COMBINATION PHASE I II STUDY OF IRINOTECAN HYDROCHLORIDE (CPT-11) ANDCARBOPLATIN IN RELAPSED OR REFRACTORY NON-HODGKINS-LYMPHOMA/

Irinotecan hydrochloride (CPT-11) is a new derivative of camptothecin which inhibits topoisomerase I. Phase II studies have demonstrated tha t CPT-11 is active against a broad spectrum of neoplasms including int ractable non-Hodgkin's lymphoma. An early phase II study in lymphoma s uggested that a schedule of daily infusions of 40 mg/m(2)/day for thre e or five consecutive days is more effective than a single infusion of 200 mg/m(2) every three to four weeks. Carboplatin is also an active agent against lymphoma, and preclinical studies have shown that CPT-11 and its active metabolite have a synergistic effect with platinum com pounds. To evaluate the maximal tolerated dose (MTD) and the therapeut ic efficacy of CPT-11 in combination with carboplatin in relapsed or r efractory non-Hodgkin's lymphoma, we conducted a combination phase I/I I study. The starting dose of CPT-11 was 20 mg/m(2)/day (days 1 throug h 3 and 8 through 10), and dose escalations of 5 mg/m(2)/day increment s were planned, with a fixed dose of carboplatin (300 mg/m(2), day 1). Six of the eight patients receiving both agents at the starting dose level developed critical toxicities such as grade 4 hematologic (neutr openia 6/8, thrombocytopenia 1/8) and grade 3 non-hematologic toxiciti es (diarrhea 2/8, transaminase elevation 1/8). Further dose escalation of CPT-11 was halted, and the starting doses were judged to be the MT Ds. The response rate (25%, 2/8) to the combination of the MTDs was no t superior to that of CPT-11 alone in a previous phase II study (38%, 26/69), and the MTD of CPT-11 in combination with carboplatin was less than half the single-agent dose. We conclude that carboplatin is not recommendable for combination with CPT-11 in lymphoma patients. Other suitable agents for such a combination should be sought.