A Study of ASP2215 (Gilteritinib) by Itself, ASP2215 Combined With Azacitidine or Azacitidine by Itself to Treat Adult Patients Who Have Recently Been Diagnosed With Acute Myeloid Leukemia With a FLT3 Gene Mutation and Who Cannot Receive Standard Chemotherapy

Inclusion Criteria:

• Subject is considered an adult according to local regulation at the time ofobtaining informed consent.

• Subject has a diagnosis of previously-untreated AML according to World HealthOrganization (WHO) classification [Swerdlow et al, 2008] as determined by pathologyreview at the treating institution.

• Subject is positive for FLT3 mutation (internal tandem duplication [ITD] or tyrosinekinase domain [TKD] [D835/I836] mutation) (or for Korea only: ITD alone or ITD withconcurrent TKD activating mutation) in bone marrow or whole blood as determined bycentral laboratory. Note: Only requirement of FLT3 mutation assessment by centrallaboratory is only applicable to the randomization portion of the study.

• Subject is ineligible for intensive induction chemotherapy by meeting at least 1 ofthe following criteria:

• Subject is ≥ 65 years of age and ineligible for intensive inductionchemotherapy.

• Subject is ≥ 18 to 64 years of age and has any of the following comorbidities: [Ex-US Only]: Congestive heart failure (New York Heart Association {NYHA} class ≤ 3) or ejection fraction (Ef) ≤ 50%; [US Only]: Severe cardiac disorder e.g.congestive heart failure (New York Heart Association [NYHA] class ≤ 3)requiring treatment, ejection fraction ≤ 50%, or chronic stable angina; [Ex-USOnly]: Creatinine > 2 mg/dL (177 µmol/L), dialysis or prior renal transplant; [US Only]: Creatinine clearance < 45 mL/min; ECOG performance status ≥ 2;

• [Ex-US Only]: Known pulmonary disease with decreased diffusion capacity of lungfor carbon monoxide (DLCO) and/or requiring oxygen ≤ 2 liters per minute; [USOnly] Severe pulmonary disorder (e.g., diffusion capacity of lung for carbonmonoxide [DLCO] ≤ 65% or forced expiratory volume in the first second [FEV1] ≤ 65%); Prior or current malignancy that does not require concurrent treatment;Subject has received a cumulative anthracycline dose above 400 mg/m2 ofdoxorubicin (or cumulative maximum dose of another anthracycline). Any othercomorbidity incompatible with intensive chemotherapy must be reviewed andapproved by the Medical Monitor during screening and before randomization.

• Subject must meet the following criteria as indicated on the clinical laboratorytests:

• Serum AST and ALT ≤ 3.0 x Institutional upper limit of normal (ULN)

• Serum total bilirubin ≤ 1.5 x Institutional ULN

• Serum potassium ≥ Institutional lower limit of normal (LLN)

• Serum magnesium ≥ Institutional LLN Repletion of potassium and magnesium levelsduring the screening period is allowed.

• Subject is suitable for oral administration of study drug.

• Female subject is eligible to participate if female subject is not pregnant and atleast one of the following conditions applies:

• Not a woman of childbearing potential (WOCBP); OR

• WOCBP agrees to follow the contraceptive guidance starting at screening andcontinue throughout the study period, and for at least 180 days after the finalstudy drug administration.

• Female subject must agree not to breastfeed starting at screening and throughout thestudy period, and for 60 days after the final study drug administration.

• Female subject must not donate ova starting at screening and throughout the studyperiod, and for 180 days after the final study drug administration.

• Male subject with female partners of childbearing potential must agree to usecontraception as detailed in Contraception Requirements, starting at screening andcontinue throughout the study period, and for 120 days after the final study drugadministration.

• Male subject must not donate sperm starting at screening and throughout the studyperiod and for 120 days after the final study drug administration.

• Subject agrees not to participate in another interventional study while ontreatment.

Exclusion Criteria:

• Subject was diagnosed as acute promyelocytic leukemia (APL).

• Subject has BCR-ABL-positive leukemia (chronic myelogenous leukemia in blastcrisis).

• Subject has received previous therapy for AML, with the exception of the following:

• Emergency leukapheresis

• Hydroxyurea

• Preemptive treatment with retinoic acid prior to exclusion of APL ≤ 7 days

• Growth factor or cytokine support

• Steroids

• Subject has clinically active central nervous system leukemia.

• Subject has been diagnosed with another malignancy that requires concurrenttreatment (with the exception of hormone therapy limited to those therapies thatprevent recurrence and/or spread of cancer) or hepatic malignancy regardless of needfor treatment.

• Subject requires treatment with concomitant drugs that are strong inducers ofcytochrome P450 CYP3A/P-glycoprotein (P-gp).

• Subject requires treatment with concomitant drugs that are strong inhibitors orinducers of P-gp with the exception of drugs that are considered absolutelyessential for the care of the subject.

• Subject requires treatment with concomitant drugs that target serotonin 5-hydroxytryptamine receptor 2B (5HT2BR) or sigma nonspecific receptor with theexception of drugs that are considered absolutely essential for the care of thesubject.

• Subject has congestive heart failure classified as New York Heart Association ClassIV.

• Subject with mean Fridericia-corrected QT interval (QTcF) > 480 ms at screeningbased on central reading.

• Subject with a history of Long QT Syndrome at screening.

• [Ex-US Only]: Subject has known pulmonary function tests with diffusion capacity oflung for carbon monoxide (DLCO) ≤ 50%, forced expiratory volume in the first second (FEV1) ≤ 60%, dyspnea at rest or requiring oxygen or any pleural neoplasm (Transientuse of supplemental oxygen is allowed.)

• Subject has active hepatitis B or C or other active hepatic disorder.

• Subjects with positive hepatitis B surface antigen (HBsAg) or detectablehepatitis B DNA are not eligible.

• Subjects with negative HBsAg, positive hepatitis B core antibody and negativehepatitis B surface antibody will be eligible if hepatitis B DNA isundetectable.

• Subjects with antibodies to hepatitis C virus will be eligible if hepatitis CRNA is undetectable

• Subject has any condition which makes the subject unsuitable for studyparticipation, including any contraindications of azacitidine.

• Subject has a known or suspected hypersensitivity to ASP2215, azacitidine or anycomponents of the formulations used.

• [US Only]: Subject is ≥ 65 to 74 years of age, suitable for and willing to receiveintensive induction chemotherapy.