Phase I/II Study of Clofarabine Plus Cyclophosphamide in Adults with Relapsed and Refractory Acute Lymphoblastic Leukemia (ALL).

Clofarabine (CLO) is a nucleoside analog with activity in pediatric ALL salvage where it has received FDA approval. Less experience with CLO exists in adult ALL. As CLO inhibits DNA repair following exposure to DNA damaging agents, we designed a phase I/II study of the combination of CLO with cyclophosphamide (CY) for therapy of adult patients (pts) with primary refractory or relapsed ALL. Pts with NYHA class ≥ 3 and a cardiac ejection fraction < 45% were excluded. The continual reassessment method (CRM) was applied to determine MTD from 4 dose levels. The starting dose level was CLO 40 mg/m² i.v. daily x 3d and CY 200 mg/m² i.v. q12h x 3d. For cohort 2, the dose of CY was increased to 300 mg/m². Cohorts 3 and 4 maintained these doses with the treatment duration extended to 4 and 5 days, respectively. Additional samples for clinical pharmacology were obtained from consenting pts prior to and following CY on d1 and d2 and prior to CLO on d2.Thirteen pts have been enrolled. Median age was 34 yrs (range 21–72 yrs). Eight pts had pre-B ALL, 2 pts T ALL/LL, 1 pt mature B ALL, and 2 pts biphenotypic acute leukemias. Karyotype was abnormal in 9 pts (no Ph). Median number of prior regimens was 2 (1–6). Two (15%) pts were primary refractory. Median remission duration to initial induction was 11 mos (0–29.8 mos). Three patients were treated in cohort 1 and 10 in cohort 2. Four pts in cohort 2 experienced DLTs (≥ grade 3): elevation of creatinine/renal failure (1), diarrhea (1), transaminase elevations (2), and hyperbilirubinemia (2). Twelve patients were evaluable for response. One pt (70 yrs, prim. refr. pre-B ALL, complex karyotype) of cohort 1 achieved CR after 2 courses, which lasted for 10.3 months. Four pts died on study from infectious complications (days 2, 15, 34, and 41, respectively). Although no MTD has been defined yet and accrual continues in cohort 2, it appears unlikely that the MTD will exceed the dose levels of cohort 2. More information on efficacy will be obtained in the phase II extension part of the study.