National Cancer Institute, Research Contracts Branch, PCCS, 6120 Executive Blvd, EPS/Room 635, Bethesda, MD 20892-7226

A -- PRECLINICAL TOXICOLOGY OF CHEMOPREVENTIVE AGENTS SOL N01-CN-65006-05 DUE 020896 POC Gary Topper, Contract Specialist, (301)496-8603; Victor S. Buyny, Contracting Officer, (301)496-8603. The National Cancer Institute, Division of Cancer Prevention and Control (DCPC), Chemoprevention Branch, wishes to award Master Agreement contracts for the above study. The required services will be defined by Master Agreement Orders issued during the period of performance. A primary function of the chemoprevention program is the identification and evaluation of agents for possible utilization in clinical trials in humans. Candidate agents, whether from natural sources or synthesized, have been evaluated for anti-cancer efficacy in various screening tests. However, before a decision can be made as to their suitability for the Phase I clinical trials in humans, they must be evaluated for toxicity in animals. The basic objectives of this project will be to evaluate the acute, subacute/subchronic and chronic toxicity of designated agents. These studies will be performed in animals (rodents and dogs) and will include conventional short-term studies, life-time studies in rodents and dogs, and multi-generation teratogenecity studies. The agents would be given primarily by the oral route. A summary of the tasks required in the project are as follows: TASK I - Perform acute toxicity, pilot dose range finding, and 13-week subchronic toxicity in rats and dogs by the oral route. Include, where appropriate, complete gross necropsies, histopathological examinations, and clinical laboratory studies. TASK II - Develop a protocol for a pharmacokinetic profile for each investigational agent. The protocol and profile may build upon published data and data provided by the manufacturer of the agent or NCI staff. Additional studies necessary to complete the pharmacokinetic profiles for the rat and dog shall be performed by the Contractor. Pharmacokinetic studies will provide parameters of absorption, blood concentration-time profiles, distribution, and excretion. Data on tissue concentration of the test agent, determined as part of the toxicology testing shall contribute to the pharmacokinetic profile. Information on major metabolites shall be included in order to provide as compete a picture as possible of the overall distribution and fate of the test agent. Appropriate modeling shall be applied to determine probable pattern of distribuiton and compartmentalization. The first studies performed shall be designed to provide absorption and half-life information necessary to plan the 90-day rat and dog toxicology studies. TASK III - Develop and perform teratogenicity studies on chemopreventive agents that have the prospect of being administered to women of childbearing potential. These will be the standard segment I, II, and III studies as described in the Guildelines for Reproduction Studies for Safety Evaluation of Drugs for Human Use, available from the Contract Specialist, upon request. For efficiency, the male rats from the 3-month oral study may be used to initiate the male-related reproductive toxicity studies. TASK IV - Perform chronic one-year oral toxicity in rats and dogs. Clinical laboratory studies and gross and microscopic necropsy findings are to be included. Suitable facilities and equipment appropriate to accomplish tasks should be available. Animal-holding facilities for dogs must be provided with adequate environmental containment. Offerors are to comply with the NIH Guide for Care and Use of Laboratory Animals. Facility must have design and maintenance capability to meet chemical and biological control; must comply with NCI carcinogens and handling standards; must comply with federal and state occupational health and environmental laws and regulations. On-site data handling (computer), chemical, and pathological facilities and equipment should be available. Must comply with the requirements set forth in the FDA Good Laboratory Practice Regulations. The purpose of this acquisition is to qualify contractors to a pool of Master Agreement Holders. The Standard Industrial Code for this procurement is 8731. The period of performance of the Master Agreement pool will be 18 months. The Master Agreement Announcement will be available on approximately December 11, 1995, written requests for MAA/RFP N01-CN-65006-05 must be sent to Mr. Gary Topper, National Cancer Institute, Research Contracts Branch, Executive Plaza South, Room 635, 6120 Executive Boulevard, MSC 7226, Bethesda, MD 20892-7226 (0325)

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