Tamibarotene/Venetoclax/Azacitidine in Previously Untreated Patients Selected for RARA-positive AML (SELECT-AML-1)

Prior treatment

• Patients have not adequately recovered from a major surgery within 4 weeks of starting study drug administration.
• Prior treatment (before Cycle 1 Day1) for the diagnosis of AML, MDS, or antecedent hematologic malignancy with any hypomethylating agent, venetoclax, chemotherapy, or hematopoietic stem cell transplantation (HSCT), with the exception of prior treatment with hydroxyurea.
• Patients with a diagnosis of hypervitaminosis A or patients taking vitamin A supplements >10,000 IU/day, unless treatment is discontinued at least 7 days prior to the first dose of the study drug.
• Patients received any other investigational agents within 4 weeks of the Screening Visit or <5 half-lives since completion of previous investigational therapy have elapsed, whichever is shorter.
• Patients require concurrent treatment with any investigational or approved oncology agent, except for hydroxyurea.
• Patients for whom treatment with tamibarotene, azacitidine, or venetoclax is contraindicated
• Patients have a known active or chronic hepatitis B or active hepatitis C virus (HCV) infection. Patients with a history of HCV infection who have completed curative therapy for HCV at least 12 weeks before the Screening Visit and have a documented undetectable viral load at the Screening Visit are eligible for enrollment.
• Patients received prior treatment with all-trans retinoic acid (ATRA) or systemic retinoid for a hematologic malignancy.

Other illness

• Patients who have a hypersensitivity to tamibarotene, azacitidine, venetoclax or to any of their excipients.
• Participants with a history of other cancers must not be receiving active treatment (with radiation or chemotherapy) and must be free of disease for 2 years prior to the Screening Visit with the exception of localized prostate cancer treated with hormone therapy, breast cancer treated with hormone therapy, localized basal cell carcinoma, nonmelanoma skin cancer, or cervical carcinoma in situ
• Patients have an active, life-threatening, or clinically-significant uncontrolled systemic infection requiring hospitalization.
• Patients have a known malabsorption syndrome or other condition that may impair absorption of study medication (e.g., gastrectomy).

Lab values

• Patients with Grade ≥2 hypertriglyceridemia, defined as >300 mg/dL (Common Terminology Criteria for Adverse Events [CTCAE], version 5).
• QTc >450 msec for male patients, QTc >470 msec for female patients, or QTc >480 msec in male or female patients with bundle branch block based on triplicate electrocardiogram (ECG) readings at the Screening Visit. NOTE: The QTc in this study should be the QT interval corrected for heart rate according to Fridericia formula (QTcF).
• Immunocompromised patients with increased risk of opportunistic infections, including known human immunodeficiency virus (HIV)-positive patients with CD4 counts ≤350 cells/mm3 or history of opportunistic infection in the last 12 months. Note: To ensure that effective anti-retroviral therapy (ART), when used in eligible HIV-positive patients, is tolerated and that toxicities are not confused with investigational drug toxicities, patients should be on an established ART for at least 4 weeks and have an HIV viral load less than 400 copies/mL prior to the Screening Visit.
• Patients have other severe acute or chronic medical conditions (and/or psychiatric conditions or laboratory abnormalities) that may increase the expected risk to the patient (i.e., the risk associated with the study participation or study drug administration) or that may interfere with the interpretation of study results or, in the judgment of the investigator, would make the patient inappropriate for entry into this study.

Other

• Patients have APL
• Pregnant females, breastfeeding females, and males not willing to comply with contraceptive requirements or females of childbearing potential not willing to comply with contraceptive requirements.
• Patients have known active central nervous system involvement with AML
• Protected persons (legally protected adults [under judicial protection, guardianship, or supervision] and persons deprived of their liberty).

• Patients must be at least 18 years old at the time of signing of an informed consent
• All patients must have obtained a blood sample for RARA biomarker investigational assay testing prior to starting treatment on Cycle 1 Day 1. The results of the investigational biomarker assay for all patients must be confirmed as RARA-positive by Cycle 1 Day 8 to enroll (Part 1) or to be randomized (Part 2) in the study
• Patients must have ND, previously untreated non-APL AML with a bone marrow or peripheral blood blast count ≥20% and must be unlikely to tolerate standard intensive chemotherapy at the time of Cycle 1 Day 1 Visit due to age, performance status, or comorbidities based on at least one of the following criteria (Ferrara 2013): a. age ≥75 years old OR b. age <75 years old, with at least one of the following: o Eastern Cooperative Oncology Group (ECOG) performance status of 3 o cardiac history of congestive heart failure (CHF) or documented ejection fraction (EF) ≤50% o pulmonary disease with diffusing capacity of the lungs for carbon monoxide (DLCO) ≤65% or forced expiratory volume in one second (FEV1) ≤65% o creatinine clearance ≥30 mL/min to <45 mL/min based on the Cockcroft-Gault glomerular filtration rate estimation o hepatic impairment with total bilirubin >1.5 to ≤3.0 × upper limit of normal (ULN) o any other comorbidity that the investigator judges to be incompatible with intensive chemotherapy, and reviewed and approved by the sponsor
• Patients must have ECOG of 0 to 3 (if <75 years old) or 0 to 2 (if ≥75 years old)
• Patients must have a white blood cell (WBC) count <25,000/μL at the time of initiation of study drug (leukapheresis may be performed and/or hydroxyurea may be administered to decrease the WBC count to <25,000/μL)
• Patients must have minimum baseline organ function, as defined by: a. total bilirubin ≤3.0 × ULN (if <75 years old) or ≤1.5 × ULN (if ≥75 years old) b. alanine aminotransferase (ALT) and aspartate aminotransferase (AST)≤3 × ULN or ≤5 × ULN (if documented liver infiltration with leukemia cells) c. creatinine clearance ≥30 mL/min (if <75 years old) or ≥45 mL/min (if ≥75 years old) based on the Cockcroft-Gault glomerular filtration rate estimation
• Patients must have a high-sensitive urine or serum pregnancy test (for females of childbearing potential) that is negative at the Screening Visit and immediately prior to initiation of treatment (first dose of study drug).
• Patients must be willing and able to comply with the scheduled study visits, treatment plans, laboratory tests, use of 2 methods of birth control (including a barrier method) for women of childbearing potential (WOCBP) and male patients (as described in Appendix 4), and other procedures
• Patients must be capable of giving signed and dated Institutional Review Board (IRB) or Independent Ethics Committee (IEC) approved informed consent