Phase I/II Study of the Combination of Low-Intensity Chemotherapy and Venetoclax (ABT-199) in Patients With Relapsed/Refractory Acute Lymphoblastic Leukemia (ALL)

简要总结

详细描述

PRIMARY OBJECTIVES: I. Determine the maximum tolerated dose (MTD) and dose-limited toxicities (DLTs) of venetoclax in combination with low-intensity chemotherapy in patients with relapsed/refractory acute lymphoblastic leukemia (ALL) (Phase I). II. Evaluate the overall response rate (complete response \[CR\] + CR with inadequate count recovery \[CRi\]) of the regimen after 2 cycles. (Phase II) SECONDARY OBJECTIVES: I. Evaluate other clinical efficacy endpoints (minimal residual disease \[MRD\] negativity, duration of response \[DOR\], event-free survival \[EFS\] and overall survival \[OS\]). II. Determine the safety of the combination regimen. EXPLORATORY OBJECTIVES: I. To correlate apoptotic protein expression and Bcl-2 dependency on response and resistance to the combination regimen. OUTLINE: This is a phase I, dose-escalation study of venetoclax, followed by a phase II study. CHEMOTHERAPY AND VENETOCLAX: CYCLE 1: Patients receive venetoclax orally (PO) once daily (QD) on days 1-21, vincristine intravenously (IV) over 15 minutes on days 7 and 17, cyclophosphamide IV twice daily (BID) over 3 hours on days 7-9, and dexamethasone IV over 30 minutes or PO QD on days 7-10 and 17-20. Patients may also receive rituximab IV over 4-6 hours on days 7 and 17 per physician discretion. CYCLES 2, 4, 6, and 8: Patients receive venetoclax PO QD on days 1-21, methotrexate IV over 24 hours on day 1, and cytarabine IV BID over 3 hours on days 2 and 3. Patients may also receive rituximab IV over 4-6 hours on days 1 and 8 per physician discretion. CYCLES 3, 5, and 7: Patients receive venetoclax PO QD on days 1-21, cyclophosphamide IV BID over 3 hours on days 1-3, vincristine IV over 15 minutes on days 1 and 11, and dexamethasone IV over 30 minutes or PO QD on days 1-4 and 11-14. Patients may also receive rituximab IV over 4-6 hours on days 1 and 11 per physician discretion. T-CELL ALL: After the first 4 cycles, patients receive nelarabine IV over 2 hours on days 1-5 and pegaspargase IV over 2 hours on day 5. Cycles repeat every 28 days for 2 cycles (after cycle 4 and 5) in the absence of disease progression or unacceptable toxicity. MAINTENANCE THERAPY: Patients may receive prednisone PO QD on days 1-5, vincristine IV over 15 minutes on day 1, and venetoclax, PO QD on days 1-21. Cycles repeat every 28 days for 2 years in the absence of disease progression or unacceptable toxicity. T-CELL ALL (MAINTENANCE THERAPY): After the first 5 cycles of maintenance therapy, patients who received nelarabine and pegaspargase will receive nelarabine IV QD over 2 hours on days 1-5 and pegaspargase IV over 2 hours on day 5 during maintenance cycles 6 and 7 instead of prednisone, vincristine, and venetoclax. After completion of study treatment, patients are followed up for 30 days and then every 3 months thereafter.

主要结局

次要结局

• Overall response rate (Phase II)(Up to 56 days (2 courses))
• Minimal residual disease (MRD) negativity(Up to 4 years)
• Duration of response (DOR)(Up to 4 years)
• Event-free survival (EFS)(From the first day of treatment until any failure (resistant disease, relapse, or death), assessed up to 4 years)
• Overall survival (OS)(From the first day of treatment to time of death from any cause, assessed up to 4 years)
• Incidence of adverse events(Up to 4 years)