FK973 is a novel, substituted dihydrobenzoxazine structurally similar to mitomycin. FK973 lacks cross-resistance with mitomycin, doxorubicin, and vincristine in murine tumor models. A phase I study of FK973 was initiated using a 30-minute infusion repeated every 4 weeks. Of 17 patients enrolled on the study, a minimum of three patients were entered at each dose level: 7, 14, 21, 30, and 45 mg/m2. The dose-limiting toxicity was a vascular leak syndrome (VLS) characterized by pericardial and pleural effusions, ascites, and subcutaneous edema. These conditions were observed in two patients treated with a dose of 30 mg/m2 and in four who received 45 mg/m2. VLS was observed 2 weeks after the third dose of 30 mg/m2 and one week after the second dose of 45 mg/m2. Of nine patients treated with a cumulative dose greater than 60 mg/m2, five experienced this toxic reaction. Reversible drug-related pneumonitis was noted in one patient after the third course of 30 mg/m2. Moderate nausea and vomiting were initially observed at a dose of 14 mg/m2 and alopecia at 30 mg/m2. Grade 3-4 granulocytopenia was observed in two patients treated with 45 mg/m2. Extensive myocardial degeneration was observed at autopsy in a patient who had received three courses of 30 mg/m2. One patient with metastatic colon carcinoma and another with metastatic pancreatic carcinoma experienced partial clinical responses. Although the drug's clinical activity appears promising, additional investigation is needed into the mechanism of toxicity prior to further clinical development.