Developing safety criteria for introducing new agents into neoadjuvant trials

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 U.S. Food and Drug Administration (FDA) has issued guidance designed to accelerate drug approval through the use of neoadjuvant studies in which the surrogate short-term endpoint, pathologic 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.

Figure 1

Schema of the I-SPY2 trial. In the screening phase of I-SPY2, consented patients have core breast tumor biopsies that undergo profiling on a 44K microarray that includes MammaPrint under an IDE. Patients who are ER⁺/MammaPrint high, ER⁻, or Her2⁺ are eligible for the study, provided they meet other eligibility criteria (including ability to obtain tumor volume by MRI and adequate organ function). Patients who are screen-eligible are then randomized and sign treatment consent to either standard neoadjuvant chemotherapy with weekly paclitaxel (with trastuzumab for Her2⁺) or paclitaxel combined with one of several investigational agents. This is followed in all patients by 4 cycles of doxorubicin/cyclophosphamide. Patients on treatment undergo serial tissue collection and imaging. An adaptive design uses pathologic response at surgery and imaging response to modify randomization probabilities, increasing efficiency, and minimizing exposure to less efficacious agents. AC, Adriamycin/cyclophosphamide; R, randomized.