Phase I/II clinical trial of didemnin B in non-small-cell lung cancer: neuromuscular toxicity is dose-limiting.
Didemnin B (NSC 325,319), a cyclic depsipeptide isolated from a Caribbean tunicate, exhibits potent preclinical antitumor activity. In previous phase I studies, 3.47 mg/m2 was the maximally tolerated dose, with nausea and vomiting being the dose-limiting toxicity. The drug was given in a single bolus infusion over 30 min every 28 days. In the current study, 30 patients presenting with previously treated non-small-cell lung cancer (NSCLC) received 46 courses of the drug at doses ranging from 3.47 to 9.1 mg/m2. Neuromuscular toxicity was dose-limiting. Nausea and vomiting appeared to be correlated with dose levels and were ameliorated by a combination of antiemetics including dexamethasone. Other side effects included a mild rise in hepatic enzymes and an allergic reaction that was preventable by the addition of corticosteroids to the premedication regimen. In all, 2 minor responses were seen among 24 evaluable patients. Because neuromuscular toxicity is dose-limiting, we recommend that routine measurements of creatine kinase and aldolase, a careful neurologic evaluation, and electromyography and muscle biopsy (if indicated) be incorporated into phase II trials. The recommended dose for phase II studies using a single bolus schedule is 6.3 mg/m2, following the premedication of patients with antiemetics.
Shin
D M
DM
Department of Medical Oncology, University of Texas M.D. Anderson Cancer Center, Houston 77030.
Holoye
P Y
PY
Murphy
W K
WK
Forman
A
A
Papasozomenos
S C
SC
Hong
W K
WK
Raber
M
M
D000328:Adult; D000368:Aged; D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000009:adverse effects*; D002289:Carcinoma, Non-Small-Cell Lung / Q000188:drug therapy*; D047630:Depsipeptides; D004334:Drug Administration Schedule; D004341:Drug Evaluation; D005260:Female; D006801:Humans; D007262:Infusions, Intravenous; D008175:Lung Neoplasms / Q000188:drug therapy*; D008297:Male; D008875:Middle Aged; D009132:Muscles / Q000187:drug effects*; D009469:Neuromuscular Junction / Q000187:drug effects; D010456:Peptides, Cyclic / Q000008:administration & dosage / Q000009:adverse effects*
D000970:Antineoplastic Agents; D047630:Depsipeptides; D010456:Peptides, Cyclic; C030051:didemnins