A PHASE-I TRIAL AND PHARMACOKINETIC EVALUATION OF CI-980 IN PATIENTS WITH ADVANCED SOLID TUMORS

CI-980 is a synthetic mitotic inhibitor that binds to the colchicine b inding site of tubulin. It demonstrates broad activity against human a nd murine tumor models and shows no cross resistance with tumor models whose mechanism of resistance is mediated by P-glycoprotein (MDR-1). A phase I study was completed in 25 patients with solid tumors using a 24-hour infusion schedule, with courses repeated every 3 weeks. Eight dose levels were tested between 1.2 and 15.6 mg/m(2). The maximum tol erated dose was 14.4 mg/m(2). Neutropenia was dose-related but not dos e-limiting; thrombocytopenia was infrequent. CNS toxicities were dose- limiting and consisted of dizziness, headache, loss of coordination, l oss of consciousness, nervousness, and other symptoms. These events oc curred near the end of the infusion and were reversible, usually withi n 24 hours. One patient who was to be treated at dose level 8 (intende d dose was 19.2 mg/m(2); actual dose was 15.6 mg/m(2)) became encephal opathic prior to completion of the infusion. Other adverse events incl uded gastrointestinal toxicities (nausea, vomiting, anorexia, constipa tion, stomatitis, dyspepsia, bleeding, cheilitis), IV site erythema, f ever, and fatigue. A partial response was observed in one patient with colon cancer and reductions in CA-125 levels were observed in 2 patie nts with ovarian cancer. Pharmacokinetics were linear and dose-proport ional. Results indicate high systemic clearance and wide tissue distri bution. Mean pharmacokinetic parameter values: T-1/2 = 5.52 hours, pla sma clearance 1163 mL/min/m(2), and Vd(ss) 376 L/m(2).