be colored. Any pharmaceutically acceptable coating may be used, but in some embodiments, the tablet is coated with OPADRY®.

In some embodiments, cedazuridine is present in the solid oral dosage form in an amount of about 17-22% by weight, such as about 17.0; 17.2; 17.4; 17.6; 17.8; 18.0; 18.2; 18.4; 18.6; 18.8; 19.0; 19.2; 19.4; 19.6; 19.8; 20.0; 20.2; 20.4; 20.6; 20.8; 21.0; 21.2; 21.4; 21.6; 21.8 or 22.0 wt.%, or in any range, such as approximately 19.42 wt.%.

In some embodiments, decitabine is present in the solid oral dosage form in an amount of about 4-8 wt.%, such as about 4.0; 4.2; 4.4; 4.6; 4.8; 5.0; 5.2; 5.4; 5.6; 5.8; 6.0; 6.2; 6.4; 6.6; 6.8; 7.0; 7.2; 7.4; 7.6; 7.8 or 8.0 wt.%, or in any range, such as approximately 6.8 wt.%.

In some embodiments, the diluent (e.g., lactose monohydrate) is present in the solid oral dosage form in an amount of about 55-70% by weight, such as about 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65 , 66, 67, 68, 69 or 70 wt.%, or in any range, such as approximately 62.62 wt.%.

In some embodiments, the binder (eg, hypromellose) is present in the solid oral dosage form in an amount of about 1-3 weight percent, such as about 1.0; 1.2; 1.4; 1.6; 1.8; 2.0; 2.2; 2.4; 2.6; 2.8 or 3.0 wt.%, or in any range, for example at

- 7 045934 approximately 1.94 wt.%.

In some embodiments, the disintegrant (eg, croscarmellose sodium) is present in the solid oral dosage form in an amount of about 3-7% by weight, such as about 3.0; 3.2; 3.4; 3.6; 3.8; 4.0; 4.2; 4.4; 4.6; 4.8; 5.0; 5.2; 5.4; 5.6; 5.8; 6.0; 6.2; 6.4; 6.6; 6.8 or 7.0 wt.%, or in any range, such as approximately 4.85 wt.%.

In some embodiments, the glidant (eg, colloidal silica) is present in the solid oral dosage form in an amount of about 0.5-2 wt.%, for example, about 0.5; 0.6; 0.7; 0.8; 0.9; 1.0; 1.1; 1.2; 1.3; 1.4; 1.5; 1.6; 1.7; 1.8; 1.9 or 2.0 wt.% or in any range, for example, approximately 0.97 wt.%.

In some embodiments, the lubricant (eg, magnesium stearate) is present in the solid oral dosage form in an amount of about 0.1-2 weight percent, such as about 0.1; 0.2; 0.3; 0.4; 0.5; 0.6; 0.7; 0.8; 0.9; 1.0; 1.1; 1.2; 1.3; 1.4; 1.5; 1.6; 1.7; 1.8; 1.9 or 2.0 wt.%, or in any range, such as approximately 0.49 wt.%.

In some embodiments, the solid oral dosage form contains the components listed in table. 1.

Table 1

Component Function Content (mass%) Cedazuridine Active substance 17-22 Decitabine Active substance 4-8 Lactose monohydrate Diluent 55-70 Hypromellose Binding agent 1-3 Croscarmellose sodium Disintegrant 3-7 Colloidal silicon dioxide Glidant 0.5-2 Magnesium stearate Lubricant 0.1-2

In some embodiments, the solid oral dosage form contains the components listed in Table. 2.

table 2

Component Function Content (mass%) Cedazuridine Active substance 19.42 Decitabine Active substance 6.80 Lactose monohydrate Diluent 62.62 Hypromellose Binder 1.94 Croscarmellose sodium Disintegrant 4.85 Colloidal silicon dioxide Glidant 0.97 Magnesium stearate Lubricant 0.49 Whole tablet core 97.09 Coating Film casing 2.91 Whole tablet with coating 100.0

Another aspect of the present invention relates to a single-dose dosage form and a kit containing at least one single-dose dosage form, wherein the single-dose dosage form contains decitabine and cedazuridine. In some embodiments, the kit provides single-dose dosage forms containing cedazuridine and decitabine, wherein when administered daily to a subject (e.g., a human), the 5-day AUC of decitabine in plasma is equivalent to the 5-day AUC for a daily intravenous dose of 20 mg/m ² decitabine infusion in for one hour (1 hour). Alternatively or additionally, in some embodiments, kits are provided containing single-dose dosage forms comprising decitabine and cedazuridine, wherein when administered daily to a subject (e.g., a human), a pharmacodynamic effect is provided that is equivalent to the pharmacodynamic effect of a daily intravenous dose of decitabine 20 mg/m ² per day. as a one-hour (1 hour) infusion. Thus, a kit may include 1, 2, 3, 4, 5 or more solid oral dosage forms in accordance with an embodiment of the invention. In some embodiments, the kit includes 5, 6, or 7 single-dose tablets containing about 35 mg decitabine and about 100 mg cedazuridine, and at least one pharmaceutically acceptable excipient.

The kit may further comprise a container and/or packaging suitable for commercial sale. The container may be any conventional shape, or a shape known in the art, that is made of a pharmaceutically acceptable material, such as a paper or cardboard box, glass or plastic bottle or jar, resealable pouch, or extruded unit dose blister pack. according to the therapeutic regimen. More than one container can be used in one package. For example, tablets may be contained in a blister pack, which in turn is contained within a box. In some embodiments, the container is a bottle, such as a 30 mL white high-density polyethylene bottle, containing single-dose dosage forms (eg, about 5 single-dose dosage forms). The bottle may further contain a desiccant, such as silica-based desiccant containers. In some embodiments, the container is a blister pack, such as formed from aluminum

- 8 045934 mini foil on a foil lid containing one tablet per cavity. Blister packs may be in cardboard packaging.

The set may additionally contain information. Information may be provided on a readable medium. The readable medium may contain a label. The information may be addressed to the doctor, pharmacist or patient. The information may indicate that the single-dose dosage form may cause one or more side effects. The information may include instructions for administering the single-dose dosage form, for example, in the manner described herein. These instructions can be provided in a variety of ways.

The information may be associated with the container, for example, by identification on a label (eg, instructions for use or separate label) affixed to the container; included inside the container in the form of a written insert; applied directly to the container, for example, to the wall of a box or blister pack; or attached by strapping or adhesive tape, such as an instruction card attached to the neck of a bottle by string, cord, or other device such as a rope, strap, or cord.

Methods using solid oral dosage forms of the invention

In accordance with embodiments of the invention, methods are provided for administering to a subject a solid oral dosage form containing cedazuridine and decitabine. In specific embodiments, methods are provided for administering to a subject a solid oral dosage form comprising cedazuridine and decitabine, wherein the solid oral dosage form, when administered daily to a subject (e.g., a human), provides decitabine plasma levels with a 5-day AUC for decitabine that is equivalent to 5-day AUC for a daily intravenous dose of decitabine 20 mg/m ² administered as a one-hour (1 hour) infusion. In some embodiments, when administered daily to a subject, the AUC ratio for decitabine on day 2 compared to day 1 is about 1.5:1 to 2:1. In some embodiments of the present invention, the methods comprise administering to a subject a solid oral dosage form containing decitabine and cedazuridine, wherein the solid oral dosage form, when administered daily to the subject, provides a pharmacodynamic effect that is equivalent to the pharmacodynamic effect of a daily intravenous dose of decitabine 20 mg/day. m ² in the form of a one-hour (1 hour) infusion. In specific embodiments, the pharmacodynamic effect is DNA demethylation. The solid oral dosage form used may be any solid oral dosage form described herein.

In addition, methods are provided for treating a disorder amenable to decitabine in a subject in need thereof, comprising administering to the subject a solid oral dosage form in accordance with an embodiment of the invention that provides treatment for the disorder in the subject. In some embodiments, the disorder that is treatable with decitabine is a hyperproliferative disease, such as cancer. The methods can be used to treat any cancer that is known or later discovered to be effective in treating decitabine. In specific embodiments, the disorder is a cancer selected from hematologic malignancies and solid cancers. Examples of hematologic malignancies include myelodysplastic syndromes (MDS), leukemia (eg, 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, solid cancers include pancreatic cancer, ovarian cancer, peritoneal cancer, non-small cell lung cancer, breast cancer, neuroectodermal tumors, and/or sarcomas.

In some embodiments, the present invention provides a method for treating a hyperproliferative disorder, such as cancer, where the cancer is MDS. MDS is a group of cancers characterized by a common abnormal maturation of blood cells originating from the bone marrow, and symptoms can vary. The International Prognostic Scoring System (IPSS) ranks the severity of MDS across several risk groups based on the patient's hemoglobin level, absolute neutrophil count (ANC), platelet count, and percentage of bone marrow blasts. Risk groups include low, medium-1, medium-2 and high risk. There are other methodologies for assessing risk groups, such as the revised IPSS (IPSS-R) and the WHO prognostic scoring system (WPSS), as described in the NCCN Patient Guidelines, Myelodysplastic Syndromes, 2018. The methods of the present invention can be used to treating a hyperproliferative disorder, such as cancer, in a subject (eg, a human patient) who has been diagnosed at any risk group for MDS based on any assessment methodology. In some embodiments, a subject in need of the present invention may include a subject diagnosed with low-risk MDS (defined as IPSS low and/or intermediate-1 risk).

Some embodiments of the invention provide methods for inhibiting degradation

- 9 045934 administration of decitabine to a subject in need thereof, comprising administering to the subject a solid oral dose in accordance with an embodiment of the invention providing inhibition of degradation of decitabine in the subject.

In some embodiments, the present invention provides a method of reducing DNA methylation in a subject in need thereof, comprising administering to the subject a solid oral dosage form in accordance with an embodiment of the invention that reduces DNA methylation in the subject (e.g., providing a drug substrate that reduces DNA methylation CDA). DNA methylation may be reduced compared to the subject's pre-treatment methylation level. In some embodiments, use reduces LINE-1 DNA methylation. LINE-1 is a long interspersed nuclear element found in human (e.g., subject) DNA known in the art, and its methylation levels can be measured using standard methods in the art to determine the genetic effects of hypomethylating agents such as drugs CDA substrates (eg, decitabine).

The present inventors have demonstrated that administration of a solid oral dosage form in accordance with an embodiment of the present invention to a subject in need thereof produces multiple beneficial responses in the subject. For example, in some embodiments, use reduces DNA methylation in a 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 thereof) compared to a reference measurement, e.g., compared to the subject's DNA methylation prior to use (e.g., the subject's baseline DNA methylation). DNA methylation in a subject can be quantitatively and/or qualitatively assessed using any standard method in the art, for example, by a marker of relative overall methylation compared to control, for example, LINE-1 methylation compared to control. For example, in some embodiments, administration reduces LINE-1 methylation in a 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 the subject's LINE-1 methylation before administration (e.g., to the subject's baseline LINE-1 methylation). For example, in some embodiments, administration may reduce LINE-1 methylation in a 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 a subject by about 5-20%, about 6-15%, or about 8-10%.

In some embodiments, administration may reduce the subject's absolute neutrophil count (ANC) to less than 0.5 x 10 ⁹ cells/L of blood for no more than two weeks (e.g., no more than 14, 13, 12, 11, 10, 9 , 8, 7, 6, 5, 4, 3 or 2 days in a row or any value or range therein) after a 28-day cycle. In some embodiments, the administration reduces the subject's absolute neutrophil count (ANC) to less than 0.5 x 10 ⁹ cells/L of blood for no more than two weeks (e.g., no more than two, three, four, five, six weeks, etc. .d.) during treatment (for example, between several repeating 28-day cycles).

In some embodiments, administration increases the number of fetal hemoglobin expressing cells (i.e., F cells) by at least 5% (e.g., at least 5, 6, 7, 8, 9, 10, 15, 20, 25 or 30% or more), optionally measured as % F cells/RBCs per sample (eg, in a patient's blood sample) compared to baseline control % F cells/RBCs (eg, compared to % F cells/RBCs in patient before treatment, for example, compared with the average % of F cells/RBCs in a population of patients not undergoing treatment (for example, in a population of healthy patients)). For example, in some embodiments, administration may increase the % of F cells in a subject by at least 5%, at least 8%, at least 10%, at least 15%, or at least 23%, or more compared to the original control level. In some embodiments, administration may increase the % of F cells in a subject by about 5-30%, about 6-24%, or about 8-20% compared to the baseline control.

In some embodiments, the use increases F cells to a total of at least 10% to 30% or more of the total red blood cells (e.g., at least 15%, 16%, 17%, 18%, 19%, 20%, 21%, 22%, 23%, 24%, 25%, 26%, 27%, 28%, 29%, or 30% or more F cells/RBCs, or any value or range thereof) per sample (eg, in a blood sample patient). For example, in some embodiments, the application may increase F cells to a total of at least 15%, at least 20%, at least 23%, at least 35%, or more of the total red blood cells in the sample. In some embodiments, the application may increase F cells to a total of about 15 to 30%, about 18 to 25%, or about 15 to 35% of the total red blood cells in the sample.

In some embodiments of the methods of the present invention, the subject may be

- 10 045934 mammals. In some embodiments of the methods of the present invention, the subject may be a human.

Any dosing regimen well known to those skilled in the art for controlling the timing and sequence of drug delivery can be used and repeated as necessary to effect treatment with the methods of the invention. For example, the solid oral dosage forms of the invention can be administered 1, 2, 3, or 4 times daily as a single dose, multiple discrete doses, or continuous infusion. In specific embodiments, the oral solid dosage form is administered once daily.

In some embodiments, administration of solid oral dosage forms in accordance with an embodiment of the invention may be administered for about 1 day to 28 days during a 28-day cycle (e.g., about 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 or 28 days in a 28-day cycle). In specific embodiments, the administration of solid oral dosage forms is administered once daily for five days (eg, 5 consecutive days) in a 28-day cycle. In some embodiments, administration of solid oral dosage forms in accordance with an embodiment of the invention may be administered on consecutive days within a 28-day cycle. For example, solid oral dosage forms according to an embodiment of the invention can be administered for 5 consecutive days. In some embodiments, the solid oral dosage forms of an embodiment of the invention may be administered on any 3 consecutive days (e.g., Monday, Tuesday, and Wednesday MonTues; Tuesday, Wed., and Thursday Tue WedThu; Wednesday, Thursday, and Friday WedThu Fri; Thursday, Friday and Saturday Thu Fri Sat; on Friday, Saturday and Sunday Fri Sat Su; on Saturday, Sunday and Monday Sat Su Mon and/or on Sunday, Monday and Tuesday Su Mon Tue, etc.). In some embodiments, the administration of solid oral dosage forms in accordance with an embodiment of the invention may be administered over 5 consecutive days (e.g., MWWWWFt or any other combination of 5 consecutive days), for 7 consecutive days (MWWWWWWWW or any other combination of 7 days consecutive), 14 days in a row (for example, two weeks in a row); 21 consecutive days (eg, three weeks in a row) and/or 28 consecutive days (eg, four weeks in a row) in a 28-day cycle. Consecutive one-day treatment can be repeated one or more times during a 28-day cycle, for example every week, every other week.

In some embodiments, administration of solid oral dosage forms in accordance with an embodiment of the invention may be administered on non-consecutive days during a 28-day cycle, for example, on 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 consecutive days. Non-consecutive days may include a schedule of every other day (for example, Mon-Wed-Fri), every two days, every three days, every four days, every five days, every six days, every seven days, etc. in a 28-day cycle. Non-consecutive days may include administration on several consecutive days (eg, on), followed by several days without administration (eg, off), followed by use on several consecutive days (eg, on), etc. over a 28 day cycle. For example, in some embodiments, application may be administered over 2 consecutive days (eg, every Monday and Friday, or any other combination of 2 consecutive days). In some embodiments, administration may be administered over 3 consecutive days (eg, PnSrPt or any other combination of 3 non-consecutive days). A non-consecutive one-day treatment may be repeated one or more times during a 28-day cycle, for example every week, every other week.

In some embodiments, a time 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) may occur between multiple 28-day treatment cycles of the present invention. A period of no treatment may be necessary to allow the subject (eg, a human patient) of the present invention to recover sufficiently to continue treatment. The period of time between treatment cycles can be determined by a physician using standard methods in the art and can be determined individually for each subject, for example, based on an adequate blood test, for example, adequate absence of neutropenia (for example, absolute neutrophil count (ANC) in the subject not less than or higher than 0.5x10 ⁹ cells/l) and can be adjusted during the course of treatment based on the decision of the attending physician. In some embodiments, the time period between treatment cycles may be minimal, such as no time period, such as immediately starting in the next 28-day time 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.

In some embodiments, application may be administered, for example, over 10 days in a 28-day cycle, wherein 10 days of application include 5 consecutive days

- 11 045934 applications (eg 5 days on) followed by 2 consecutive days without use (eg 2 days off) followed by 5 consecutive days of use (eg 5 days on) over a 28-day cycle. In some embodiments, application may be administered over, for example, 14 days, wherein 14 days of application comprises 7 days on, followed by 7 days off, and then 7 days on, in a 28-day cycle. In some embodiments, administration may be administered over, for example, 9 days, wherein 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 days off, followed by 3 days of administration, in a 28-day cycle. In some embodiments, application may be administered over, for example, 9 days, wherein 9 days of application comprises 3 non-consecutive days of dosing (e.g., PnSrPt) followed by 1 day off, followed by 3 non-consecutive days of dosing (e.g., PnSrPt ), followed by 1 day off, followed by 3 non-consecutive days on during a 28-day cycle.

In some embodiments, administration of a solid oral dosage form in accordance with an embodiment of the invention may be administered over one or more weeks over a 28-day cycle, such as one week, two weeks, three weeks, or four weeks over a 28-day cycle. . The weeks can be sequential and/or non-consecutive.

The regimen may include pre-treatment and/or co-administration with at least one additional therapeutic agent. In such a case, a solid oral dosage form containing decitabine and cedazuridine can be administered with at least one additional therapeutic agent simultaneously, separately or sequentially. An additional therapeutic agent may also be included in the solid oral dosage form.

Examples of the chemotherapeutic agent include alkylating agents (eg, which may include doxorubicin, cyclophosphamide, estramustine, carmustine, mitomycin, bleomycin, and the like); antimetabolites (eg, which may include 5-fluorouracil, capecitabine, gemcitabine, nelarabine, fludarabine, methotrexate, and the like); platinating agents (eg, which may include cisplatin, oxaliplatin, carboplatin, and the like); topoisomerase inhibitors (eg, which may include topotecan, irinotecan, etoposide and the like); tubulin agents (eg, which may include paclitaxel, docetaxel, vinorelbine, vinblastine, vincristine, other taxanes, epothilones, and the like); signal transduction inhibitors (eg, kinase inhibitors, antibodies, farnesyltransferase inhibitors, etc.); and other chemotherapeutic agents (eg, tamoxifen, antimitotic agents such as polo-like kinase inhibitors or Aurora kinase inhibitors, etc.), but are not limited to them.

In some embodiments, the present invention provides about 35 mg per daily dose of decitabine, and therefore, for example, for a five-day treatment regimen, a cumulative dose of about 175 mg per 28-day decitabine treatment cycle is anticipated. Dosage levels, route of administration, and dosage schedule may be varied by those skilled in the art using known methods as deemed appropriate for the subject (eg, patient).

In some embodiments, the present invention provides about 100 mg per daily dose of cedazuridine, and thus, for a five-day treatment regimen, a cumulative dose of about 500 mg per 28-day treatment cycle is anticipated. Dosage levels, route of administration, and mode of administration may be modified by those skilled in the art using known methods as deemed necessary for the subject (eg, patient).

In some embodiments, the methods of the present 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 contained in the solid oral dosage forms of the present invention and using the same and the same application schemes.

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 aspects, as well as other aspects, and may cover one, some, or all of the above and below embodiments, as well as also other embodiments.

Except in the working examples or where otherwise indicated, all numbers expressing quantities of ingredients, reaction conditions, etc., used in the specification and claims are to be understood as modified by the term about. Accordingly, unless otherwise stated, such numbers are approximate values that may vary depending on the desired properties to be achieved by the present invention. At a minimum, each numeric parameter should be interpreted in light of the number of significant figures and normal rounding techniques, but not

- 12 045934 for the purpose of attempting to limit the application of the doctrine of equivalents to the scope of the claims.

While the numerical ranges and parameters defining the broad scope of the invention are approximate, the numerical values stated in the worked examples are presented as accurately as possible. However, any numerical value inherently contains certain errors, necessarily arising from the standard deviation found in the corresponding test measurements.

Having described the present invention, it will be explained in more detail in the following examples, which are included herein for illustrative purposes only and are not intended to limit the invention.

Examples

Example 1: ASTX727 Phase 1 Test

The phase 1 trial of ASTX727 was a dose-escalation study designed to establish the recommended doses of cedazuridine and decitabine that achieve AUC equivalence with the standard dose of decitabine when administered intravenously (decitabine 20 mg/ ^m2 IV). In fig. Figure 1 provides an overview of the study design. In Cycle 1, each patient received a cohort-specific dose of oral decitabine on day -3, a 1-hour intravenous infusion of decitabine 20 mg/m ² on day 1, and a cohort-specific dose of oral decitabine plus cedazuridine on days 2-5. In Cycles 2 onwards, decitabine and cedazuridine were administered orally on days 1–5. The cedazuridine dose was increased first, and the decitabine dose was increased once CDA inhibition by cedazuridine approached maximal effect. Only one drug dose was increased in the cohort. Fixed doses were administered without adjustment for body weight or body surface area. Days -3, 1, 2, and 5 for decitabine included full-day pharmacokinetic analysis. The starting dose was 20 mg for oral decitabine and 40 mg for cedazuridine (an equivalent human dose approximately 100 times the safety margin compared with the level at which no adverse events were observed in cynomolgus monkeys). Dosage escalations of each drug were made if the mean AUC of oral decitabine was less than 90% of that of intravenous decitabine in the cohort and if no dose-limiting toxicity was observed. Dose-limiting toxicity was defined as grade 4 or grade 3 hematologic toxicity lasting more than 14 days and unrelated to the underlying disease. Once the decitabine AUC target range adopted as the primary endpoint and established for intravenous decitabine was achieved at a dose considered safe, the cohort that most closely matched intravenous decitabine was expanded to 18 evaluable patients. Dose increases for patients previously receiving a lower dose were permitted at the discretion of the investigator if the patient tolerated the initially prescribed doses.

The pharmacokinetic profile of decitabine was characterized by analyzing EDTA (edetic acid)-treated plasma using validated liquid chromatography-tandem mass spectrometry with tetrahydrouridine (Santa Cruz Biotechnology, Dallas, TX) for stabilization and with a linear assay range of 0.5-100 ng /ml for decitabine. Serial plasma samples (from predose to 24 hours postdose) were collected on days -3, 1, 2, and 5 (also immediately predose on days 3 and 4) during the first cycle. Specifically, pharmacokinetic samples were obtained predose and at 0.25, 0.5, 1.0 (for IV only 1.083 hours), 1.5, 2, 3, 4, 6, 8, and 24 hours after dose administration.

Patients could discontinue treatment or be excluded from the study due to disease progression, unacceptable toxicity, patient request, withdrawal of consent, or at the discretion of the investigator due to lack of benefit.

The results of the Phase 1 study are shown in Table. 3 and in fig. 2.

Table 3. AUC of Phase 1 dose escalation

Oral dose (mg) ^a AUCo-tB day (h ng/ml) Geometric mean (gKV%) Total value of AUCo-t3a 5 days Cohort DEC CED N D-3 (DEC separately) D2 (ASTX7 27) D5 (ASTX7 27) BBD1 Orally BB (N=41) % AUC (Oral/IV) 1 20 40 6 10.7 (108) 42.8 (136) 70.3 (86) 159 (53) 324 40 5 ^b 7.90 (58) 29.0 (45) 53.6 (40) 138 (41) 243 thirty 2 20 60 6 7.49 (52) 30.5 (62) 68.9 (44) 170 (39) 306 ^821d 37 3 20 100 6 7.90 (147) 53.5 (44) 94.8 (46) 192 (47) 433 53 4 40 100 6 29.8 (100) 167 (45) 221 (74) 153 (50) 1050 128 5 thirty 100 ^19th 15.3 (92) 81.7 (59) 146 (50) 166 (41) 667 81

CED = cedazuridine;

DEC = decitabine;

gCV%=geometric coefficient of variation.

^aOral dosage was not adjusted based on body weight or body surface area; intravenous

- 13 045934 dose was 20 mg/ ^m2 in all cohorts.

^b One subject in Cohort 1 was excluded as an outlier.

^c IV data for 18 patients, one patient was excluded as being out of sample.

^d The geometric mean of the overall 5-day IV AUC _0-t was calculated for the entire IV population (N=41).

In fig. In Figure 2, the two highlighted curves show the exposure to cedazuridine at a dose of 100 mg and oral decitabine at doses of 30 and 40 mg (groups 4 and 5 in Table 3). At these doses, oral decitabine exposure ranged from 81% to 128% of intravenous decitabine exposure. Based on this, it was predicted that the average dose of decitabine between 30 and 40 mg, which is 35 mg, would be closest to intravenous administration.

Example 2: Phase 2 Dose Confirmation Study of ASTX727

The Phase 2 ASTX727 trial was a randomized crossover trial of decitabine 20 mg/m2 ^IV daily (for 5 days) versus oral decitabine/cedazuridine once daily (for 5 days) in Cycle 1 with patients switching to the other drug. in Cycle 2 (see Fig. 3). Beginning with Cycle 3, all patients continued to take decitabine/cedazuridine orally once daily (for 5 days), each cycle every 28 days, until progression.

Baseline characteristics of patients in phase 2 are shown in Table. 4.

Table 4. Baseline characteristics of Phase 2 patients

Characteristic Sequence A (N=41) ASTX727 -+ DEC IV Sequence B (N=39) DEC IV -+ ASTX727 Median age (min-max) 71 (32, 90) Years 71 (41, 86) years Gender, Men/Women % 78/22% 74/26% Median body weight (min-max) 78.8 (40-122) kg 86.2 (42-118) kg Median 1P1T 1.96 (1.3-2.4) ^m2 2.05 (1.3-2.4) ^m2 ECOG PC 0-1 93% 90% 2 7% 10% IPSS Intermediate-1 risk 46% 41% Intermediate-2 or high 34% 36% risk html 20% 23% Median hemoglobin (min-max) 8.75 (7.1-14.9) g/dl 9.25 (6.8-13.9) g/dl Median neutrophils (min-max) 0.94 (0.03-73.6) 10% 0.76 (0.06-63.4) 10 ⁹ /l Median platelets (min-max) 58.5 (2-523) 10 ⁹ /l 60.0 (8-569) 10 ⁹ /l Dependence on red blood cell transfusion 48.8% 46.2% Platelet transfusion dependence 19.5% 10.3% Median VM blasts (min-max) 7% (0-19%) 5% (0-17%)

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

Table 5. Composition of ASTX727 tablet

Component Function Standard Composition (wt.%) Amount (mg/tablet) Cedazuridine Active substance Internal specification 19.42 100.0 Decitabine Active substance Internal specification 6.80 35.0 Lactose monohydrate Diluent NF 62.62 322.5 Hypromellose Binding agent Pharm. USA 1.94 10.0 Croscarmellose sodium Desinte grant NF 4.85 25.0 Colloidal silica Glidant NF 0.97 5.0 Magnesium stearate Lubricant NF 0.49 2.5 Whole tablet core 97.09 500.0 Opadry II 85F15458 Red Film casing Provider 2.91 15.0 Whole tablet coated 100.00 515.0

The 5-day AUC0-t of decitabine in plasma for individual decitabine (35 mg) and cedazuridine (100 mg) capsules is shown in Table. 6A, and the 5-day AUC of _0-t decitabine in plasma for one tablet of ASTX727 is shown in table. 6B.

- 14 045934

Table 6A. Phase 2 PK (cedazuridine + decitabine capsules versus IV decitabine)

N BB Geo. LSM Oral Geo. LSM Relation Geo. LSM Oral/IV, % (80% CI) Intraindividual variability (%CV) Decitabine, 5-day AUCo-t (Ng/ml) 40 802.81 750.82 93.52 (82.10; 106.5) 47.0

IV = 20 mg/m intravenous infusion (1 hour) of decitabine. Oral = 100 mg cedazuridine and 35 mg decitabine, capsules.

CI = confidence interval;

IV = intravenous;

Geo. LSM = least squares geometric means;

CV = coefficient of variation.

Table 6B. Phase 2 PK (ASTX727 versus IV DEC)

N BB Geo. LSM Oral ASTX727 FDC Geo. LSM Relation Geo. LSM oral/IV, % (80% CI) Intra-individual variability (% CV) Decitabine, 5-day AUCo-t (ppg/ml) 24 745.26 727.29 97.59% (80.48; 118.3) 53.8

,Λ,Λ 2π , 2 1 Ζ, X ζBB = 20 mg/m intravenous infusion (1 hour) of decitabine.

Oral = ASTX727 FDC tablet (100/35 mg cedazuridine/decitabine)

CI = confidence interval;

IV = intravenous;

Geo. LSM = least squares geometric means;

CV = coefficient of variation.

In fig. Figure 4 shows the individual and geometric mean AUC of _0-24 decitabine in plasma following oral administration of 100 mg cedazuridine and 35 mg decitabine compared with a single infusion of 20 mg/m ² decitabine. The 5-day exposure of oral decitabine was approximately 98% of that of intravenous decitabine, confirming that the doses selected for cedazuridine and decitabine tablets were similar to those of intravenous decitabine.

Hematology and global DNA methylation were assessed on days 1, 8, 15, 22, and 29 of the first cycle using bisulfite sequencing analysis of long interspersed nuclear element-1 (LINE-1) methylation (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 (%) calculated as: 100x ([methylation on a given day after treatment] - [baseline methylation]. Assessing adverse events by physical examination and laboratory monitoring (hematology, metabolic profile and liver enzymes ) were performed before treatment on day 1 of each cycle (weekly for hematology studies in the first two cycles). After discontinuation of treatment, patients were monitored for survival and transformation to acute myeloid leukemia. Dose reduction or delay was allowed at the discretion of the investigators to allow recovery after drug-related myelosuppression.

The results of the LINE-1 study are shown in FIG. 5A-5B and 6A-6B. Efficacy and safety data from the phase 2 study are shown in Table 1. 7 and 8 respectively.

Table 7. Phase 2 efficacy (best response and transfusion independent ¹³ )

Best answer (N=80) % 95% CI Complete response (CR) 21.3% 13-32% Partial answer 0 Bone marrow complete response (mCR) mCR + HI 22.5% 7.5% 14-32% 2.8-15.6% Hematological Improvement (HI) HI-E HI-N HI-P 16.3% 10% 2.5% 13.8% 9-26% 4-19% 0.3-8.7% 7-23% General answer (CP + PR + mCR + HI) 60% 48-71% Independence from red blood cell transfusion (N=38) ^b 50% 33-67% Independence of platelet transfusion (N=12) ^b 50% 21-79%

^a IWG 2006 criteria;

^b at least 8 weeks of transfusion independence in patients who were dependent at baseline.

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Table 8. Phase 2 Trials, Safety-Related Adverse Events ____________________Grade > 3 in >5% of Patients_______________

BB DEC (Cycle 1 or 2) Ν=75 η (%) ASTX727 (Cycle 1 or 2) Ν=78η (%) Any associated AEs grade > 3 24 (32%) 21 (27%) Neutropenia 16(21.3%) 11 (14.1%) Thrombocytopenia 11 (14.7%) 9(11.5%) Leukopenia 6 (8.0%) 6 (7.7%) Anemia 4 (5.3%) 5 (6.4%) Febrile neutropenia 4 (5.3%) 3 (3.8%)

Example 3: Phase 3 Trials

Phase 3 was a randomized crossover format in which patients with MDS and CMML eligible to receive decitabine were randomly assigned to Program A, in which they received ASTX727 in Cycle 1, then IV decitabine in Cycle 2, and Program B, in which in reverse order. All patients received ASTX727 starting in Cycle 3 to assess long-term efficacy and safety. 118 evaluable patients were required to show AUC equivalence between oral and intravenous administration. See fig. 7. Main criteria for inclusion of subjects: (1) candidates for IV administration of decitabine; (2) ECOG PS 0-2; (3) life expectancy of at least 3 months; (4) adequate organ function; and (5) one previous HMA cycle is allowed. The primary endpoint included 5-day AUC equivalence of total decitabine plasma levels (oral/IV 90% CI 80 to 125%). Secondary endpoints were: efficacy, including response rate, transfusion independence, duration of response, leukemia freedom, and overall survival; safety ASTX727; and maximal demethylation of LINE-1.

Of the 133 patients treated in Phase 3, 123 completed both intravenous and oral 5-day cycles to assess decitabine AUC for both types of administration. The 5-day oral/IV plasma decitabine AUC ratio was approximately 99% with a 90% confidence interval of approximately 93 to 106%. Sensitivity and secondary analyzes of all patients assessed for pharmacokinetics confirmed the results of the primary analysis (see Table 9).

Table 9. Primary endpoint (decitabine AUC equivalence at 5 days)

BB DEC Oral ASTX727 5-day AUCo-24 (h-ng/ml) N Geo, L.S.M. N Geo, L.S.M. Geo ratio, LSM, Oral/IV, % (90% CI) Intraindividual variability (%CV) Primary _π „1 Pair Analysis 123 864.9 123 855.7 98.9 (92.7; 105.6) 31.7

1Paired patient population: patients who received both ASTX727 and decitabine IV in a randomized first two cycles with adequate PK samples.

The primary endpoint of the study was met with high confidence: oral/IV 5-day plasma decitabine AUC -99% with 90% CI -93-106%. All sensitivity analyzes and secondary pharmacokinetic AUC analyzes confirmed the results of the primary analysis.

Fig. 8 shows individual patient exposures for both ASTX727 on days 1, 2 and 5 and intravenous decitabine on days 1 and 5. As can be seen, individual exposures in patients receiving oral or intravenous decitabine overlap significantly with each other, despite the fact that oral decitabine was administered at a fixed dose and intravenous administration was based on body surface area. The AUC for decitabine on day 1 is slightly lower than the AUC on days 2-5 and the AUC when administered intravenously. The AUC ratio for decitabine on day 2 compared to day 1 ranges from about 1.5:1 to about 2:1.

Fig. 9 shows that the pharmacodynamic effect of global DNA demethylation measured by the LINE-1 assay was also nearly identical with oral versus intravenous administration in cycles 1 and 2. The difference in DNA methylation between oral and intravenous administration was <1% and was not significant.

In summary, oral ASTX727 fixed-dose tablet (cedazuridine/decitabine 100/35 mg) achieved -99% of the 5-day systemic plasma exposure of decitabine compared to intravenous decitabine 20 mg/ ^m2 (primary endpoint). Additionally, consistent results were confirmed in all AUC sensitivity analyzes and secondary analyses. Additionally, oral ASTX727 achieved nearly the same pharmacodynamic effect as intravenous decitabine (<1% difference in LINE-1% DNA demethylation). Additionally, the durable clinical response, 50% transfusion independence, and median survival of 18.3 months observed in Phase 2 long-term follow-up are consistent with intravenous decitabine. Additionally, there were no significant differences in adverse events, including gastrointestinal adverse events, between oral and intravenous ASTX727.

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Claims (23)

administration of decitabine in a randomized first 2 cycles. The foregoing is illustrative of the present invention and should not be construed as limiting it. The invention is defined by the following claims, taking into account the equivalents of the claims that are to be included. CLAIM 1. Immediate-release solid oral dosage form containing cedazuridine 100 mg, decitabine 35 mg, microcrystalline cellulose, lactose monohydrate, hydroxypropylcellulose, croscarmellose sodium, colloidal silicon dioxide and magnesium stearate. 2. The solid oral dosage form of claim 1, which, when administered daily to a human, provides decitabine plasma levels with a 5-day area under the curve (AUC) for decitabine that is equivalent to the 5-day AUC for a daily intravenous dose of 20 mg/m ² decitabine as a 1-hour infusion. 3. The solid oral dosage form of claim 1 or 2, wherein when administered daily to a human, the AUC ratio for decitabine on day 2 compared to day 1 is from 1.5:1 to 2:1. 4. A solid oral dosage form according to any one of claims 1-3, providing, when administered daily to a person, a pharmacodynamic effect that is equivalent to the pharmacodynamic effect of a daily intravenous dose of decitabine 20 mg/m ² administered as a 1-hour infusion. 5. Solid oral dosage form according to claim 4, where the pharmacodynamic effect is DNA demethylation. 6. Solid oral dosage form according to any one of claims 1 to 5, which is a tablet. 7. Solid oral dosage form according to any one of claims 1-5, which is a capsule. 8. Solid oral dosage form according to any one of claims 1-7, additionally containing a shell. 9. The solid oral dosage form according to claim 8, wherein the coating is a colored coating. 10. Solid oral dosage form according to claim 9, in which the shell is Opadry II 85F15458 Red. 11. A method of treating a hyperproliferative disease in a subject in need thereof, comprising administering to the subject a solid oral dosage form according to any one of claims 1 to 10, thereby treating the disease. 12. The method of claim 11, wherein the hyperproliferative disease is cancer. 13. The method according to claim 12, where the cancer is selected from hematological malignancies and solid cancers. 14. The method according to claim 13, where the hematological malignancy is selected from myelodysplastic syndromes (MDS), leukemia and lymphoma. 15. The method of claim 14, wherein the leukemia is acute lymphocytic leukemia, acute myelogenous leukemia, chronic myelogenous leukemia, myeloproliferative neoplasia or chronic myelomonocytic leukemia. 16. The method of claim 14, wherein the lymphoma is Hodgkin's lymphoma, non-Hodgkin's lymphoma or T-cell lymphoma. 17. The method of claim 14, wherein the myelodysplastic syndromes (MDS) are low-risk MDS, such as IPSS low level and/or IPSS intermediate level 1. 18. The method 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 sarcomas. 19. The method according to any one of claims 11 to 18, wherein the solid oral dosage form is administered for 1 day to 28 days during a 28-day cycle, such as 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 or 28 days in a 28-day cycle. 20. The method according to any one of claims 11 to 19, wherein the solid oral dosage form is administered on consecutive days during a 28-day cycle, wherein said consecutive days may be 3 days MonWtW, TuWWT, WedWF, etc.; 5 days MonTueWedThuFri, etc.; 7 days, Mon Tue Wed Thu Fri Sat Sun; 14 days, in particular two weeks in a row; 21 days, specifically three weeks in a row. 21. The method according to any one of claims 11 to 19, wherein the solid oral dosage form is administered non-sequentially over a 28-day cycle, wherein said consecutive days may be 3 days of PnSrPt; 10 days, in particular 5 days of admission, 2 days of break, 5 days of admission; 14 days, in particular 7 days on, 7 days off, 7 days on. 22. The method according to any one of claims 11 to 19, wherein the solid oral dosage form is administered for one week in a 28-day cycle. 23. The method according to any one of claims 11-19, where the solid oral dosage form is used in -