Liposomal Cytarabine and Daunorubicin (CPX-351) and Quizartinib for the Treatment of Acute Myeloid Leukemia and High Risk Myelodysplastic Syndrome

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PRIMARY OBJECTIVES: I. To determine the safety and maximum tolerable dose (MTD) of liposomal cytarabine and daunorubicin (CPX-351) in combination with quizartinib in patients with newly diagnosed or relapsed refractory acute myeloid leukemia (AML) and high-risk myelodysplastic syndrome (HR-MDS). II....

PRIMARY OBJECTIVES: I. To determine the safety and maximum tolerable dose (MTD) of liposomal cytarabine and daunorubicin (CPX-351) in combination with quizartinib in patients with newly diagnosed or relapsed refractory acute myeloid leukemia (AML) and high-risk myelodysplastic syndrome (HR-MDS). II. To determine the overall response rate (ORR) rate including CR (complete remission) + CRp (complete remission with incomplete platelet recovery) + CRi (complete remission with incomplete count recovery) + partial remission (PR) within 3 months of treatment initiation of CPX-351 and quizartinib combination. SECONDARY OBJECTIVE: I. To assess the overall survival (OS), event-free survival (EFS) and duration of response (DOR) of patients treated with this combination. EXPLORATORY OBJECTIVES: I. To evaluate the ORR, EFS (event free survival) and OS (overall survival) in FLT3 mutated/NPM1 wild-type patients versus FLT3 mutated/NPM1 mutated versus FLT3 wild-type/NPM1 mutated patients treated with CPX-351 and quizartinib. II. Quantitative changes of FLT3-ITD allelic burden and longitudinal evaluation to identify emergence of FLT3 non-ITD mutations with time in patients treated with the combination. III. To determine the effect of this treatment combination on responding patients transitioning to hematopoietic stem cell transplant (HSCT). IV. To store and/or analyze surplus blood or tissue including bone marrow, if available, for potential future exploratory research into factors that may influence development of AML and/or response to the combination (where response is defined broadly to include efficacy, tolerability or safety). OUTLINE: This is a dose-escalation study of CPX-351, followed by a phase II study. INDUCTION: Patients receive CPX-351 intravenously (IV) over 90 minutes on days 1, 3 and 5 and quizartinib orally (PO) on days 6-19. Patients who do not respond to treatment during cycle 1 receive CPX-351 IV on days 1 and 3 and quixartinib PO on days 6-19 during cycle 2. Treatment repeats every 28 days for up 2 cycles in the absence of disease progression or unacceptable toxicity. CONSOLIDATION: Patients receive CPX-351 over 90 minutes on days 1 and 3 and quizartinib PO on days 4-28 of cycle 1. Treatment with CPX-351 repeats every 28 days for 2 cycles in the absence of disease progression or unacceptable toxicity. MAINTENANCE: Patients receive quizartinib PO on days 1-28 in the absence of disease progression or unacceptable toxicity. After completion of study treatment, patients are followed up at 30 days, then every 3-6 months for up to 5 years.

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