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Early clinical trials of chemopreventive and biologic agents: Designs, populations, and endpoints
1Division of Clinical Trials Design and Analysis, Office of Therapeutics, Center for Biologics Evaluation and Research, US Food and Drug Administration, Rockville, Maryland 20852-1445, USA. keegan@cber.fda.gov
Abstract:
The optimal design for initial clinical trials of chemopreventive agents for cancer has not been determined. A single design is unlikely to be the model for chemoprevention of cancer, even for prevention of a single subtype of cancer, because of the heterogeneity of drugs under investigation and the variety of biologic effects being targeted. Factors that are important in designing initial clinical trials include the proposed mechanisms of drug action, the ability and types of assays available to detect that activity or pharmacodynamic effect, and the extent of prior clinical experience. In this article, we present a discussion of the factors to be considered in initial activity studies, followed by a specific example of early clinical assessment of a noncytotoxic agent (R-flurbiprofen, E-7869) as a potential chemopreventive agent for prostate cancer.
Insights
Designing cancer chemoprevention trials requires careful consideration of drug mechanisms and available assays. A flexible approach is needed due to diverse agents and targets, as illustrated by R-flurbiprofen for prostate cancer.
Area of Science:
- Oncology
- Clinical Pharmacology
- Drug Development
Background:
- Optimal design for early-phase cancer chemoprevention trials remains undefined.
- Heterogeneity of chemopreventive agents and their targeted biological effects necessitates tailored trial designs.
- Key design factors include proposed mechanisms of action, assay availability for pharmacodynamic effects, and prior clinical experience.
Purpose of the Study:
- To discuss critical factors for designing initial clinical trials of cancer chemopreventive agents.
- To present a case study of early clinical assessment for a specific chemopreventive agent.
Main Methods:
- Review of factors influencing the design of early clinical activity studies for chemopreventive agents.
- Detailed examination of the early clinical assessment of R-flurbiprofen (E-7869), a non-cytotoxic agent, for prostate cancer chemoprevention.
Main Results:
- Identified key considerations for designing chemoprevention trials, including drug mechanism, pharmacodynamic assays, and clinical experience.
- Demonstrated the application of these considerations through the assessment of R-flurbiprofen for prostate cancer.
Conclusions:
- A one-size-fits-all trial design is unsuitable for cancer chemoprevention due to drug and target variability.
- A comprehensive approach considering drug properties and assay capabilities is essential for effective early-phase chemoprevention trials.