The duocarmycins represent a new group of antitumor antibiotics produced by Streptomyces that bind to the minor groove of DNA. KW-2189 is a water- soluble semisynthetic derivative of duocarmycin B2, with significant activity in murine and human tumor models. We conducted a Phase I trial of KW-2189 in patients who had solid tumors that were refractory to standard chemotherapy or for whom no more effective therapy existed. KW-2189 was administered as a rapid i.v. bolus daily for 5 days every 6 weeks. Twenty- two patients were enrolled and received a total of 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/m2/day dose level. Nonhematological toxicities were mild, although one patient developed grade 3 fatigue. Four patients had stable disease over two to four cycles of treatment and showed no cumulative toxicity. The mean t(1/2), plasma clearance, and steady-state volume of distribution were 13.5 min, 1,287 ml/min/m2, and 10,638 ml/m2, respectively. Pharmacokinetics were similar on days 1 and 5, with no drug accumulation in plasma. The active metabolite DU-86 was not consistently found in patient plasma. For Phase II trials, when the 5 days every 6 weeks schedule was used, 0.04 mg/m2/day KW-2189 appears to be the maximal tolerated dose, especially for patients who have received prior chemotherapy. At this dose level, the drug was well tolerated, and the toxicities were acceptable.
|Original language||English (US)|
|Number of pages||7|
|Journal||Clinical Cancer Research|
|State||Published - Sep 1 1998|
ASJC Scopus subject areas
- Cancer Research