Phase I study of the duocarmycin semisynthetic derivative KW-2189 given daily for five days every six weeks

Steven R. Alberts, Charles Erlichman, Joel M. Reid, Jeff A. Sloan, Matthew M. Ames, Ronald L. Richardson, Richard M. Goldberg

Research output: Contribution to journalArticle

22 Scopus citations

Abstract

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 languageEnglish (US)
Pages (from-to)2111-2117
Number of pages7
JournalClinical Cancer Research
Volume4
Issue number9
StatePublished - Sep 1 1998

    Fingerprint

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

Cite this