Phase I study of weekly maytansine given by iv bolus or 24 hour infusion

Maytansine was administered weekly by iv bolus or by 24-hour infusion to 71 patients with leukemia, lymphoma, or carcinoma. The most prominent toxicity was neurologic, consisting of a variable combination of a peripheral, predominantly sensory polyneuropathy and a generalized psychomotor depression of apparently central origin. Neurologic toxicity occurred with unacceptable frequency and severity when a cumulative dose of 6 mg/m ² was exceeded at weekly doses ranging from 0.4 to 1.3 mg/m ² by iv bolus. Even one or two doses at 1.4-1.6 mg/m ²/week produced severe neurologic toxicity. Nerve conduction velocities and electromyography were not clearly correlated with clinical neuropathy. Gastrointestinal toxicity, manifested by nausea, vomiting, diarrhea, and abdominal cramps, was frequent at dose levels of ≥ 1.1 mg/m ²/week. A few patients experienced severe hepatotoxic effects and myelosuppression, especially after the 24-hour infusion schedule. Paravenous infiltration produced local cellulititis or phlebitis. Skin rash and fever were uncommon. One patient each with carcinoma of the lung, thymoma, and diffuse histiocytic lymphoma responsed with >50% regression of tumor. The recommended dose for phase II trials is 1 mg/m ²/week by iv bolus for a total of six courses. Careful neurologic assessment is mandatory above this total dose level. Because of the lack of significant myelosuppression from this drug, further studies using maytansine, particularly in combination with other drugs in induction programs, are warranted.