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

This is a clinical study for adult patients who have recently been diagnosed with acute myeloid leukemia or AML. AML is a type of cancer. It is when bone marrow makes white blood cells that are not normal. These are called leukemia cells. Some patients with AML have a mutation, or change, in the FLT3 gene. This gene helps leukemia cells make a protein called FLT3. This protein causes the leukemia cells to grow faster.

For patients with AML who cannot receive standard chemotherapy, azacitidine (also known as Vidaza®) is a current standard of care treatment option in the United States. This clinical study is testing an experimental medicine called ASP2215, also known as gilteritinib. Gilteritinib works by stopping the leukemia cells from making the FLT3 protein. This can help stop the leukemia cells from growing faster.

This study will compare two different treatments. Patients are assigned to one of these two groups by chance: a medicine called azacitidine, also known as Vidaza®, or an experimental medicine gilteritinib in combination with azacitidine. There is a twice as much chance to receive both medicines combined than azacitidine alone. The clinical study may help show which treatment helps patients live longer.

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

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

Eligibility Criteria:
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 requirement of FLT3 mutation assessment by central laboratory is only applicable to the randomization portion of the study.
* Subject is ineligible for intensive induction chemotherapy by meeting at least 1 of the following criteria:

  * Subject is ≥ 65 years of age and ineligible for intensive induction chemotherapy.
  * 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; \[Ex-US Only\]: 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 lung for carbon monoxide (DLCO) and/or requiring oxygen ≤ 2 liters per minute; \[US Only\] Severe pulmonary disorder (e.g., diffusion capacity of lung for carbon monoxide \[DLCO\] ≤ 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 of doxorubicin (or cumulative maximum dose of another anthracycline). Any other comorbidity incompatible with intensive chemotherapy must be reviewed and approved by the Medical Monitor during screening and before randomization.
* Subject must meet the following criteria as indicated on the clinical laboratory tests:

  * 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 levels during 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 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 limited to those therapies that prevent recurrence and/or spread of cancer) or hepatic malignancy regardless of need for treatment.
* Subject requires treatment with concomitant drugs that are strong inducers of cytochrome P450 CYP3A/P-glycoprotein (P-gp).
* 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) \> 480 ms at screening based 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 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 active hepatitis B or C or other active hepatic disorder.

  * Subjects with positive hepatitis B surface antigen (HBsAg) or detectable hepatitis B DNA are not eligible.
  * Subjects with negative HBsAg, positive hepatitis B core antibody and negative hepatitis B surface antibody will be eligible if hepatitis B DNA is undetectable.
  * Subjects with antibodies to hepatitis C virus will be eligible if hepatitis C RNA is undetectable
* Subject has any condition which makes the subject unsuitable for study participation, including any contraindications of azacitidine.
* Subject has a known or suspected hypersensitivity to ASP2215, azacitidine or any components of the formulations used.
* \[US Only\]: Subject is ≥ 65 to 74 years of age, suitable for and willing to receive intensive induction chemotherapy.