Pharmaceutical compositions and methods of using the same for treating cancer

Abstract

Pharmaceutical compositions and methods of treating cancer using the same are provided. In accordance with an embodiment of the present application, there is provided a method of treating a condition in a subject in need thereof, comprising administering to the subject an effective amount of chidauridine, an effective amount of decitabine, and an effective amount of vincracle, thereby treating the condition in the subject. In some embodiments of the application, the condition is a hyperproliferative disease, such as cancer. In some embodiments, the condition is a hematological cancer, such as myelodysplastic syndrome (MDS), myeloproliferative tumor (MPN), leukemia (e.g., acute myelogenous leukemia), or lymphoma.

Description

(19) State Intellectual Property Office (12) Invention Patent Application (10) Application Publication Number (43) Application Publication Date (21) Application Number 202610493906.4 (22) Application Date 2021.10.27 (30) Priority Data 63 / 107,010 2020.10.29 US (62) Divisional Application Data 202180052939.0 2021.10.27 (71) Applicant: Taiho Pharmaceutical Co., Ltd. Address: Tokyo, Japan (72) Inventor: A. Euganes Ankin-Sheen Dao H. Cole (74) Patent Agency: Beijing Shifeng Intellectual Property Agency Co., Ltd. 11713 Patent Attorney: Wang Jianxiu Liu Xiaoli (51) Int.Cl. A61K 31 / 7068 (2006.01) A61K 31 / 706 (2006.01) A61K 31 / 635 (2006.01) A61P 35 / 00 (2006.01) A61P 35 / 02 (2006.01) (54) Invention Title: Pharmaceutical Composition and Method of Using the Same to Treat Cancer (57) Abstract: This application provides a pharmaceutical composition and a method of using the same to treat cancer. According to embodiments of this application, a method of treating a condition in a subject who requires the same is provided, comprising administering to the subject an effective amount of chidamide, an effective amount of decitabine, and an effective amount of veneclade, thereby treating the subject's condition. In some embodiments of this application, the condition is a hyperproliferative disease, such as cancer. In some embodiments, the condition is a hematologic cancer, such as myelodysplastic syndrome (MDS), myeloproliferative neoplasm (MPN), leukemia (e.g., acute myeloid leukemia), or lymphoma. Claims (2 pages), Description (15 pages), CN 122182592 A, 2026.06.12, CN 1 22 18 25 92 A 1. A method of treating a condition in a subject requiring it, comprising administering to the subject an effective amount of chidamide, an effective amount of decitabine, and an effective amount of veneclade, thereby treating the subject's condition. 2. The method of claim 1, wherein the condition is a hyperproliferative disorder. 3. The method of claim 2, wherein the condition is cancer. 4. The method of claim 3, wherein the cancer is selected from hematologic malignancies and solid tumors. 5. The method of claim 4, wherein the hematologic malignancies are selected from at least one of myelodysplastic syndrome (MDS), myeloproliferative neoplasm (MPN), leukemia, and lymphoma. 6. The method of claim 5, wherein the leukemia is ALL, AML, CML, MPN, or CMML. 7. The method of claim 6,8. The leukemia described herein is AML. 9. The method of any one of claims 1-7, wherein the subject is 75 years of age or older. 10. The method of any one of claims 1-7, wherein the subject has comorbidities that prevent the use of standard induction chemotherapy (e.g., one or more of the following: (i) severe heart disease, (ii) severe lung disease, (iii) creatinine clearance greater than or equal to 30 mL / min and less than 45 mL / min, and (iv) moderate hepatic impairment with total bilirubin greater than 1.5 times and less than or equal to 3.0 times the upper limit of normal (ULN)). 11. The method of any one of claims 1-7, wherein the effective amount of chidamide, the effective amount of decitabine, and the effective amount of verneclax are administered simultaneously, sequentially, or separately. 12. The method of any one of claims 1-7, wherein the effective amount of chidamide, the effective amount of decitabine, and the effective amount of verneclax are each administered as an oral dosage form. 13. The method of claim 11, wherein each oral dosage form is a solid oral dosage form. 13. The method of claim 12, wherein the effective amount of chidanilide and the effective amount of decitabine are administered together in a combined solid oral dosage form. 14. The method of any one of claims 1-7, wherein the effective amount of chidanilide and the effective amount of decitabine are administered on days 1 to 5 of a 28-day cycle, and the effective amount of vernacle is administered daily during the 28-day cycle. 15. The method of any one of claims 1-7, wherein the effective amount of chidanilide and the effective amount of decitabine are contained in a first solid oral dosage form comprising 100 mg chidanilide, 35 mg decitabine, and at least one pharmaceutically acceptable excipient, and wherein the effective amount of vernacle is contained in at least one second solid oral dosage form comprising 50 mg or 100 mg vernacle and at least one pharmaceutically acceptable excipient. 16. The method according to any one of claims 1-7, wherein on day 1 of the cycle, the subject is administered an effective amount of chidanilide, an effective amount of decitabine, and 100 mg of veneclax; on day 2 of the cycle, the subject is administered an effective amount of chidanilide, an effective amount of decitabine, and 200 mg of veneclax; on days 3 to 5 of the cycle, the subject is administered an effective amount of chidanilide, an effective amount of decitabine, and 400 mg of veneclax; and on days 6 to 28 of the cycle, the subject is administered 400 mg of veneclax. 17. The method according to any one of claims 1-7, wherein on days 1 to 5 of the cycle, the subject is administered an effective amount of chidanilide, an effective amount of decitabine, and 400 mg of veneclax.And the subject was given 400 mg of veneclade from day 6 to day 28 of the cycle. 18. An oral dosage form comprising chidamide, decitabine and veneclade, and at least one pharmaceutically acceptable excipient. 19. The oral dosage form according to claim 18, wherein the oral dosage form is a solid oral dosage form. Claims 1 / 2 page 2 CN 122182592 A 20. A medicament comprising an effective amount of veneclade for treating a condition of a subject, which is used simultaneously, separately or sequentially in combination with an effective amount of chidamide and an effective amount of decitabine. 21. An effective amount of veneclade for treating a condition of a subject, characterized in that veneclade is administered in combination with an effective amount of chidamide and an effective amount of decitabine, wherein the three drugs are administered simultaneously, separately or sequentially. 22. A combination of an effective amount of veneclade, an effective amount of chidamide and an effective amount of decitabine for treating a condition of a subject, wherein the three drugs are administered simultaneously, separately or sequentially. 23. A pharmaceutical composition comprising an effective amount of veneclade, used in combination with an effective amount of chidamide and an effective amount of decitabine, wherein the three drugs are administered simultaneously, separately, or sequentially for treating a condition of a subject. 24. The pharmaceutical composition of claim 23, wherein the pharmaceutical composition comprises an effective amount of veneclade, the veneclade being used in combination with a solid dosage form comprising an effective amount of chidamide and an effective amount of decitabine, wherein the two are administered simultaneously, separately, or sequentially for treating a condition of a subject. Claims 2 / 2 Page 3 CN 122182592 A Pharmaceutical Composition and Method of Using the Same to Treat Cancer

[0001] This application is a divisional application of application filed on October 27, 2021, with application number 202180052939.0, entitled "Pharmaceutical Composition and Method of Using the Same to Treat Cancer". Priority Claim

[0002] This application claims the benefit of U.S. Provisional Application No. 63 / 107,010, filed October 29, 2020, the entire contents of which are incorporated herein by reference. Technical Field

[0003] The present invention relates to pharmaceutical compositions and methods for treating cancers (such as leukemia). Background Art

[0004] Decitabine (5-aza-2'-deoxycytidine), a cytidine analog, is an antitumor agent and hypomethylating agent (HMA) used to treat myelodysplastic syndromes (MDS).It also has potential utility in the treatment of acute myeloid leukemia (AML) and chronic myelomonocytic leukemia (CMML).

[0005]

[0006] 5-aza-2'-deoxycytidine (decitabin) Cedazuridine ((4R)-2'-deoxy-2',2'-difluoro-3,4,5,6-tetrahydrouridine; also known as E7727) is a CDA inhibitor. Cedazuridine and methods of manufacture and / or use thereof are further disclosed in U.S. Patent Nos. 8,268,800 and 9,834,576, the contents of each of which are incorporated herein by reference in their entirety.

[0007] Cedazuridine is a fixed-dose combination of decitabine and cedazuridine from Astex Pharmaceuticals, Inc., which is marketed by Taiho Oncology, Inc. under the trademark INQOVI®.

[0008] Venetoclax (4-[4-[[2-(4-chlorophenyl)-4,4-dimethylcyclohexen-1-yl]methyl]piperazin-1-yl]-N-[3-nitro-4-(oxa-4-ylmethylamino)phenyl]sulfonyl-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide; CAS 1257044-40-8) is a BH3 mimic that has been shown to block the B-cell lymphoma-2 (Bcl-2) protein. Venetoclax has been used to treat adult chronic lymphocytic leukemia (CLL), small lymphocytic lymphoma (SLL) and acute myeloid leukemia (AML).

[0009] While the use of a combination of active pharmaceutical agents with Venecella may provide beneficial therapeutic effects to patients, there may also be drug interactions that alter the pharmacokinetic effects of the active agents or make them toxic or otherwise harmful to patients. Summary of the Invention

[0010] According to embodiments of the invention, a method of treating a condition in a subject who requires it is provided, comprising administering to the subject an effective amount of chidamide, an effective amount of decitabine, and an effective amount of Venecella to treat the subject's condition. In some embodiments of the invention, the condition is a hyperproliferative disease, such as cancer. In some embodiments, the condition is a hematologic malignancy, such as myelodysplastic syndrome (MDS), myeloproliferative neoplasm (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.

[0011] In some embodiments of the invention, the effective amounts of chidamide, decitabine, and Venecella are administered in an oral solid dosage form. In some embodiments,An effective amount of chidanilide and an effective amount of decitabine are administered together in a combined solid oral dosage form. In some embodiments, the effective amounts of chidanilide and decitabine are administered on days 1 through 5 of a 28-day cycle, and the effective amount of veneclax is administered daily throughout the 28-day cycle.

[0012] Embodiments of the invention also provide a solid oral dosage form comprising chidanilide, decitabine, and veneclax and at least one pharmaceutically acceptable excipient. Detailed Description

[0013] The invention will now be explained in more detail. This description is not intended to enumerate all the different ways in which the invention may be practiced, or all the features that may be added to the invention. For example, features described with respect to one embodiment may be incorporated into other embodiments, and features described with respect to a particular embodiment may be removed from that embodiment. Furthermore, many variations and additions to the various embodiments suggested herein without departing from the invention will be apparent to those skilled in the art based on this disclosure. Therefore, the following description is intended to illustrate some specific embodiments of the invention, rather than to exhaustively describe all permutations, combinations, and variations thereof.

[0014] Unless the context otherwise requires, it is particularly important to note that the various features of the invention described herein can be used in any combination. Furthermore, the invention is also contemplated that in some embodiments of the invention, any feature or combination of features described herein may be excluded or omitted. For example, if the specification indicates that a complex comprises components A, B, and C, it is particularly desirable that any one or a combination of A, B, or C may be omitted or abandoned, individually or in any combination.

[0015] 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 pertains. The terminology used herein in describing the invention is merely for the purpose of describing particular embodiments and is not intended to limit the invention. Specification 2 / 15 pages 5 CN 122182592 A

[0016] All publications, patent applications, patents, nucleotide sequences, amino acid sequences, and other references mentioned herein are incorporated herein by reference in their entirety.

[0017] As defined in describing the invention and the appended claims, the singular forms “a” and “the” also include the plural forms, unless the context clearly indicates otherwise.

[0018] As used herein, “and / or” means and includes any and all possible combinations of one or more of the associated listed items, and no combination when interpreted in the alternative sense (“or”).

[0019] Furthermore, the invention also contemplates that, in some embodiments of the invention, any feature or combination of features described herein may be excluded or omitted.

[0020] Furthermore, when referring to measurable values ​​such as the amount, dosage, time, temperature, etc. of the compounds or agents of the invention,As used herein, the term “about” means including variations of ±10%, ±5%, ±1%, ±0.5%, or even ±0.1% of the specified amount.

[0021] As used herein, the transitional phrase “consistent with…” should be interpreted as including the said material or step as well as the material or step that does not substantially affect the essential and novel features of the claimed invention. Therefore, the term “consistent with…” as used herein should not be interpreted as equivalent to “comprising”.

[0022] “Effective amount” means the amount required to produce the desired effect (e.g., enhancing the half-life, bioavailability, or efficacy of a therapeutic agent for treating a subject’s cancer, or reducing DNA methylation in a subject).

[0023] “Pharmaceutical acceptable” means those properties and / or substances that are acceptable to patients from a pharmacological and / or toxicological perspective, and / or those properties and / or substances that are acceptable to pharmaceutical chemists from a physical and / or chemical perspective in terms of formulation, formulation, stability, patient acceptability, bioavailability, and compatibility with other ingredients.

[0024] "Pharmaceutically acceptable salt" refers to an acid salt or base salt of the compounds of the present invention, which has the desired pharmacological activity and is neither biologically adverse nor otherwise adverse. Salts can be formed from acids, including but not limited to acetates, adipates, alginates, aspartates, benzoates, benzenesulfonates, hydrogen sulfates, butates, citrates, camphorates, camphorsulfonates, cyclopentylpropionates, digluconate, dodecyl sulfates, ethanesulfonates, fumarates, glucono-p-ethylhexanoates, glycerol phosphates, hemisulfates, heptanates, hexanoates, hydrochlorides, hydrobromide, hydroiodates, 2-hydroxyethanesulfonate, lactates, maleates, methanesulfonates, 2-naphthalenesulfonate, nicotinate, oxalate, thiocyanate, toluenesulfonate, 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 containing organic bases such as dicyclohexylamine salts, N-methyl-D-glucanamine, and salts containing amino acids such as arginine and lysine. In some embodiments, the basic nitrogen-containing group 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 dipentyl sulfates; long-chain halides such as decyl, lauryl, myristyl, and stearyl chlorides, bromides, and iodides; and aralkyl halides such as phenethyl bromide.

[0025] "Pharmaceuticalally acceptable excipient" can refer to any substance that is not itself a therapeutic agent but is used as a carrier, diluent, adjuvant, binder, and / or a medium for delivering a therapeutic agent to a subject, or added to a pharmaceutical composition to improve its handling or storage properties.Or allow or facilitate the formation of a unit dosage form of a compound or composition for administration.

[0026] A “unit dosage form” means a physical discrete unit suitable as a single dose for human or other animal subjects. Each unit dosage form may contain a predetermined amount of an active substance (e.g., chidamide, decitabine, and / or veneclade) calculated to produce the intended effect.

[0027] “Optional” or “optionally” means that the event or situation described below may or may not occur, and the description includes instances of the event or situation occurring and instances of its non-occurrence. For example, “optionally substituted” alkyl groups include unsubstituted alkyl groups of the specification 3 / 15 page 6 CN 122182592 A and substituted alkyl groups.

[0028] The terms “enhancement” or “increase” mean an increase in a particular 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.

[0029] As used herein, the terms “inhibition” or “reduction” or their grammatical variations refer to a reduction or attenuation of a particular level or activity by at least about 15%, 25%, 35%, 40%, 50%, 60%, 75%, 80%, 90%, 95%, or more. In certain embodiments, inhibition or reduction results in very low or essentially no detectable activity (at most an insignificant amount, e.g., less than about 10% or even 5%).

[0030] “Subject” means a cell or tissue in or outside an animal or human body. An animal or human subject may also be referred to as a “patient.”

[0031] “Animal” means a living organism with sensory and voluntary motor abilities that requires oxygen and organic food for survival.

[0032] “Mammalian” means a warm-blooded vertebrate with hair or soft fur. Examples include, but are not limited to, members of the species of humans, horses, pigs, cattle, rats, dogs, or cats.

[0033] The terms “treat,” “treating,” or “treatment of” (or grammatically equivalent terms) mean reducing or at least partially improving or alleviating the severity of a subject’s condition, and / or at least one clinical symptom being relieved, alleviated, or reduced in some way. “Treatment” for a disease, symptom, or condition may mean: (i) inhibiting the disease, symptom, or condition, for example, preventing its development; (ii) alleviating the disease, symptom, or condition, for example, leading to the disappearance of clinical symptoms; and / or (iii) stabilizing or controlling the progression of the disease, symptom, or condition, including preventing recurrence or disease progression after a detectable level of disease reduction or absence.

[0034] The terms “administering” or “administration” refer to administering the compounds and / or compositions of the present invention to a subject, including pathways for introducing or delivering the compounds to the subject to achieve their intended function.

[0035] “Cancer” refers to the abnormal growth of cells,It often proliferates uncontrollably and, in some cases, metastasizes (spreads). Specific cancer types include, but are not limited to, those described in publication number US 2006 / 0014949 and the following: Cardiac: sarcomas (e.g., angiosarcoma, fibrosarcoma, rhabdomyosarcoma, liposarcoma, etc.), myxoma, rhabdomyosarcoma, fibroma, lipoma, and teratoma; Lung: bronchial carcinomas (e.g., squamous cell carcinoma, undifferentiated small cell carcinoma, undifferentiated large cell carcinoma, etc.), Adenocarcinoma, etc.); alveolar (e.g., bronchiolar) carcinoma, bronchial adenoma, sarcoma, lymphoma, chondromatoid hamartoma, 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, insulinoma, glucagonoma, gastrinoma, carcinoid tumor, vipoma, etc.), small intestine (e.g., adenocarcinoma, lymphoma, carcinoid tumor, Kaposi's sarcoma, leiomyosarcoma, hemangioma, lipoma, neurofibroma, fibroma, etc.) and large intestine (e.g., adenocarcinoma, tubular adenoma, villous adenoma, hamartoma, leiomyosarcoma, etc.); genitourinary tract: 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); and testes (e.g., seminoma, teratoma, embryonal carcinoma, choriocarcinoma, sarcoma, stromal cell carcinoma, fibroma, fibroadenoma, adenoma-like tumor, lipoma, etc.); liver: hepatocellular carcinoma (e.g., hepatocellular carcinoma, etc.), bile duct carcinoma, hepatoblastoma, angiosarcoma, hepatocellular adenoma, and hemangioma; bone: osteosarcoma (e.g., osteosarcoma, etc.), fibrosarcoma, malignant fibrous histiocytoma, chondrosarcoma, Ewing's sarcoma, malignant lymphoma (e.g., reticulum cell sarcoma), multiple myeloma, malignant giant cell tumor, chordoma, osteochondroma (e.g., osteocartilaginous osteophyte). Exostoses), benign chondromas, chondroblastomas, chondromycinomas, osteomyxofibromas, osteoid osteomas, and giant cell tumors; Nervous system: Skull (e.g., osteoma, hemangioma, granuloma, xanthoma, osteitis deformans, etc.), Meninges (e.g., meningioma, meningeal sarcoma, gliomatosis, etc.), Brain (e.g., astrocytoma, medulloblastoma, glioma, ependymoma, germ cell tumor [pineal tumor], glioblastoma multiforme, oligodendroglioma, schwannoma, retinoblastoma, congenital tumors, etc.) and spinal cord (e.g., neurofibroma, meningioma, glioma, sarcoma, etc.), Gynecological: Uterus (e.g., endometrial cancer, etc.), Cervix (e.g.,Examples of cancers include: cervical cancer, precancerous cervical dysplasia, etc.; ovaries (e.g., ovarian cancer [serous cystadenocarcinoma, mucinous cystadenocarcinoma, unclassified carcinoma], granulosa cell-theca cell tumor, Sertoli-Leydig cell tumor, dysgerminoma, malignant teratoma, etc.); vulva (e.g., squamous cell carcinoma, intraepithelial carcinoma, adenocarcinoma, fibrosarcoma, melanoma, etc.); vagina (e.g., clear cell carcinoma, squamous cell carcinoma, botryoid sarcoma (embryonic rhabdomyosarcoma), fallopian tube (cancer), etc.); hematology: blood (e.g., myeloid leukemia [acute and chronic], acute lymphoblastic leukemia, chronic lymphocytic leukemia, myeloproliferative disorders, multiple myeloma, myelodysplastic syndromes, etc.), Hodgkin's disease and non-Hodgkin's lymphoma; skin: Malignant melanoma, basal cell carcinoma, squamous cell carcinoma, Kaposi's sarcoma, nevus, dysplastic nevus, lipoma, hemangioma, dermatofibroma, keloid, psoriasis, etc.; and adrenal: neuroblastoma.

[0036] As used herein, “complete remission” (CR) means less than 5% bone marrow blasts; no circulating blasts and blasts with Auer rods; no extramedullary disease; an absolute neutrophil count of less than 1.0 × 10⁹ / L (1000 / µL); and a platelet count of less than 100 × 10⁹ / L (100,000 / µL). This definition follows the European Leukemia Network (ELN) 2017 AML classification, and these criteria may change with further iterations of the ELN. Other diseases, including MDL / CMML, may have different remission criteria according to ELN or other working group standards.

[0037] As used herein, “complete remission with incomplete recovery of hematologic count” (CRi) refers to all CR criteria other than residual neutropenia [less than 1.0 × 10⁹ / L (1,000 / µL)] or thrombocytopenia [less than 100 × 10⁹ / L (100,000 / µL)]. This definition follows the European Leukemia Network (ELN) 2017 AML classification, and these criteria may change with further iterations of the ELN. Other diseases, including MDL / CMML, may have different remission criteria according to ELN or other working group standards.

[0038] As used herein, “complete remission with partial recovery of hematologic count” (CRh) refers to all CR criteria other than not meeting the count recovery criteria; and has an absolute neutrophil count less than or equal to 0.5 × 10⁹ / L (1,000 / µL) and a platelet count less than or equal to 50 × 10⁹ / L (100,000 / µL). This is the commonly used definition for AML. Other conditions, including MDL / CMML,Different relief criteria may exist depending on ELN or other working group standards.

[0039] “AUC0-t” is the definite integral of a curve describing the change in plasma drug concentration over time (t).

[0040] For decitabine “5-day cumulative AUC”, the primary endpoint pharmacokinetic (PK) analysis set was used to calculate the 5-day cumulative AUC0-t exposure following administration of the dosage form. The following assumptions were used: 1) steady state was reached on day 2 of solid dosage form administration; and 2) based on the steady state reached on day 2, AUC0-t from day 2 to day 5 represents the daily AUC0-t from day 2 to day 5 during the assumed 5-day solid dosage form administration. Therefore, to calculate the total 5-day oral AUC0-t exposure of decitabine using PK data from consecutive 3-day PK sampling, the day 1 AUC0-t (first solid dosage form dose) was added to (day 2 AUC0-t + day 5 AUC0-t) × 2. If AUC0-t is not available on day 2, AUC0-t on day 5 is used instead; and vice versa.

[0041] “Cmax” is the maximum (or peak) serum concentration of the drug in the blood or other matrix after drug administration and before administration of the second dose. Therefore, Cmax can be measured on any day of the cycle.

[0042] As used herein, “cycle” means 28 consecutive days during which chidanilide, decitabine, and veneclade are administered. In some embodiments, chidanilide and decitabine are administered from day 1 to day 5 of each 28-day cycle. In some embodiments, veneclade is administered daily during the 28-day cycle. Multiple cycles can be performed consecutively, or there can be interruptions between cycles. In addition, other cycle lengths and different dosing regimens can be used. Specification 5 / 15 pages 8 CN 122182592 A

[0043] The present invention provides oral dosage forms of decitabine, chidanilide, and veneclade or any pharmaceutically acceptable salt of the above, wherein the three drugs can be administered simultaneously, sequentially, or separately. As used herein, decitabine, chidamide, and veneclax, and their pharmaceutically acceptable salts, are collectively referred to as “therapeutic agents.” Furthermore, when referring to a therapeutic agent (e.g., veneclax), it should be understood that a pharmaceutically acceptable salt of that therapeutic agent is also included in this reference. Oral dosage forms may include each therapeutic agent individually, a combination of all therapeutic agents, or a combination of any two therapeutic agents. In certain embodiments, a first oral dosage form comprises decitabine and chidamide, and a second oral dosage form comprises veneclax. In certain embodiments, a solid oral dosage form comprises decitabine, chidamide, and veneclax. In some embodiments, the solid oral dosage forms of the present invention also include pharmaceutically acceptable excipients.

[0044] In some embodiments of the present invention, one or more oral dosage forms are solid oral dosage forms.Such as solid oral dosage forms. The term "solid oral dosage form" refers to a pharmaceutical composition that is in solid form and formulated for oral administration. Any suitable solid oral dosage form can be used. Examples of solid oral dosage forms according to embodiments of the invention include tablets (e.g., tablets targeted for buccal, sublingual, or systemic absorption), capsules, bolus, powders, granules, pastes applied to the tongue, capsules (including hard gelatin capsules and soft gelatin capsules), oral sprays, troch, lozenges, and pellets. Pharmaceutical compositions can be formulated as immediate-release, sustained-release, or controlled-release.

[0045] Many possible oral dosage forms can be used in the methods of the 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, 20 mg, 25 mg, 30 mg, 35 mg, 40 mg, 45 mg, 50 mg, 55 mg, 60 mg, 65 mg, 70 mg, 75 mg, 80 mg, 90 mg, or 100 mg, or any range thereof). As another example, chidanilide may be present in oral dosage forms in the range of about 10 mg to about 150 mg, about 70 mg to 120 mg, or about 90 mg to about 110 mg (e.g., about 50 mg, 60 mg, 70 mg, 80 mg, 85 mg, 90 mg, 95 mg, 100 mg, 105 mg, 110 mg, 115 mg, 120 mg, 125 mg, 130 mg, 140 mg, or 150 mg, or any range thereof). As another example, veneclade can be present in 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 200 mg (e.g., about 10 mg, 20 mg, 30 mg, 40 mg, 50 mg, 60 mg, 70 mg, 80 mg, 90 mg, 100 mg, 110 mg, 120 mg, 150 mg, 200 mg, 250 mg, 300 mg, 400 mg, 450 mg, 500 mg, 550 mg, 600 mg, or any range thereof). However, in some embodiments of the invention, a solid oral dosage form is a unit dosage form containing about 35 mg of decitabine. In some embodiments of the invention, a solid oral dosage form is a unit dosage form containing about 100 mg of chidamide. Furthermore, in some embodiments, a solid oral dosage form is a unit dosage form containing about 35 mg of decitabine and about 100 mg of chidamide. In some embodiments of the invention,One unit dosage form comprises about 35 mg of decitabine and about 100 mg of chidamide and at least one pharmaceutically acceptable excipient. In some embodiments of the invention, a solid oral dosage form is a unit dosage form comprising about 10 mg, 50 mg, 100 mg, 200 mg, 400 mg, or 600 mg of veneclax and at least one pharmaceutically acceptable excipient. In some embodiments of the invention, a solid oral dosage form is a unit dosage form comprising about 35 mg of decitabine, about 100 mg of chidamide, and about 10 mg, 50 mg, 100 mg, 200 mg, 400 mg, or 600 mg of veneclax. In some embodiments of the invention, a solid oral dosage form is a unit dosage form comprising about 35 mg of decitabine, about 100 mg of chidamide, about 10 mg, 50 mg, 100 mg, 200 mg, 400 mg, or 600 mg of veneclax and at least one pharmaceutically acceptable excipient.

[0046] Pharmaceutically acceptable excipients are well known in the pharmaceutical industry and are described, for example, in the Remington Pharmacy Compendium (Mack Publishing Co., Easton, Pa) (e.g., 20th edition, 2000) and the Handbook of Pharmaceutical Excipients (American Pharmaceutical Association, Washington, D.C.) (e.g., 1st, 2nd, and 3rd editions, 1986, 1994, and 2000, respectively). As those skilled in the art will recognize, excipients can provide a variety of functions and can be described as, for example, wetting agents, buffers, suspending agents, diluents, binders, lubricants, flow aids, emulsifiers, disintegrants, absorbents, preservatives, surfactants, colorants, flavoring agents, and / or sweeteners. Examples of pharmaceutically acceptable excipients include, but are not limited to: (1) sugars, such as lactose, glucose and sucrose; (2) starches, such as corn starch and potato starch; (3) cellulose and its derivatives, such as sodium carboxymethyl cellulose, ethyl cellulose, cellulose acetate, hydroxypropyl methyl cellulose (hydroxypropyl methyl cellulose) and hydroxypropyl cellulose; (4) powdered tragacanth gum; (5) malt; (6) gelatin; (7) talc; (8) excipients, such as cocoa butter and suppository waxes; (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 glycerol, sorbitol, mannitol and polyethylene glycol; (12) esters, such as ethyl oleate and ethyl laurate; (13) agar; (14) buffers.Examples of diluents include magnesium hydroxide and aluminum hydroxide; (15) alginic acid; (16) pyrogen-free water; (17) isotonic saline; (18) Ringer's solution; (19) ethanol; (20) pH buffer; (21) polyester, polycarbonate and / or polyanhydride; and (22) other non-toxic and compatible substances used in pharmaceutical preparations.

[0047] Examples of diluents include lactose, lactose monohydrate, cellulose, microcrystalline cellulose, sorbitol, anhydrous calcium hydrogen phosphate and anhydrous calcium sulfate. Examples of binders include gelatin, glucose, lactose, cellulose, methylcellulose, ethylcellulose, hydroxypropyl methylcellulose (hydroxypropyl methylcellulose), hydroxypropyl cellulose, starch, polyvinylpyrrolidone, sodium alginate, carboxymethyl cellulose and gum arabic. Examples of disintegrants include croscarmellose sodium, cross-linked polyvinyl cellulose, sodium glycolate starch and starch. Examples of flow aids include colloidal silica, corn starch and talc. Examples of lubricants include stearic acid, magnesium stearate, calcium stearate, talc, paraffin, sodium lauryl sulfate, sodium benzoate, and polyethylene glycol.

[0048] In some embodiments, the solid oral dosage form includes one or more of a diluent, a binder, a disintegrant, a flow aid, and a lubricant. In some embodiments, the solid oral dosage form includes a diluent, a binder, a disintegrant, a flow aid, and a lubricant. In a particular embodiment of the invention, the solid oral dosage form includes decitabine and / or chidamide and the following excipients: lactose monohydrate as a diluent; hydroxypropyl methylcellulose as a binder; croscarmellose sodium as a disintegrant; colloidal silica as a flow aid; and magnesium stearate as a lubricant. In some embodiments of the invention, these components are formulated into tablets. In some embodiments, the tablets are immediate-release tablets. Furthermore, in certain embodiments, the tablets are coated with a film, which may or may not be colored. Any pharmaceutically acceptable coating may be used, but in some embodiments, the tablets are coated with Opadry® coating.

[0049] In some embodiments, dicdarurine is present in the solid oral dosage form in an amount from about 17% w / w to 22% w / w, for example, 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% w / w or any range thereof (e.g., about 19.42% w / w). In some embodiments, decitabine is present in the solid oral dosage form in an amount from about 4% w / w.For example, 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% w / w or any range thereof (e.g., about 6.8% w / w). In some embodiments, the diluent (e.g., lactose monohydrate) is present in the solid oral dosage form in an amount from about 55% w / w to 70% w / w, for example, about 55%, 56%, 57%, 58%, 59%, 60%, 61%, 62%, 63%, 64%, 65%, 66%, 67%, 68%, 69%, or 70% w / w or any range thereof (e.g., about 62.62% w / w). In some embodiments, the binder (e.g., hydroxypropyl methylcellulose) is present in the solid oral dosage form in an amount of about 1% w / w to 3% w / w, 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% w / w or any range thereof (e.g., about 1.94% w / w). In some embodiments, the disintegrant (e.g., croscarmellose sodium) is present in the solid oral dosage form in an amount of about 3% w / w to 7% w / w, 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% w / w or any range thereof (e.g., about 4.85% w / w). In some embodiments, the gliding agent (e.g., colloidal silica) is present in the solid oral dosage form in an amount of about 0.5% w / w to 2% w / w, 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% w / w or any range thereof (e.g., about 0.97% w / w). In some embodiments, the lubricant (e.g., magnesium stearate) is present in the solid oral dosage form in an amount of about 0.1% w / w to 2% w / w.For example, 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% w / w or any range thereof (e.g., about 0.49% w / w).

[0050] In some embodiments, the solid oral dosage form comprises the ingredients listed in Table 1.

[0051] Table 1

[0052] In some embodiments, the solid oral dosage form comprises the ingredients listed in Table 2.

[0053] Table 2

[0054] For more information on compositions and formulations of chidamide and decitabine, please see the Inqovi® Prescribing Information and www.inqovi.com.

[0055] In some embodiments of the invention, veneclade is present in a solid oral dosage form (e.g., tablets) at a concentration of 10 mg veneclade together with one or more of the following excipients: calcium hydrogen phosphate, colloidal silica, cropovidone, iron oxide yellow, polyethylene glycol, polysorbate 80, polyvinyl alcohol, sodium stearoyl fumarate, talc, and titanium dioxide.

[0056] In some embodiments of the invention, veneclade is present in a solid oral dosage form (e.g., tablets) at a concentration of 50 mg veneclade together with one or more of the following excipients: calcium hydrogen phosphate, colloidal silica, cropovidone, iron oxide black, iron oxide red, iron oxide yellow, polyethylene glycol, polysorbate 80, polyvinyl alcohol, sodium stearoyl fumarate, talc, and titanium dioxide.

[0057] In some embodiments of the invention, veneclade is present at a concentration of 100 mg veneclade in a solid oral dosage form (e.g., tablets) with one or more of the following excipients listed in the specification (page 8 / 15, CN 122182592 A): calcium hydrogen phosphate, colloidal silica, crospovidone, iron oxide yellow, polyethylene glycol, polysorbate 80, polyvinyl alcohol, sodium stearoyl fumarate, talc, and titanium dioxide.

[0058] The pharmaceutical compositions of the invention can be prepared using known materials and techniques, including but not limited to mixing and / or blending decitabine and chidamide with pharmaceutically acceptable excipients. The pharmaceutical compositions of the invention may also include mixing and / or blending veneclade with pharmaceutically acceptable excipients.

[0059] Another aspect of the invention relates to unit dosage forms and kits comprising at least one unit dosage form containing decitabine, at least one unit dosage form containing chidamide, and at least one unit dosage form containing veneclade. In certain embodiments, the kit comprises at least one unit formulation containing decitabine and chidamide and at least one unit formulation containing verneclax. In some embodiments,The kit provides unit dosage forms comprising about 35 mg decitabine and about 100 mg chidamide, and at least one pharmaceutically acceptable excipient, and at least one unit dosage form comprising about 10 mg, 50 mg, and / or 100 mg veneclax. Other unit dosage forms may be used and may vary depending on availability. Daily doses of chidamide, decitabine, and / or veneclax may require more than one unit dosage form per day. For example, if 400 mg of veneclax is prescribed daily, the kit may include four 100 mg veneclax unit dosage forms per day.

[0060] The kit may include solid oral dosage forms of each therapeutic agent for a daily dose (e.g., one tablet containing 35 mg decitabine and 100 mg chidamide, and four tablets each containing 100 mg veneclax). The kit may also include unit dosage forms for use over a period of time (e.g., 5 days or a week) or for the entire cycle. Therefore, in some embodiments of the present invention, the kit may include 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28 or more solid oral dosage forms containing chidamide and decitabine according to embodiments of the present invention, and 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, The kit may contain 20, 21, 22, 23, 24, 25, 26, 27, 28, or more solid oral dosage forms containing veneclade. In some embodiments, the kit may include 5 solid oral dosage forms containing chidanilide and decitabine (for days 1 to 5 of the cycle) and at least 28 solid oral dosage forms of veneclade (for days 1 to 28 of the cycle). Alternatively, all three therapeutic agents may be included in one solid oral dosage form, or each therapeutic agent may be present in its own separate solid oral dosage form. In some embodiments, the kit may include 5 solid oral dosage forms containing chidanilide, decitabine, and veneclade (for days 1 to 5 of the cycle) and multiple solid oral dosage forms of veneclade (e.g., 23 solid oral dosage forms) for the remainder of the cycle (e.g., for days 6 to 28 of the cycle). In some embodiments, the unit dosage form for a single therapeutic agent may differ in the kit. For example, in some embodiments, the kit may include a unit dosage form of 100 mg veneclade for the first day of the cycle.And for another day of the cycle, a unit dosage form comprising 400 mg of Venecella.

[0061] The kit may also include containers and / or packaging suitable for commercial sale. Containers may be any conventional shape or form known in the art, made of pharmaceutically acceptable materials, such as paper or cardboard boxes, glass or plastic bottles or jars, resealable bags, or blister packs (from which individual doses are extruded according to the treatment regimen). More than one container may be used in one package. For example, tablets may be contained in blister packs, which in turn are contained in a box. In some embodiments, the container is a bottle, such as a 30 cc white high-density polyethylene bottle containing a unit dosage form (e.g., about 5 unit dosage forms). The bottle may also contain a desiccant, such as a silica desiccant canister. In some embodiments, the container is, for example, a blister pack formed of aluminum foil or a foil cap, with each cavity containing one tablet. The blister pack may be present in a carton.

[0062] The kit may also include information. The information may be provided on a readable medium. The readable medium may include a label. This information may be directed to a doctor, pharmacist, or patient. This information may indicate that the unit dosage form may cause one or more adverse reactions. This information may include instructions for administering the unit dosage form (e.g., in the manner described herein). These instructions may be provided in a variety of ways.

[0063] The information may be associated with the container, for example, by being written on a label affixed to the container (e.g., a prescription label or a separate label); included inside the container as a written packaging insert; applied directly to the container, e.g., printed on the wall of a box or blister pack; or attached by binding or tape, e.g., as an instruction card attached to the neck of the container by a string, thread, or other cord, tether, or rope-like object.

[0064] According to embodiments of the invention, a method is provided for administering chidamide, decitabine, and veneclade to a subject in one or more oral dosage forms of the invention. In certain embodiments, methods are provided for administering to a subject oral dosage forms comprising chidamide (e.g., 100 mg) and decitabine (e.g., 35 mg) and pharmaceutically acceptable excipients, and methods for administering one or more oral dosage forms comprising veneclade (e.g., 100 mg, 200 mg, or 400 mg total) and pharmaceutically acceptable excipients. 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.

[0065] Any administration regimen known to those skilled in the art for adjusting the timing and sequence of drug delivery may be used and repeated as needed to achieve the therapeutic effect of the method of the invention. For example, the oral dosage forms of the invention may be administered once, twice, three times, or four times daily by a single dose, multiple discrete doses, or continuous infusion. In certain embodiments,At least one solid oral dosage form is administered once daily. In some embodiments, administration of at least one solid oral dosage form according to embodiments of the invention may be performed for one or more weeks in 28-day cycles, for example, one, two, three, or four weeks in 28-day cycles. The weeks may be consecutive and / or non-consecutive. In a particular embodiment, dicouridine and decitabine are administered daily for five days (days 1 to 5) of a 28-day cycle, and veneclade is administered daily on each day of the 28-day cycle.

[0066] In some embodiments of the invention, a solid oral dosage form comprising chidamide and decitabine is administered to the subject once daily for 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28 or more days. In some embodiments, the solid oral dosage form comprising chidamide and decitabine is administered to the subject once daily from day 1 to day 5 of a 28-day cycle. In some implementations, a second solid oral dosage form containing veneclade is administered once daily to the same subject for 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28 or more days. In some implementations, on days 1 through 5 of the cycle, the subject is given cidaluridine, decitabine and veneclade daily, and on days 6 through 28 of the cycle, veneclade alone is given daily. This solid oral dosage form may be administered concurrently (also called simultaneously), sequentially, or at different times on the same day (also called separately). In specific implementations, all solid oral dosage forms are administered simultaneously or nearly simultaneously (e.g., within 5 minutes, 10 minutes, 15 minutes, 20 minutes, 25 minutes, or 30 minutes).

[0067] In some embodiments, a single unit formulation comprising 35 mg decitabine and 100 mg chidamide may be administered daily from day 1 to day 5 of the cycle. In some embodiments, the dose of verenaclava may vary depending on the day of the cycle. For example, on day 1, the subject may be given 100 mg verenaclava (e.g., as a single 100 mg unit formulation), on day 2, the subject may be given 200 mg verenaclava (e.g., as two 100 mg unit formulations), and from day 3 to day 28, the subject may be given 400 mg verenaclava (e.g., as four 100 mg unit formulations). However, in some embodiments, the doses of chidamide and decitabine may vary, and in some embodiments,The dose of veneclade can be the same throughout the cycle. For example, in some embodiments of the invention, the subject may administer 400 mg of veneclade daily on each day of the cycle. This may be suitable, for example, when the subject is in a second or later cycle (see page 10 / 15 of CN 122182592 A). For more information on possible dosing regimens and administration of chidanilide and decitabine, please see the Inqovi® Prescribing Information and www.inqovi.com.

[0068] In some embodiments, time periods of 0 to 31 days or longer (e.g., 0 days, 1 day, 2 days, 3 days, 4 days, 5 days, 6 days, 7 days, 8 days, 9 days, 10 days, 11 days, 12 days, 13 days, 14 days, 15 days, 16 days, 17 days, 18 days, 19 days, 20 days, 21 days, 22 days, 23 days, 24 days, 25 days, 26 days, 27 days, 28 days, 29 days, 30 days, 31 days or longer) may pass between the multiple cycles of the invention. Treatment-free periods may be desirable to allow subjects of the invention (e.g., human patients) to be sufficiently healthy to continue treatment. The time interval between treatment cycles can be determined by the physician using standard techniques in the art and can be determined individually for each subject, for example, based on sufficient blood cell counts, such as complete absence of neutropenia (e.g., an absolute neutrophil count (ANC) of at least or greater than 0.5 × 10⁹ cells / L in the subject), and can be adjusted during treatment based on the administering physician's judgment. In some embodiments, the time interval between treatment cycles can be minimal, for example, without such a time interval, for example, immediately starting the next 28-day period. In some embodiments, the time interval between treatment cycles can 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.

[0069] In some embodiments, the administration regimen may include pretreatment and / or co-administration with at least one additional therapeutic agent. In this case, a solid oral dosage form containing decitabine and chidamide may be administered simultaneously, sequentially, or at different times or on different days on the same day, with at least one additional therapeutic agent. Additional therapeutic agents may also be included in one or more solid oral dosage forms. As used herein, the term "therapeutic agent" includes immunomodulators.

[0070] Examples of chemotherapeutic agents include, but are not limited to: alkylating agents (e.g., which may include doxorubicin, cyclophosphamide, estradiol, carmustine, mitomycin, bleomycin, etc.); antimetabolites (e.g., which may include 5-fluorouracil, capecitabine, gemcitabine, nerabine, fludarabine, methotrexate, etc.); platinum-plating agents (e.g., which may include cisplatin, oxaliplatin, carboplatin, etc.); topoisomerase inhibitors (e.g., which may include topotecan, irinotecan, etoposide, etc.); and microtubule agents (e.g.,It may include paclitaxel, docetaxel, vinorelbine, vincristine, other taxanes, epothilone, etc.; signal inhibitors (e.g., kinase inhibitors, antibodies, farnesyltransferase inhibitors, etc.); and other chemotherapeutic agents (e.g., tamoxifen, antimitotic agents such as polo-like kinase inhibitors or aurora kinase inhibitors, etc.).

[0071] Furthermore, a method is provided for treating a condition treatable with decitabine, veneclax, and / or chidamide in a subject who requires it, comprising administering one or more oral dosage forms according to embodiments of the invention to the subject to treat the subject's condition. Any method of administration described herein may be used to treat the condition or any other treatment method described herein.

[0072] In some embodiments of the invention, the condition treatable with decitabine, veneclax, and / or chidamide is a hyperproliferative disease, such as cancer. The method may be used to treat any cancer known or subsequently found to be effectively treatable with decitabine, veneclax, and / or chidamide. In a particular embodiment, the condition is a cancer selected from hematologic malignancies and solid tumors. Examples of hematologic malignancies include myelodysplastic syndromes (MDS), leukemias (such as ALL, AML, CML, MPN, or CMML), lymphomas (such as Hodgkin's lymphoma, non-Hodgkin's lymphoma, or T-cell lymphoma), and plasma cell dyscrasias (such as multiple myeloma). 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 hyperproliferative disorders such as cancer, wherein the cancer is acute myeloid leukemia (AML).

[0073] Administration of one or more solid oral dosage forms of the present invention, or any combination of decitabine, veneclade, and / or chidamide, to a subject in need of it can provide a variety of beneficial responses to the subject. For example, in some embodiments, compared to a control measurement, such as compared to the subject's DNA methylation before administration (e.g., the subject's "baseline" DNA methylation), administration reduces the subject's DNA methylation 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). The subject's DNA methylation can be quantitatively and / or qualitatively assessed using any standard technique in the art, for example, by a marker of relative overall methylation compared to a control, such as by long-spread nuclear element-1 (LINE-1) methylation compared to a control. For example, in some embodiments, compared to a control measurement, such as compared to LINE-1 methylation in the subject before administration (e.g., ...Compared to baseline LINE-1 methylation in the subject, administration reduces LINE-1 methylation in the subject by at least 5% (e.g., at least 5%, 6%, 7%, 8%, 9%, 10%, 11%, 12%, 13%, 14%, or 15% or more). For example, in some embodiments, administration may reduce LINE-1 methylation in the subject by at least 5%, at least 8%, at least 10%, or at least 15% or more. In some embodiments, administration may reduce LINE-1 methylation in the subject by about 5% to about 20%, about 6% to about 15%, or about 8% to about 10%.

[0074] In some embodiments, after a 28-day cycle, administration is given to reduce the subject's absolute neutrophil count (ANC) to less than 0.5 x 10⁹ cells / L of blood for no more than two, three, or four weeks (e.g., no more than consecutive 28, 27, 26, 25, 24, 23, 22, 21, 20, 19, 18, 17, 16, 15, 14, 13, 12, 11, 10, 9, 8, 7, 6, 5, 4, 3, 2, or 1 day or any value or range thereof). In some embodiments, administration is given during treatment (e.g., between multiple repeated 28-day cycles) to reduce the subject's absolute neutrophil count (ANC) to less than 0.5 × 10⁹ cells / L of blood for no more than two, three, or four weeks.

[0075] In some embodiments, optionally measured by %F cells / red blood cells per sample (e.g., in a patient's blood sample), the administration increases hemoglobin F-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) compared to “baseline” control %F cells / red blood cells (e.g., compared to the patient's %F cells / red blood cells before treatment, or, for example, compared to the average %F cells / red blood cells of an untreated patient population (e.g., a healthy patient population)). For example, in some embodiments, the administration may increase the subject's %F cells by at least 5%, at least 8%, at least 10%, at least 15%, or at least 23% or more compared to a baseline control. In some embodiments, the administration may increase the subject's %F cells by about 5% to about 30%, about 6% to about 24%, or about 8% to about 20% compared to a baseline control.

[0076] In some embodiments, the administration increases the number of F cells in each sample (e.g., in a patient's blood sample) to at least 10% to at least 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 of F cells / red blood cells or any value or range thereof). For example, in some embodiments,Administration may increase the number of F cells in a sample to at least 15%, at least 20%, at least 23%, at least 35%, or more of the total red blood cells. In some embodiments, administration may increase the number of F cells in a sample to about 15% to about 30%, about 18% to about 25%, or about 15% to about 35% of the total red blood cells.

[0077] In some embodiments of the method described in this invention, the subject may be a mammal. In some embodiments of the method described in this invention, the subject may be a human. In some embodiments of this invention, the subject is 75 years of age or older. In a particular embodiment, the subject is 18 years of age or older and is unsuitable for induction chemotherapy due to one or more comorbidities. Such comorbidities include, for example, (i) an Eastern Cooperative Oncology Group (ECOG) baseline performance status of 2 or 3, (ii) severe cardiac disease (e.g., congestive heart failure requiring treatment, ejection fraction less than or equal to 50%, or chronic stable angina), (iii) severe lung disease (e.g., pulmonary carbon monoxide diffusion capacity (DLCO) less than or equal to 65%, or forced expiratory volume in one second (FEV1) less than or equal to 65%, (iv) creatinine clearance greater than or equal to 30 mL / min and less than 45 mL / min, and / or (v) moderate hepatic impairment with total bilirubin greater than 1.5 times and less than or equal to 3.0 times the upper limit of normal (ULN).

[0078] Dosage levels, administration methods, and administration regimens may be modified by those skilled in the art using known techniques as needed by the subject (e.g., a patient) (if deemed necessary). Specification 12 / 15 pages 15 CN 122182592 A

[0079] It will be apparent to those skilled in the art that specific embodiments of the invention may be directed toward one, some, or all of the foregoing aspects and other aspects, and may include one, some, or all of the embodiments indicated above and below, and other embodiments.

[0080] Except in working examples, or if otherwise stated, all figures used in the specification and claims to represent quantities of ingredients, reaction conditions, etc., should be understood to be modified by the term “about”. Thus, unless stated to the contrary, these figures are approximate values ​​that may vary according to the desired properties sought to be obtained according to the invention. At least, and without attempting to apply the principle of equivalence to the scope of the claims, each numerical parameter should be interpreted according to the number of significant figures and common rounding techniques.

[0081] While the numerical ranges and parameters that illustrate the broad scope of the invention are approximate values, the values ​​described in working examples are reported as accurately as possible. However, any numerical value inherently contains a certain degree of error, which is necessarily caused by the standard deviation found in the respective test measurements.

[0082] Although the invention has been described, it will be illustrated in more detail in the following examples.The examples contained herein are for illustrative purposes only and are not intended to limit the invention.

[0083] The examples are part of a single-arm, open-label, multicenter, non-randomized interventional study to evaluate the pharmacokinetic (PK) interactions, safety, and preliminary efficacy of ASTX727 (chidanilide plus decitabine) in combination with veneclade in the treatment of newly diagnosed acute myeloid leukemia (AML) in adults aged 75 years or older and / or with comorbidities that preclude the use of intensive induction chemotherapy. Any drug-drug interactions between ASTX727 and veneclade in combination therapy will be assessed by evaluating the area under the curve (AUC) and maximum plasma concentration (Cmax) exposure. Enrollment of 35 participants is expected in a single-arm, treatment-primary-purpose interventional model.

[0084] Dosing regimen: Oral administration of ASTX727 and Venecla in combination for Cycle 1: ASTX727 was administered in combination with Venecla (Day 1 = 100 mg daily; Day 2 = 200 mg daily; and Days 3 through 28 = 400 mg daily) for 28 days according to the prescribed dosing regimen.

[0085] Cycle 2 and thereafter: ASTX727 was administered in combination with Venecla (400 mg daily) for 28 days according to the prescribed dosing regimen.

[0086] The primary outcome measure to be measured was the area under the curve (AUC) of Venecla from 0 to 24 hours with and without ASTX727, measured on Day 5 and Day 15 of Cycle 2 (each cycle is 28 days).

[0087] Veneclav Cmax – The maximum observed concentration of veneclax with and without ASTX727 was measured on days 5 and 15 of cycle 2 (28 days per cycle).

[0088] Secondary outcome measure of decitabine AUC0-24 – The area under the curve of decitabine from 0 to 24 hours was measured on days 1, 2, and 5 of cycle 2 (28 days per cycle).

[0089] Decitabine and chidanilide Cmax – The maximum observed concentrations of decitabine and chidanilide were measured on days 1, 2, and 5 of cycle 2 (28 days per cycle).

[0090] Chidanilide AUC0-8 – The area under the curve of chidanilide from 0 to 8 hours was measured on days 1, 2, and 5 of cycle 2 (28 days per cycle).

[0091] Decitabine 5-day AUC—Measured on days 1 to 5 of cycle 2 (each cycle is 28 days). See product manual page 13 / 15, 16 CN 122182592 A for 5-day cumulative AUC.

[0092] Participants who experienced TEAEs—maximum 24 months.The number of adverse events (TEAEs) during treatment was measured.

[0093] Complete remission (CR) – up to 24 months, measured the number of participants who achieved CR, CR+ complete remission with partial hematologic recovery (CRh), and CR+ incomplete recovery of blood cell count (CRi).

[0094] Time to remission – up to 24 months, measured the number of days from the first dose to the first written evidence of complete remission or CRh.

[0095] Duration of remission – up to 24 months, measured the number of days from the onset of remission (CR or CRh) to disease progression, initiation of alternative anti-leukemia therapy, or death.

[0096] Overall remission – up to 24 months, measured the number of days from the date of the first dose to death from any cause.

[0097] Eligibility criteria Age eligible for study: 18 years or older Sex eligible for study: All Based on sex: No Accepted Healthy volunteers: No Inclusion criteria Participants must be 18 years or older.

[0098] Histopathological confirmation of newly diagnosed AML according to the World Health Organization (WHO) 2016 criteria.

[0099] Life expectancy is at least 3 months.

[0100] Participants must be deemed ineligible for intensive induction chemotherapy as defined below: a) 75 years of age or older, or b) 18–74 years of age, and have at least one of the following comorbidities: (i) severe heart disease (e.g., congestive heart failure requiring treatment, ejection fraction less than or equal to 50%, or chronic stable angina), (ii) severe lung disease (e.g., pulmonary carbon monoxide diffusion capacity (DLCO) less than or equal to 65%, or forced expiratory volume in one second (FEV1) less than or equal to 65%, (iii) creatinine clearance greater than or equal to 30 mL / min and less than 45 mL / min, and (iv) moderate hepatic impairment with total bilirubin greater than 1.5 times the upper limit of normal (ULN) and less than or equal to 3.0 times the upper limit of normal (ULN).

[0101] Eastern Cooperative Oncology Group (ECOG) performance status 0–2.

[0102] Women of childbearing potential (as recommended by the Clinical Trials Facilitation Group (CTFG)) must not be pregnant or breastfeeding. And a negative pregnancy test is required at screening.

[0103] Participants of reproductive potential and their partners must agree to use at least two effective contraceptive methods, including avoiding sperm donation, during the study period and for 3 months after the last administration of the study treatment. Effective contraceptive methods include oral contraceptives or double barrier methods (such as the use of condoms and diaphragms with spermicides).

[0104] Participants must be able to provide signed informed consent, which includes compliance with the informed consent form and the requirements and limitations listed in the study protocol, and a willingness to participate in this study.

[0105] Exclusion criteria include a history of standard myeloproliferative neoplasms.This includes myelofibrosis, idiopathic thrombocythemia, polycythemia vera, chronic myeloid leukemia with or without BCR-ABL1 translocation, and AML with BCR-ABL1 translocation.

[0106] 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.

[0107] AML is known to involve an active central nervous system.

[0108] Human immunodeficiency virus (HIV) infection is known (due to potential drug-drug interactions between antiretroviral drugs and veneclax, as per the specification page 14 / 15, 17 CN 122182592 A). HIV testing is only performed at screening when directed according to local guidelines or institutional standards.

[0109] Hepatitis B or C infection is known (detectable viral load). Hepatitis B or hepatitis C testing will only be performed at screening when directed by local guidelines or institutional standards.

[0110] Severe hepatic impairment is defined as: bilirubin >1.5xULN (participants ≥75 years old) or >3xULN (participants <75 years old); or aspartate aminotransferase (AST) / serum glutamic-glutamyl transferase (SGOT) or alanine aminotransferase (ALT) / serum alanine aminotransferase (SGPT) >3xULN (unless it is believed to be due to organ involvement by leukemia).

[0111] Severe renal impairment is defined as: calculated creatinine clearance or glomerular filtration rate <30 mL / min.

[0112] Malabsorption syndrome or other conditions that prevent enteral administration.

[0113] Cardiovascular disability status is New York Heart Association functional class >2. Class 2 is defined as heart disease in which the patient is comfortable at rest but experiences fatigue, palpitations, shortness of breath, or angina with general physical activity.

[0114] Chronic respiratory diseases requiring continuous oxygen supply, or a history of significant kidney, neurological, psychiatric, endocrine, metabolic, immune, liver, or cardiovascular diseases, any other disease deemed by the investigator to adversely affect participation in this study, or known hypersensitivity to any study drug.

[0115] Clinically uncontrolled systemic infections (viral, bacterial, or fungal) requiring treatment.

[0116] History of other malignancies prior to entry into the study, excluding: adequately treated breast or cervical carcinoma in situ; localized basal cell carcinoma or squamous cell carcinoma of the skin; previously confined and surgically removed malignancies (or adequately treated and controlled by other means); and any early-stage malignancies not requiring targeted treatment.

[0117] White blood cell (WBC) count >25,000 / µL (hydroxyurea treatment is permitted to meet this criterion).

[0118] Treatment with the following drugs: a) hypomethylating agents (azacitidine or decitabine) or veneclade,This includes: b) prior treatment for myelodysplastic syndrome (MDS), chimeric antigen receptor (CAR)-T cell therapy, and c) investigational therapeutic agents for MDS or AML.

[0119] Participants who cannot discontinue concomitant prophylactic antifungal therapy with CYP3A inhibitor activity or other concomitant medications with moderate or strong CYP3A inhibitor activity for ≥7 days or 5 half-lives (whichever is longer) before Day 1 of Cycle 1 (C1D1).

[0120] Participants who cannot discontinue concomitant medications with strong CYP3A or P-gp inhibitors for ≥7 days or 5 half-lives (whichever is longer) before C1D1.

[0121] Participants who cannot avoid concomitant medications referred to as moderate or strong CYP3A inducers.

[0122] Participants currently involved in another study or observational study.

[0123] Participants with known or suspected hypersensitivity to decitabine, chidanilide, veneclade, or any of their excipients.

[0124] Known to have severe mental illness or other conditions deemed by the investigator to be at high risk of participants being unable to comply with the study protocol, such as alcoholism or other substance abuse or addiction.

[0125] Patients who consumed grapefruit, grapefruit products, Seville oranges (including jams containing Seville oranges) or star fruit ≤7 days prior to C1D1.

[0126] The foregoing embodiments are illustrative of the invention and should not be construed as limiting it. Although the invention has been described in detail with reference to preferred embodiments,However, variations and modifications exist within the scope and spirit of the invention as described and defined in the following claims. Specification 15 / 15 pages 18 CN 122182592 A Abstract This application provides pharmaceutical compositions and methods of using the same for treating cancer. Provided according to embodiments of the invention are methods of treating a disorder in a subject in need thereof that include administering to the subject an effective amount of cedazuridine, an effective amount of decitabine, and an effective amount of venetoclax, thereby treating the disorder in the subject. In some embodiments of this application, the disorder is a hyperproliferative disorder such as cancer. In some embodiments, the disorder is a hematological cancer such as myelodysplastic syndromes (MDS), myeloproliferative neoplasms (MPN), leukemia (e.g., acute myeloid leukemia), or lymphoma.

Claims

1. A method for treating a condition in a subject who requires it, comprising administering to the subject an effective amount of dicouridine, an effective amount of decitabine, and an effective amount of veneclade, thereby treating the subject's condition.

2. The method according to claim 1, wherein the condition is a hyperproliferative disease.

3. The method of claim 2, wherein the disease is cancer.

4. The method of claim 3, wherein the cancer is selected from hematologic malignancies and solid tumors.

5. The method according to claim 4, wherein the hematologic malignancy is selected from at least one of myelodysplastic syndrome (MDS), myeloproliferative neoplasm (MPN), leukemia, and lymphoma.

6. The method of claim 5, wherein the leukemia is ALL, AML, CML, MPN, or CMML.

7. The method of claim 6, wherein the leukemia is AML.

8. The method according to any one of claims 1-7, wherein the subject is 75 years of age or older.

9. The method according to any one of claims 1-7, wherein the subject has comorbidities that prevent the use of standard induction chemotherapy (e.g., one or more of the following: (i) severe heart disease, (ii) severe lung disease, (iii) creatinine clearance greater than or equal to 30 mL / min and less than 45 mL / min, and (iv) moderate hepatic impairment with total bilirubin greater than 1.5 times and less than or equal to 3.0 times the upper limit of normal (ULN)).

10. The method according to any one of claims 1-7, wherein the effective amount of dicofuridine, the effective amount of decitabine and the effective amount of verneclax are administered simultaneously, sequentially or separately.

11. The method according to any one of claims 1-7, wherein the effective amount of dicofuridine, the effective amount of decitabine, and the effective amount of verneclax are each administered as an oral dosage form.

12. The method of claim 11, wherein each oral dosage form is a solid oral dosage form.

13. The method of claim 12, wherein the effective amount of dicofuridine and the effective amount of decitabine are administered together in a combined solid oral dosage form.

14. The method according to any one of claims 1-7, wherein the effective amount of cidaloside and the effective amount of decitabine are administered on days 1 to 5 of a 28-day cycle, and the effective amount of vernacle is administered daily during the 28-day cycle.

15. The method according to any one of claims 1-7, wherein the effective amount of chidamide and the effective amount of decitabine are contained in a first solid oral dosage form comprising 100 mg chidamide, 35 mg decitabine and at least one pharmaceutically acceptable excipient, and wherein the effective amount of vernacle is contained in at least one second solid oral dosage form comprising 50 mg or 100 mg vernacle and at least one pharmaceutically acceptable excipient.

16. The method according to any one of claims 1-7, wherein on day 1 of the cycle, the subject is given an effective amount of chidanilide, an effective amount of decitabine, and 100 mg of veneclax; on day 2 of the cycle, the subject is given an effective amount of chidanilide, an effective amount of decitabine, and 200 mg of veneclax; on days 3 to 5 of the cycle, the subject is given an effective amount of chidanilide, an effective amount of decitabine, and 400 mg of veneclax; and on days 6 to 28 of the cycle, the subject is given 400 mg of veneclax.

17. The method according to any one of claims 1-7, wherein an effective amount of chidamide, an effective amount of decitabine and 400 mg of veneclax are administered to the subject on days 1 to 5 of the cycle, and 400 mg of veneclax is administered to the subject on days 6 to 28 of the cycle.

18. An oral dosage form comprising chidamide, decitabine and veneclade, and at least one pharmaceutically acceptable excipient.

19. The oral dosage form according to claim 18, wherein the oral dosage form is a solid oral dosage form.

20. A medicine comprising an effective amount of veneclade for treating a patient’s condition, which is used concurrently, separately or sequentially in combination with an effective amount of dicouridine and an effective amount of decitabine.

21. An effective amount of veneclade for treating a subject's condition, characterized in that... Veneclare is administered in combination with an effective amount of cidaluridine and an effective amount of decitabine, wherein the three drugs are administered simultaneously, separately, or sequentially.

22. A combination of an effective amount of veneclade, an effective amount of dicouridine, and an effective amount of decitabine for treating a condition of a subject, wherein the three drugs are administered simultaneously, separately, or sequentially.

23. A pharmaceutical composition comprising an effective amount of vernacle, used in combination with an effective amount of dicouridine and an effective amount of decitabine, wherein the three drugs are administered simultaneously, separately or sequentially for the treatment of a subject’s condition.

24. The pharmaceutical composition of claim 23, wherein the pharmaceutical composition comprises an effective amount of veneclade, the veneclade being used in combination with a solid dosage form comprising an effective amount of dicouridine and an effective amount of decitabine, wherein the two are administered simultaneously, separately or sequentially for the treatment of the subject's condition.