PHASE-I CLINICAL-STUDY OF DIDEMNIN-B - A NATIONAL-CANCER-INSTITUTE OFCANADA CLINICAL-TRIALS GROUP-STUDY

Didemnin B (NSC-325319), a new depsipeptide isolated from a Caribbean tunicate, has been evaluated in a clinical phase I study. The drug was administered in a schedule of a 4 weekly intravenous injection in a s ix-weeks cycle. Fifty-three patients received 71 evaluable cycles in a n escalated dose ranging from 0.4 mg/m(2)/week to 2.5 mg/m(2)/week. No hematological toxicity was demonstrated at any dose level. Without pr ophylactic antiemetics nausea and vomiting was dose limiting at 1.2 mg /m(2)/week. Due to the use of Cremophor EL as a solvent, hypersensitiv ity reactions occurred in 9 patients. These reactions occurred followi ng prior exposure to the drug and were commonly seen at the 3rd dose. They were not dose related but became more frequent at 1.5 mg/m(2)/wee k necessitating prophylactic treatment with H-1 and H-2 receptor block ing agents. Non-hematological toxicities included mild diarrhea, mucos itis, anorexia, headaches, and local phlebitis. The dose- limiting tox icity was generalized weakness which became severe and disabling in 3 of 6 patients treated at 2.5 mg/m(2)/week. No objective responses were documented in 39 patients with evaluable disease. The recommended dos e for phase II studies was 2.3 mg/m(2)/week x 4 in a 6-weeks cycle giv en with prophylactic antiemetics and H-1 and H-2 receptor blocking age nts.