Classifications

• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K31/00—Medicinal preparations containing organic active ingredients
  • A61K31/70—Carbohydrates; Sugars; Derivatives thereof
  • A61K31/7042—Compounds having saccharide radicals and heterocyclic rings
  • A61K31/7052—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides
  • A61K31/706—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing six-membered rings with nitrogen as a ring hetero atom
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K31/00—Medicinal preparations containing organic active ingredients
  • A61K31/70—Carbohydrates; Sugars; Derivatives thereof
  • A61K31/7042—Compounds having saccharide radicals and heterocyclic rings
  • A61K31/7052—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides
  • A61K31/706—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing six-membered rings with nitrogen as a ring hetero atom
  • A61K31/7064—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing six-membered rings with nitrogen as a ring hetero atom containing condensed or non-condensed pyrimidines
  • A61K31/7068—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing six-membered rings with nitrogen as a ring hetero atom containing condensed or non-condensed pyrimidines having oxo groups directly attached to the pyrimidine ring, e.g. cytidine, cytidylic acid
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K9/00—Medicinal preparations characterised by special physical form
  • A61K9/0012—Galenical forms characterised by the site of application
  • A61K9/0053—Mouth and digestive tract, i.e. intraoral and peroral administration
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K9/00—Medicinal preparations characterised by special physical form
  • A61K9/20—Pills, tablets, discs, rods
  • A61K9/2004—Excipients; Inactive ingredients
  • A61K9/2009—Inorganic compounds
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K9/00—Medicinal preparations characterised by special physical form
  • A61K9/20—Pills, tablets, discs, rods
  • A61K9/2004—Excipients; Inactive ingredients
  • A61K9/2013—Organic compounds, e.g. phospholipids, fats
  • A61K9/2018—Sugars, or sugar alcohols, e.g. lactose, mannitol; Derivatives thereof, e.g. polysorbates
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K9/00—Medicinal preparations characterised by special physical form
  • A61K9/20—Pills, tablets, discs, rods
  • A61K9/2004—Excipients; Inactive ingredients
  • A61K9/2022—Organic macromolecular compounds
  • A61K9/205—Polysaccharides, e.g. alginate, gums; Cyclodextrin
  • A61K9/2054—Cellulose; Cellulose derivatives, e.g. hydroxypropyl methylcellulose
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K9/00—Medicinal preparations characterised by special physical form
  • A61K9/20—Pills, tablets, discs, rods
  • A61K9/28—Dragees; Coated pills or tablets, e.g. with film or compression coating
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P35/00—Antineoplastic agents
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P35/00—Antineoplastic agents
  • A61P35/02—Antineoplastic agents specific for leukemia
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K2300/00—Mixtures or combinations of active ingredients, wherein at least one active ingredient is fully defined in groups A61K31/00 - A61K41/00

Definitions

• the present invention relates to methods for the treatment of cancer.
• the present invention relates to methods for the treatment of myelodysplastic syndromes.
• MDS Myelodysplastic syndromes
• Patients with MDS typically have low blood cell counts that may cause infection, anemia, spontaneous bleeding, and/or bruising.
• mature blood cells may be dysplastic and so may not function properly.
• scoring systems have been developed.
• a patient’s score is determined based on the percentage of leukemic blast cells in the patient’s marrow, the type of chromosomal changes, if any, in the patient’s marrow cells, and the presence of one or more cytopenias.
• a patient’s score is determined based on the percentage of blasts in the patient’s bone marrow, the type and number of chromosome abnormalities in the patient’s cells, and the level of red blood cells, platelets, and/or neutrophils in the patient’s blood.
• a patient’s score is determined based on the type of MDS the patient has (based on the WHO classification system), the type of chromosomal abnormalities, and whether or not the patient needs regular blood transfusions.
• Cedazuridine ((4R)-2’-deoxy-2’,2’-difluoro-3,4,5,6-tetrahydrouridine; also known as E7727) is a cytidine deaminase (CD A) inhibitor.
• Cedazuridine and methods of making and/or using thereof are further disclosed in U.S. Patent Nos. 8,268,800 and 9,834,576, the contents of which are incorporated by reference herein in their entirety.
• Astex Pharmaceuticals, Inc. received FDA approval for a fixed dose combination of decitabine and cedazuridine, which is sold under the brand name INQOVI® by Taiho Oncology, Inc., for the treatment of adults with MDS.
• MDS has also been treated by the administration of hypomethating agents alone.
• patients were either treated with decitabine (15 mg/m 2 given intraveneously over 3 hours, every 8 hours for 3 days) or given best supportive care (BSC) measures only.
• BSC best supportive care
• Kantarjian H, et al. Decitabine improves patient outcomes in myelodysplastic syndromes, Cancer, April 15, 2006, 106 (8).
• Azacitidine is another hypomethylating agent that has been used to treat MDS.
• CRC multicenter clinical trial
• patients with MDS were randomized between azacitidine and best supportive care (BSC) measures only.
• the median time to leukemic transformation or death was 21 months in patients treated with azacitidine versus 12 months in the BSC arm.
• Silverman LR et al., Randomized controlled trial of azacitidine in patients with the Myelodysplastic Syndrome: A study of the Cancer and Leukemia Group B, J Clin Oncol 2002:20(10):2429-2440.
• CMML Chronic Myelomonocytic Leukemia
• MDS myelodysplastic syndromes
• DNMTi DNA methyltransferase inhibitors
• Approved intravenous or subcutaneous regimens require 5-7 days of treatment every month, burdening older cancer patients due to daily travel and treatment time and may increase potential risk from pandemic SARS-CoV-2 infection.
• parenteral therapy also increases contact with medical settings with increased infection risk.
• MDS myelodysplastic syndromes
• methods of treating myelodysplastic syndromes include administering to the subject an effective amount of cedazuridine and an effective amount of decitabine, thereby treating the MDS.
• administering an effective amount of cedazuridine and an effective amount of decitabine increases the subject’s survival (e.g., overall median survival) to about 130% to about 400% relative to survival obtained by treatment with a hypomethylating agent alone.
• the MDS is lower-risk MDS.
• the MDS is chronic myelomonocytic leukemia (CMML).
• CMML chronic myelomonocytic leukemia
• administering an effective amount of cedazuridine and an effective amount of decitabine increases the MDS subject’s survival to about 200% to about 400%, relative to survival obtained when the subject only receives best supportive care (BSC).
• administering an effective amount of cedazuridine and an effective amount of decitabine to a subject with MDS provides the subject with a survival of at least about 28, 30, 32, 34, or 36 months.
• administering an effective amount of cedazuridine and an effective amount of decitabine to a subject with MDS provides the subject with a leukemia-free survival of at least about 26, 28, 30, 32, or 34 months.
• treatment of lower-risk MDS includes treatment of a lower-risk MDS subject as determined by the International Prognostic Scoring System (IPPS), including the Low and Intermediate- 1 subgroups.
• IPPS International Prognostic Scoring System
• treatment of lower-risk MDS includes treatment of a lower-risk MDS subject as determined by the International Prognostic Scoring System-Revised (IPPS-R), including the Very Low, Low, and Intermediate subgroups.
• IPPS-R International Prognostic Scoring System-Revised
• treatment of lower-risk MDS includes treatment of a lower-risk MDS subject as determined by the WHO Classification-based Prognostic Scoring System (WPSS), including the Very Low, Low, and Intermediate subgroups.
• treatment of lower-risk MDS includes treatment of a lower-risk MDS subject as determined by the French- American-British (FAB) criteria.
• FAB French- American-British
• administering an effective amount of cedazuridine and an effective amount of decitabine to a subject includes administering to a subject cedazuridine and decitabine in one or more oral dosage forms. In some embodiments, administering an effective amount of cedazuridine and an effective amount of decitabine to a subject includes administering a single solid oral dosage form that includes cedazuridine and decitabine.
• Figure 1 shows patient randomization and disposition.
• CMML chronic myelomonocytic leukemia
• MDS myelodysplastic syndrome
• FIGs 2A-2B show mean plasma decitabine concentration-time profiles following single and multiple doses of IV decitabine and Oral decitabine/cedazuridine on Days 1, 2, and 5. Linear and semi-log scales.
• A Mean plasma decitabine concentration-time profiles on days 1, 2, and 5.
• B Lower limit of quantification (LLOQ) of plasma decitabine concentration-time profiles on days 1, 2, and 5.
• Figure 3 is a Kaplan-Meier plot for leukemia-free survival of the subjects in a Phase 3 trial for the use of oral decitabine/cedazuridine to treat MDS.
• Figure 4 is a Kaplan-Meier plot for the overall survival of the subjects in a Phase 3 trial for the use of oral decitabine/cedazuridine to treat MDS.
• Figure 5 is a Kaplan-Meier plot for leukemia-free survival of the subjects with CMML or Int-1 or low risk MDS in a Phase 3 trial for the use of oral decitabine/cedazuridine to treat MDS.
• Figure 6 is a Kaplan-Meier plot for the overall survival of the subjects with CMML or Int-1 or low risk MDS in a Phase 3 trial for the use of oral decitabine/cedazuridine to treat MDS.
• Figure 7 shows a Kaplan-Meier plot for the TP53 mutation population compared to the wild-type population.
• Figure 8 shows a Kaplan-Meier plot for the mono-allelic TP53 mutation population compared to the bi-allelic TP53 population.
• Effective amount refers to the amount required to produce a desired effect (e.g., enhancing the half-life, bioavailability or efficacy of a therapeutic agent treating cancer in a subject, or reducing DNA methylation in a subject).
• “Pharmaceutically acceptable” refers to those properties and/or substances that are acceptable to the patient from a pharmacological and/or toxicological point of view, and/or to the manufacturing pharmaceutical chemist from a physical and/or chemical point of view regarding composition, formulation, stability, patient acceptance, bioavailability, and compatibility with other ingredients.
• “Pharmaceutically acceptable salt” refers to an acid or base salt of a compound of the invention, which salt possesses the desired pharmacological activity and is neither biologically nor otherwise undesirable.
• the salt can be formed with acids that include without limitation acetate, adipate, alginate, aspartate, benzoate, benzenesulfonate, bisulfate butyrate, citrate, camphorate, camphorsulfonate, cyclopentanepropionate, digluconate, dodecyl sulfate, ethanesulfonate, fumarate, glucoheptanoate, glycerophosphate, hemisulfate, heptanoate, hexanoate, hydrochloride hydrobromide, hydroiodide, 2-hydroxyethane-sulfonate, lactate, maleate, methanesulfonate, 2-naphthalenesulfonate, nicotinate, ox
• Examples of a base salt include without limitation ammonium salts, alkali metal salts such as sodium and potassium salts, alkaline earth metal salts such as calcium and magnesium salts, salts with organic bases such as dicyclohexylamine salts, N-methyl-D- glucamine, and salts with amino acids such as arginine and lysine.
• the basic nitrogen-containing groups can be quaternized with agents including lower alkyl halides such as methyl, ethyl, propyl and butyl chlorides, bromides and iodides; dialkyl sulfates such as dimethyl, diethyl, dibutyl and diamyl sulfates; long chain halides such as decyl, lauryl, myristyl and stearyl chlorides, bromides and iodides; and aralkyl halides such as phenethyl bromides.
• lower alkyl halides such as methyl, ethyl, propyl and butyl chlorides, bromides and iodides
• dialkyl sulfates such as dimethyl, diethyl, dibutyl and diamyl sulfates
• long chain halides such as decyl, lauryl, myristyl and stearyl chlorides, bromides and
• “Pharmaceutically acceptable excipient” can mean any substance, not itself a therapeutic agent, used as a carrier, diluent, adjuvant, binder, and/or vehicle for delivery of a therapeutic agent to a subject, or added to a pharmaceutical composition to improve its handling or storage properties or to permit or facilitate formation of a compound or composition into a unit dosage form for administration.
• Unit dosage form refers to a physically discrete unit suitable as a unitary dosage for human or other animal subjects. Each unit dosage form may contain a predetermined amount of an active substance (e.g., cedazuridine and/or decitabine) calculated to produce a desired effect.
• active substance e.g., cedazuridine and/or decitabine
• Optional or “optionally” means that the subsequently described event or circumstance may or may not occur, and that the description includes instances where the event or circumstance occurs and instances in which it does not.
• an alkyl that is “optionally substituted” encompasses both an alkyl that is unsubstituted and an alkyl that is substituted.
• the term “enhance” or “increase” refers to an increase in the specified parameter of at least about 1.25-fold, 1.5-fold, 2-fold, 3-fold, 4-fold, 5-fold, 6-fold, 8-fold, 10-fold, twelve-fold, fifteen-fold, etc.
• inhibitor or “reduce” or grammatical variations thereof as used herein refers to a decrease or diminishment in the specified level or activity of at least about 15%, 25%, 35%, 40%, 50%, 60%, 75%, 80%, 90%, 95% or more. In particular embodiments, the inhibition or reduction results in little or essentially no detectible activity (at most, an insignificant amount, e.g., less than about 10% or even 5%).
• Subject refers to a human. A subject may also be referred to as a patient.
• treat By the term “treat,” “treating,” or “treatment of’ (or grammatically equivalent terms), it is meant that the severity of the subject’s condition is reduced or at least partially improved or ameliorated and/or that some alleviation, mitigation or decrease in at least one clinical symptom is achieved.
• Treating” in reference to a disease, disorder or condition may refer to: (i) inhibiting a disease, disorder or condition, e.g., arresting its development, (ii) relieving a disease, disorder or condition, e.g., causing regression of the clinical symptoms; and/or (iii) stabilizing or controlling the progression of a disease, disorder or condition, including delaying progression to AML, or preventing a relapse or disease progression after a reduction in or absence of a detectable level of disease.
• a subject is “in need of’ treatment for MDS, higher-risk MDS, or lower-risk MDS if the subject has MDS, higher-risk MDS, or lower-risk MDS, respectively, as determined by the IPSS, IPSS-R,WPSS, and/or FAB.
• a subject is “in need of’ treatment for chronic myelomonocytic leukemia (CMML) if the subject meets the French- American-British (FAB) classification for CMML, or any other known criteria for identifying CMML.
• CMML chronic myelomonocytic leukemia
• FAB French- American-British
• administering or “administration” of a compound and/or composition of the present invention to a subject includes a route of introducing or delivering to a subject a compound to perform its intended function.
• lower-risk MDS refers to MDS in subjects that are deemed lower-risk by the International Prognostic Scoring System (IPSS), International Prognostic Scoring System - Revised (IPSS-R), and/or the WHO Classification-based Prognostic Scoring System (WPSS).
• IPSS International Prognostic Scoring System
• IPSS-R International Prognostic Scoring System - Revised
• WPSS WHO Classification-based Prognostic Scoring System
• a lower-risk MDS subject may be classified as Low or Intermediate- 1 (also referred to herein as Int-1) as determined by the IPSS; Very Low, Low, or Intermediate, as determined by the IPSS-R; and/or Very Low, Low, or Intermediate, as determined by the WPSS.
• Lower-Risk MDS may also be determined using the French- American-British (FAB) criteria.
• FAB French- American-British
• a “cycle,” as used herein, refers to 28 consecutive days.
• cedazuridine and decitabine are administered for days 1-5 of each 28-day cycle. Multiple cycles or a plurality of cycles may be performed, either consecutively or with a break between cycles. Additionally, other cycle lengths and different dosing regimens may also be used.
• a “hypomethylating agent,” as used herein refers to an administered drug that inhibits or reduces DNA methylation.
• hypomethylating agents include, but are not limited to, decitabine, cytidine, azacitidine (5-azacytidine), and guadecitabine.
• a subject “overall survival time” is the number of days (or months) from the date of randomization in a clinical trial, or the first day of the subject’s treatment with decitabine and cedazuridine, to the date of death for the subject.
• the “median overall survival time” is the number of days (or months) from the date of randomization in a clinical trial, or the first day of the subject’s treatment with decitabine and cedazuridine, or the first day of the subject’s treatment, until half of the patients remain alive, as determined by Kaplan-Meier estimates.
• a subject As used herein, a subject’s “leukemia-free survival time” is the number of days (or months) from the date of randomization to the date when bone marrow or peripheral blood blasts reach >20%, or death.
• a subject “median leukemia-free survival time” is the number of days (or months) from the date of randomization to the date when half of the patients have bone marrow or peripheral blood blasts >20%, or have died, as determined by Kaplan-Meier estimates.
• best supportive care refers to any care or treatment as needed for the subject that improves or optimizes the subject’s quality of life but is not a chemotherapeutic agent (e.g., a hypomethylating agent) for the treatment of MDS.
• chemotherapeutic agent e.g., a hypomethylating agent
• examples of BSC include the administration of narcotic or non-narcotic analgesics, corticosteroids, and gastrointestinal medications.
• MDS myelodysplastic syndromes
• methods of treating myelodysplastic syndromes include administering to the subject an effective amount of cedazuridine and an effective amount of decitabine, thereby treating the MDS.
• administering an effective amount of cedazuridine and an effective amount of decitabine increases the subject’s survival (e.g., overall median survival) to about 130% to about 400% relative to survival obtained by treatment with a hypomethylating agent alone.
• administering an effective amount of cedazuridine and an effective amount of decitabine increases the subject’s survival to about 130%, 135%, 140%, 145%, 150%, 155%, 160%, 165%, 170%, 175%, 180%, 185%, 190%, 195%, 200%,
• administering an effective amount of cedazuridine and an effective amount of decitabine increases the subject’s survival (e.g., overall median survival) at least about 130%, at least about 200%, at least about 250%, at least about 300%, at least about 320%, and/or at least about 330%, relative to survival obtained by treatment with a hypomethylating agent alone.
• survival e.g., overall median survival
• administering an effective amount of cedazuridine and an effective amount of decitabine increases the subject’s leukemia-free survival (e.g., median leukemia-free survival) to about 130% to about 400% relative to leukemia-free survival obtained by treatment with a hypomethylating agent alone.
• administering an effective amount of cedazuridine and an effective amount of decitabine increases the subject’s leukemia-free survival to about 130%, 135%, 140%, 145%, 150%, 155%, 160%, 165%, 170%, 175%, 180%, 185%, 190%, 195%, 200%, 205%, 210%, 215%, 220%, 225%, 230%, 235%,
• administering an effective amount of cedazuridine and an effective amount of decitabine increases the subject’s leukemia-free survival (e.g., median leukemia-free survival) at least about 130%, at least about 200%, at least about 250%, at least about 300%, at least about 320%, and/or at least about 330%, relative to the leukemia-free survival obtained by treatment with a hypomethylating agent alone.
• leukemia-free survival e.g., median leukemia-free survival
• administering an effective amount of cedazuridine and an effective amount of decitabine increases the MDS subject’s survival (e.g., overall median survival) to about 200% to about 400% relative to survival obtained when the subject only receives best supportive care (BSC).
• survival e.g., overall median survival
• administering an effective amount of cedazuridine and an effective amount of decitabine increases the subject’s survival to about 200%, 205%, 210%, 215%, 220%, 225%, 230%, 235%, 240%, 245%, 250%, 255%, 260%, 265%, 270%, 275%, 280%, 285%, 290%, 295%, 300%, 305%, 310%, 315%, 320%, 325%, 330%, 335%, 340%, 345%, 350%, 355%, 360%, 365%, 370%, 375%, 380%, 385%, 390%, 395%, or 400%, relative to survival obtained with BSC measures alone.
• administering an effective amount of cedazuridine and an effective amount of decitabine increases the MDS subject’s leukemia-free survival (e.g., median leukemia-free survival) to about 200% to about 400% relative to the leukemia-free survival obtained when the subject only receives best supportive care (BSC).
• leukemia-free survival e.g., median leukemia-free survival
• BSC best supportive care
• administering an effective amount of cedazuridine and an effective amount of decitabine increases the subject’s leukemia-free survival to about 200%, 205%, 210%, 215%, 220%, 225%, 230%, 235%, 240%, 245%, 250%, 255%, 260%, 265%, 270%, 275%, 280%,
• administering an effective amount of cedazuridine and an effective amount of decitabine to a subject with MDS provides the subject with a survival (e.g., overall median survival) of at least about 28, 30, 32, 34, or 36 months, including at least about 28, 30, 31, 32, 33, 34, 35, or 36 months.
• a survival e.g., overall median survival
• administering an effective amount of cedazuridine and an effective amount of decitabine to a subject with MDS provides the subject with a leukemia-free survival (e.g., median leukemia-free survival) of at least about 26, 28, 30, 32, or 34 months, including at least about 26, 28, 30, 31, 32, 33, 34 months.
• a leukemia-free survival e.g., median leukemia-free survival
• kits for treating lower-risk MDS in a subject in need thereof include administering to the subject an effective amount of cedazuridine and an effective amount of decitabine, thereby treating the lower-risk MDS.
• administering an effective amount of cedazuridine and an effective amount of decitabine increases the subject’s survival (e.g., overall median survival) to about 130% to about 400% relative to survival obtained by treatment with a hypomethylating agent alone.
• administering an effective amount of cedazuridine and an effective amount of decitabine increases the subject’s survival to about 130%, 135%, 140%, 145%, 150%, 155%, 160%, 165%, 170%, 175%, 180%, 185%, 190%, 195%, 200%, 205%, 210%, 215%, 220%, 225%, 230%, 235%, 240%, 245%, 250%,
• administering an effective amount of cedazuridine and an effective amount of decitabine increases the lower-risk MDS subject’s leukemia-free survival (e.g., median leukemia-free survival) to about 130% to about 400% relative to the leukemia-free survival obtained by treatment with a hypomethylating agent alone.
• administering an effective amount of cedazuridine and an effective amount of decitabine increases the subject’s leukemia-free survival to about 130%, 135%, 140%, 145%, 150%, 155%, 160%, 165%, 170%, 175%, 180%, 185%, 190%, 195%, 200%, 205%, 210%,
• administering an effective amount of cedazuridine and an effective amount of decitabine increases the lower-risk MDS subject’s survival to about 200% to about 400% relative to survival obtained when the subject only receives best supportive care (BSC).
• BSC best supportive care
• administering an effective amount of cedazuridine and an effective amount of decitabine increases the subject’s survival to about 200%, 205%, 210%, 215%, 220%, 225%, 230%, 235%, 240%, 245%, 250%, 255%, 260%, 265%, 270%, 275%,
• administering an effective amount of cedazuridine and an effective amount of decitabine increases the lower-risk MDS subject’s leukemia-free survival (e.g., median leukemia-free survival) to about 200% to about 400% relative to the leukemia-free survival obtained when the subject only receives best supportive care (BSC).
• leukemia-free survival e.g., median leukemia-free survival
• BSC best supportive care
• administering an effective amount of cedazuridine and an effective amount of decitabine to a subject with lower-risk MDS provides the subject with a survival (e.g., overall median survival) of at least about 28, 30, 32, 34, or 36 months, including at least about 28, 30, 31, 32, 33, 34, 35, or 36 months.
• administering an effective amount of cedazuridine and an effective amount of decitabine to a subject with lower-risk MDS provides the subject with a leukemia-free survival (e.g., median leukemia-free survival) of at least about 26, 28, 30, 32, or 34 months, including at least about 26, 28, 30, 31, 32, 33, 34 months.
• a leukemia-free survival e.g., median leukemia-free survival
• treatment of MDS includes treatment of a lower-risk MDS subject as determined by the International Prognostic Scoring System (IPPS), including Low and Int-1 subgroups.
• IPPS International Prognostic Scoring System
• treatment of MDS includes treatment of a lower-risk MDS subject as determined by the International Prognostic Scoring System-Revised (IPPS-R), including the Intermediate, Low, and Very Low subgroups.
• IPPS-R International Prognostic Scoring System-Revised
• treatment of MDS includes treatment of a lower-risk MDS subject as determined by the WHO Classification-based Prognostic Scoring System (WPSS), including Intermediate, Low, and Very Low subgroups.
• treatment of MDS includes treatment of a lower-risk MDS subject as determined by the French-American-British (FAB) criteria.
• FAB French-American-British
• CMML chronic myelomonocytic leukemia
• methods of treating chronic myelomonocytic leukemia include administering to the subject an effective amount of cedazuridine and an effective amount of decitabine, thereby treating the CMML.
• administering an effective amount of cedazuridine and an effective amount of decitabine increases the subject’s survival (e.g., overall median survival) to about 130% to about 400% relative to survival obtained by treatment with a hypomethylating agent alone.
• administering an effective amount of cedazuridine and an effective amount of decitabine increases the subject’s survival to about 130%, 135%, 140%, 145%, 150%, 155%, 160%, 165%, 170%, 175%, 180%, 185%, 190%, 195%, 200%, 205%, 210%, 215%, 220%, 225%, 230%, 235%, 240%, 245%, 250%, 255%, 260%, 265%, 270%, 275%, 280%, 285%, 290%, 295%, 300%, 305%, 310%, 315%, 320%, 325%, 330%, 335%, 340%, 345%, 350%, 355%, 360%, 365%, 370%, 375%, 380%, 385%, 390%, 395%, or 400% or more, or any range defined therebetween, relative to survival obtained by treatment with a hypomethylating agent alone.
• administering an effective amount of cedazuridine and an effective amount of decitabine increases the subject’s leukemia-free survival (e.g., median leukemia-free survival) to about 130% to about 400% relative to the leukemia-free survival obtained by treatment with a hypomethylating agent alone.
• administering an effective amount of cedazuridine and an effective amount of decitabine increases the subject’s leukemia-free survival to about 130%, 135%, 140%, 145%, 150%, 155%, 160%, 165%, 170%, 175%, 180%, 185%, 190%, 195%, 200%, 205%, 210%, 215%, 220%,
• administering an effective amount of cedazuridine and an effective amount of decitabine increases the CMML subject’s survival to about 200% to about 400% relative to survival obtained when the subject only receives best supportive care (BSC).
• BSC best supportive care
• administering an effective amount of cedazuridine and an effective amount of decitabine increases the subject’s survival to about 200%, 205%, 210%, 215%, 220%, 225%, 230%, 235%, 240%, 245%, 250%, 255%, 260%, 265%, 270%, 275%, 280%, 285%, 290%, 295%, 300%, 305%, 310%, 315%, 320%, 325%, 330%, 335%, 340%, 345%, 350%, 355%, 360%, 365%, 370%, 375%, 380%, 385%, 390%, or 400%, relative to the survival obtained with BSC measures alone.
• administering an effective amount of cedazuridine and an effective amount of decitabine increases the CMML subject’s leukemia-free survival to about 200% to about 400% relative to the leukemia-free survival obtained when the subject only receives best supportive care (BSC).
• BSC best supportive care
• administering an effective amount of cedazuridine and an effective amount of decitabine increases the subject’s leukemia- free survival to about 200%, 205%, 210%, 215%, 220%, 225%, 230%, 235%, 240%, 245%, 250%, 255%, 260%, 265%, 270%, 275%, 280%, 285%, 290%, 295%, 300%, 305%, 310%, 315%, 320%, 325%, 330%, 335%, 340%, 345%, 350%, 355%, 360%, 365%, 370%, 375%, 380%, 385%, 390%, or 400%, relative to the leukemia-free survival obtained with BSC measures alone.
• administering an effective amount of cedazuridine and an effective amount of decitabine to a subject with CMML provides the subject with a survival (e.g., overall median survival) of at least about 28, 30, 32, 34, or 36 months, including at least about 28, 30, 31, 32, 33, 34, 35, or 36 months.
• a survival e.g., overall median survival
• administering an effective amount of cedazuridine and an effective amount of decitabine to a subject with CMML provides the subject with a leukemia-free survival (e.g., median leukemia-free survival) of at least about 26, 28, 30, 32, or 34 months, including at least about 26, 28, 30, 31, 32, 33, 34 months.
• leukemia-free survival e.g., median leukemia-free survival
• treatment of CMML includes treatment of a CMML subject that meets the French-American-British (FAB) criteria.
• FAB French-American-British
• TP53mut Mutations in the TP53 gene (TP53mut) encoding p53 protein in MDS and CMML patients have been characterized as an independent prognostic factor for poor outcome.
• the present invention has been demonstrated to provide improved outcomes in overall survival and leukemia-free survival for patients with TP53 mutations, either mono-allelic or bi-allelic.
• the TP53 mutation may be any mutation in the gene that results in decreased TP53 mRNA and/or p53 protein levels or results in decreased p53 activity.
• kits for treating MDS or CMML in a TP53mut subject in need thereof include administering to the subject an effective amount of cedazuridine and an effective amount of decitabine, thereby treating the MDS or CMML.
• administering an effective amount of cedazuridine and an effective amount of decitabine increases the subject’s survival (e.g., overall median survival) to about 130% to about 400% relative to survival obtained by treatment with a hypomethylating agent alone.
• administering an effective amount of cedazuridine and an effective amount of decitabine increases the subject’s survival to about 130%, 135%, 140%, 145%, 150%, 155%, 160%, 165%, 170%, 175%, 180%, 185%, 190%, 195%, 200%, 205%, 210%, 215%, 220%, 225%, 230%,
• administering an effective amount of cedazuridine and an effective amount of decitabine increases the TP53mut subject’s leukemia-free survival (e.g., median leukemia-free survival) to about 130% to about 400% relative to the leukemia-free survival obtained by treatment with a hypomethylating agent alone.
• leukemia-free survival e.g., median leukemia-free survival
• administering an effective amount of cedazuridine and an effective amount of decitabine increases the subject’s leukemia-free survival to about 130%, 135%, 140%, 145%, 150%, 155%, 160%, 165%, 170%, 175%, 180%, 185%, 190%, 195%, 200%, 205%, 210%,
• administering an effective amount of cedazuridine and an effective amount of decitabine increases the TP53mut subject’s survival to about 200% to about 400% relative to survival obtained when the subject only receives best supportive care (BSC).
• BSC best supportive care
• administering an effective amount of cedazuridine and an effective amount of decitabine increases the subject’s survival to about 200%, 205%, 210%, 215%, 220%, 225%, 230%, 235%, 240%, 245%, 250%, 255%, 260%, 265%, 270%, 275%,
• administering an effective amount of cedazuridine and an effective amount of decitabine increases the TP53mut subject’s leukemia-free survival (e.g., median leukemia-free survival) to about 200% to about 400% relative to the leukemia-free survival obtained when the subject only receives best supportive care (BSC).
• leukemia-free survival e.g., median leukemia-free survival
• BSC best supportive care
• administering an effective amount of cedazuridine and an effective amount of decitabine increases the subject’s leukemia-free survival to about 200%, 205%, 210%, 215%, 220%, 225%, 230%, 235%, 240%, 245%, 250%, 255%, 260%, 265%, 270%, 275%, 280%, 285%, 290%, 295%, 300%, 305%, 310%, 315%, 320%, 325%, 330%, 335%, 340%, 345%, 350%, 355%, 360%, 365%, 370%, 375%, 380%, 385%, 390%, 395%, or 400%, or any range defined therebetween, relative to the leukemia-free survival obtained with BSC measures alone.
• administering an effective amount of cedazuridine and an effective amount of decitabine to a MDS or CMML subject with a mono-allelic TP53mut provides the subject with a survival (e.g., overall median survival) or leukemia-free survival of at least about 20, 22, 24, 26, 28, 30, 32, 34, or 36 months.
• a survival e.g., overall median survival
• leukemia-free survival of at least about 20, 22, 24, 26, 28, 30, 32, 34, or 36 months.
• administering an effective amount of cedazuridine and an effective amount of decitabine to a MDS or CMML subject with a bi-allelic TP53mut provides the subject with a survival (e.g., overall median survival) or leukemia-free survival of at least about 10, 12, 14, 16, 18, or 20 months.
• a survival e.g., overall median survival
• leukemia-free survival of at least about 10, 12, 14, 16, 18, or 20 months.
• administering an effective amount of cedazuridine and an effective amount of decitabine to a subject includes administering to a subject cedazuridine and decitabine in one or more oral dosage forms of the invention.
• each oral dosage form is a solid oral dosage form.
• a single solid oral dosage form that includes cedazuridine and decitabine is administered.
• any administration regimen known to those skilled in the art for regulating the timing and sequence of drug delivery can be used and repeated as necessary to effect treatment in the methods of the invention.
• the oral dosage forms may be administered 1, 2, 3 or 4 times daily, by a single dose, multiple discrete doses, or continuous infusion.
• at least one solid oral dosage form is administered once daily.
• administering at least one solid oral dosage form according to an embodiment of the invention may be performed for one or more weeks per 28-day cycle, e.g., one week, two weeks, three weeks, or four weeks per 28-day cycle. The weeks may be consecutive and/or non- consecutive.
• cedazuridine and decitabine are administered daily for 5 days (days 1-5) of a 28-day cycle.
• a solid oral dosage form comprising cedazuridine and decitabine is administered to a 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.
• a solid oral dosage form comprising cedazuridine and decitabine is administered to a subject once daily for days 1-5 of a 28-day cycle.
• cedazuridine and decitabine are each administered to the subject daily and on days 6-28 of the cycle, neither cedazuridine nor decitabine is administered.
• Such solid oral dosage forms may be administered concurrently, sequentially, or at different times during the same day. In particular embodiments, all solid oral dosage forms are administered concurrently or at approximately the same time (e.g., within 5, 10, 15, 20, 25, or 30 minutes).
• a single unit dosage form comprising 35 mg decitabine and 100 mg cedazuridine may be administered daily on each of days 1-5 in the cycle.
• the doses of cedazuridine and decitabine may be varied. This may be appropriate, for example, when it is a second or later cycle for the subject. More information regarding possible dosing schedules and administration for cedazuridine and decitabine may be found in the Inqovi® prescribing information and at www.inqovi.com.
• a time period of 0 to 31 days or more may pass between multiple cycles of the present invention.
• the time period of no treatment may be desirable to allow a subject (e.g., a human patient) of the present invention to have adequate health to continue treatment.
• the time period between treatment cycles can be determined by a physician using standard techniques in the art and may be determined individually on a persubject basis, for example, as based on adequate blood count, e.g., adequate lack of neutropenia (e.g., absolute neutrophil count (ANC) in the subject of at least or greater than 0.5 x 10 9 cells/L), and may be adjusted over the course of treatment based on the judgement of the administering physician.
• the time period between treatment cycles may be minimal, e.g., no time period, e.g., immediately starting on the next 28-day time period.
• the time period between treatment cycles may be 1 week, 2 weeks, 3 weeks, 4 weeks, 5 weeks, 6 weeks, or more.
• the administration regimen may include pretreatment and/or coadministration with at least one additional therapeutic agent.
• the decitabine and cedazuridine may be administered with the at least one additional therapeutic agent simultaneously, separately, or sequentially.
• the additional therapeutic agent may also be included within the one or more solid oral dosage forms.
• additional therapeutic agents includes, but is not limited to, chemotherapeutic agents and immunomodulatory agents.
• chemotherapeutic agents include without limitation: alkylating agents (e.g., which may include doxorubicin, cyclophosphamide, estramustine, carmustine, mitomycin, bleomycin and the like); antimetabolites (e.g., which may include 5-fluoro-uracil, capecitabine, gemcitabine, nelarabine, fludarabine, methotrexate and the like); platinating agents (e.g., which may include cisplatin, oxaliplatin, carboplatin and the like); topoisomerase inhibitors (e.g., which may include topotecan, irinotecan, etoposide and the like); tubulin agents (e.g., which may include paclitaxel, docetaxel, vinorelbine, vinblastine, vincristine, other taxanes, epothilones, and the like); signaling inhibitors (e.g.,
• Administering to a subject in need thereof of a combination of decitabine and cedazuridine may provide multiple beneficial responses to the subject.
• the administering reduces DNA methylation in the subject by at least 5% (e.g, at least 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, or 15% or more or any value or range therein) as compared to a control measurement, e.g, as compared to DNA methylation in the subject prior to the administering (e.g., subject “baseline” DNA methylation).
• DNA methylation in the subject may be quantitatively and/or qualitatively evaluated by any standard technique in the art, e.g., as measured by a marker of relative global methylation as compared to a control, e.g., as measured by Long interspersed element-1 (LINE-1) methylation as compared to a control.
• the administering 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) as compared to a control measurement, e.g., as compared to LINE-1 methylation in the subject prior to the administering (e.g., subject baseline LINE-1 methylation).
• the administering may reduce LINE-1 methylation in the subject by at least 5%, at least 8%, at least 10% or at least 15% or more. In some embodiments, the administering may reduce LINE-1 methylation in the subject by about 5% to about 20%, about 6% to about 15%, or by about 8% to about 10%.
• administering decitabine and cedazuridine to the subject may reduce absolute neutrophil count (ANC) in the subject to less than 0.5 x 10 9 cells/L of blood for no more than two, three, or four weeks (e.g., no more than 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 consecutive days or any value or range therein) following a 28-day cycle.
• administering decitabine and cedazuridine to the subject reduces absolute neutrophil count (ANC) in the subject to less than 0.5 x 10 9 cells/L of blood for no more than two, three, or four weeks during treatment (e.g., between multiple, repeated 28-day cycles).
• administering decitabine and cedazuridine to the subject expands 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), optionally as measured by % F cells/erythrocytes per sample (e.g., in a patient blood sample) as compared to a “baseline” control % F cells/erythrocytes (e.g., as compared to % F cells/erythrocytes of the patient prior to treatment, e.g., as compared to the average % F cells/erythrocytes of a patient population not undergoing treatment (e.g., a healthy patient population)).
• % F cells/erythrocytes per sample e.g., in a patient blood sample
• a “baseline” control % F cells/erythrocytes e.g., as compared to % F cells/erythrocytes of the patient prior to treatment,
• administering decitabine and cedazuridine to the subject may expand % F cells in the subject by at least 5%, at least 8%, at least 10%, at least 15%, or at least 23% or more as compared to a baseline control.
• the administering may expand % F cells in the subject by about 5% to about 30%, about 6% to about 24%, or by about 8% to about 20% as compared to a baseline control.
• administering decitabine and cedazuridine to the subject expands F cells to a total amount of at least 10% to at least 30% or more of total erythrocytes (e.g., at least 15%, 16%, 17%, 18%, 19%, 20%, 21%, 22%, 23%, 24%, 25%, 26%, 27%, 28%, 29%, or 30% or more F cells/erythrocytes or any value or range therein) per sample (e.g., in a patient blood sample).
• total erythrocytes e.g., at least 15%, 16%, 17%, 18%, 19%, 20%, 21%, 22%, 23%, 24%, 25%, 26%, 27%, 28%, 29%, or 30% or more F cells/erythrocytes or any value or range therein
• administering decitabine and cedazuridine to the subject may expand F cells to a total amount of at least 15%, at least 20%, at least 23%, at least 35% or more of total erythrocytes in a sample.
• administering decitabine and cedazuridine to the subject may expand F cells to a total amount of about 15% to about 30%, about 18% to about 25%, or about 15% to about 35%, of total erythrocytes in a sample.
• the subject is aged 75 years or older. In particular embodiments, the subject is aged 18 years or older and ineligible for induction chemotherapy due to one or more comorbidities.
• Such comorbidities include, for example, (i) a baseline Eastern Cooperative Oncology Group (ECOG) performance status of 2 or 3, (ii) severe cardiac disorder (e.g., congestive heart failure requiring treatment, ejection fraction less than or equal to 50%, or chronic stable angina), (iii) severe pulmonary disorder (e.g., diffusing lung capacity for carbon monoxide DLCO less than or equal to 65% or forced expiratory volume in 1 second (FEV1) of 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 and less than or equal to 3.0 x the upper limit of normal (ULN).
• EOG Eastern Cooperative Oncology Group
• severe cardiac disorder e.g., congestive heart failure requiring treatment, ejection fraction less than or equal to 50%, or chronic stable angina
• severe pulmonary disorder e.
• Dose levels, mode of administration, and administration regimen may be modified by those skilled in the art using known techniques as judged necessary for the subject e.g., the patient).
• the methods described herein may use any form of decitabine and cedazuridine and/or a pharmaceutically acceptable salt of either compound.
• decitabine and cedazuridine, and their pharmaceutically acceptable salts may be referred to collectively as “therapeutic agents.” Additionally, when a therapeutic agent is referenced, it is to be understood that the therapeutic agent’s pharmaceutically acceptable salts are also included in this reference.
• the therapeutic agents are administered in oral dosage forms, such as solid oral dosage forms. Such oral dosage forms may include each therapeutic agent separately or may be include a combination dosage form.
• subjects are administered a solid oral dosage form that includes decitabine and cedazuridine.
• the one or more of the oral dosage forms is a solid oral dosage form, such as a solid oral unit dosage form.
• solid oral dosage form means that the pharmaceutical compositions are in solid form and are formulated for oral administration. Any suitable solid oral dosage form may be used. Examples of solid oral dosage forms according to embodiments of the invention include tablets (for example, those targeted for buccal, sublingual and systemic absorption), caplets, boluses, powders, granules, pastes for application to the tongue, capsules including hard gelatin capsules and soft gelatin capsules, mouth sprays, troches, lozenges, and pellets.
• the pharmaceutical compositions may be formulated for immediate, sustained, or controlled release.
• decitabine may be present in an oral dosage form in a 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, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 90, or 100 mg).
• cedazuridine may be present in an oral dosage form in a 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, 60, 70, 80, 85, 90, 95, 100, 105, 110, 115, 120, 125, 130, 140, or 150 mg).
• one solid oral dosage form is a unit dosage form that comprises about 35 mg decitabine. In some embodiments of the invention, one solid oral dosage form is unit dosage form that comprises about 100 mg of cedazuridine. Furthermore, in some embodiments, one solid oral dosage form is a unit dosage form (e.g., a fixed-dose combination) that comprises about 35 mg decitabine and about 100 mg of cedazuridine. In some embodiments of the invention, one unit dosage form comprises about 35 mg decitabine and about 100 mg of cedazuridine and at least one pharmaceutically acceptable excipient.
• compositions are well known in the pharmaceutical arts and are described, for example, in Remington’s Pharmaceutical Sciences, Mack Publishing Co., Easton, Pa (e.g., 20th Ed., 2000), and Handbook of Pharmaceutical Excipients, American Pharmaceutical Association, Washington, D.C., (e.g., 1st, 2nd and 3rd Eds., 1986, 1994 and 2000, respectively).
• excipients may provide a variety of functions and may be described as, e.g., wetting agents, buffering agents, suspending agents, diluents, binders, lubricating agents, glidants, emulsifiers, disintegrants, absorbents, preservatives, surfactants, colorants, flavorants, and sweeteners.
• Examples of pharmaceutically acceptable excipients include without limitation: (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, hydroxypropylmethylcellulose (hypromellose), and hydroxypropylcellulose; (4) powdered tragacanth; (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 glycerin, sorbitol, mannitol and polyethylene glycol; (12) esters, such as ethyl oleate and ethyl laurate; (13) a
• diluents include lactose, lactose monohydrate, cellulose, microcrystalline cellulose, sorbitol, dibasic calcium phosphate dehydrate, and calcium sulfate dehydrate.
• binders include gelatin, glucose, lactose, cellulose, methyl cellulose, ethyl cellulose, hydroxypropyl methyl cellulose (hypromellose), hydroxypropyl cellulose, starch, poly vinyl pyrrolidone, sodium alginate, carboxymethylcellulose, and acacia.
• disintegrants include croscarmellose sodium, crospovidone, sodium starch glycollate, and starch.
• glidants include colloidal silicon dioxide, cornstarch and talc.
• lubricants include stearic acid, magnesium stearate, calcium stearate, talc, paraffin, sodium lauryl sulphate, sodium benzoate, and polyethylene glycol.
• a solid oral dosage form includes one or more of a diluent, binder, disintegrant, glidant, and lubricant.
• a solid oral dosage form includes a diluent, binder, disintegrant, glidant, and lubricant.
• the solid oral dosage form includes decitabine and/or cedazuridine and the following excipients: lactose monohydrate as a diluent; hydroxypropyl methylcellulose as a binder; croscarmellose sodium as a disintegrant; colloidal silicon dioxide as a glidant; and magnesium stearate as a lubricant.
• such components are formed into a tablet.
• the tablet is an immediate release tablet.
• the tablet is coated with a film, which may be colored. Any pharmaceutically acceptable coating may be used but, in some embodiments, the tablet is coated with an Opadry® coating.
• cedazuridine is present in a solid oral dosage form in an amount of about 17-22 % w/w, e.g, about 17.0, 17.2, 17.4, 17.6, 17.8, 18.0, 18.2, 18.4, 18.6, 18.8, 19.0,
• decitabine is present in the solid oral dosage form in an amount of about 4-8 % w/w, e.g., about 4.0, 4.2, 4.4, 4.6, 4.8, 5.0,
• the diluent e.g., lactose monohydrate
• the solid oral dosage form in an amount of about 55-70 % w/w, e.g, about 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66, 67, 68, 69, or 70 % w/w or any range therein, e.g., about 62.62 %w/w.
• the binder e.g., hypromellose
• the binder is present in the solid oral dosage form in an amount of about 1-3 % w/w, e.g., 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 therein, e.g., about 1.94 %w/w.
• the disintegrant e.g., croscarmellose sodium
• the solid oral dosage form in an amount of about 3-7 % w/w, e.g., 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 therein, e.g., about 4.85 %w/w.
• the glidant e.g., colloidal silicon dioxide
• the solid oral dosage form in an amount of about 0.5-2 % w/w, e.g., 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 therein, e.g., about 0.97 %w/w.
• the lubricant e.g., magnesium stearate
• the solid oral dosage form in an amount of about 0.1-2 % w/w, e.g., 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 therein, e.g., about 0.49 %w/w.
• the solid oral dosage form comprises the components listed in
• the solid oral dosage form comprises the components listed in
• compositions and formulations for cedazuridine and decitabine may be found in the Inqovi® prescribing information and at www.inqovi.com.
• compositions of the invention can be prepared using known materials and techniques, which may include, but are not limited to, mixing and/or blending decitabine and cedazuridine with the pharmaceutically acceptable excipients.
• kits comprising at least one unit dosage form comprising decitabine and at least one unit dosage form comprising cedazuridine.
• a kit comprises at least one unit dosage form comprising decitabine and cedazuridine.
• the kit provides one unit dosage form that includes about 35 mg decitabine and about 100 mg of cedazuridine and at least one pharmaceutically acceptable excipient.
• Other unit dosage forms may be used and may vary depending on availability. The daily dose for cedazuridine and/or decitabine may require more than one unit dosage form per day.
• a kit may include the solid oral dosage forms for one day’s dose of each therapeutic agent (e.g., one tablet comprising 35 mg decitabine and 100 mg cedazuridine).
• a kit may also include unit dosage forms for more than one day of the cycle (e.g., a week) or for the full cycle.
• a 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 comprising cedazuridine and decitabine according to an embodiment of the invention.
• a kit may include 5 solid oral dosage forms comprising cedazuridine and decitabine (for days 1-5 of the cycle).
• the kit may further comprise a container and/or a package suitable for commercial sale.
• the container can be in any conventional shape or form known in the art which is made of a pharmaceutically acceptable material, such as a paper or cardboard box, a glass or plastic bottle or jar, a re-sealable bag, or a blister pack with individual dosages for pressing out of the pack according to a therapeutic schedule. More than one container can be used together in a single package. For example, tablets may be contained in a blister pack which is in turn contained within a box.
• the container is a bottle, e.g., a 30-cc white high-density polyethylene bottles containing unit dosage forms (e.g., about 5-unit dosage forms).
• the bottle may further contain desiccant, e.g., silica desiccant canisters.
• desiccant e.g., silica desiccant canisters.
• the container is a blister pack, e.g., formed by aluminum foil on foil lidding containing one tablet per cavity.
• the blister packs may be present in a carton.
• the kit may further comprise information.
• the information may be provided on a readable medium.
• the readable medium may comprise a label.
• the information may be directed towards a physician, pharmacist, or patient.
• the information may indicate that the unit dosage form may cause one or more adverse effects.
• the information may comprise instructions for administering the unit dosage form, such as in a manner described herein. These instructions may be provided in a variety of ways.
• the information can be associated with the container, for example, by being: written on a label (e.g, the prescription label or a separate label) adhesively affixed to a container; included inside a container as a written package insert; applied directly to the container such as being printed on the wall of a box or blister pack; or attached as by being tied or taped, for example as an instructional card affixed to the neck of a bottle via a string, cord or other line, lanyard or tether type device.
• a label e.g, the prescription label or a separate label
• the information can be associated with the container, for example, by being: written on a label (e.g, the prescription label or a separate label) adhesively affixed to a container; included inside a container as a written package insert; applied directly to the container such as being printed on the wall of a box or blister pack; or attached as by being tied or taped, for example as an instructional card affixed to the neck of a bottle via a string, cord
• EXAMPLE 1 Oral Decitabine/Cedazuridine vs. IV Decitabine in MDS including Lower- Risk MDS and CMML ⁇ Phase 3 Clinical Trial)
• MDS Myelodysplastic syndromes
• HSCT allogeneic hematopoietic stem cell transplantation
• DNMTi DNA methyltransferase inhibitors
• a phase 1, dose-finding study identified the doses of oral decitabine and cedazuridine (30-40 and 100 mg, respectively) that produced systemic exposure closest to that of the standard 5-day regimen for IV decitabine in MDS.
• 11 A phase 2, randomized, crossover trial established that oral decitabine 35 mg and oral cedazuridine 100 mg, given simultaneously as separate capsules and then as a fixed-dose combination, generated decitabine exposure, DNA demethylation, and safety comparable to those of IV decitabine with clinical responses similar to those previously reported for IV decitabine.
• 12 13 Here, the results of a phase 3 trial are presented comparing intrapatient total systemic exposure of oral decitabine/cedazuridine and IV decitabine over 5 days. Pharmacodynamics (DNA demethylation), clinical response, survival, and safety were also assessed.
• the primary endpoint analysis was based on data from patients who received the full treatment dose in cycles 1 and 2, and had decitabine daily AUC0-24 for both oral decitabine/cedazuridine and IV decitabine (i.e., paired cycles).
• decitabine daily AUC0-24 for both oral decitabine/cedazuridine and IV decitabine (i.e., paired cycles).
• treatment had to occur within 3 hours of intended dosing time, without vomiting within 6 hours of dosing.
• At least one of either day 1 or 5 decitabine AUC0-24 measurement during the IV decitabine cycle was required to be evaluable.
• Peak decitabine plasma concentrations were detected after 1 hour following both oral and IV therapy, except on day 5 after IV treatment when they were attained earlier at 30 minutes after treatment. Descriptive statistics were calculated for pharmacokinetic values.
• MDS myelodysplastic syndrome
• BSA body surface area
• CMML chronic myelomonocytic leukemia
• ECOG Eastern Cooperative Oncology Group
• DNMTi DNA methyltransferase inhibitor
• IPSS International Prognostic Scoring System
• RBC red blood cells
• SD standard deviation.
• Pharmacokinetics and pharmacodynamics' The geometric LSM ratio of decitabine 5- day AUCo -24 between oral decitabine/cedazuridine and IV decitabine was 98.9% (90% CI 92.7%, 105.6%), which was within the prespecified range of 80%-125% (Table 2). Secondary pharmacokinetic parameters support these findings (Table S2). Peak concentrations were higher after IV vs oral administration (FIG. 2A). Plasma concentrations remained above the lower limit of quantification for up to 4 hours in most patients after IV administration and for up to 6 hours in most patients following oral administration (FIG. 2B).
• D/C decitabine/cedazuridine
• CI confidence interval
• LINE-1 long interspersed nuclear element-1
• LSM least squares means
• FIG. 3 is a Kaplan-Meier plot for leukemia-free survival of the subjects.
• FIG. 4 is a Kaplan-Meier plot for the overall survival of the subjects.
• FIG. 5 is a Kaplan-Meier plot for leukemia-free survival of the subjects with CMML or Int-1 or low risk MDS.
• FIG. 6 is a Kaplan-Meier plot for the overall survival of the subjects with CMML or Int-1 or low risk MDS.
• Sequence A refers to subjects having oral decitabine/cedazuridine in Cycle 1 and IV decitabine in Cycle 2.
• Sequence B refers to subjects having IV decitabine in Cycle 1 and oral decitabine/cedazuridine in Cycle 2.
• the median overall survival for all MDS subjects is 966 days, or approximately 32 months. This is significantly higher than the overall median survival seen with treatment of MDS with azacitidine. This is also significantly higher than the overall median survival seen with treatment of MDS with decitabine alone. As such, administering oral cedazuridine and decitabine to treat MDS patients provides an unexpectedly superior improvement in median overall survival.
• Treatment-emergent adverse events were coded using Medical Dictionary for Regulatory Activities Version 22.0 and are listed in descending order of incidence in oral decitabine/cedazuridine (D/C) population. *>10% of oral decitabine/cedazuridine population.
• Oral formulations of cancer therapies are important for patients’ health-related quality of life.
• the majority of patients receiving parenteral DNMTi therapy reported in an online survey that IV and subcutaneous treatment interfered with their social activities (72% and 81%, respectively) and daily activities (70% and 87%), and caused pain (66% and 92%).
• 4 A literature review reported that in general, patients prefer oral to IV cancer therapies and value convenience, as well as the ability to receive treatment at home.
• CC-486 an oral form of the DNMTi azacitidine, is now available as a maintenance therapy for AML after first CR after demonstrating improved OS over placebo in patients aged >55 years who received an average of one cycle of consolidation chemotherapy while in CR.
• CC- 486 is not approved for treatment of MDS or CMML; however, it has been tested in prolonged dosing schemata (e.g., 14-21 days of a 28-day cycle in AML or MDS), 26,27 and in a phase 3 study in lower-risk MDS. 28 In the latter study, it resulted in increased early death rate, despite improvement in RBC transfusion independence.
• CC-486/oral azacitidine is active, it is not bioequivalent to or interchangeable with the injectable form of azacitidine used for MDS and CMML.
• An oral combination of cedazuridine/azacitidine in patients with MDS, CMML, or AML is in progress (ClinicalTrials.gov NCT04256317).
• a strength of the present study is its crossover design in which patients served as their own control, thereby facilitating intrapatient comparison between the oral and IV formulations during the first 2 treatment cycles. All patients received oral decitabine/cedazuridine after cycle 2, and thus the safety and efficacy of the oral and IV formulations were not compared for the full duration of the trial. Given the bioequivalence of oral decitabine/cedazuridine and parenteral decitabine and a clinical profile consistent with IV decitabine, a noninferiority assessment was not deemed necessary per the regulatory authorities.
• this is the first phase 3 trial to demonstrate pharmacologic equivalence between an oral and an IV formulation of a DNMTi for use in the treatment of patients with MDS or CMML.
• Data are in preparation from a pharmacokinetics study of oral decitabine/cedazuridine in patients with refractory anemia with excess blasts in transformation or AML with ⁇ 30% blasts.
• the availability of an oral DNMTi reduces the treatment burden for patients, potentially increasing the initiation of and persistence with this therapy, and improving OS and patients’ health-related quality of life. It also facilitates the development of all-oral combination therapy for MDS.
• Venetoclax an oral B-cell lymphoma-2 protein, is under study in MDS in combination with oral decitabine/cedazuridine (ClinicalTrials.gov NCT04655755).
• Oral cedazuridine/decitabine for MDS and CMML a phase 2 pharmacokinetic/pharmacodynamic randomized crossover study. Blood 2020;136:674-83. Steensma DP, Baer MR, Slack JL, et al. Multicenter study of decitabine administered daily for 5 days every 4 weeks to adults with myelodysplastic syndromes: the alternative dosing for outpatient treatment (ADOPT) trial. J Clin Oncol 2009;27:3842-8. Dacogen. Prescribing information. Otsuka America Pharmaceutical, Inc.; 2021. Yang AS, Estecio MR, Doshi K, Kondo Y, Tajara EH, Issa JP.
• EXAMPLE 2 Prolonged survival in bi-allelic //fU-mutated MDS subjects treated with oral decitabine/cedazuridine
• TP53 mutations (7/ ⁇ 53mut) in MDS patients have been characterized as an independent prognostic factor for poor outcome. These patients may have similar response rates to hypomethylating agents (HMAs) but markedly diminished overall survival (OS) compared to those with wild-type (WT) TP53 status (9.4 vs. 20.7 months; See Takahashi et al., Oncotarget, 2016, 7: 14172-14187). Further analyses have defined monoallelic (MA) and bi-allelic (BA)/multi- hit 7P53mut populations with very different survival outcomes (8.4 vs. 30 months; See Bernard et al., Nat. Med., 2020 Oct; 26(10): 1549-1556).
• MA monoallelic
• BA bi-allelic
• Oral decitabine/cedazuridine is a fixed dose combination of decitabine (35 mg) and the cytidine deaminase inhibitor cedazuridine (100 mg) with pharmacokinetic (PK) exposure equivalent to the standard intravenous (IV) decitabine regimen of 20 mg/m 2 daily x 5 days on a 28-day cycle.
• 133 subjects with MDS/CMML were enrolled to ASCERTAIN and were randomly assigned either IV decitabine for cycle 1 and oral decitabine/cedazuridine for cycle 2 or the opposite treatment sequence. All subjects continuing beyond cycle 2 received oral decitabine/cedazuridine fir all subsequence cycle until treatment discontinuation for disease progression, toxicity, patient’s decision, or hematopoietic stem cell transplantation.
• Whole blood collected prior to treatment was used for DNA isolation and molecular abnormalities identified using next generation sequencing (NGS) hematologic malignancy panel of 179 genes including 30 genes from the NCCN MDS panel.
• NGS next generation sequencing
• NGS analysis was available for 125 subjects.
• the percentage of subjects with mutations in the following genes were: TET2 (36.8%), TP53 (35.2%), ASXL1 (28%), DNMT3A (25.6%), SRSF2 MFSD11 (17.6%), SF3B1 (15.2%), STAG2 (12.8%), EZH2 (11.2%), RUNX1 (11.2%), U2AF1 (10.4%, BCOR (10.4%), CBL (8.8%).
• TP53, EZH2, RUNX1, CBL, DNMT3A, SF3 1, and ASXL1 were selected for further analysis based on their reported negative impact on OS and leukemia-free survival (LFS).
• TP53 and CBL mutations were closely associated with a worse OS (Hazard Ratio (HR) and 95% CI: 1.70 (1.00, 2.87) and 2.54 (1.19, 5.43), respectively) and LFS (HR and 95% CI: 1.63 (0.98, 2.72) and 2.01 (0.95, 4.26), respectively) compared with WT gene status, while subjects with DNMT3A mutation showed a trending advantageous relationship with OS and LFS over WT gene status.
• the median OS and LFS of the TP53mut population were 25.5 and 22.1 months, respectively, compared to the TP53 WT group and mOS and LFS estimates of 33.7 and 31.7 months, respectively (FIG. 7).
• the 7/ ⁇ 53mut population was further characterized by allelic status and found to have 14 subjects with BA mutations and 30 subjects with MA TP 53 mutations without other chromosomal deletions.
• the respective estimated mOS and 95% CI in the BA vs. MA were 13.0 (5.3, 29.1) months vs. 29.2 (19.8, NE) months (FIG. 8).
• the NGS mutational profile of MDS and CMML subjects in the ASCERTAIN trial included 35% with 7/ ⁇ 53mut and this group had a worse survival than those with WT TP53 apparently driven by the poor outcome of those with BA TP53mut.
• treatment with oral decitabine/cedazuridine in the ASCERTAIN study resulted in an estimated survival of 13 months for BA TP53mut which compares favorably with historical results.

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