A study to investigate the effect of adding venetoclax to treatment with ivosidenib and azacitidine in patients with acute myeloid leukemia (AML) with a specific gene abnormality who have not previously been treated and who are not eligible for intensive chemotherapy.

Prior treatment

• Patient with a currently active second malignancy. However, patients with the following history/concurrent conditions are allowed: Basal or squamous cell carcinoma of the skin; Carcinoma in situ of the cervix; Carcinoma in situ of the breast; Incidental histologic finding of prostate cancer.
• Receipt of live, attenuated vaccine within 30 days prior to the study inclusion.
• Participation in other prospective studies with anti-leukemic and/or investigational agents.
• Patient taking Dabigatran unless they can be transferred to other medications at least 3 days prior to dosing. Patients taking other P-gP transporter-sensitive medications should be properly monitored during the study if they cannot be transferred to other medications.
• Patients taking known strong cytochrome P450 (CYP) 3A4 inducers unless they can be transferred to other medications within ≥5 half-lives prior to dosing.
• History of stroke or intracranial hemorrhage within 6 months prior to randomization.
• Active infection, including hepatitis B or hepatitis C or Human Immunodeficiency Virus (HIV) infection, that is uncontrolled prior to first dose of study treatment and may interfere with the study objectives or which could expose the patient to undue risk through the participation in the clinical trial; an infection controlled with an approved antibiotic/ antiviral/ antifungal treatment that is not a strong or moderate CYP3A inducer is allowed. Patients with COVID-19 infection can be enrolled, if the patient has no symptoms and was tested negative twice by PCR test prior to inclusion in the trial.

Other illness

• Immediate life-threatening, severe complications of leukemia such as uncontrolled bleeding and/or disseminated intravascular coagulation.
• Conditions that limit the ingestion or gastrointestinal absorption of orally administered drugs.
• Severe neurological or psychiatric disorder interfering with ability to give an informed consent.
• Familial history of sudden death or polymorphic ventricular arrhythmia
• Severe obstructive or restrictive ventilation disorder.

Lab values

• Subject has previously been treated for AML; a treatment period with hydroxyurea to control WBC counts is allowed; prior treatment with a hypomethylating agent for MDS-EB is not allowed; prior treatment with erythropoiesis-stimulating agents or luspatercept for MDS is allowed.
• Significant active cardiac disease within 3 months prior to the start of study treatment, including: New York Heart Association (NYHA) class III or IV congestive heart failure; Myocardial infarction; Unstable angina; Severe cardiac arrhythmias; Congenital long QT syndrome of family member with this condition; QTcF >450 msec on screening electrogram for males and >470 msec on screening electrogram for females (mean of triplicate recordings, calculated using Fridericia’s correction).

Other

• Contraindication to any of the anti-leukemic agents used (as per SmPC)
• The patient is a pregnant or lactating woman, or plans to become pregnant during the study.
• Acute promyelocytic leukemia (APL) with t(15;17)(q24.1;q21.2); PML-RARA; or one of the other pathognomonic variant chromosomal translocations / fusion genes.
• Patient who has once been screened and randomized into this HO173 trial but was considered ineligible cannot re-enter this trial at a later date.
• AML with BCR-ABL1; or myeloid blast crisis of CML.
• Clinical symptoms suggestive of active central nervous system (CNS) leukemia or known CNS leukemia. Evaluation of cerebrospinal fluid (CSF) during screening is only required if there is a clinical suspicion of CNS involvement by leukemia during screening.

• Patient with newly diagnosed IDH1-mutated AML, or IDH1-mutated MDS/AML according to the 2022 International Consensus Classification. Patients with AML with both IDH1 and IDH2 mutation are eligible as well
• Men must agree to avoid to father a child (while on therapy and for 6 months after the final study drug administration).
• Male patient must not donate sperm starting at screening and throughout the study period and for 6 months after the final study drug administration.
• Able to understand and willing to sign an informed consent form (ICF).
• Institutional Review Board/Independent Ethics Committee-approved written informed consent as per national regulations must be obtained from the patient prior to any study-related procedures (including consent for withdrawal of prohibited medication, if applicable).
• Central confirmation of IDH1 mutation in one of the dedicated central genetic laboratories.
• Age ≥ 18 years, no upper age limit.
• Patient is ineligible for intensive induction chemotherapy by meeting at least 1 of the following criteria: ≥ 75 years of age: ineligible for intensive chemotherapy per physician’s discretion (with an ECOG performance status 0-2. 18-74 years: patient is not eligible for standard chemotherapy because any of the following co-morbidities: ECOG performance status 2 or 3; Cardiac history of chronic heart failure requiring treatment; or with an ejection fraction ≤50%; or chronic stable angina; DLCO ≤ 65% or FEV1 ≤ 65%; Creatinine clearance ≥ 30 mL/min to <45 ml/min calculated by the Cockcroft Gault formula; Moderate hepatic impairment with total bilirubin > 1.5 to < 3.0 x upper limit of normal (ULN); Any other comorbidity that the local physician assesses to be incompatible with intensive chemotherapy.
• Patient must have a projected life expectancy of at least 12 weeks (as assessed by the treating physician).
• Patient must have a white cell blood (WBC) count of < 25 x 109/L.
• Adequate renal function as evidenced by serum creatinine ≤ 2.0 × upper limit of norm (ULN) or creatinine clearance ≥ 30 mL/min based on the Cockcroft-Gault glomerular filtration rate (GFR).
• Adequate hepatic function as evidenced by: Serum total bilirubin ≤ 3.0 × ULN unless considered due to Gilbert’s disease, or leukemic involvement ; Aspartate aminotransferase (AST), alanine aminotransferase (ALT), and alkaline phosphatase (ALP) ≤ 3.0 × ULN, unless considered due to leukemic involvement.
• Female patients: must be of nonchildbearing potential or when of childbearing potential must agree to avoid pregnancy during the study and for 6 months after the final study drug administration; must agree not to breastfeed starting at screening and throughout the study period, and for 2 months and 1 week after the final study drug administration; must agree not to donate ova starting at screening and throughout the study period, and for 6 months after the final study drug administration.