The purpose of this study was to compare relapse-free survival (RFS) between participants with FMS-like tyrosine kinase 3 (FLT3) / internal tandem duplication (ITD) acute myeloid leukemia (AML) in first complete remission (CR1) and who were randomized to receive gilteritinib or placebo beginning after completion of induction/consolidation chemotherapy for a two-year period.

Participants in CR1 were approached for this study after induction/consolidation therapy was complete and a decision not to proceed with transplantation was made or a suitable donor could not be identified. Participants were randomized in a 2:1 ratio to receive gilteritinib or placebo. Participants entered the screening period up to 14 days prior to the start of treatment. Participants were administered treatment over continuous 28-day cycles. Gilteritinib or placebo was given daily for up to 2 years. After treatment discontinuation, participants had a 30-day follow-up visit for safety, after which the participants entered the long-term follow up period for collection of subsequent AML treatment, remission status, and survival (cause of death and date of death). Final database lock will occur when last subject last follow-up visit is reached, per protocol. Study drug was not provided during the follow-up period.

Inclusion Criteria:

• Subject is considered an adult according to local regulation at the time of obtaining consent form (ICF).

• Subject consents to allow access to subject's diagnostic bone marrow aspirate or peripheral blood sample and/or the DNA derived from that sample, if available, that may be used to validate a companion diagnostic test for gilteritinib.

• Subject has confirmed morphologically documented AML, excluding acute promyelocytic leukemia (APL), in CR1 (including CRp and CRi). For the purposes of enrollment, CR will be defined as < 5% blasts in the bone marrow with no morphologic characteristics of acute leukemia (e.g., Auer rods) in the bone marrow with no evidence of extramedullary disease such as central nervous system involvement or granulocytic sarcoma.

• Subject will not proceed with transplantation as either a decision not to proceed with transplantation has been made either on the recommendation of the treating physician or by the patient or a suitable donor could not be identified.

• Subject is < 2 months from the start of the last cycle of consolidation and should have completed the recommended number of consolidations per local practice.

• Subject has had no use of investigational agents, with the exception of FLT3 inhibiting agents during induction and/or consolidation therapy, within the prior 4 weeks.

• Subject has had presence of the FLT3/ITD activating mutation in the bone marrow or peripheral blood as determined by the local institution at diagnosis.

• Subject has an ECOG performance status 0 to 2.

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

  • Serum creatinine ≤ 1.5 x institutional upper limit of normal (ULN), or if serum creatinine outside normal range, then glomerular filtration rate (GFR) > 40 mL/min/1.73m^2 as calculated with the 4-parameter Modification of Diet in Renal Disease (MDRD) equation.
  • Serum total bilirubin ≤ 2.5 mg/dL (43 μmol/L), except for subjects with Gilbert's syndrome.
  • Serum aspartate aminotransferase (AST) and alanine aminotransferase (ALT) < 3 x ULN.
  • Serum potassium and serum magnesium ≥ institutional lower limit of normal (LLN).
  • Absolute neutrophil count (ANC) ≥ 500/μl and platelets ≥ 20000/μl (unsupported by transfusions).

• Subject is suitable for oral administration of study drug.

• Female subject must either:

  • Be of nonchildbearing potential:
  • Postmenopausal (defined as at least 1 year without any menses) prior to screening, or
  • Documented surgically sterile or status posthysterectomy (at least 1 month prior to screening)
  • Or, if of childbearing potential,
  • Agree not to try to become pregnant during the study and for 6 months after the final study drug administration
  • And have a negative urine or serum pregnancy test at screening
  • 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 6 months after the final study drug administration.

• Female subject must agree not to breastfeed starting at screening and throughout the study period, and for 2 months and 1 week after the final study drug administration.

• Female subject must not donate ova starting at screening and throughout the study period, and for 6 months after the final study drug administration.

• Male subject and subject's 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 4 months and 1 week after the final study drug administration.

• Male subject must not donate sperm starting at screening and throughout the study period and for 4 months and 1 week after the final study drug administration.

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

Exclusion Criteria:

• Subject has had prior allogeneic transplant.
• Subject has QTcF interval > 450 msec (average of triplicate determinations based on central reading).
• Subject with Long QT Syndrome.
• Subject with hypokalemia and hypomagnesemia at screening (defined as values below LLN).
• Subject has clinically active central nervous system leukemia.
• Subject is known to have human immunodeficiency virus infection.
• Subject has active hepatitis B or C.
• Subject has an uncontrolled infection. If a bacterial or viral infection is present, the subject must be receiving definitive therapy and have no signs of progressing infection for 72 hours prior to randomization. If a fungal infection is present, the subject must be receiving definitive systemic anti-fungal therapy and have no signs of progressing infection for 1 week prior to randomization.
• Subject has progressing infection 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 has uncontrolled angina, severe uncontrolled ventricular arrhythmias, electrocardiographic evidence of acute ischemia, congestive heart failure New York Heart Association (NYHA) class 3 or 4 or subject has a history of congestive heart failure NYHA class 3 or 4 in the past, unless a screening echocardiogram or multigated acquisition (MUGA) scan performed within 1 month prior to study entry results in a left ventricular ejection fraction that is ≥ 45%.
• Subject requires treatment with concomitant drugs that are strong inducers of cytochrome P450 (CYP) 3A.
• Subject 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.
• Subject 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.
• Subject has a serious medical or psychiatric illness likely to interfere with participation in this clinical study.
• Subject has prior malignancies, except resected basal cell carcinoma or treated cervical carcinoma in situ. Cancer treated with curative intent ≥ 5 years previously will be allowed. Cancer treated with curative intent < 5 years previously will not be allowed.
• Subject has any condition which makes the subject unsuitable for study participation.

Access to anonymized individual participant level data collected during the study, in addition to study-related supporting documentation, is planned for studies conducted with approved product indications and formulations, as well as products terminated during development. Studies conducted with product indications or formulations that remain active in development are assessed after study completion to determine if Individual Participant Data can be shared. Further details on Astellas' data sharing policy can be found at https://www.clinicaltrials.astellas.com/transparency/.

Access to participant level data is offered to researchers after publication of the primary manuscript (if applicable) and is available as long as Astellas has legal authority to provide the data.

Researchers must submit a proposal to conduct a scientifically relevant analysis of the study data. The research proposal is reviewed by an Independent Research Panel. If the proposal is approved, access to the study data is provided in a secure data sharing environment after receipt of a signed Data Sharing Agreement.