A Phase I study of bizelesin (NSC 615291) in patients with advanced solid tumors

Purpose: To evaluate the toxicities, characterize the pharmacokinetics, and determine the maximum-tolerated dose of bizelesin administered once every 4 weeks. Patients and Methods: Patients with advanced solid tumors received escalating doses of bizelesin as an i.v. push every 4 weeks. Pharmacokinetic studies were performed with the first treatment cycle. Results: Nineteen eligible patients received a total of 54 courses of bizelesin at doses ranging from 0.1 to 1 μg/m². Dose-limiting toxicity of neutropenia was seen in 2 of 4 patients treated at the 1 μg/m² dose level. Nonhematological toxicity was generally mild with maximum toxicity being ≤ grade 2 per National Cancer Institute Common Toxicity Criteria. No objective responses were seen in the 19 eligible patients. An L1210 bioassay was used to determine bizelesin plasma levels. The terminal elimination half-life was 140 min at the recommended Phase II dose. The area under the concentration time curve increased in proportion to administered dose, and the clearance remained constant over the dose range studied. Correlation analysis demonstrated relationships between dose and area under the concentration with cycle 1 hematological parameters, including absolute neutrophil and leukocyte nadirs. Conclusion: Bizelesin administered every 4 weeks as an i.v. push is well tolerated with dose-limiting toxicity of neutropenia. The maximum-tolerated dose (and recommended Phase II dose) is 0.8 μg/m² administered once every 4 weeks.