From U Penn: Developing Safety Criteria for Introducing New Agents into Neoadjuvant Trials

http://www.ncbi.nlm.nih.gov/pubmed/23470967

Clin Cancer Res. 2013 Mar 7. [Epub ahead of print]

Developing Safety Criteria for Introducing New Agents into Neoadjuvant Trials.

Demichele A, Berry DA, Zujewski J, Hunsberger S, Rubinstein L, Tomaszewski JE, Kelloff G, Perlmutter J, Buxton M, Lyandres J, Albain KS, Benz CC, Chien AJ,Haluska P, Leyland-Jones B, Liu MC, Munster PN, Olopade OI, Park JW, Parker BA, Pusztai L, Tripathy D, Rugo H, Yee D, Esserman LJ.

Source

Abramson Cancer Center, University of Pennsylvania School of Medicine.

Abstract

New approaches to drug development are critically needed to lessen the time, cost and resources necessary to identify and optimize active agents. Strategies to accelerate drug development include testing drugs earlier in the disease process such as the neoadjuvant setting. The FDA has issued guidance designed to accelerate drug approval through the use of neoadjuvant studies in which the surrogate short-term endpoint, pathological response, can be used to identify active agents and shorten the time to approval of both efficacious drugs and biomarkers identifying patients most likely to respond. However, this approach has unique challenges. In particular, issues of patient safety are paramount, given the exposure of potentially curable patients to investigational agents with limited safety experience. Key components to safe drug development in the neoadjuvant setting include defining a study population at sufficiently poor prognosis with standard therapy to justify exposure to investigational agents, defining the extent and adequacy of safety data from phase I, detecting potentially harmful interactions between investigational and standard therapies, improving study designs, such as adaptive strategies, that limit patient exposure to ineffective agents, and intensifying safety monitoring in the course of the trial. The I-SPY2 Trial is an example of a phase II neoadjuvant trial of novel agents for breast cancer in which these issues have been addressed, both in the design and conduct of the trial. These adaptations of phase II design enable acceleration of drug development by reducing time and cost to screen novel therapies for activity without compromising safety.