PHASE-I TRIAL OF DACARBAZINE WITH CYCLOPHOSPHAMIDE, CARMUSTINE, ETOPOSIDE, AND AUTOLOGOUS STEM-CELL TRANSPLANTATION IN PATIENTS WITH LYMPHOMA AND MULTIPLE-MYELOMA

Purpose: We investigated the feasibility of escalating doses of dacarbazine (DTIC) in combination with high-dose cyclophosphamide, carmustine, and etoposide (CBV) given with autologous stem-cell transplantation in 33 patients with relapsed or refractory lymphoma or multiple myeloma. Patients and Methods: Eligible patients were treated in this phase I study with cyclophosphamide (7.2 g/m(2)), carmustine (BCNU) (600 mg/m(2)), etoposide (2.4 g/m(2)), and escalating doses of DTIC (3,000 to 6,591 mg/m(2)) administered either as a 2- (in 23 patients) or a 6- (in 10 patients) hour infusion to determine the maximum-tolerated dose (MTD) of DTIC and the toxicity profile of this combination. Results: The MTD of DTIC infused over 2 hours and given with the CBV regimen was 3,900 mg/m(2), with the dose-limiting toxicity being hypotension. Seven patients experienced transient acute hypocalcemia in association with the DTIC infusion. Prolonging the DTIC infusion to 6 hours or administration of supplemental calcium did not allow further dose escalation of DTIC to occur. Other non-hematologic toxicities observed with this regimen have been reported with CBV alone. Of 25 patients assessable for tumor response at first evaluation posttransplant, 13 (52%) were in complete remission (CR), four (16%) were in partial remission (PR), five (20%) had stable disease (SD), and three (12%) had progressive disease (PROG). Of 31 patients assessable for relapse-free survival, 22 are alive with 13 in CR, one in PR, two with SD, and six with FROG at a median follow-up duration of 313 days (range, 35 to 749+). Treatment-related mortality occurred in six patients (18%). Conclusion: The feasibility of combining DTIC in high doses with the CBV regimen has been demonstrated. Dose-limiting hypotension is transient and reversible when DTIC is administered at 3,900 mg/m(2) with CBV. Future trials to evaluate the effect of the addition of DTIC to the CBV regimen on response rate and relapse-free survival are encouraged. (C) 1994 by American Society of Clinical Oncology.