PHASE-I STUDY OF THE DUOCARMYCIN SEMISYNTHETIC DERIVATIVE KW-2189 GIVEN DAILY FOR 5 DAYS EVERY 6 WEEKS

The duocarmycins represent a new group of antitumor antibiotics produc ed by Streptomyces that bind to the minor groove of DNA. KW-2189 is a water-soluble semisynthetic derivative of duocarmycin B-2, with signif icant activity in murine and human tumor models. We conducted a Phase I trial of KW-2189 in patients who had solid tumors that were refracto ry to standard chemotherapy or for whom no more effective therapy exis ted. KW-2189 was administered as a rapid i.v. bolus daily for 5 days e very 6 weeks. Twenty-two patients were enrolled and received a total o f 31 cycles of KW-2189, Leukopenia, neutropenia, and thrombocytopenia were the dose-limiting toxicities, with nadirs occurring at medians of 36, 38, and 29 days, respectively, at the 0.04 mg/m(2)/day dose level . Nonhematological toxicities were mild, although one patient develope d grade 3 fatigue, Four patients had stable disease over two to four c ycles of treatment and shelved no cumulative toxicity. The mean t(1/2) , plasma clearance, and steady-state volume of distribution were 13.5 min, 1,287 ml/min/m(2), and 10,638 ml/m(2), respectively, Pharmacokine tics were similar on days 1 and 5, with no drug accumulation in plasma . The active metabolite DU-86 was not consistently found in patient pl asma. For Phase II trials, when the 5 days every 6 weeks schedule was used, 0.04 mg/m(2)/day KW-2189 appears to be the maximal tolerated dos e, especially for patients who have received prior chemotherapy, At th is dose level, the drug was well tolerated, and the toxicities were ac ceptable.