Decitabine, Cedazuridine for Acute myeloid leukemia

Inclusion criteria

• {"criterion_text":"- Participant must be 18 years of age or older\n- Histological confirmation of newly diagnosed AML by World Health Organization (WHO) 2016 criteria (Swerdlow et al 2017).\n- Projected life expectancy of at least 3 months.\n- Participants must be considered ineligible for intensive induction chemotherapy defined by the following: a) Age 75 years or older, or b) Age 18 to 74 years with at least one of the following comorbidities: i) Severe cardiac disorder (eg, congestive heart failure requiring treatment, ejection fraction ≤50%, or chronic stable angina). ii) Severe pulmonary disorder (eg, diffusing capacity of the lung for carbon monoxide (DLCO) ≤65% or forced expiratory volume in 1 second [FEV1] ≤65%). iii) Creatinine clearance ≥30 mL/min to <45 mL/min. iv) Moderate hepatic impairment with total bilirubin >1.5 to ≤3.0 ×upper limit of normal (ULN). v) Phase 1: Eastern Cooperative Oncology Group (ECOG) Performance Status of 2 (subjects with ECOG ≥3 are not eligible); Phase 2: ECOG Performance Status of 2 or 3 (subjects with ECOG 4 are not eligible).\n- For Phase 1, ECOG 0-2. For Phase 2, ECOG 0-3. Sex and Contraceptive Barrier Requirements\n- Participant can be male or female. Due to section size limitations, please refer to Protocol Section 10.2 for contraception requirements.\n- Capable of giving legally effective informed consent (as described in Appendix 1 [Section 10.1.3]), which includes compliance with the requirements and restrictions listed in the informed consent form (ICF) and in this protocol, and willing to participate in the study."}

Exclusion criteria

• {"criterion_text":"- History of myeloproliferative neoplasm including myelofibrosis, essential thrombocythemia, polycythemia vera, chronic myeloid leukemia with or without BCR-ABL1 translocation and AML with BCR-ABL1 translocation.\n- Significant history of renal, neurologic, psychiatric, endocrinologic, metabolic, immunologic, hepatic, cardiovascular or pulmonary disease, any other medical condition or known hypersensitivity to any of the study medications that in the opinion of the investigator would adversely affect his/her participating in this study.\n- Clinically significant uncontrolled systemic infection requiring therapy (viral, bacterial, or fungal).\n- History of other malignancies prior to study entry, with the exception of adequately treated in situ carcinoma of the breast or cervix uteri; localized basal cell carcinoma or squamous cell carcinoma of the skin; previous malignancy confined and surgically resected (or adequately treated and controlled with other modalities); and any early stage malignancy for which no definitive therapy is required.\n- WBC count >25,000/μL. (Hydroxyurea treatment is permitted to meet this criterion.)\n- Treatment with the following: a) A hypomethylating agent (azacitidine or decitabine), or venetoclax including prior treatment for MDS. b) Chimeric Antigen Receptor (CAR)-T cell therapy. c) Investigational therapies for MDS or AML.\n- Participants who cannot discontinue concomitant prophylactic antifungal therapy with CYP3A inhibitor activity or other concomitant medications with moderate or strong CYP3A inhibitor activity ≥7 days or 5 half-lives, whichever is greater, prior to C1D1.\n- Participants who cannot discontinue concomitant drugs that are strong CYP3A or P-gp inhibitors ≥7 days or 5 half-lives, whichever is greater, prior to C1D1.\n- Participants who cannot avoid concomitant drugs known as moderate or strong CYP3A inducers\n- Current participation in another research requiring interventions such as drug therapy or study procedures\n- Known or suspected hypersensitivity to decitabine, cedazuridine, venetoclax, or any of their excipients\n- The following karyotype abnormalities: t(8;21), inv(16) or t(15;17), or other acute promyelocytic leukemia variants that remain sensitive to all-trans retinoic acid (ATRA) therapy\n- Known significant mental illness or other condition such as active alcohol or other substance abuse or addiction that, in the opinion of the investigator, predisposes the subject to high risk of noncompliance with the protocol.\n- Patients who consume grapefruit, grapefruit products, Seville oranges (including marmalade containing Seville oranges) or starfruit ≤7 days prior to C1D1\n- Known active central nervous system involvement from AML.\n- Known human immunodeficiency virus (HIV) infection (due to potential drug-drug interactions between antiretroviral medications and venetoclax). Human immunodeficiency virus testing will be performed at Screening, only if indicated per local guidelines or institutional standards.\n- Known active hepatitis B or C infection (detectable viral load). Hepatitis B or C testing will be performed at Screening, only if indicated per local guidelines or institutional standards.\n- Severe hepatic impairment defined as: bilirubin >1.5×upper limit of normal (ULN) for subjects ≥75 years or >3×ULN for subjects <75 years; or aspartate aminotransferase (AST)/serum glutamic oxaloacetic transaminase (SGOT) or alanine aminotransferase (ALT)/serum glutamic pyruvic transaminase (SGPT) >3×ULN (unless abnormalities are considered to be due to leukemic organ involvement or bilirubinemia is due to known Gilbert's Syndrome).\n- Severe renal impairment defined as: calculated creatinine clearance or glomerular filtration rate <30 mL/min.\n- A malabsorption syndrome or other condition that precludes enteral route of administration\n- Cardiovascular disability status of New York Heart Association Class >2. Class 2 is defined as cardiac disease in which patients are comfortable at rest but ordinary physical activity results in fatigue palpitations, dyspnea, or anginal pain."}

Primary endpoints

• {"endpoint_text":"- Ph.1 Venetoclax AUC0-24 and Cmax on Day 5 with ASTX727 and Day 15 without ASTX727 in Cycle 2","definition_or_measurement_approach":"PK parameters: venetoclax AUC0-24 and Cmax measured on Day 5 (with ASTX727) and Day 15 (without ASTX727) in Cycle 2."}
• {"endpoint_text":"- Phase 2 Part A and B: CR rate","definition_or_measurement_approach":""}
• {"endpoint_text":"- Phase 2 Part A: Venetoclax AUC0-24 and Cmax on Day 5 with ASTX727 and Day 15 without ASTX727 in Cycle 2.","definition_or_measurement_approach":"PK parameters: venetoclax AUC0-24 and Cmax measured on Day 5 (with ASTX727) and Day 15 (without ASTX727) in Cycle 2."}

Secondary endpoints

• {"endpoint_text":"- Phase I: Decitabine and cedazuridine AUC0-24 and Cmax on Day 5 with venetoclax and cedazuridine AUC0-8 and on Day 5 with venetoclax in Cycle 2.","definition_or_measurement_approach":"PK parameters for decitabine and cedazuridine: AUC0-24 and Cmax on Day 5 with venetoclax; cedazuridine AUC0-8 on Day 5 with venetoclax in Cycle 2."}
• {"endpoint_text":"- Phase I, Phase II Part A and B: Incidence and severity of adverse events (AEs) as well as other safety assessments.","definition_or_measurement_approach":"Safety assessed by incidence and severity of AEs and other standard safety assessments (as per protocol)."}
• {"endpoint_text":"- Phase I, Phase II Part A and B: •\tCR rate •\tCR+CRh rate •\tCR+CRi rate","definition_or_measurement_approach":"Response rates (CR, CR+CRh, CR+CRi) as assessed per protocol-defined response criteria."}
• {"endpoint_text":"- Phase I, Phase II Part A and B: •\tTime to CR or CRh •\tDuration of CR or CRh •\tOverall survival","definition_or_measurement_approach":"Time-to-event endpoints: time to CR/CRh, duration of CR/CRh, and overall survival measured per protocol."}
• {"endpoint_text":"- Phase I: •\t5-day cumulative decitabine AUC in Cycle 2. •\tDecitabine AUC0-24 and Cmax on Days 1 and 2 in Cycle 2 •\tCedazuridine AUC0-8 on Days 1, 2, and 5 in Cycle 2; AUC0-24, AUC0-inf, and Cmax on Days 1, 2, and 5 in Cycle 2. •\tCmax, Cmin, Tmax, T1/2 and other secondary PK parameters.","definition_or_measurement_approach":"Various PK parameters for decitabine and cedazuridine measured at specified days in Cycle 2 (AUC metrics, Cmax, Cmin, Tmax, T1/2, etc.)."}
• {"endpoint_text":"- Phase II, Part A and B: Decitabine and cedazuridine AUC0-24, Cmax, AUC0-8, and AUC0-inf on Day 5 with venetoclax in Cycle 2.","definition_or_measurement_approach":"PK parameters for decitabine and cedazuridine on Day 5 with venetoclax in Cycle 2 (AUC0-24, Cmax, AUC0-8, AUC0-inf)."}
• {"endpoint_text":"- Phase II, Part A and B: Cmax, Cmin, Tmax, T1/2, and other secondary PK parameters.","definition_or_measurement_approach":"Secondary PK parameters including Cmax, Cmin, Tmax, T1/2 measured per protocol."}

Spain

Earliest CTIS Part Ii Submission Date

25-07-2024

Latest Decision Or Authorization Date

14-08-2024

Processing Time Days

20

Number Of Sites

7

Number Of Participants

40

Primary sponsor

Full Name

Taiho Oncology Inc.

Organisation Type

Pharmaceutical company

Country Of Registered Address

United States

Contract research organisations

Name

IQVIA Limited

Responsibilities

sponsorDuties codes: ["1","12","13","2","5","6","8"]

Name

Endpoint Clinical Inc.

Responsibilities

sponsorDuties codes: ["3"]

Third parties

• {"country":"United States","full_name":"Endpoint Clinical Inc.","duties_or_roles":"sponsorDuties codes: [\"3\"]","organisation_type":"Pharmaceutical company"}
• {"country":"United States","full_name":"Frontage Laboratories Inc.","duties_or_roles":"PK bioanalysis","organisation_type":"Pharmaceutical company"}
• {"country":"United States","full_name":"Certara USA Inc.","duties_or_roles":"PK analysis","organisation_type":"Pharmaceutical company"}
• {"country":"United States","full_name":"Edetek Inc.","duties_or_roles":"sponsorDuties codes: [\"10\"]","organisation_type":"Pharmaceutical company"}
• {"country":"United Kingdom (Northern Ireland)","full_name":"Almac Clinical Services Limited","duties_or_roles":"QP certification, primary/secondary labeling and packaging","organisation_type":"Pharmaceutical company"}
• {"country":"United States","full_name":"Personal Genome Diagnostics Inc.","duties_or_roles":"Molecular profiling","organisation_type":"Pharmaceutical company"}
• {"country":"United Kingdom","full_name":"IQVIA Limited","duties_or_roles":"sponsorDuties codes: [\"1\",\"12\",\"13\",\"2\",\"5\",\"6\",\"8\"]","organisation_type":"Pharmaceutical company"}