A Phase I Dose-Escalation Study of Clofarabine in Patients with Relapsed or Refractory Low-Grade or Intermediate-Grade B-Cell or T-Cell Lymphoma.

LESSONS LEARNED: Clofarabine can be active in relapsed and refractory lymphoid malignancies on a weekly dosing schedule.Responses were seen in patients with T-cell lymphomas, including cutaneous T-cell lymphoma, but not in patients with aggressive B-cell lymphomas.

BACKGROUND: Clofarabine is a second-generation purine nucleoside analog currently approved for the treatment of pediatric relapsed or refractory acute lymphoblastic leukemia. In adults, clofarabine has been investigated in several phase I and II trials as a single agent and in combination for relapsed or refractory acute leukemia. These studies have shown that clofarabine has activity and an acceptable safety profile in patients with hematological malignancies. In this phase I dose escalation trial, clofarabine was evaluated in patients with relapsed or refractory, low-grade or intermediate-grade, B-cell or T-cell lymphoma.

METHODS: The starting dose of 10 mg/m2 per week was administered intravenously (IV) for 3 consecutive weeks every 28 days, and doses were escalated in cohorts of three. The study objectives were to determine the maximum tolerated dose (MTD), characterize and quantify the toxicity profile, and determine the overall response rate of clofarabine administered once a week for 3 weeks and repeated every 4 weeks. Eligible patients were over the age of 18, had a histologically confirmed low-grade or intermediate-grade B-cell or T-cell lymphoma, and must have previously been treated with one standard chemotherapy regimen, excluding single-agent rituximab. The primary objectives included in statistical analyses were MTD, toxicity, and overall response rate (ORR). Four patients were enrolled in cohort 1 (clofarabine 10 mg/m2 ), four in cohort 2 (clofarabine 15 mg/m2 ), three in cohort 3 (clofarabine 20 mg/m2 ), two in cohort 4 (clofarabine 30 mg/m2 ), and one in cohort 5 (clofarabine 40 mg/m2 ) (Table 2).

RESULTS: MTD was not reached in the study. The most common toxicity observed was myelosuppression. A total of four (29%) patients experienced grade 3 leukopenia, with three (21%) patients experiencing grade 4 neutropenia. The myelosuppression was not considered to be a dose-limiting toxicity, as it resolved within 7 days.Fourteen patients were enrolled: 10 patients with T-cell non-Hodgkin lymphoma (NHL) and 4 patients with B-cell NHL (see Table 1). All 14 patients received at least one dose of clofarabine and were evaluable for response. One patient with cutaneous T-cell lymphoma (CTCL) had a partial response; five (36%) had stable disease, and eight patients (57%) had no response. The one patient with a response had stage III erythroderma and was treated in the 10 mg/m2 cohort; a nodal complete response by positron emission tomography scan was observed with a partial response of the skin.

CONCLUSION: In this study, weekly administration of clofarabine was demonstrated to be safe and associated with minimal hematologic toxicity at doses ranging from 10-40 mg/m2 . In prior studies when dosed daily for 5 consecutive days, the MTD was shown to be 4 mg/m2 . Weekly dosing within this dose range did not result in dose modifications, and the MTD was not reached. Clinical efficacy was observed in one patient with CTCL who was treated in the lowest-dose cohort.