Evaluation of Two Dose Levels of Quizartinib as Maintenance in FLT3-ITD (+) Acute Myeloid Leukemia Patients in Complete Remission

A Phase 2, Multicenter, Randomized, Open-label Trial to Evaluate Safety and Efficacy of Two Dose Levels of Quizartinib as Maintenance for Adult Patients With Newly Diagnosed FLT3-ITD (+) Acute Myeloid Leukemia in Complete Remission

This clinical two-arm trial is designed to evaluate two doses of quizartinib as maintenance therapy after induction/consolidation in participants with FMS-like tyrosine kinase 3 (FLT3)-internal tandem duplication (ITD) (+) acute myeloid leukemia (AML) in first complete remission (CR) who have not received allogeneic hematopoietic stem cell transplantation (allo-HSCT).

This study also involves the Holter sub-study, which is designed to assess the impact of rapid acceleration in heart rate on the cardiac safety of quizartinib.

Key Inclusion Criteria:

1. Adults ≥18 years of age or the minimum legal adult age (whichever is greater) on the day of signing the ICF (no upper limit of age).

2. Newly diagnosed, morphologically documented primary AML or AML secondary to myelodysplastic syndrome or a myeloproliferative neoplasm based on the World Health Organization (WHO) 2008/2016 classification.

3. Participant has confirmed FLT3-ITD-positive (≥0.05 SR or ≥5% VAF) activating mutation from initial diagnosis in bone marrow or peripheral blood as determined by a local institution's validated molecular testing.

4. Participants must have confirmed, morphologically documented CR1, on the most recent BMA, based on the local laboratory results, performed within 28 days prior to C1D1 of maintenance therapy. Complete remission will be defined as <5% blasts in the bone marrow with no morphologic characteristics of acute leukemia (e.g., Auer Rods), no evidence of extramedullary disease, and no leukemic blasts in the peripheral blood.

   Complete blood count recovery is required with absolute neutrophil count of more than 1.000 × 109/L and platelets more than 100 × 109/L (IWG criteria).27

5. Participant must meet the following prior therapy requirements:

   1. Has received at least one cycle of induction therapy but no more than two to achieve CR1. The induction cycles can be the same regimen or different regimens and may contain conventional agents only (e.g., cytarabine + daunorubicin or idarubicin: "7 + 3" or "5 + 2"), or a combination with FLT3 inhibitors.
   2. Has not received more than four cycles of consolidation therapy. Regimens may contain conventional agents only.
   3. FLT3 inhibitors are permitted as part of the induction or consolidation treatment.

   Participants who received FLT3 inhibitors before enrollment in the trial will need a washout period of 14 days.

6. Able to begin the maintenance phase within 60 days of D1 of the last consolidation cycle received.

7. Eastern Cooperative Oncology Group (ECOG) PS of 0 to 2.

Key Exclusion Criteria:

1. Diagnosis of acute promyelocytic leukemia (APL), French-American-British classification M3 or WHO classification of APL with translocation, t(15;17)(q22;q12), or BCR-ABL positive leukemia (i.e., chronic myelogenous leukemia in blast crisis); participants who undergo diagnostic workup for APL and treatment with all-trans retinoic acid (ATRA), but who are found not to have APL, are eligible (treatment with ATRA must be discontinued before starting induction chemotherapy).

2. Diagnosis of AML secondary to prior chemotherapy or radiotherapy for other neoplasms.

3. Prior treatment for AML, except for the following allowances:

   1. Induction and consolidation therapy, as previously described (inclusion criterion #5)
   2. Leukapheresis
   3. Hydroxyurea to treat hyperleukocytosis
   4. Cranial radiotherapy for central nervous system (CNS) leukostasis
   5. Prophylactic intrathecal chemotherapy
   6. Growth factor/cytokine support

4. Participant had received allo-HSCT as part of AML treatment.

5. Treatment with any strong or moderate CYP3A inducers within 2 weeks or 5 half-lives of randomization whichever is longer

6. Uncontrolled or significant cardiovascular disease, including the following:

   1. QTcF interval >450 ms (based on average of triplicate ECG at Screening)
   2. Diagnosed or suspected congenital long QT syndrome or known family history of congenital long QT syndrome
   3. History of clinically relevant ventricular arrhythmias, such as ventricular tachycardia, ventricular fibrillation, or Torsade de Pointes
   4. Participant has bradycardia of less than 50 beats per minute (bpm; as determined by central reading), unless the participant has a pacemaker
   5. History of second- or third-degree heart block. Candidates with a history of heart block may be eligible if they currently have pacemakers and have no history of fainting or clinically relevant arrhythmia with pacemakers.
   6. Myocardial infarction within 6 months prior to screening
   7. Uncontrolled angina pectoris within 6 months prior to screening
   8. New York Heart Association Class 3 or 4 congestive heart failure
   9. LVEF ≤45% or institutional lower limit of normal
   10. Uncontrolled hypertension (resting systolic blood pressure >180 mmHg or diastolic blood pressure >110 mmHg despite optimal medical management)
   11. Complete left or right bundle branch block
   12. Severe aortic stenosis