Review of phase I clinical studies with topotecan.
Topotecan (Hycamtin; SmithKline Beecham Pharmaceuticals, Philadelphia, PA), a camptothecin analog, is a novel and specific inhibitor of the nuclear enzyme topoisomerase I. In preclinical studies, topotecan demonstrated significant in vitro activity in a variety of solid tumor explants derived from colorectal, breast, ovarian, renal cell, non-small cell lung cancer, and gastrointestinal sources. Notable activity was also demonstrated in vivo in a wide range of animal tumor models. A large number of phase I studies with topotecan have been conducted since 1992 in both adults and children with a broad range of refractory malignancies and as many as 14 different dosing schedules. Complete, partial, or minor responses were demonstrated in patients with recurrent or refractory neuroblastoma, non-small cell lung cancer, small cell lung cancer, ovarian cancer, breast cancer, colon cancer, esophageal cancer, renal cell carcinoma, and squamous cell carcinoma. The antitumor activity of topotecan in these phase I evaluations was associated more often with frequent or continuous dosing schedules compared with less frequent or short exposure schedules. Maximum tolerated doses were predominantly dependent on the dosing schedule used. Myelosuppression was the major dose-limiting toxicity across all schedules, and nonhematologic toxicities were generally mild. Data from phase I studies have provided valuable information about antitumor responses, maximum tolerated doses, and dose-limiting toxicities associated with different dosing schedules. Based on this information, there was substantial enthusiasm for further evaluating topotecan in a wide range of cancer patients in phase II studies.
Rowinsky
E K
EK
Institute for Drug Development, Cancer Therapy and Research Center, San Antonio, TX 78229, USA.
Verweij
J
J
D000328:Adult; D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000627:therapeutic use*; D002166:Camptothecin / Q000031:analogs & derivatives*; D002648:Child; D017321:Clinical Trials, Phase I as Topic; D004334:Drug Administration Schedule; D016179:Granulocyte Colony-Stimulating Factor / Q000627:therapeutic use; D006801:Humans; D059004:Topoisomerase I Inhibitors; D019772:Topotecan / Q000008:administration & dosage / Q000627:therapeutic use*
D000970:Antineoplastic Agents; D059004:Topoisomerase I Inhibitors; D016179:Granulocyte Colony-Stimulating Factor; D019772:Topotecan; D002166:Camptothecin