A Study of Gilteritinib, Venetoclax and Azacitidine as a Combined Treatment for People Newly Diagnosed With Acute Myeloid Leukemia

Inclusion criteria

• Participant has a diagnosis of previously untreated Acute Myeloid Leukemia (AML) according to World Health Organization classification as determined by pathology review at the treating institution.
• Participant is positive for FMS-like tyrosine kinase 3 (FLT3) mutation (internal tandem duplication [ITD] and/or tyrosine kinase domain [TKD] [D835/I836] mutation) in bone marrow or whole blood as determined by the central laboratory. A participant with rapidly proliferative disease and unable to wait for the central laboratory results can be enrolled from a local test result.
• Participant is ineligible for intensive induction chemotherapy by meeting at least 1 of the following criteria:

• Participant is >= 75 years of age with Eastern Cooperative Oncology Group (ECOG) performance status 0, 1, or 2.
• Participant is >= 18 to 75 years of age and has any of the following comorbidities: ECOG performance status 2 or 3, cardiac history of congestive heart failure requiring treatment or ejection fraction <= 50% or chronic stable angina, known history of diffusion capacity of lung for carbon monoxide (DLCO) <= 65% or forced expiratory volume in the first second (FEVI) <= 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 incompatible with intensive chemotherapy during screening and before enrollment.
• Participant must have a projected life expectancy of at least 12 weeks.
• Participant must have adequate organ and bone marrow function prior to enrollment, as specified per protocol's laboratory parameters.
• Participant is suitable for oral administration of study drug (gilteritinib and venetoclax) and is willing/able to swallow oral tablets/capsules.
• Participant with a known history of human immunodeficiency virus (HIV) on effective antiretroviral therapy must have a viral load undetectable for 6 months prior to Cycle 1 Day 1 (C1D1).
• Female participant is eligible to participate if she is not pregnant and at least one of the following conditions apply:

• Not a woman of childbearing potential (WOCBP) OR
• WOCBP agrees to follow the contraceptive guidance starting at screening and continue through the study treatment period, and for at least 180 days after the final study regimen administration.

WOCBP must have a negative pregnancy test during screening.

• Female participant must agree not to breastfeed starting at screening, throughout the study treatment period and for 60 days after the last dose of the study treatment regimen.
• Female participant must not donate ova starting at screening, throughout the study treatment and for 180 days after the last dose of the study treatment regimen.
• Male participant with female partner(s) of childbearing potential must agree to use contraception starting at screening and continue through the study treatment, and for at least 120 days after the last dose of the study treatment regimen.
• Male participant must not donate sperm starting at screening, throughout the study treatment and for 120 days after the last dose of the study treatment regimen. (Venetoclax may cause a decrease in spermatogenesis. Male participant considering preservation of fertility should bank sperm before initiating treatment with venetoclax.)
• Male participant with a pregnant or breastfeeding partner(s) must agree to remain abstinent or use a condom for the duration of the pregnancy or time partner is breastfeeding throughout the treatment period, and for 120 days after the final study drug administration.
• Participant agrees not to participate in another interventional study while on treatment in this study.

Exclusion criteria

• Participant with the following conditions:

• Acute promyelocytic leukemia (APL)
• Active, symptomatic central nervous system (CNS) involvement with AML
• History of myeloproliferative neoplasm (MPN), including myelofibrosis, essential thrombocythemia, polycythemia vera, chronic myeloid leukemia (CML) with or without BCR-ABL1 translocation or AML with BCR-ABL1 translocation
• Participant previously treated with CAR-T cell therapy for AML or MDS. Exceptions for prior treatment of AML are (i.e., the following treatments are allowed):

• Hydroxyurea for increased blast count (No washout period required. It can be continued throughout the first cycle of therapy).
• Leukapheresis for leukocytosis (No washout period required. It can be continued during the study).
• Preemptive treatment with retinoic acid prior to exclusion of APL < 7 days.
• Participant who is receiving treatment with any other investigational agents.
• Participant requires treatment with concomitant drugs that are strong or moderate inducers of cytochrome P450 (CYP)3A or P glycoprotein (P-gp) during study treatment.
• Participant who has consumed grapefruit, grapefruit products, Seville oranges (including marmalade containing Seville oranges) or starfruit <= 3 days prior to C1D1.
• Participant with a cardiovascular disability status of New York Heart Association (NYHA) Class >= 3.
• Participant with mean QTcF > 450 msec at screening based on local reading performed in triplicate.
• Participant with a history of Long QT Syndrome at screening.
• Participant has been diagnosed with another malignancy within 2 years prior to screening for the study, with the following exceptions:

• Adequately treated in situ carcinoma of the cervix uteri or carcinoma in situ of breast;
• Basal cell carcinoma of the skin or localized squamous cell carcinoma of the skin;
• Previous malignancy confined and surgically resected (or treated with other modalities) with curative intent
• Participants who are on maintenance therapy for malignancies with no evidence of active malignancy for >= 2 years and the maintenance therapy can be discontinued.
• Participant who has an uncontrolled intercurrent illness including, but not limited to any of the following conditions:

• Uncontrolled hypertension
• Active, uncontrolled infection (viral, bacterial or fungal): An infection controlled with an approved or closely monitored antibiotic/antifungal treatment is allowed.
• Symptomatic, congestive heart failure
• Unstable angina pectoris
• Chronic respiratory disease that requires continuous oxygen
• Psychiatric illness/social situations that would limit compliance with study requirements
• Any other illness or condition that would interfere with study compliance or would compromise the participant's safety or study endpoints, including any contraindications to gilteritinib, azacitidine or venetoclax listed in the country package insert.
• Participant who has gastrointestinal disorders, malabsorption or other abnormalities that would interfere with absorption of the oral study drug.
• Participant has active hepatitis B or C or other active hepatic disorder.

• Participant with positive hepatitis B surface antigen (HBsAg) or detectable hepatitis B virus (HBV) deoxyribonucleic acid (DNA) are not eligible.
• Participant with negative HBsAg, positive hepatitis B core antibody and negative hepatitis B surface antibody will be eligible if HBV DNA is undetectable.
• For participant with a known history of chronic HBV infection, the HBV viral load must be undetectable on suppressive therapy, if indicated, to be eligible for this study.
• Participant with antibodies to hepatitis C virus (HCV) will be eligible if hepatitis C ribonucleic acid (RNA) viral load is undetectable.
• Participant with a known history of HCV infection must have been treated and cured to be eligible for this study. Participants with HCV infection who are currently on treatment are eligible if they have an undetectable HCV viral load.
• Participant has had major surgery within 4 weeks prior to the first study dose.
• Participant has a known or suspected hypersensitivity to gilteritinib, azacitidine or venetoclax or any components of the formulations used.
• Participant with recent positive test for SARS-CoV-2 ( or diagnosed with COVID-19) and no follow up test with negative result cannot be enrolled. Participant with contact to persons with COVID-19 and participants with signs and symptoms for COVID-19 infection must be tested before enrolling.
• Participant who requires concomitant treatment with a strong or moderate P-gp or CYP3A iinhibitor, with the exception of posaconazole, for antifungal prophylaxis during cycle 1 of the Dose Ranging Phase (phase 1). Note: Posaconazole is the only strong CYP3A inhibitor antifungal allowed during the cycle 1 DLT evaluation period. Post-DLT evaluation period, other antifungals including strong or moderate CYP3A inhibitors are allowed throughout the study.
• Participant does not have any of the following mutations:

FLT3-ITD, FLT3-TKD/D835 or FLT3-TKD/I836.