PRECLINICAL TOXICOLOGY OF CHEMOPREVENTIVE AGENTS

NIH GUIDE, Volume 23, Number 15, April 15, 1994



RFP AVAILABLE:  NCI-CN-45001-05



P.T.





Keywords:



National Cancer Institute



The National Cancer Institute (NCI), 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.  It is estimated that four to five Master Agreement

Orders will be issued per year pursuant to the Master Agreement

contracts.  This solicitation is the annual announcement to expand

the current pool of MA Holders qualified to perform this type of

work.  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 Phases 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

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 agents.  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 to 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 complete a picture as possible of the

overall distribution and fate of the test agent. Appropriate modeling

shall be applied to determine probable pattern of distribution and

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 Guidelines 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

requirements set forth in the FDA Good Laboratory Practice

Regulations.  The period of performance of the Master Agreement pool

will be approximately three years.  The Master Agreement

Announcement/Request for Proposal (MAA/RFP) will be available on

approximately April 29, 1994.  The due date for proposals is

approximately June 30, 1994.



INQUIRIES



Copies of the MAA/RFP NCI-CN-45001-05 may be obtained by sending a

written request to:



Mr. Gary P. Topper

Prevention and Control Contracts Section

National Cancer Institute

Executive Plaza South, Suite 635

Bethesda, MD  20892

Telephone:  (301) 496-8603

No collect calls will be accepted



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