Phase I and pharmacologic study of BMS-181174 given as a 6 h infusion every 4 weeks to patients with advanced solid tumors

BMS-181174, a new mitomycin C (MMC) analog, showed more activity than the p arent compound in tumor xenografts. In a phase I study with a 5-30 min slow bolus administration, hematologic and vascular toxicity were observed as m ajor side effects. A prolonged infusion was suggested to circumvent the vas cular toxicity. In this phase I study BMS-181174 was administered as a 6 h infusion every 4 weeks; the doses studied were 3.2, 6.4, 11.5, 19.0, 32.0, 50.0, 75.0 and 100 mg/m(2). Twenty-eight patients were enrolled in the stud y, the majority with colorectal cancer, Hematologic side effects consisted of thrombocytopenia, and mild leuko- and granulocytopenia. The most distres sing non-hematologic side effect was vascular toxicity consisting of phlebo sclerosis and phlebitis, becoming dose limiting at 100 mg/m(2). One patient developed a hemolytic uremic syndrome at a cumulative dose of 350 mg/m(2). Pharmacokinetic data are available for 24 patients. The AUC ranged from 3. 35 to 41.49 (mu g.h/ml) and was highly correlated with the dose administere d (r=0.83). The kinetics appeared to be linear. One patient with metastatic colon cancer had a partial response of liver metastases. BMS-181174 is a M MC analog with a toxicity profile comparable to that of the parent compound . As doses above 50 mg/m(2) are complicated by vascular toxicity precluding multiple administrations, further exploration of BMS-181174 will not be pe rformed. [(C) 1999 Lippincott Williams & Wilkins.].