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Preclinical Guidelines: Development of Radioprotective / Mitigative Agents

Preclinical Guidelines: Development of Radioprotective / Mitigative Agents. Julie L. Ryan, PhD, MPH. Departments of Dermatology & Radiation Oncology University of Rochester Medical Center Rochester, New York, USA. Radioprotector / Mitigator Development Program. Primary Objective:.

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Preclinical Guidelines: Development of Radioprotective / Mitigative Agents

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  1. Preclinical Guidelines: Development of Radioprotective/Mitigative Agents Julie L. Ryan, PhD, MPH Departments of Dermatology & Radiation Oncology University of Rochester Medical Center Rochester, New York, USA

  2. Radioprotector/Mitigator Development Program Primary Objective: Development of agents which selectively protect normal tissues (NOT tumors) against radiation. Secondary Objective: Development of these agents will improve patient quality of life through the prevention and/or reduction of radiation treatment-related toxicities.

  3. Radioprotector/Mitigator Development Program Radiation Protectors:Agents given before radiation exposure to prevent or reduce damage to normal tissues. Radiation Mitigators:Agents given after radiation exposure but before symptoms occur with the intention of preventing or reducing damage to normal tissues. Radiation Treatments:Agents given after radiation exposure and after symptoms occur with the intention of reducing damage to normal tissues. Regardless of time of administration Program will develop agents that most effectively protect normal tissues, NOT tumors, against radiation exposure.

  4. Preclinical Guidelines Selection Stage I: Toxicity & Maximum Tolerated Dose Stage II: Radiation Protection/Mitigation Activity Stage III: Drug Evaluation, Production & Formulation for Clinical Trials.

  5. Selection of Candidate Agents (NIAID’s CMCR, drug companies, CTEP, independent labs, etc) Candidate Agent MUST satisfy one or more of the following criteria: General protection /mitigation/rescue of normal tissue from radiation damage. Protect ion/mitigation/rescue of specific normal tissue from radiation damage. Does NOT protect tumors from radiation.

  6. Stage I: Toxicity & Maximum Tolerated Dose Maximum Tolerated Dose (MTD) Single Dose Multiple Repeated Dose MTD Determined Toxicities Reviewed Pharmacokinetics/Levels in Plasma No Toxicities Acceptable Toxicities Unacceptable toxicities NFT

  7. Stage II: Radiation Protection/Mitigation Activity Protection of Normal Tissues Protection of Tumors Biological Mechanism of Action

  8. Stage II: Radiation Protection/Mitigation Activity Normal Tissue Protection Tumor Protection In vitro (clonogenic) In vivo (xenograft) Decision YES for at least one organ; Bone Marrow Skin Gut Lung CNS/Brain N Y Y N N N Y Y GO GO NFT NFT

  9. Stage II: Radiation Protection/Mitigation Activity Biological Mechanism (Normal Tissue Protection) No Yes More in vitro/in vivo testing Proceed with continued mechanistic studies

  10. Stage III: Drug Evaluation, Production & Formulation for Clinical Trials • Must know the following: • Preliminary toxicity profile (MTD or NOEAL) • Degree, duration, and scope of protection of normal tissues • Biological activity & mechanism (normal tissue protection) • Bioavailability via intended route of administration • Duration & degree of exclusion of drug from tumor • Concentration ratios: plasma/normal tissue/tumor • Toxicity in non-tumor-bearing rodents • Suitable dose formulation (pharmacological data) • Feasibility for large scale production

  11. Stage III: Drug Evaluation, Production & Formulation for Clinical Trials OPTIONAL: Combination Treatment Evaluation: • Test for multi-organ protection using combination of promising candidate agents. • Combination treatments evaluated for toxicities & lack of protection of normal tissue. • Potential Issue: Agent may protect one type of normal tissue from radiation damage but could sensitize another type of normal tissue.

  12. Discussion What are the minimal, acceptable and preferred procedures & guidelines? • 50% reduction in radiation toxicity for specified organ (i.e., normal tissue). • Must use clonogenic assays for survival  MTT assays are unacceptable (NCI-60 tumor panel not required). • Clonogenic assays performed on 2 relevant tumor cell lines  Acceptable. • Biological mechanism of agent must be known before clinical study OR mechanism can be researched simultaneously with clinical trial?

  13. Discussion FDA Animal Rule: Compounds without clinical experience will follow FDA animal rule (one rodent species & one non-rodent specie) for toxicological and pharmacological testing?? • Funding options: • Use clinical samples from pre-existing clinical trial. • CCOP clinical trials and supplements.

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