Question ID: WS-23
Submitted by: Pawel Kalinski
February 2, 2011
Background: Accumulating data indicate that clinical benefit of immmunotherapies of cancer, including cancer vaccines, may take place in the absence of objective clinical responses (as measured by RECIST rriteria). Recent FDA guidance discusses the differences in the mode of anticancer effects of vaccination (indirect and delayed in time )versus the killing of tumor cells by cytostatic drugs (direct adn immediate) (http://www.fda.gov/BiologicsBloodVaccines/GuidanceComplianceRegulatoryInformation/Guidances/Vaccines/ucm182443.htm), reflecting the observations that vaccines and potentially other immunotherapeutic drugs may prolong overall survival even in the presence of early progression of the disease. In this situation, the classical design of early phase clinical trials, and the emphasis on RECIST criteria of response developed to evaluate the effectiveness of chemotherapeutic agents (that directly target tumor cells), may limit our ability to identify new immunotherapeutic drugs, and potentially other cancer drugs that target cancer only indirectly (for example, targeting tumor stroma). The same time, the use of Overall Survival as the primary endpoint in the currently-used clinical trial designs translates into large size of study cohorts, long follow-up times, and the resulting high costs of trials, making it difficult to use in early-phase clinical testing. In this situation, addressing the folllowing questions would help to accelerate the development of new cancer treatments, especially these treatments that aim to change the pattern of interactions of cancer cells with the the host (immunotherapies and stroma-targeting approaches): 1) Can alternative endpoints and novel trial designs be developed to reduce the size of study cohorts in early-phase clinical trials and accelerate the development of biologic therapies of cancer? 2) Can selection of particular inclusion criteria be used to reduce the variation in a) natural course of disease and b) response to therapies, allowing to reduce the study cohorts in early phase clinical trials using overall survival as the primary endpoint of efficacy? 3) Why only a fraction of patients treated with individual biologic agents fulfils the RECIST criteria of response? Can the response to this question facilitate the development of improved therapies? Can it be used to stratify the patients on prospective clinical trials?
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