A PHASE 3 OPEN-LABEL RANDOMIZED STUDY OF QUIZARTINIB (AC220) MONOTHERAPY VERSUS SALVAGE CHEMOTHERAPY IN SUBJECTS WITH FLT3-ITD POSITIVE ACUTE MYELOID LEUKEMIA (AML) REFRACTORY TO OR RELAPSED AFTER FIRST-LINE TREATMENT WITH OR WITHOUT HEMATOPOIETIC STEM CELL TRANSPLANTATION (HSCT) CONSOLIDATION

Summary

This is a Phase 3, randomized, open-label, 2-arm study to compare the effect of quizartinib monotherapy and salvage chemotherapy on oS in subjects with FLT3-iTD( +) aML that is refractory or relapsed within 6 months, after first-line therapy with or without consolidating hematopoietic stem cell transplant (HSCT).

The initial target sample size will be approximately 326 subjects, randomized in a 2: 1 ratio to receive quizartinib monotherapy (217 subjects) or salvage chemotherapy (i09 subjects). The study has an adaptive design. one formal interim analysis will be performed by an independent statistical analysis center (SaC) and evaluated by an independent data monitoring committee (DMC), according to statistical procedures defined a priori. Based on the results of the interim analysis, the DMC may recommend that the study be terminated early for futility or for efficacy, or continue as planned. additionally, the DMC may recommend the enrollment of additional subjects, up to a maximum of 473 subjects. The precise rules for implementing the adaptive change are fully specified in a confidential statistical procedures appendix to the DMC charter. The Sponsor will have no involvement in the interim data analysis, interpretation, or the adaptive decision. These tasks will be performed by the SaC and DMC and are described in the DMC charter.

Prior to randomization, the investigator will pre-select a salvage chemotherapy regimen for each subject; options include low dose cytarabine (LoDaC); mitoxantrone, etoposide, and intermediate-dose cytarabine (MeC); or fludarabine, cytarabine, and granulocyte colony stimulating factor (G-CSF) with idarubicin (FLaG-iDa).

Participant Eligibility

1. Provision of written informed consent approved by the Institutional Review Board
(IRB) or Independent Ethics Committee (IEC) with privacy language in accordance
with national regulations (e.g., HIPAA authorization for US sites) prior to any
study-related procedures, including withdrawal of prohibited medications if
applicable.
2. Age >=18 years at the time of informed consent.
3. Morphologically documented primary AML or AML secondary to myelodysplastic
syndrome (MDS), as defined by World Health Organization criteria, as determined by
pathology review at the study site.
4. Refractory or relapsed AML after first-line therapy, with or without HSCT. First-line
therapy can consist of 1 or 2 induction blocks with or without consolidation.
Induction therapy must have included at least 1 cycle of an
anthracycline/mitoxantrone-containing induction block at a standard dose.

* Refractory to first-line therapy is defined as:
o After 1 cycle, lack of achievement of CR, CRp, or CRi and a reduction in
bone marrow blasts of less than 50%.
o After 2 cycles, lack of achievement of CR, CRp, or CRi.

* Relapse within 6 months or less after first-line therapy is defined as (all criteria
must be met):
o Achievement of CR, CRi, or CRp, as defined by 2003 International
Working Group criteria after initial AML therapy with or
without consolidation or maintenance, and with or without HSCT as
consolidation
o Duration of CR, CRi or CRp is measured from the date of the bone
marrow assessment which confirmed response to the date of the bone
marrow assessment that identified relapse or the appearance of peripheral
blasts
5. Presence of the FLT3-ITD activating mutation in bone marrow or peripheral blood
(allelic ratio as determined by a central laboratory with a cutoff of >3%
FLT3-ITD/total FLT3).
6. Eligibility for pre-selected salvage chemotherapy, according to the Investigator[Single Quote]s
assessment.
7. ECOG performance score 0-2.
8. Discontinuation of prior AML treatment before the start of study treatment (except
hydroxyurea, which is permitted for blast control up to the day of starting study
treatment) for at least 2 weeks for cytotoxic agents, or for at least 5 half-lives for
non-cytotoxic agents.
9. Serum creatinine <=1.5xupper limit of normal (ULN), or glomerular filtration rate
>25 mL/min/1.73m2, as calculated with the modified Cockcroft-Gault formula.
10. Serum potassium, magnesium, and calcium (serum calcium corrected for
hypoalbuminemia) within institutional normal limits. Subjects with electrolytes
outside the normal range will be eligible if these values are corrected upon retesting
following any necessary supplementation.
11. Total serum bilirubin <=1.5xULN.
12. Serum aspartate transaminase (AST) and/or alanine transaminase (ALT) <=2.5xULN.