Pharmaceutical composition for treating cancer and method of use thereof

Abstract

Providing a device for use in treating cancer in subjects requiring treatment of said cancer. [Solution] A dosage form or kit used to treat cancer in a subject that requires treatment for cancer, wherein the cancer is a hematological cancer and a solid tumor, and the subject contains an effective amount of sedazulidine, an effective amount of decitabine, and an effective amount of venetoclax.

Description

[Technical Field]

[0001] Priority statement This application claims the benefits of U.S. Provisional Patent Application No. 63 / 107,010, filed on 29 October 2020, which is incorporated herein by reference in its entirety.

[0002] The present invention relates to pharmaceutical compositions and methods for the treatment of cancer, such as leukemia. [Background technology]

[0003] Decitabine (i.e., 5-aza-2'-deoxycytidine), a cytidine analog, is an anti-cancer drug and a hypomethylating agent (HMA) for the treatment of myelodysplastic syndrome (MDS), and also has potential applications in the treatment of acute myeloid leukemia (AML) and chronic myelomonocytic leukemia (CMML).

[0004] [ka]

[0005] Cedazuridine (i.e., (4R)-2'-deoxy-2',2'-difluoro-3,4,5,6-tetrahydrouridine, also known as E7727) is a CDA inhibitor. Cedazuridine and methods for preparing 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 entirety.

[0006] [ka]

[0007] Astex Pharmaceuticals, Inc. has received FDA approval for a fixed-dose combination of decitabine and sedazulidine, marketed by Taiho Pharmaceutical Co., Ltd. under the trade name INQOVI®.

[0008] Venetoclax (i.e., 4-[4-[[2-(4-chlorophenyl)-4,4-dimethylcyclohexen-1-yl]methyl]piperazine-1-yl]-N-[3-nitro-4-(oxan-4-ylmethylamino)phenyl]sulfonyl-2-(1H-pyrrolo[2,3-b]pyridine-5-yloxy)benzamide, CAS 1257044-40-8) is a BH3 mimetic that has been shown to inhibit the B-cell lymphoma-2 (Bcl-2) protein. Venetoclax has been used in adults to treat chronic lymphocytic leukemia (CLL), small lymphocytic lymphoma (SLL), and acute myeloid leukemia (AML).

[0009] [ka]

[0010] The use of combinations of active pharmaceuticals may provide beneficial therapeutic effects to patients, but drug interactions may also exist that alter the pharmacokinetic effects of the active pharmaceuticals or become toxic or otherwise harmful to the patient. [Overview of the project] [Means for solving the problem]

[0011] A method is provided for treating a disorder in a subject that requires treatment of the disorder, comprising administering to the subject an effective amount of sedazulidine, an effective amount of decitabine, and an effective amount of venetoclax, thereby treating the disorder in the subject. In some embodiments of the present invention, the disorder is a hyperproliferative disorder, such as cancer. In some embodiments, the disorder is a hematological malignancy, such as myelodysplastic syndromes (MDS), myeloproliferative neoplasms (MPN), leukemia (e.g., acute myeloid leukemia), or lymphoma. In some embodiments, the subject is 75 years of age or older and / or has one or more comorbidities that prevent the use of standard induction chemotherapy.

[0012] In some embodiments of the present invention, the effective amount of sedazulidine, the effective amount of decitabine, and the effective amount of venetoclax are administered as a solid oral dosage form. In some embodiments, the effective amount of sedazulidine and the effective amount of decitabine are administered together as a combined solid oral dosage form. In some embodiments, the effective amount of sedazulidine and the effective amount of decitabine are administered on days 1 to 5 of a 28-day cycle, and the effective amount of venetoclax is administered daily throughout the 28-day cycle.

[0013] Furthermore, according to embodiments of the present invention, a solid oral dosage form is provided comprising sedazulidine, decitabine, and venetoclax, and at least one pharmaceutically acceptable excipient. [Modes for carrying out the invention]

[0014] The present invention will be described in more detail below. This description is not intended to be an exhaustive catalog of all the ways in which the invention may be implemented or of all the features that may be added to the invention. For example, features illustrated with respect to one embodiment may be incorporated into other embodiments, and features shown with respect to a particular embodiment may be deleted from that embodiment. Additionally, various modifications and additions to the disclosed embodiments that do not depart from the invention will become apparent to those skilled in the art in light of the present disclosure. Accordingly, the following specification is intended to illustrate some particular embodiments of the invention and is not intended to identify all permutations, combinations, and variations thereof.

[0015] Unless the context dictates otherwise, it is specifically intended that the various features of the invention described herein may be used in any combination. Further, the invention contemplates that in some embodiments of the invention, any feature or combination of features described herein may be excluded or omitted. To illustrate, if the specification states that a certain composite includes components A, B, and C, it is specifically intended that any one of A, B, or C, or any combination thereof, may be omitted or waived, either singly or in any combination.

[0016] 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 terminology used in the description of the invention herein is for the purpose of describing particular embodiments only and is not intended to be limiting of the invention.

[0017] All publications, patent applications, patents, nucleotide sequences, amino acid sequences, and other references mentioned herein are incorporated by reference in their entirety.

[0018] definition In the description of this invention and the appended claims, the singular forms “a,” “an,” and “the” are intended to also encompass the plural forms unless the context otherwise explicitly indicates.

[0019] As used herein, "and / or" means and includes any possible combination of one or more of the related items listed, and, when interpreted as an alternative ("or"), the absence of any combination.

[0020] Furthermore, the present invention also intends that, in some embodiments of the present invention, any feature or combination of features described herein may be excluded or omitted.

[0021] Furthermore, as used herein, the term "approximately" means that when referring to a measurable value, such as the amount, dose, time, or temperature of the compound or agent of the present invention, it includes variations of ±10%, ±5%, ±1%, ±0.5%, or even ±0.1% of the specified amount.

[0022] The transitional phrase "essentially derived from" as used herein should be interpreted as encompassing the enumerated materials or processes, and those that do not substantially affect one or more fundamental and novel features of the claimed invention. Accordingly, the phrase "essentially derived from" as used herein should not be interpreted as equivalent to "containing".

[0023] "Effective dose" refers to the amount required to produce the desired effect (for example, an increase in half-life, an improvement in the bioavailability or efficacy of a therapeutic agent treating cancer in a subject, or a reduction in DNA methylation in a subject).

[0024] "Pharmacologically acceptable" means properties and / or substances that are acceptable to the patient from a pharmacological and / or toxicological standpoint, and / or acceptable to the pharmacist involved in the manufacture from a physical and / or chemical standpoint, with respect to the composition, formulation, stability, patient tolerance, bioavailability and compatibility with other components.

[0025] "Pharmacologically acceptable salt" means an acid or base salt of the compound of the present invention that has the desired pharmacological activity and is also biologically and otherwise desirable. The salt can be formed using an acid and includes, but is not limited to, acetate, adipine, alginate, aspartic acid, benzoate, benzenesulfonate, bisulfate, 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 basic salts include, but are not limited to, 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 and N-methyl-D-glucamine, and salts with amino acids such as arginine and lysine. In some embodiments, the basic nitrogen-containing group can be quaternized with active substances including lower alkyl halides such as methyl chloride, bromide and iodide, ethyl, propyl and butyl; dialkyl sulfates such as dimethyl sulfate, diethyl, dibutyl and diamyl; long-chain halides such as decyl chloride, bromide and iodide, lauryl, myristyl and stearyl; and aralkyl halides such as phenethyl bromide.

[0026] "Pharmacologically acceptable excipients" can mean any substance that is not a therapeutic agent in itself but is used as a carrier, diluent, adjuvant, binder, and / or vehicle for delivering a therapeutic agent to a target, or is added to a pharmaceutical composition to improve the handling or storage properties of the pharmaceutical composition, or to enable or facilitate the formation of a compound or composition into a unit dosage form for administration.

[0027] A "unit dosage form" refers to a physically distinct unit suitable as a unit dose for human or other animal subjects. Each unit dosage form may contain a predetermined amount of the active substance (e.g., sedazulidine, decitabine, and / or venetoclax) calculated to produce the desired effect.

[0028] "Optional" or "optionally" means that the event or situation described thereafter may or may not occur, and that the description encompasses both cases in which the event or situation occurs and cases in which it does not. For example, "optionally substituted" alkyls include both unsubstituted alkyls and substituted alkyls.

[0029] The words "to enhance" or "to increase" refer to an increase of at least approximately 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., of a specified parameter.

[0030] As used herein, the terms “inhibit” or “reduce” or their grammatical variations mean a reduction or decrease in a specified level or activity of at least about 15%, about 25%, about 35%, about 40%, about 50%, about 60%, about 75%, about 80%, about 90%, about 95%, or more. In certain embodiments, the inhibition or reduction results in little or virtually no detectable activity (at most a very small amount, e.g., less than about 10% or even 5%).

[0031] "Subject" refers to in vitro or in vivo cells or tissues of an animal or human. An animal or human subject may also be called a "patient."

[0032] "Animals" refer to living organisms that possess the senses and power of voluntary movement and require oxygen and organic food for their existence.

[0033] "Mammals" are warm-blooded vertebrates that have hair or fur. Examples include, but are not limited to, members of the species humans, horses, pigs, cattle, mice, dogs, or cats.

[0034] The words “to treat,” “to treat,” or “to treat” (or grammatically equivalent terms) mean that the severity of the condition in question is reduced, at least partially improved, or restored, and / or some reduction, mitigation, or decrease of at least one clinical symptom is achieved. “To treat” referring to a disease, disorder, or condition may mean (i) inhibiting the disease, disorder, or condition, e.g., preventing its onset; (ii) mitigating the disease, disorder, or condition, e.g., causing regression of clinical symptoms; and / or (iii) preventing relapse or progression of the disease, disorder, or condition after the disease has been reduced to a detectable level or is no longer present.

[0035] The terms “administer” or “dosage” to a subject of the compound and / or composition of the present invention include a route for introducing or delivering the compound to a subject in order to perform the intended function of the compound.

[0036] "Cancer" refers to the abnormal growth of cells that tend to proliferate uncontrollably and, in some cases, metastasize (spread). Specific cancer types include, but are not limited to, those identified in U.S. Patent Application Publication No. 2006 / 0014949, and the following: Heart: sarcomas (e.g., angiosarcoma, fibrosarcoma, rhabdomyosarcoma, liposarcoma, etc.), myxoma, rhabdomyomas, fibromas, lipomas, and teratomas; Lung: bronchial cancers (e.g., squamous cell carcinoma, anaplastic small cell carcinoma, anaplastic large cell carcinoma, adenocarcinoma, etc.), alveolar (e.g., bronchiolar carcinoma, etc.), bronchial adenoma, sarcoma, lymphoma, chondrodysartoma, and mesothelioma; Gastrointestinal tract: esophagus (e.g., squamous cell carcinoma, adenocarcinoma, leiomyosarcoma, lymphoma, etc.), stomach (e.g., carcinoma, lymphoma, leiomyosarcoma, etc.), pancreas (e.g., ductal adenocarcinoma, islet cell adenoma, glucagon Tumors producing gastrin, carcinoid tumors, VIP-producing tumors, etc.), small intestine (e.g., adenocarcinoma, lymphoma, carcinoid tumor, Kaposi's sarcoma, leiomyoma, hemangioma, lipoma, neurofibroma, fibroma, etc.), and large intestine (e.g., adenocarcinoma, tubular adenoma, chorioadenoma, hamartoma, leiomyoma, etc.); urogenital system: kidney (e.g., adenocarcinoma, Wilms' tumor (nephroblastoma), lymphoma, leukemia, etc.), bladder and urethra (e.g., squamous cell carcinoma, transitional cell carcinoma, adenocarcinoma, etc.), prostate (e.g., adenocarcinoma, sarcoma, etc.), and testes (For example, seminomas, teratomas, embryonic carcinomas, teratocarcinomas, choriocarcinomas, sarcomas, stromal cell carcinomas, fibromas, fibroadenomas, adenomatous tumors, lipomas, etc.); Liver: liver cancer (for example, hepatocellular carcinoma, etc.), cholangiocarcinoma, hepatoblastoma, angiosarcoma, hepatocellular adenoma, and hemangioma; Bone: osteogenic sarcoma (for example, osteosarcoma, etc.), fibrosarcoma, malignant fibrous histiocytoma, chondrosarcoma, Ewing's sarcoma, malignant lymphoma (for example, reticulum sarcoma, etc.), multiple myeloma, malignant giant cell tumor of bone, osteochondroma (for example, osteochondrodystosomatous sarcoma, etc.), benign chondroma, chondroblastoma, cartilage Myxofibroma (chondromyxofibroma), osteoid osteoma, and giant cell tumor; nervous system: skull (e.g., osteoma, hemangioma, granuloma, xanthomas, osteoosteitis, etc.), meninges (e.g., meningioma, meningiosarcoma, gliomas, etc.), brain (e.g., astrocytoma, medulloblastoma, glioma, ependymoma, germ cell tumor [pineal glandoma], glioblastoma multiforme, oligodendroglioma, schwannoma, retinoblastoma, congenital tumors, etc.), and spinal cord (e.g., neurofibroma, meningioma, glioma, sarcoma, etc.);Gynecology: Uterus (e.g., endometrial cancer), cervix (e.g., cervical cancer, pre-tumor cervical malformations, etc.), ovaries (e.g., ovarian cancer [serous cystadenocarcinoma, mucinous cystadenocarcinoma, unclassified carcinoma], granulosa cell-theca cell tumor, Sertoli-Leydig cell tumor, undifferentiated germ cell tumor, malignant teratoma, etc.), vulva (e.g., squamous cell carcinoma, carcinoma in situ, adenocarcinoma, fibrosarcoma, melanoma, etc.), vagina (e.g., detailed Squamous cell carcinoma, squamous cell carcinoma, staphylosarcoma (embryonic rhabdomyosarcoma), fallopian tube carcinoma, etc.; hematological: blood (e.g., myeloleukemia [acute and chronic], acute lymphoblastic leukemia, chronic lymphocytic leukemia, myeloproliferative disorders, multiple myeloma, myelodysplastic syndrome, etc.), Hodgkin's disease, and non-Hodgkin 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.

[0037] As used herein, "Complete Response" (CR) means the absence of less than 5% myeloblasts, circulating blasts, and blasts containing Auer bodies, the absence of extramedullary disease, and 1.0 × 10⁻⁶ 9 Absolute neutrophil count less than / L (1,000 / μL), and 100 × 10⁻⁶ 9 This refers to a platelet count of less than 100,000 / μL. This definition follows the European LeukemiaNet (ELN) 2017 classification for AML, and such criteria may change during further revisions (iterations) by the ELN. Other diseases encompassing MDL / CMML may have different response criteria based on ELN or other working group criteria.

[0038] As used herein, "Complete Response with incomplete blood count recovery" (CRi) refers to residual neutropenia [1.0 × 10⁻¹⁰]. 9 / L (1,000 / μL)] or thrombocytopenia [100×10 9Refers to all CR criteria except for [<100,000 / μL]. This definition follows the classification for AML by European LeukemiaNet (ELN) 2017, and such criteria may be changed upon further revision by ELN. Other diseases including MDL / CMML may have different response criteria based on the criteria of ELN or other working groups.

[0039] As used herein, "complete response with partial hematologic recovery" (CRh) refers to all CR criteria except for not meeting the blood cell count recovery criteria and having an absolute neutrophil count of ≤0.5 × 10 9 / L (1,000 / μL) or less and a platelet count of ≤50 × 10 9 / L (100,000 / μL) or less. This is the currently commonly used definition for AML. Other diseases including MDL / CMML may have different response criteria based on the criteria of ELN or other working groups.

[0040] "AUC 0~t " is the definite integral of the curve describing the temporal (t) variation of the plasma drug concentration.

[0041] For the "5-day cumulative AUC" of decitabine, the primary endpoint pharmacokinetic (PK) analysis population is used to calculate the cumulative AUC 0~t exposure over 5 days after administration of the dosage form. The following assumptions are used: 1) Steady state is achieved on the second day after administration of the solid dosage form, and 2) Based on the achievement of steady state on the second day, the AUC 0~t on the second and fifth days represents the daily AUC 0~t from the second day to the presumed fifth day after administration of the solid dosage form until the fifth day. Therefore, to calculate the total oral AUC 0~t exposure of decitabine over 5 days, the AUC 0~t on the first day (the first dose of the solid dosage form) is calculated as (AUC 0~t on the second day + AUC 0~tThis is added to (x2). AUC on day 2 0~t If it is unavailable, this is the AUC on day 5. 0~t It can be replaced by, and vice versa.

[0042] "Cmax" is the maximum (or peak) serum concentration of the drug achieved in the blood or other matrix after the drug has been administered and before the second dose has been administered. Therefore, Cmax can be determined on any day of the cycle.

[0043] As used herein, a “cycle” refers to a continuous 28-day period during which sedazulidine, decitabine, and venetoclax are administered. In some embodiments, sedazulidine and decitabine are administered on days 1 through 5 of each 28-day cycle. In some embodiments, venetoclax is administered daily throughout the 28-day cycle. Multiple cycles may be performed consecutively or with rest periods in between. In addition, other cycle lengths and different dosing regimens may be used.

[0044] The present invention provides oral dosage forms for decitabine, sedazuridine, and venetoclax, or any pharmaceutically acceptable salt thereof, which may be administered simultaneously, sequentially, or separately. Decitabine, sedazuridine, and venetoclax as used herein, and their pharmaceutically acceptable salts, may be collectively referred to as “therapeutic agents.” In addition, when a therapeutic agent (e.g., venetoclax) is referred to, it should be understood that this reference also includes pharmaceutically acceptable salts of the therapeutic agent. The oral dosage forms may contain each therapeutic agent separately, all of the therapeutic agents in combination, or any two of the therapeutic agents in combination. In certain embodiments, the first oral dosage form contains decitabine and sedazuridine, and the second oral dosage form contains venetoclax. In certain embodiments, the solid oral dosage form comprises decitabine, sedazulidine, and venetoclax. In some embodiments, the solid oral dosage form of the present invention further comprises pharmaceutically acceptable excipients.

[0045] In some embodiments of the present invention, one or more of the oral dosage forms are solid oral dosage forms, such as solid oral unit dosage forms. The term “solid oral dosage form” means that the pharmaceutical composition is in a solid form and is formulated for oral administration. Any suitable solid oral dosage form may be used. Examples of solid oral dosage forms according to embodiments of the present invention include tablets (e.g., tablets targeted for oral buccal, sublingual, or systemic absorption), caplets, boluses, powders, granules, pastes for tongue administration, capsules including hard gelatin capsules and soft gelatin capsules, oral sprays, lozenges, and pellets. The pharmaceutical composition may be formulated for immediate release, sustained release, or controlled release.

[0046] Several possible oral dosage forms could be used in the method of the present invention. For example, decitabine may be present in oral dosage forms in the range of about 10 mg to about 100 mg, about 20 mg to about 45 mg, or about 30 mg to about 40 mg (e.g., about 10 mg, about 20 mg, about 25 mg, about 30 mg, about 35 mg, about 40 mg, about 45 mg, about 50 mg, about 55 mg, about 60 mg, about 65 mg, about 70 mg, about 75 mg, about 80 mg, about 90 mg, or about 100 mg, or any range in between). As another example, sedazulidine may be present in oral dosage forms in the range of approximately 10 mg to approximately 150 mg, approximately 70 mg to approximately 120 mg, or approximately 90 mg to approximately 110 mg (for example, approximately 50 mg, approximately 60 mg, approximately 70 mg, approximately 80 mg, approximately 85 mg, approximately 90 mg, approximately 95 mg, approximately 100 mg, approximately 105 mg, approximately 110 mg, approximately 115 mg, approximately 120 mg, approximately 125 mg, approximately 130 mg, approximately 140 mg, or approximately 150 mg, or any range in between). As yet another example, venetoclax may exist in solid oral dosage forms in the range of about 10 mg to about 600 mg, about 50 mg to about 400 mg, or about 50 mg to about 200 mg (for example, about 10 mg, about 20 mg, about 30 mg, about 40 mg, about 50 mg, about 60 mg, about 70 mg, about 80 mg, about 90 mg, about 100 mg, about 110 mg, about 120 mg, about 150 mg, about 200 mg, about 250 mg, about 300 mg, about 400 mg, about 450 mg, about 500 mg, about 550 mg, about 600 mg, or any range in between). However, in some embodiments of the present invention, one solid oral dosage form is a unit dosage form containing about 35 mg of decitabine. In some embodiments of the present invention, one solid oral dosage form is a unit dosage form containing about 100 mg of sedazulidine. Furthermore, in some embodiments, one solid oral dosage form is a unit dosage form comprising about 35 mg of decitabine and about 100 mg of sedazulidine. In some embodiments of the present invention, one unit dosage form comprises about 35 mg of decitabine, about 100 mg of sedazulidine and at least one pharmaceutically acceptable excipient.In some embodiments of the present invention, one solid oral dosage form is a unit dosage form comprising about 10 mg, about 50 mg, about 100 mg, about 200 mg, about 400 mg, or about 600 mg of venetoclax and at least one pharmaceutically acceptable excipient. In some embodiments of the present invention, one solid oral dosage form is a unit dosage form comprising about 35 mg of decitabine, about 100 mg of sedazulidine, and about 10 mg, about 50 mg, about 100 mg, about 200 mg, about 400 mg, or about 600 mg of venetoclax. In some embodiments of the present invention, one solid oral dosage form is a unit dosage form comprising about 35 mg of decitabine, about 100 mg of sedazulidine, about 10 mg, about 50 mg, about 100 mg, about 200 mg, about 400 mg, or about 600 mg of venetoclax and at least one pharmaceutically acceptable excipient.

[0047] Pharmaceutically acceptable excipients are well known in the field of compounding and are described, for example, in Remington's Pharmaceutical Sciences, Mack Publishing Co., Easton, Pa (e.g., 20th edition, 2000) and Handbook of Pharmaceutical Excipients, American Pharmaceutical Association, Washington, DC (e.g., 1st, 2nd, and 3rd editions, 1986, 1994, and 2000, respectively). As will be known to those skilled in the art, excipients can provide a variety of functions and may be described, for example, as wetting agents, buffers, suspending agents, diluents, binders, lubricants, flow enhancers, emulsifiers, disintegrants, absorbents, preservatives, surfactants, colorants, flavoring agents, and / or sweeteners. Examples of pharmaceutically acceptable excipients include: (1) sugars, e.g., lactose, glucose and sucrose; (2) starches, e.g., corn starch and potato starch; (3) cellulose and its derivatives, e.g., sodium carboxymethylcellulose, ethylcellulose, cellulose acetate, hydroxypropylmethylcellulose (hypromellose), and hydroxypropylcellulose; (4) powdered tragacanth; (5) malt; (6) gelatin; (7) talc; (8) excipients, e.g., cocoa butter and suppository wax; (9) oils, e.g., peanut oil, cottonseed oil, safflower oil, sesame oil, olive oil, corn oil, and soybean oil; (10) (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 and aluminum hydroxide, (15) Alginic acid, (16) Water free of pyrogens, (17) Isotonic saline, (18) Ringer's solution, (19) Ethyl alcohol, (20) pH buffer, (21) Polyesters, polycarbonates, and / or polyacid anhydrides, and (22) Other suitable nontoxic substances used in pharmaceutical formulations, including but not limited to these.

[0048] Examples of diluents include lactose, lactose monohydrate, cellulose, microcrystalline cellulose, sorbitol, calcium hydrogen phosphate dihydrate, and calcium sulfate dihydrate. Examples of binders include gelatin, glucose, lactose, cellulose, methylcellulose, ethylcellulose, hydroxypropyl methylcellulose (hypromellose), hydroxypropylcellulose, starch, polyvinylpyrrolidone, sodium alginate, carboxymethylcellulose, and acacia. Examples of disintegrants include croscarmellose sodium, crospovidone, sodium starch glycolate, and starch. Examples of flow enhancers 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.

[0049] In some embodiments, the solid oral dosage form comprises one or more of the following: a diluent, a binder, a disintegrant, a flow enhancer, and a lubricant. In some embodiments, the solid oral dosage form comprises a diluent, a binder, a disintegrant, a flow enhancer, and a lubricant. In certain embodiments of the present invention, the solid oral dosage form comprises decitabine and / or sedazulidine, and the following excipients: lactose monohydrate as a diluent, hydroxypropyl methylcellulose as a binder, croscarmellose sodium as a disintegrant, colloidal silicon dioxide as a flow enhancer, and magnesium stearate as a lubricant. In some embodiments of the present invention, such components are formed into a tablet. In some embodiments, the tablet is an immediate-release tablet. In addition, in certain embodiments, the tablet is coated with a film, which may or may not be colored. Any pharmaceutically acceptable coating may be used, but in some embodiments, the tablet is coated with Opadry® coating.

[0050] In some embodiments, sedazuridine is present in solid oral dosage forms at concentrations of approximately 17-22 w / w%, for example, approximately 17.0 w / w%, 17.2 w / w%, 17.4 w / w%, 17.6 w / w%, 17.8 w / w%, 18.0 w / w%, 18.2 w / w%, 18.4 w / w%, 18.6 w / w%, 18.8 w / w%, 19.0 w / w%, 19.2 w / w%, and 19.4%. It exists in amounts of w / w%, approximately 19.6 w / w%, approximately 19.8 w / w%, approximately 20.0 w / w%, approximately 20.2 w / w%, approximately 20.4 w / w%, approximately 20.6 w / w%, approximately 20.8 w / w%, approximately 21.0 w / w%, approximately 21.2 w / w%, approximately 21.4 w / w%, approximately 21.6 w / w%, approximately 21.8 w / w%, or approximately 22.0 w / w%, or any range in between, for example, approximately 19.42 w / w%. In some embodiments, decitabine is present in the solid oral dosage form in an amount of about 4 to 8 w / w%, for example, about 4.0 w / w%, about 4.2 w / w%, about 4.4 w / w%, about 4.6 w / w%, about 4.8 w / w%, about 5.0 w / w%, about 5.2 w / w%, about 5.4 w / w%, about 5.6 w / w%, about 5.8 w / w%, about 6.0 w / w%, about 6.2 w / w%, about 6.4 w / w%, about 6.6 w / w%, about 6.8 w / w%, about 7.0 w / w%, about 7.2 w / w%, about 7.4 w / w%, about 7.6 w / w%, about 7.8 w / w%, or about 8.0 w / w%, or any range in between, for example, about 6.8 w / w%. In some embodiments, the diluent (e.g., lactose monohydrate) is present in the solid oral dosage form in an amount of about 55–70 w / w%, for example, about 55 w / w%, about 56 w / w%, about 57 w / w%, about 58 w / w%, about 59 w / w%, about 60 w / w%, about 61 w / w%, about 62 w / w%, about 63 w / w%, about 64 w / w%, about 65 w / w%, about 66 w / w%, about 67 w / w%, about 68 w / w%, about 69 w / w%, or about 70 w / w%, or any range in between, for example, about 62.62 w / w%.In some embodiments, the binder (e.g., hypromellose) is present in the solid oral dosage form in an amount of about 1 to 3 w / w%, for example, about 1.0 w / w%, about 1.2 w / w%, about 1.4 w / w%, about 1.6 w / w%, about 1.8 w / w%, about 2.0 w / w%, about 2.2 w / w%, about 2.4 w / w%, about 2.6 w / w%, about 2.8 w / w%, or about 3.0 w / w%, or any range in between, for example, about 1.94 w / w%. In some embodiments, the disintegrant (e.g., croscarmellose sodium) is present in the solid oral dosage form at a concentration of about 3-7 w / w%, for example, about 3.0 w / w%, about 3.2 w / w%, about 3.4 w / w%, about 3.6 w / w%, about 3.8 w / w%, about 4.0 w / w%, about 4.2 w / w%, about 4.4 w / w%, about 4.6 w / w%, It is present in amounts of approximately 4.8 w / w%, 5.0 w / w%, 5.2 w / w%, 5.4 w / w%, 5.6 w / w%, 5.8 w / w%, 6.0 w / w%, 6.2 w / w%, 6.4 w / w%, 6.6 w / w%, 6.8 w / w%, or 7.0 w / w%, or any range in between, for example, approximately 4.85 w / w%. In some embodiments, the flow promoter (e.g., colloidal silicon dioxide) is present in the solid oral dosage form in an amount of about 0.5 to 2 w / w%, for example, about 0.5 w / w%, about 0.6 w / w%, about 0.7 w / w%, about 0.8 w / w%, about 0.9 w / w%, about 1.0 w / w%, about 1.1 w / w%, about 1.2 w / w%, about 1.3 w / w%, about 1.4 w / w%, about 1.5 w / w%, about 1.6 w / w%, about 1.7 w / w%, about 1.8 w / w%, about 1.9 w / w%, or about 2.0 w / w%, or any range in between, for example, about 0.97 w / w%.In some embodiments, the lubricant (e.g., magnesium stearate) is present in the solid oral dosage form in an amount of about 0.1 to 2 w / w%, for example, about 0.1 w / w%, about 0.2 w / w%, about 0.3 w / w%, about 0.4 w / w%, about 0.5 w / w%, about 0.6 w / w%, about 0.7 w / w%, about 0.8 w / w%, about 0.9 w / w%, about 1.0 w / w%, about 1.1 w / w%, about 1.2 w / w%, about 1.3 w / w%, about 1.4 w / w%, about 1.5 w / w%, about 1.6 w / w%, about 1.7 w / w%, about 1.8 w / w%, about 1.9 w / w%, or about 2.0 w / w%, or any range in between, for example, about 0.49 w / w%.

[0051] In some embodiments, the solid oral dosage form contains the components listed in Table 1 below.

[0052] [Table 1]

[0053] In some embodiments, the solid oral dosage form contains the components listed in Table 2 below.

[0054] [Table 2]

[0055] Further information regarding the compositions and formulations of sedazulidine and decitabine can be found in the Inqovi® formulation information and at www.inqovi.com.

[0056] In some embodiments of the present invention, venetoclax is present in a solid oral dosage form (e.g., a tablet) at a concentration of 10 mg of venetoclax, together with one or more of the following excipients: dibasic calcium phosphate, colloidal silicon dioxide, copovidone, yellow iron oxide, polyethylene glycol, polysorbate 80, polyvinyl alcohol, sodium stearyl fumarate, talc, and titanium dioxide.

[0057] In some embodiments of the present invention, venetoclax is present in a solid oral dosage form (e.g., a tablet) at a concentration of 50 mg of venetoclax, together with one or more of the following excipients: dibasic calcium phosphate, colloidal silicon dioxide, copovidone, black iron oxide, red iron oxide, yellow iron oxide, polyethylene glycol, polysorbate 80, polyvinyl alcohol, sodium stearyl fumarate, talc, and titanium dioxide.

[0058] In some embodiments of the present invention, venetoclax is present in a solid oral dosage form (e.g., a tablet) at a concentration of 100 mg of venetoclax, together with one or more of the following excipients: dibasic calcium phosphate, colloidal silicon dioxide, copovidone, yellow iron oxide, polyethylene glycol, polysorbate 80, polyvinyl alcohol, sodium stearyl fumarate, talc, and titanium dioxide.

[0059] The pharmaceutical compositions of the present invention may be prepared using known materials and techniques, including, but not limited to, mixing and / or blending decitabine and sedazulidine with a pharmaceutically acceptable excipient. The pharmaceutical compositions of the present invention may also include mixing and / or blending venetoclax with a pharmaceutically acceptable excipient.

[0060] Another aspect of the present invention relates to unit dosage forms and kits comprising at least one unit dosage form comprising decitabine, at least one unit dosage form comprising sedazulidine, and at least one unit dosage form comprising venetoclax. In certain embodiments, the kit comprises at least one unit dosage form comprising decitabine and sedazulidine, and at least one unit dosage form comprising venetoclax. In some embodiments, the kit provides one unit dosage form comprising about 35 mg of decitabine and about 100 mg of sedazulidine, and at least one pharmaceutically acceptable excipient, and at least one unit dosage form comprising about 10 mg, 50 mg, and / or 100 mg of venetoclax. Other unit dosage forms may be used, but the unit dosage forms may vary depending on availability. The daily dose for sedazulidine, decitabine, and / or venetoclax may require two or more unit dosage forms per day. For example, if 400 mg of venetoclax is prescribed per day, the kit may contain four 100 mg units of venetoclax per day.

[0061] The kit may contain the solid oral dosage form for a daily dose of each therapeutic agent (for example, one tablet containing 35 mg of decitabine and 100 mg of sedazuridine, and four tablets each containing 100 mg of venetoclax). The kit may also contain unit dosage forms for two or more days of the cycle (for example, five days or one week) or for the entire cycle. Accordingly, in some embodiments of the present invention, the kit may contain one, two, three, four, five, six, seven, eight, nine, ten, eleven, twelve, thirteen, fourteen, fifteen, sixteen, seventeen, eighteen, nineteen, twenty The kit may include a solid oral dosage form containing cedazuridine and decitabine, and one, two, three, four, five, six, seven, eight, nine, ten, eleven, twelve, thirteen, fourteen, fifteen, sixteen, seventeen, eighteen, nineteen, twenty In some embodiments, the kit may include five solid oral dosage forms containing sedazulidine, decitabine, and venetoclax (for days 1-5 of the cycle), and solid oral dosage forms of venetoclax for the remainder of the cycle (e.g., for days 6-28 of the cycle) (e.g., 23 solid oral dosage forms). In some embodiments, the unit dosage form for a single therapeutic agent may vary by the kit. For example, in some embodiments, the kit may include a 100 mg unit dosage form of venetoclax for day 1 of the cycle, and a unit dosage form containing 400 mg of venetoclax for another day of the cycle.

[0062] The kit may further include a container and / or packaging suitable for commercial sale. The container may be any conventional shape or form known in the art, made from pharmaceutically acceptable materials, such as a paper or cardboard box, a glass or plastic bottle or jar, a resealable bag, or a blister pack containing individual doses for dispensing from the pack according to a treatment schedule. Two or more containers may be used together in a single package. For example, tablets may be placed in a blister pack, which may then be placed in a box. In some embodiments, the container is a bottle containing unit dosage forms (e.g., about five unit dosage forms), such as a 30cc white high-density polyethylene bottle. The bottle may further contain a canister of a desiccant, such as a silica desiccant. In some embodiments, the container is a blister pack formed by aluminum foil or a foil lid, containing one tablet in each cavity. The blister pack may be present in a carton.

[0063] The kit may further include information. This information may be provided in a readable medium, which may include a label. This information may be directed to a physician, pharmacist, or patient. This information may indicate that the unit dosage form may cause one or more adverse effects. This information may include instructions for administering the unit dosage form, for example, in the manner described herein. These instructions may be provided in a variety of ways.

[0064] The information can be associated with the container by, for example, writing on a label (e.g., a prescription label or a separate label) that is adhered to the container, being included inside the container as a written package insert, being applied directly to the container, for example, by being printed on the wall of a box or blister pack, or being attached to the container by, for example, a string, cord or other line, strap or mooring device, as an instruction card attached to the neck of the bottle or by being taped.

[0065] A method is provided for administering sedazulidine, decitabine, and venetoclax to a subject in one or more oral dosage forms of the present invention, according to embodiments of the present invention. In certain embodiments, a method is provided for administering to a subject one or more oral dosage forms comprising sedazulidine (e.g., 100 mg) and decitabine (e.g., 35 mg) and a pharmaceutically acceptable excipient, and one or more oral dosage forms comprising venetoclax (e.g., a total of 100 mg, 200 mg, or 400 mg) and a pharmaceutically acceptable excipient. In some embodiments, each oral dosage form is a solid oral dosage form. The oral dosage form used may be any solid oral dosage form described herein.

[0066] Any dosing regimen known to those skilled in the art may be used to adjust the timing and sequence of drug delivery and may be repeated as many times as necessary to perform the treatment in the method of the present invention. For example, the oral dosage forms of the present invention may be administered once, twice, three or four times daily by single dose, multiple separate doses or continuous infusion. In certain embodiments, at least one solid oral dosage form is administered once daily. In some embodiments, the administration of at least one solid oral dosage form according to embodiments of the present invention may be carried out for one week or more per 28-day cycle, for example, one, two, three or four weeks per 28-day cycle. The multiple weeks may be consecutive and / or non-consecutive. In certain embodiments, sedazulidine and decitabine are administered daily over five days (days 1-5) of the 28-day cycle, and venetoclax is administered daily throughout the 28-day cycle.

[0067] In some embodiments of the present invention, a solid oral dosage form containing sedazuridine and decitabine is administered to a subject once daily for a period of 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 days, or longer. In some embodiments, a solid oral dosage form containing sedazuridine and decitabine is administered to a subject once daily on days 1 through 5 of a 28-day cycle. In some embodiments, a second solid oral dosage form containing venetoclax is administered to the same subject daily for 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28 days, or longer. In some embodiments, sedazuridine, decitabine, and venetoclax are administered to the subject daily on days 1–5 of the cycle, and venetoclax alone is administered daily on days 6–28 of the cycle. Such solid oral dosage forms may be administered in parallel (also referred to herein as “simultaneously”), sequentially, or at different times on the same day (also referred to herein as “separately”). In certain embodiments, all solid oral dosage forms are administered in parallel or at approximately the same time (for example, within 5 minutes, 10 minutes, 15 minutes, 20 minutes, 25 minutes, or 30 minutes).

[0068] In some embodiments, a single unit dosage form containing 35 mg of decitabine and 100 mg of sedazuridine may be administered daily on days 1 through 5 of the cycle. In some embodiments, the dose of venetoclax may vary from day to day in the cycle. For example, on day 1, the subject may be administered 100 mg of venetoclax (e.g., as a single 100 mg unit dosage form), on day 2, 200 mg of venetoclax (e.g., as two 100 mg unit dosage forms), and on days 3 through 28, 400 mg of venetoclax (e.g., as four 100 mg unit dosage forms). However, in some embodiments, the doses of sedazuridine and decitabine may vary, and in some embodiments, the dose of venetoclax may remain the same throughout the entire cycle. For example, in some embodiments of the present invention, the subject may be administered 400 mg of venetoclax daily during the cycle. This may be appropriate for the subject, for example, in a second or subsequent cycle. Further information regarding possible dosing schedules and administration for sedazulidine and decitabine can be found in the Inqovi® prescription information and at www.inqovi.com.

[0069] In some embodiments, periods of 0 to 31 days or longer (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 longer) may be placed between multiple cycles of the present invention. These periods without treatment may be desirable to allow the subject of the present invention (e.g., a human patient) to be in good health to continue treatment. The duration between treatment cycles can be determined by a physician using standard techniques in the art, and for each subject, for example, appropriate blood cell counts, for example, adequate neutropenia (e.g., at least 0.5 × 10⁻⁶ in the subject). 9This can be determined individually based on an absolute neutrophil count (ANC) of cells / L or greater, and can be adjusted throughout the treatment course at the discretion of the administering physician. In some embodiments, the interval between treatment cycles is minimal, for example, nonexistent, and for example, the next 28-day period may begin immediately. In some embodiments, the interval between treatment cycles may be 1 day, 2 days, 3 days, 4 days, 5 days, or 6 days, or 1 week, 2 weeks, 3 weeks, 4 weeks, 5 weeks, 6 weeks, or longer.

[0070] In some embodiments, the administration regimen may include pretreatment and / or concomitant administration with at least one further therapeutic agent. In such cases, the solid oral dosage form comprising decitabine and sedazulidine may be administered sequentially, on the same day, or at different times on different days, in parallel with the at least one further therapeutic agent. The further therapeutic agent may also be included in the one or more solid oral dosage forms. As used herein, the term “therapeutic agent” includes immunomodulators.

[0071] Examples of chemotherapeutic agents include alkylating agents (e.g., doxorubicin, cyclophosphamide, estramustine, carmustine, mitomycin, bleomycin, etc.), antimetabolites (e.g., 5-fluorouracil, capecitabine, gemcitabine, nelarabine, fludarabine, methotrexate, etc.), platinum-based drugs (e.g., cisplatin, oxaliplatin, carboplatin, etc.), and topoisomerase inhibitors (e.g., topotecan, irino This includes, but is not limited to, tecan, etoposide, etc., tubulin agents (e.g., paclitaxel, docetaxel, vinorelbine, vinblastine, vincristine, other taxanes, epotilone, etc.), signal transduction inhibitors (e.g., 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.).

[0072] Furthermore, there is a method for treating a disorder treatable with decitabine, venetoclax, and / or sedazulidine in a subject requiring such treatment, comprising administering to the subject one or more oral dosage forms according to embodiments of the present invention, thereby treating the disorder in the subject. Any of the administration methods described herein may be used to treat the disorder or for any other therapeutic methods described herein.

[0073] In some embodiments of the present invention, the disorder treatable with decitabine, venetoclax, and / or sedazuridine is a hyperproliferative disorder, such as cancer. The method can be used to treat any cancer in which decitabine, venetoclax, and / or sedazuridine is known to be effective in treatment or is subsequently discovered. In certain embodiments, the disorder is a cancer selected from hematological cancers and solid tumors. Examples of hematological cancers include myelodysplastic syndromes (MDS), leukemia (e.g., ALL, AML, CML, MPN, or CMML), lymphoma (e.g., Hodgkin lymphoma, non-Hodgkin lymphoma, or T-cell lymphoma), and plasma cell proliferation disorders (e.g., multiple myeloma). In some embodiments, the solid tumors 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 an overproliferative disorder, such as cancer, wherein the cancer is acute myeloid leukemia (AML).

[0074] Administration of one or more solid oral dosage forms of the present invention, or any combination of decitabine, venetoclax, and / or sedazuridine, to subjects in need may result in multiple beneficial responses to the subjects. For example, in some embodiments, the administration reduces DNA methylation in the subject by at least 5% (e.g., at least 5%, at least 6%, at least 7%, at least 8%, at least 9%, at least 10%, at least 11%, at least 12%, at least 13%, at least 14%, or at least 15%, or more, or any value or range in between) compared to a control measurement, for example, DNA methylation in the subject before the administration (e.g., the subject's "baseline" DNA methylation). DNA methylation in the subject may be evaluated quantitatively and / or qualitatively by any standard technique in the art, for example, by a relative global methylation marker compared to a control, or by long-chain scattered repeat-1 (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%, at least 6%, at least 7%, at least 8%, at least 9%, at least 10%, at least 11%, at least 12%, at least 13%, at least 14%, or at least 15%, or more) compared to a control measurement compared to, for example, LINE-1 methylation in the subject before the administration (e.g., baseline LINE-1 methylation of the subject). For example, in some embodiments, the administration reduces 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 can reduce LINE-1 methylation in the subject by about 5% to about 20%, about 6% to about 15%, or about 8% to about 10%.

[0075] In some embodiments, the administration increases the absolute neutrophil count (ANC) in the subject over a period of 2 weeks or less, 3 weeks or less, or 4 weeks or less after a 28-day cycle (for example, over consecutive days of 28 days or less, 27 days or less, 26 days or less, 25 days or less, 24 days or less, 23 days or less, 22 days or less, 21 days or less, 20 days or less, 19 days or less, 18 days or less, 17 days or less, 16 days or less, 15 days or less, 14 days or less, 13 days or less, 12 days or less, 11 days or less, 10 days or less, 9 days or less, 8 days or less, 7 days or less, 6 days or less, 5 days or less, 4 days or less, 3 days or less, 2 days or less, or 1 day or less, or over any value or range in between), by 0.5 × 10 9 The number of cells / L (blood) can be reduced to less than 0.5 × 10⁻¹⁴. In some embodiments, the administration reduces the absolute neutrophil count (ANC) in the subject by 0.5 × 10⁻¹⁴ over a period of 2 weeks or less, 3 weeks or less, or 4 weeks or less during the treatment (e.g., between multiple repeated 28-day cycles). 9 Reduce to less than cells / L (blood).

[0076] In some embodiments, the administration increases hemoglobin F-expressing cells (i.e., F cells) by at least 5% (e.g., at least 5%, at least 6%, at least 7%, at least 8%, at least 9%, at least 10%, at least 15%, at least 20%, at least 25%, or at least 30%, or more) of “baseline” control F cells / red blood cell % (e.g., compared to the patient’s F cells / red blood cell % before treatment, or compared to the mean F cells / red blood cell % of an untreated patient population (e.g., a healthy patient population)), as optionally measured by F cells / red blood cell % per sample (e.g., in a patient’s blood sample). For example, in some embodiments, the administration can increase the F cell % 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 can increase the percentage of 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.

[0077] In some embodiments, the administration causes F cells to proliferate to at least 10% to at least 30% of the total red blood cells per sample (e.g., in a patient's blood sample), or more (e.g., at least 15%, at least 16%, at least 17%, at least 18%, at least 19%, at least 20%, at least 21%, at least 22%, at least 23%, at least 24%, at least 25%, at least 26%, at least 27%, at least 28%, at least 29%, or at least 30%, or more, or any value or range of F cells / red blood cells). For example, in some embodiments, the administration can cause F cells to proliferate to 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 administration can cause F cells to proliferate to approximately 15% to 30%, 18% to 25%, or the entire amount of red blood cells in the sample, approximately 15% to 35%.

[0078] In some embodiments of the method of the present invention, the subject may be a mammal. In some embodiments of the method of the present invention, the subject may be a human. In some embodiments of the present invention, the subject is 75 years of age or older. In certain embodiments, the subject is 18 years of age or older and is ineligible for induction chemotherapy due to one or more comorbidities. Such comorbidities include, for example, (i) a baseline performance status of 2 or 3 in the East Coast Cancer Group (ECOG), (ii) severe cardiac impairment (e.g., congestive heart failure requiring treatment, ejection fraction ≤50%, or chronic stable angina), (iii) severe pulmonary impairment (e.g., pulmonary diffusion capacity for carbon monoxide DLCO ≤65%, or forced expiratory volume in 1 second (FEV1) ≤65%), (iv) creatinine clearance ≥30 mL / min and <45 mL / min, and / or (v) moderate hepatic impairment with total bilirubin greater than 1.5 × the upper limit of normal (ULN) and ≤3.0.

[0079] The dose level, method of administration, and administration regimen may be modified using techniques known to those skilled in the art if deemed necessary for the subject (e.g., the patient).

[0080] It will be apparent to those skilled in the art that specific embodiments of the present invention may be directed toward one, some, or all of the previously described aspects and other aspects, and may encompass one, some, or all of the embodiments and other embodiments described herein and below.

[0081] Except in the examples, or unless otherwise indicated, all numerical values ​​used herein and in the claims, representing amounts of components, reaction conditions, etc., should be understood to be modified by the word “approximately.” Thus, such numbers are approximations that may vary depending on the desired properties to be obtained by the present invention, unless otherwise indicated. Each numerical parameter should be interpreted in terms of significant figures and common rounding techniques, at least and not as an attempt to limit the application of the doctrine of equivalents to the claims.

[0082] The numerical ranges and parameters describing the broad scope of this invention are approximations, but the numerical values ​​described in the examples are reported as accurately as possible. However, any numerical value inherently contains a certain degree of error that inevitably results from the standard deviation found in each of those test measurements.

[0083] While the present invention has been described above, it is described in more detail in the following examples, which are included herein for illustrative purposes only and are not intended to limit the present invention.

[0084] Examples A single-arm, open-label, multicenter, non-randomized intervention study is being conducted to evaluate the pharmacokinetic (PK) interactions, safety, and preliminary efficacy of ASTX727 (sedazulidine in combination with decitabine) when administered in combination with venetoclax for the treatment of newly diagnosed acute myeloid leukemia (AML) in adults aged 75 years or older and / or with comorbidities that exclude the use of intensive induction chemotherapy. The study will evaluate any drug-drug interactions between ASTX727 and venetoclax combination therapy by assessing the area under the curve (AUC) and maximum plasma concentration (Cmax) exposure. It is estimated that 35 participants will be enrolled in an intervention model with single-group assignment primarily for treatment.

[0085] Administration regimen: Oral administration of ASTX727 and venetoclax in combination. Cycle 1: ASTX727 is administered according to the prescribed dosing regimen in combination with venetoclax (100 mg per day on day 1, 200 mg per day on day 2, and 400 mg per day from day 3 to day 28) for a 28-day cycle.

[0086] Cycle 2 and beyond: ASTX727 is administered according to the prescribed dosing regimen in combination with venetoclax (400 mg daily) for 28-day cycles.

[0087] Results to be measured Primary outcome measure Venetoclax AUC 0~24 - On days 5 and 15 of Cycle 2 (28 days per cycle), measure the area under the curve (AUC) for venetoclax with and without ASTX727 from 0 to 24 hours.

[0088] Venetoclax Cmax - Observed maximum concentrations of venetoclax with and without ASTX727 are measured on days 5 and 15 of cycle 2 (28 days per cycle).

[0089] Secondary outcome scale Decitabine AUC 0~24 - On days 1, 2, and 5 of Cycle 2 (28 days per cycle), measure the area under the 0-24 hour curve for decitabine.

[0090] Decitabine and Sedazuridine Cmax - The observed maximum concentrations of decitabine and sedazuridine were measured on days 1, 2, and 5 of Cycle 2 (28 days per cycle).

[0091] AUC of sedazuridine 0~8 - On days 1, 2, and 5 of Cycle 2 (28 days per cycle), measure the area under the curve for sedazulidine from 0 to 8 hours.

[0092] Decitabine AUC on day 5 - The cumulative 5-day AUC of decitabine is measured from days 1 to 5 of cycle 2 (28 days per cycle).

[0093] Participants with TEAEs – The number of treated adverse events (TEAEs) will be measured for up to 24 months.

[0094] Complete Response (CR) - The number of participants with complete response (CR), complete response with partial hematological recovery (CRh), and complete response with incomplete recovery of blood cell counts (CRi) will be measured up to 24 months.

[0095] Time to response - Measure the number of days from the first dose to the first documented evidence of complete response or complete response (CRh), up to 24 months.

[0096] Duration of response - Measured up to 24 months, from the onset of response (CR or CRh) to disease progression, initiation of alternative anti-leukemia treatment, or death.

[0097] Overall response - Measure the number of days from the first dose to death due to any cause, up to 24 months.

[0098] Eligibility Criteria Eligible age for research: 18 years or older

[0099] Gender eligible for the study: All

[0100] Gender difference: None

[0101] Acceptance of healthy volunteers: None

[0102] Inclusion Criteria Participants must be 18 years of age or older.

[0103] Histological confirmation of newly diagnosed AML according to the World Health Organization (WHO) 2016 criteria.

[0104] The estimated average life expectancy is at least 3 months.

[0105] Participants must be deemed ineligible for intensive induction chemotherapy as defined by: a) being 75 years of age or older, or b) being 18–74 years of age and having at least one of the following comorbidities: (i) severe cardiac impairment (e.g., congestive heart failure requiring treatment, ejection fraction ≤50%, or chronic stable angina); (ii) severe pulmonary impairment (e.g., pulmonary diffusion capacity for carbon monoxide DLCO ≤65%, or forced expiratory volume in 1 second (FEV1) ≤65%); (iii) creatinine clearance ≥30 mL / min and <45 mL / min; and (iv) moderate hepatic impairment with total bilirubin greater than 1.5 × upper limit of normal (ULN) and ≤3.0.

[0106] The performance status of the Eastern Cooperative Oncology Group (ECOG) in the United States is 0-2.

[0107] Women of potential pregnancy (following the recommendations of the Clinical Trial Facilitation Group (CTFG)) must not be pregnant or breastfeeding, and must have a negative pregnancy test result in the screening.

[0108] Participants of reproductive capacity and their partners must agree to refrain from sperm donation during the study and for three months after the final dose of the study treatment, and to use at least two effective methods of contraception. Effective contraception includes methods such as oral contraceptives or double-barrier methods (e.g., the use of condoms and diaphragms in combination with spermicide).

[0109] You are able to submit a signed informed consent form and protocol, and you are willing to participate in the research, including complying with the requirements and limitations listed in the informed consent form and protocol.

[0110] Exclusion criteria A history of myeloproliferative neoplasms, including myelofibrosis, essential thrombocythemia, polycythemia vera, chronic myeloid leukemia with or without BCR-ABL1 translocation, and AML with BCR-ABL1 translocation.

[0111] The following karyotype abnormalities: t(8;21), inv(16), t(15;17), or other acute promyelocytic leukemia variants that remain sensitive to all-trans retinoic acid (ATRA) treatment.

[0112] Known involvement of AML in the active central nervous system.

[0113] Known human immunodeficiency virus (HIV) infection (resulting from a potential drug-drug interaction between antiretroviral drugs and venetoclax). HIV testing will only be performed during screening if instructed according to local guidelines or facility standards.

[0114] Known active hepatitis B or C infection (detectable viral load). Hepatitis B or C testing will only be performed during screening if instructed to do so in accordance with local guidelines or facility standards.

[0115] Severe liver dysfunction is defined as follows: bilirubin > 1.5 × ULN for participants aged 75 years or older, or > 3 × ULN for participants under 75 years of age, or aspartate aminotransferase (AST) / serum glutamic oxaloacetic transaminase (SGOT) or alanine aminotransferase (ALT) / serum glutamic pyruvic transaminase (SGPT) > 3 × ULN (except in cases thought to be due to involvement of leukemia).

[0116] Severe renal impairment is defined as follows: calculated creatinine clearance or glomerular filtration rate <30 mL / min.

[0117] Malabsorption syndrome, or other conditions that interfere with the enteral administration route.

[0118] New York Cardiology Association Class >2. Class 2 is defined as a heart condition in which the patient is comfortable at rest, but normal physical activity results in fatigue, palpitations, shortness of breath, or angina.

[0119] A chronic respiratory disease requiring continuous oxygen, or a significant history of renal, neurological, psychiatric, endocrine, metabolic, immunological, hepatic, or cardiovascular disease, any other medical condition, or a known hypersensitivity to any of the investigational drugs that, in the opinion of the principal investigator, could adversely affect participation in this study.

[0120] A clinically significant, uncontrolled systemic infection (viral, bacterial, or fungal) that requires treatment.

[0121] Prior to entry into the study, a history of other malignancies (excluding breast or cervical cancers that have been suitably treated in situ), localized basal cell carcinoma or squamous cell carcinoma of the skin, previous malignancies that have been localized and surgically removed (or suitably treated and otherwise controlled), and any early-stage malignancies that do not require definitive treatment.

[0122] White blood cell (WBC) count > 25,000 / μL (Hydroxyurea treatment is permitted if this criterion is met).

[0123] Treatments involving the following: a) venetoclax including a hypomethylating agent (azacitidine or decitabine) or pretreatment for myelodysplastic syndrome (MDS); b) chimeric antigen receptor (CAR)-T cell therapy; c) investigational treatments for MDS or AML.

[0124] Participants who cannot discontinue concomitant prophylactic antifungal therapy with CYP3A inhibitory activity, or other concomitant medications with moderate or potent CYP3A inhibitory activity (≥7 days or 5 half-lives, whichever is longer), before day 1 of cycle 1 (C1D1).

[0125] Participants who cannot discontinue concomitant medication, such as a potent CYP3A or P-gp inhibitor (with a half-life of ≥7 days or 5, whichever is longer), before C1D1.

[0126] Participants who cannot avoid concomitant medications known to be moderate or potent CYP3A inducers.

[0127] Current participation in another study or observational study.

[0128] Known or suspected hypersensitivity to decitabine, sedazulidine, venetoclax, or any of their excipients.

[0129] In the opinion of the principal investigator, any known serious mental disorder or other condition, such as severe alcohol or other substance abuse or addiction, that increases the risk of a participant not complying with the protocol.

[0130] Patients who consume grapefruit, grapefruit products, Seville oranges (including marmalade containing Seville oranges), or star fruit within 7 days prior to C1D1.

[0131] The embodiments described above are illustrative of the present invention and should not be construed as limiting the invention. While the present invention has been described in detail with reference to preferred embodiments, variations and modifications exist in the scope and spirit of the invention as described and defined in the following claims.

Claims

1. A dosage form or kit used to treat cancer in a subject requiring treatment, wherein the cancer is a hematological malignancy and a solid tumor, and the subject contains an effective amount of sedazulidine, an effective amount of decitabine, and an effective amount of venetoclax.

2. The dosage form or kit according to claim 1, wherein the blood cancer is selected from at least one of myelodysplastic syndrome (MDS), myeloproliferative neoplasm (MPN), leukemia, and lymphoma.

3. The dosage form or kit according to claim 1, wherein the leukemia is ALL, AML, CML, MPN, or CMML.

4. The dosage form or kit according to claim 3, wherein the leukemia is AML.

5. The dosage form or kit according to any one of claims 1 to 4, wherein the subject is 75 years of age or older.

6. The dosage form or kit according to any one of claims 1 to 4, wherein the subject has a comorbidity that interferes with the use of standard induction chemotherapy (for example, one or more of the following: (i) severe cardiac impairment, (ii) severe pulmonary impairment, (iii) creatinine clearance of 30 mL / min or more and less than 45 mL / min, and (iv) moderate hepatic impairment in which total bilirubin is greater than 1.5 × the upper limit of normal (ULN) and 3.0 or less).

7. The dosage form or kit according to any one of claims 1 to 4, wherein the effective amount of sedazulidine, the effective amount of decitabine, and the effective amount of venetoclax are administered simultaneously, sequentially, or separately.

8. The dosage form or kit according to any one of claims 1 to 4, wherein the effective amount of sedazulidine, the effective amount of decitabine, and the effective amount of venetoclax are each administered as an oral dosage form.

9. The dosage form or kit according to claim 8, wherein each oral dosage form is a solid oral dosage form.

10. The dosage form or kit according to claim 9, wherein the effective amount of sedazulidine and the effective amount of decitabine are administered together in a combined solid oral dosage form.

11. The dosage form or kit according to any one of claims 1 to 4, wherein the effective amount of sedazulidine and the effective amount of decitabine are administered on days 1 to 5 of a 28-day cycle, and the effective amount of venetoclax is administered daily for the duration of the 28-day cycle.

12. The dosage form or kit according to any one of claims 1 to 4, wherein the effective amount of sedazulidine and the effective amount of decitabine are present in a first solid oral dosage form comprising 35 mg of decitabine, 100 mg of sedazulidine and at least one pharmaceutically acceptable excipient, and the effective amount of venetoclax is present in at least one second solid oral dosage form comprising 50 mg or 100 mg of venetoclax and at least one pharmaceutically acceptable excipient.

13. The dosage form or kit according to any one of claims 1 to 4, wherein the subject is administered an effective amount of sedazulidine, an effective amount of decitabine, and 100 mg of venetoclax on day 1 of the cycle; an effective amount of sedazulidine, an effective amount of decitabine, and 200 mg of venetoclax on day 2 of the cycle; an effective amount of sedazulidine, an effective amount of decitabine, and 400 mg of venetoclax on days 3 to 5 of the cycle; and 400 mg of venetoclax on days 6 to 28 of the cycle.

14. The dosage form or kit according to any one of claims 1 to 4, wherein the subject is administered an effective amount of sedazulidine, an effective amount of decitabine, and 400 mg of venetoclax on days 1 to 5 of the cycle, and 400 mg of venetoclax on days 6 to 28 of the cycle.

15. An oral dosage form comprising sedazulidine, decitabine, and venetoclax, and at least one pharmaceutically acceptable excipient.

16. The oral dosage form according to claim 15, wherein the oral dosage form is a solid oral dosage form.

17. A pharmaceutical product comprising an effective amount of venetoclax for use in the treatment of cancer in a subject, wherein the cancer is a hematological malignancy and a solid tumor, and the pharmaceutical product is administered simultaneously, separately, or sequentially in combination with an effective amount of sedazulidine and an effective amount of decitabine.

18. A pharmaceutical product comprising an effective amount of venetoclax for use in the treatment of cancer in a subject, administered in combination with an effective amount of sedazulidine and an effective amount of decitabine, wherein the cancer is a hematological malignancy and a solid tumor, and wherein the three pharmaceutical products are administered simultaneously, separately, or sequentially.

19. A combination of an effective dose of venetoclax, an effective dose of sedazulidine, and an effective dose of decitabine for use in treating cancer in a subject, wherein the cancer is a hematological malignancy and a solid tumor, and the three drugs are administered simultaneously, separately, or sequentially.

20. A pharmaceutical composition comprising an effective amount of sedazulidine and an effective amount of decitabine, wherein the three pharmaceuticals are administered simultaneously, separately, or sequentially to treat cancer in a subject, the cancer being a hematological cancer and a solid tumor.

21. The pharmaceutical composition according to claim 20, wherein the pharmaceutical composition comprises an effective amount of venetoclax to be used in combination with a solid dosage form containing an effective amount of sedazulidine and an effective amount of decitabine, wherein both are administered simultaneously, separately, or sequentially to treat cancer in a subject.

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