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Chemotherapy Combinations

Leukemia Insights - Spring 2010

Phase I-II study of clofarabine plus cyclophosphamide

Clofarabine is a second-generation nucleoside analog that has been synthesized as a hybrid molecule to combine the most favorable pharmacokinetic properties of fludarabine and cladribine while avoiding some of their disadvantages. Clofarabine has been extensively studied in adult and pediatric acute leukemias and received FDA approval as salvage therapy for children with ALL who have failed at least 2 prior regimens. Preceding phase II studies in relapsed/refractory childhood ALL achieved a 31% overall response rate, including a 12% CR rate.

Since clofarabine inhibits DNA repair following exposure to DNA damaging agents, we developed a regimen combining clofarabine with cyclophosphamide in a phase I-II clinical trial. The phase I portion focused on increasing both the dose and duration of therapy (number of days) of both agents. The MTD for this combination was determined to be clofarabine 40 mg/m2 IV daily x 3 days and cyclophosphamide 200 mg/m2 IV every 12 hours x 3 days [Faderl, J Clin Oncol 2009 27:Abstract 7020]. Twenty-eight heavily pretreated patients (including 7 who were primary refractory) were evaluable for response with 3 CRs and 1 marrow CR (ORR 14%). The phase II portion of the study continues accrual in better prognostic subsets.

Phase II study of MOAD (methotrexate, vincristine, pegylated asparaginase, dexamethasone) with or without rituximab

In our prior study of MOAP (similar regimen but using prednisone instead of dexamethasone), the CR rate in a heavily pretreated population was 22% [Aguayo A, Cancer 1999 86:1203]. The methotrexate (MTX) was dosed weekly and the dose of pegylated asparaginase was “capped” owing to vial size. The regimen was modified as follows: (1) MTX frequency was changed to every other week with higher dose per administration to avoid potential antagonism of pegylated asparaginase (owing to its relatively long half-life), (2) prednisone was replaced with the more potent corticosteroid dexamethasone, (3) pegylated asparaginase was administered at full doses, and (4) standard dose rituximab was incorporated if CD20 expression was at least 20%. Accrual is ongoing.

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