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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

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

slide2

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.

slide3

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.

slide4

Preclinical Guidelines

Selection

Stage I: Toxicity & Maximum Tolerated Dose

Stage II: Radiation Protection/Mitigation Activity

Stage III: Drug Evaluation, Production & Formulation for Clinical Trials.

slide5

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.

slide6

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

slide7

Stage II: Radiation Protection/Mitigation Activity

Protection of Normal Tissues

Protection of Tumors

Biological Mechanism of Action

slide8

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

slide9

Stage II: Radiation Protection/Mitigation Activity

Biological Mechanism (Normal Tissue Protection)

No

Yes

More in vitro/in vivo testing

Proceed with continued mechanistic studies

slide10

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
slide11

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.
slide12

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?
slide13

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.