Phase 1 study of quizartinib in combination with induction and consolidation chemotherapy in patients with newly diagnosed acute myeloid leukemia

Jessica K. Altman, James M Foran, Keith W. Pratz, Denise Trone, Jorge E. Cortes, Martin S. Tallman

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29 Citations (Scopus)

Abstract

Novel therapies have potential to improve outcomes in patients with acute myeloid leukemia (AML) harboring FLT3-ITD mutations that have high risk of relapse and poor survival following standard of care (SOC) cytarabine/anthracycline-based induction/consolidation chemotherapy. Quizartinib is a selective and highly potent FLT3 inhibitor that has shown strong single-agent activity in relapsed or refractory (R/R) AML. This phase 1, open-label, sequential group dose-escalation trial (NCT 01390337) is the first evaluating safety and tolerability of quizartinib in combination with SOC chemotherapy in newly diagnosed AML (ndAML). Nineteen patients unselected for FLT3 mutational status received one of three quizartinib dihydrochloride dose levels (DL): 60 mg/d for 7 days (DL1; n=6), 60 mg/d for 14 days (DL2; n=7), and 40 mg/d for 14 days (DL-1; n=6); administered orally starting on day 4 of chemotherapy. Median age was 43.8 years. Ten patients completed induction and consolidation. Three patients experienced dose-limiting toxicities (DLTs): 2 at DL2 (1 pericardial effusion; 1 febrile neutropenia, decreased platelet count, and QT prolongation); 1 at DL-1 (pericarditis). Maximum tolerated dose (MTD) was identified as DL-1. Most common grade 3/4 adverse events were febrile neutropenia (47%), neutropenia (42%), thrombocytopenia (32%), and anemia (26%). There were no apparent additional toxicities with addition of quizartinib to chemotherapy although grade ≤1 QT prolongation was observed at MTD. Sixteen patients (84%) achieved a response; 14 (74%) composite complete response; 2 (11%) morphologic leukemia-free state. The phase 3 QuANTUM-First trial (NCT02668653) is further evaluating the effect of quizartinib plus SOC chemotherapy in ndAML FLT3-ITD mutated patients.

Original languageEnglish (US)
JournalAmerican Journal of Hematology
DOIs
StateAccepted/In press - Jan 1 2017

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Consolidation Chemotherapy
Induction Chemotherapy
Acute Myeloid Leukemia
Standard of Care
Drug Therapy
Febrile Neutropenia
Maximum Tolerated Dose
Pericarditis
Pericardial Effusion
Anthracyclines
Cytarabine
Neutropenia
Platelet Count
Thrombocytopenia
quizartinib
Anemia
Leukemia
Safety
Recurrence
Mutation

ASJC Scopus subject areas

  • Hematology

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Phase 1 study of quizartinib in combination with induction and consolidation chemotherapy in patients with newly diagnosed acute myeloid leukemia. / Altman, Jessica K.; Foran, James M; Pratz, Keith W.; Trone, Denise; Cortes, Jorge E.; Tallman, Martin S.

In: American Journal of Hematology, 01.01.2017.

Research output: Contribution to journalArticle

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