Clinical trials 101: information for basic and translational researchers.

Abstract

Abstract Abstract #ES-4 Rationale: In order to realize the potential benefits of basic science insights into breast cancer biology, findings must be translated into clinically useful drugs and biomarkers. Basic and translational scientists interested in seeing their biologic advances benefit breast cancer patients must understand and be active participants in the process of moving a laboratory observation or idea into practical, safe clinical application.
 Traditional: Traditional clinical drug development in cancer, including breast cancer, follows a path that involves a number of distinct but important steps: early dose-finding/safety testing to identify appropriate safe doses for further testing; intermediate studies to obtain evidence of potential efficacy; and finally, in a few select cases, comparative testing against appropriate controls. In breast cancer, it has been common to test new drugs first in the metastatic setting, moving to earlier stages of disease as evidence of efficacy accumulates. This process worked well for cytotoxic drugs, such as taxanes or anthracyclines widely used in breast cancer.
 Targeted Development: Drug development for treatment of breast cancer has, during the last decade, increasingly focused on targeted rather than broad spectrum cytotoxic agents. Anti-hormone and anti-Her-2/neu therapies are poster child agents that have been in wide clinical use for many years, but there is now a vast array of newer targeted agents in various stages of testing. There are unique features to these agents that may dictate different approaches to development and different study designs. For example, the agent may be cytostatic rather than cytotoxic, making measurement of tumor shrinkage virtually useless. Some agents may work best when the tumor volume is small, requiring testing in early rather than metastatic disease. Some tumors may not express or may not depend on the target (i.e. ER-negative) and therefore would not be expected to respond. Assays to reliably detect the target may not exist and often have to be developed simultaneously with the agent. As with traditional development, clinical testing progresses in a stepwise fashion, but may require innovative designs to address features unique to the agent.
 Biomarkers: As new targets have been identified, greater biologic insight and powerful genomic and proteomic technologies have unleased an avalanche of potential new biomarkers for diagnosis, prognosis, and prediction of therapeutic benefit. Aside from initial, often retrospective, proof-of-principle analyses and correlations with outcome, very few have undergone the kind of rigorous testing needed to demonstrate assay reliability and to validate clinical utility. As with development of new targeted therapies, moving new biomarkers from concept to routine clinical practice is a step-wise process, but may also have unique design requirements.
 Conclusion: Drug or biomarker development is often a slow, stepwise process, but clear understanding of the objectives of studies at each phase of development will hopefully improve study design, resulting in better decisions and more rapid translation of biologic advances into clinical benefit for breast cancer patients. Citation Information: Cancer Res 2009;69(2 Suppl):Abstract nr ES-4.