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

Patients considered an adult according to local regulation at the time of obtaining informed
consent may participate in the study.

Safety Cohort Prior to initiation of the randomized trial, 8 to 12 patients will be enrolled
to evaluate the safety and tolerability of ASP2215 given with azacitidine therapy in the
study population.

Randomized Trial Approximately 323 patients will be randomized in a 2:1 ratio to receive
ASP2215 plus azacitidine (Arm AC) or azacitidine only (Arm C).

Earlier protocol versions included a 1:1:1 randomization ratio to receive Arm A: ASP2215, Arm
AC: ASP2215 + azacitidine or Arm C: azacitidine. Randomization to Arm A was removed in the
current protocol version. Patients previously randomized to Arm A should continue following
treatment and assessments as outlined in the protocol.

Patients will enter the screening period up to 14 days prior to the start of treatment.
Patients will be administered treatment over 28-day cycles.

Inclusion Criteria:

- Subject is considered an adult according to local regulation at the time of obtaining
informed consent.

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

- Subject is positive for FLT3 mutation (internal tandem duplication [ITD] or tyrosine
kinase domain [TKD] [D835/I836] mutation) (or for Korea only: ITD alone or ITD with
concurrent TKD activating mutation) in bone marrow or whole blood as determined by
central laboratory. Note: Only applicable to the randomization portion.

- Subject is ineligible for intensive induction chemotherapy by meeting at least 1 of
the following criteria:

1. Subject is ≥ 75 years of age.

2. Subject has any of the following comorbidities:

- Congestive heart failure (New York Heart Association {NYHA} class ≤ 3) or
ejection fraction (Ef) ≤ 50%;

- Creatinine > 2 mg/dL (177 µmol/L), dialysis or prior renal transplant;

- ECOG performance status ≥ 2;

- Known pulmonary disease with decreased diffusion capacity of lung for carbon
monoxide (DLCO) and/or requiring oxygen ≤ 2 liters per minute

- Prior or current malignancy that does not require concurrent treatment;

- Subject has received a cumulative anthracycline dose above 400 mg/m2 of
doxorubicin (or cumulative maximum dose of another anthracycline).

- Subject must meet the following criteria as indicated on the clinical laboratory
tests:

- Serum AST and ALT ≤ 2.5 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

- Subject is suitable for oral administration of study drug.

- Female subject is eligible to participate if female subject is not pregnant and at
least one of the following conditions applies:

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

- WOCBP agrees to follow the contraceptive guidance starting at screening and
continue throughout the study period, and for at least 180 days after the final
study drug administration.

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

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

- Male subject with female partners of childbearing potential must agree to use
contraception as detailed in Contraception Requirements, starting at screening and
continue throughout the study period, and for 120 days after the final study drug
administration.

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

- Subject agrees not to participate in another interventional study while on treatment.

Exclusion Criteria:

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

- Subject has BCR-ABL-positive leukemia (chronic myelogenous leukemia in blast crisis).

- 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 concurrent treatment
(with the exception of hormone therapy) or hepatic malignancy regardless of need for
treatment.

- Subject has clinically significant coagulation abnormality unless secondary to AML.

- Subject has had major surgery within 4 weeks prior to the first study dose.

- Subject has radiation therapy within 4 weeks prior to the first study dose.

- Subject requires treatment with concomitant drugs that are strong inducers of
cytochrome P450 CYP3A.

- Subject requires treatment with concomitant drugs that are strong inhibitors or
inducers of P-gp with the exception of drugs that are considered absolutely essential
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 the
exception of drugs that are considered absolutely essential for the care of the
subject.

- Subject has congestive heart failure classified as New York Heart Association Class
IV.

- Subject with mean Fridericia-corrected QT interval (QTcF) > 450 ms at screening based
on central reading.

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

- Subject has known pulmonary disease with diffusion capacity of lung for carbon
monoxide (DLCO) ≤ 50%, forced expiratory volume in the first second (FEV1) ≤ 60%,
dyspnea at rest or requiring oxygen or any pleural neoplasm (Transient use of
supplemental oxygen is allowed.)

- Subject has an active uncontrolled infection. If an infection is present, the patient
must be receiving definitive therapy and have no signs of progressing infection.
Progressing infection is defined as hemodynamic instability attributable to sepsis or
new symptoms, worsening physical signs or radiographic findings attributable to
infection. Persisting fever without other signs or symptoms will not be interpreted as
progressing infection.

- Subject is known to have human immunodeficiency virus infection.

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

- Subject has any condition which makes the subject unsuitable for study participation,
including any contraindications of azacitidine.