Clinical trials of misonidazole in the United States.

This paper presents a review of the progressive clinical trials of the hypoxic cell radiosensitizer, misonidazole, in the United States. Presentation is made of all of the schemata of the recently completed and currently active Radiation Therapy Oncology Group (RTOG) phase II and phase III studies. Detailed information is presented on the clinical toxicity of the phase I and II trials, specifically regarding neurotoxicity. With limitations in drug total dose, a variety of dose schedules have proven to be tolerable, with a moderate incidence of nausea and vomiting and mild peripheral neuropathy, and a low incidence of more severe peripheral neuropathy or central neuropathy. No other organ toxicity has been seen, specifically no liver, renal, or bone marrow toxicities. The clinical pharmacologic monitoring of misonidazole blood levels has been satisfactory with good correlation between the group-wide (phase II) UV values and the HPLC values from the phase I study. The patient accrual of the trials has been rapidly increasing and an early analysis suggests efficacy which is at least comparable to previous radiation experience. A series of the five phase III trials are currently underway in the RTOG and the results of these are pending. An additional malignant glioma trial in the Brain Tumor Study Group is described.