This application requests continuing support for the Pharmacology and Experimental Therapeutics (PET, formerly Chemotherapy) Committee of the Cancer and Leukemia Group B (CALGB). The overall objectives of the PET Committee are to study the population pharmacokinetics and pharmacodynamics of new and established anti-cancer agents in a multi-institutional setting; to conduct phase I clinical trials of new anti-cancer agents or new drug combinations that can be employed in future phase II and III CALGB studies; to introduce new drugs and biological agents into the CALGB for phase II and III testing; to organize educational symposia for the Group on topics in cancer chemotherapy and pharmacology; to monitor toxicity from chemotherapy in ongoing Group protocols; to conduct protocols in disease areas for which the CALGB has expertise but no standing committees and; to initiate and conduct a program of drug resistance modulation in the CALGB. During the past grant period, the PET Committee has established a vigorous program in population pharmacology that is unique among the cooperative groups. Ongoing or completed studies have examined the pharmacokinetics and pharmacodynamics of a diverse group of drugs ranging from investigational agents such as amonafide to commonly used drugs such as doxorubicin, etoposide, 5-fluorouracil and cytarabine. During the coming grant period the Committee proposes to study individualized dosing of amonafide based on prospective acetylator phenotyping; pharmacologically guided dosing of etoposide; 5-FU pharmacodynamics and pharmacogenetics; idarubicin pharmacodynamics in patients with low grade lymphoma and taxol pharmacokinetics and pharmacodynamics in patients with impaired liver function and in newly diagnosed patients with stage Ill breast cancer. The Committee will also complete an ongoing phase I study of high dose doxorubicin + GM-CSF and ICRF-187; initiate a new phase I study of topotecan plus cis-platin; and conduct drug resistance modulation studies in patients with renal cell carcinoma and intermediate grade lymphoma. These studies will be conducted as companion protocols to CALGB treatment protocols or as phase I protocols conducted by the PET Committee. analytical laboratories at the University of Chicago, University of Maryland, University of Alabama, Duke University and McGill University will employ HPLC or other appropriate analytical techniques and biochemical analyses of human blood plasma or blood cells to achieve these goals. These studies may lead to more rational methods for dosing cancer chemotherapy resulting in an improved therapeutic index.
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