A Study of ASP2215 Versus Salvage Chemotherapy in Patients With Relapsed or Refractory Acute Myeloid Leukemia (AML) With FMS-like Tyrosine Kinase (FLT3) Mutation

The purpose of this study is to determine the clinical benefit of ASP2215 therapy in participants with FMS-like tyrosine kinase (FLT3) mutated acute myeloid leukemia (AML) who are refractory to or have relapsed after first-line AML therapy as shown with overall survival (OS) compared to salvage chemotherapy, and to determine the efficacy of ASP2215 therapy as assessed by the rate of complete remission and complete remission with partial hematological recovery (CR/CRh) in these participants.

This study will also determine the overall efficacy in event-free survival (EFS) and complete remission (CR) rate of ASP2215 compared to salvage chemotherapy.

Participants considered an adult according to local regulations at the time of signing informed consent may participate in this study. Participants will be randomized in a 2:1 ratio to receive ASP2215 or salvage chemotherapy. Participants will enter the screening period up to 14 days prior to the start of treatment. Prior to randomization, a salvage chemotherapy regimen will be pre-selected for each participant; options will include low-dose cytarabine (LoDAC), azacitidine, mitoxantrone, etoposide, and intermediate-dose cytarabine (MEC), or fludarabine, cytarabine, and granulocyte colony-stimulating factor (G-CSF) with idarubicin (FLAG-IDA). The randomization will be stratified by response to first-line therapy and pre-selected salvage chemotherapy. Participants will be administered treatment over continuous 28-day cycles.

After treatment discontinuation, participants will have a pre-hematopoietic stem cell transplant (HSCT)/end-of-treatment visit within 7 days after treatment discontinuation, followed by a 30-day follow-up for safety, in which a telephone contact with the participant is sufficient unless any assessment must be repeated for resolution of treatment-related adverse events (AEs). After that, long term follow-up will be done every 3 months up to 3 years from the participant's end-of-treatment visit.

Eligibility Criteria:
Inclusion Criteria:

* Participant has a diagnosis of primary acute myeloid leukemia (AML) or AML secondary to myelodysplastic syndrome (MDS) according to WHO classification (2008) as determined by pathology review at the treating institute.
* Participant is refractory to or relapsed after first-line AML therapy (with or without hematopoietic stem cell transplant (HSCT)).

  * Refractory to first-line AML therapy is defined as:

    1. Participant did not achieve complete remission/complete remission with incomplete hematologic recovery/complete remission with incomplete platelet recovery (CR/CRi/CRp) under initial therapy. A Participant eligible for standard therapy must receive at least one cycle of an anthracycline containing induction block in standard dose for the selected induction regimen. A Participant not eligible for standard therapy must have received at least one complete block of induction therapy seen as the optimum choice of therapy to induce remission for this subject.
  * Untreated first hematologic relapse is defined as:

    1. Participant must have achieved a CR/CRi/CRp (criteria as defined by \[Cheson et al, 2003\], see Section 5.3) with first line treatment and has hematologic relapse.
* Participant is positive for FLT3 mutation in bone marrow or whole blood as determined by the central lab. A Participant with rapidly proliferative disease and unable to wait for the central lab results can be enrolled based on a local test performed after completion of the last interventional treatment. Participants can be enrolled from a local test result if they have any of the following FLT3 mutations: FLT3 internal tandem duplication (ITD), FLT3 tyrosine kinase domain (TKD)/D835 or FLT3- TKD/I836.
* Participant has an Eastern Cooperative Oncology Group (ECOG) performance status ≤ 2.
* Participant is eligible for pre-selected salvage chemotherapy.
* Participant must meet the following criteria as indicated on the clinical laboratory tests:

  * Serum aspartate aminotransferase and alanine aminotransferase ≤ 2.5 x upper limit of normal (ULN)
  * Serum total bilirubin ≤ 1.5 x ULN
  * Serum creatinine ≤ 1.5 x ULN or an estimated glomerular filtration rate of \> 50 mL/min as calculated by the Modification of Diet in Renal Disease equation.
* Participant is suitable for oral administration of study drug.
* Female Participant must either:

  * Be of non-child bearing potential:

    1. post-menopausal (defined as at least 1 year without any menses) prior to Screening, or
    2. documented as surgically sterile (at least 1 month prior to Screening)
  * Or, if of childbearing potential,

    1. Agree not to try to become pregnant during the study and for 180 days after the final study administration
    2. And have a negative urine pregnancy test at Screening
    3. And, if heterosexually active, agree to consistently use highly effective contraception per locally accepted standards in addition to a barrier method starting at Screening and throughout the study period and for 180 days after the final study drug administration.
* Female Participant must agree not to breastfeed at Screening and throughout the study period and for 60 days after the final study drug administration.
* Female Participant must not donate ova starting at Screening and throughout the study period and for 180 days after the final study drug administration.
* Male Participant and their female partners who are of childbearing potential must be using highly effective contraception per locally accepted standards in addition to a barrier method starting at Screening and continue throughout the study period and for 120 days after the final study drug administration.
* Male Participant must not donate sperm starting at Screening and throughout the study period and 120 days after the final study drug administration.
* Participant agrees not to participate in another interventional study while on treatment.

Exclusion Criteria:

* Participant was diagnosed as acute promyelocytic leukemia (APL).
* Participant has BCR-ABL-positive leukemia (chronic myelogenous leukemia in blast crisis).
* Participant has AML secondary to prior chemotherapy for other neoplasms (except for MDS).
* Participant is in second or later hematologic relapse or has received salvage therapy for refractory disease
* Participant has clinically active central nervous system leukemia.
* Participant has been diagnosed with another malignancy, unless disease-free for at least 5 years. Participants with treated nonmelanoma skin cancer, in situ carcinoma or cervical intraepithelial neoplasia, regardless of the disease-free duration, are eligible for this study if definitive treatment for the condition has been completed. Participants with organ-confined prostate cancer with no evidence of recurrent or progressive disease are eligible if hormonal therapy has been initiated or the malignancy has been surgically removed or treated with definitive radiotherapy.
* Participant has received prior treatment with ASP2215 or other FLT3 inhibitors (with the exception of sorafenib and midostaurin used in first-line therapy regimen as part of induction, consolidation, and/or maintenance).
* Participant has clinically significant abnormality of coagulation profile, such as disseminated intravascular coagulation (DIC).
* Participant has had major surgery within 4 weeks prior to the first study dose.
* Participant has radiation therapy within 4 weeks prior to the first study dose.
* Participant has congestive heart failure New York Heart Association (NYHA) class 3 or 4, or Participant with a history of congestive heart failure NYHA class 3 or 4 in the past, unless a screening echocardiogram performed within 3 months prior to study entry results in a left ventricular ejection fraction that is ≥ 45%.
* Participant requires treatment with concomitant drugs that are strong inducers of cytochrome P450 (CYP)3A.
* Participants with mean of triplicate Fridericia-corrected QT interval (QTcF) \> 450 ms at Screening based on central reading.
* Participants with Long QT Syndrome at Screening.
* Participants with hypokalemia and hypomagnesemia at Screening (defined as values below lower limit of normal \[LLN\]).
* Participant requires treatment with concomitant drugs that are strong inhibitors or inducers of P glycoprotein (P-gp) with the exception of drugs that are considered absolutely essential for the care of the subject.
* Participant requires treatment with concomitant drugs that target serotonin 5-hydroxytryptamine receptor 1 (5HT1R) or 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.
* Participant has an active uncontrolled infection.
* Participant is known to have human immunodeficiency virus infection.
* Participant has active hepatitis B or C, or other active hepatic disorder.
* Participant has any condition which makes the Participant unsuitable for study participation.
* Participant has active clinically significant GVHD or is on treatment with systemic corticosteroids for GVHD.
* Participant has an FLT3 mutation other than the following: FLT3-ITD, FLT3-TKD/D835 or FLT3-TKD/I836.