The overall objective of this proposal is to develop new therapeutic regimens for treatment of breast, ovarian, and non-small cell lung carcinomas, based on performance of rationally designed, phase II trials of topoisomerase I inhibitors as single agents, in combination regimens, and in dose-intensive regimens. The program brings together a strong, interactive team of biochemists, pharmacologists, preclinical and clinical investigators to design, implement, and conduct pharmacokinetic and pharmacodynamic guided phase II trials to optimize the use of topoisomerase I directed agents. Microenzymatic assays of topoisomerase I and Il activities and susceptibility to camptothecin analogs will be performed on CT- or bronchoscopic-guided biopsy specimens obtained from tumors of patients participating in these studies. Intensive pharmacology monitoring .will be performed. Pharmacokinetic and pharmacodynamic parameters-will serve as the basis for developing phase II trials involving topoisomerase I inhibitors and other selected agents including cisplatin and/or alkylating agents in non-small cell lung and ovarian cancer; adriamycin and/or alkylating agents in breast cancer. Dose intensification studies of the topoisomerase I inhibitors alone and in combination regimens will be performed using hematopoietic stem cell support. Topoisomerase I inhibitors to be studied in these protocols will include topotecan, CPT-11 and 9-aminocamptothecin. The identification, design, and prioritization of phase II studies will be based on results of biochemical analysis, preclinical models, and/or phase I trials conducted at the CWRU/Ireland Cancer Center and developed in collaboration with staff of the Cancer Therapy Evaluation and Development Program of the National Cancer Institute.
