Background: I-SPY 2 is a multicenter, phase 2 trial using response-adaptive randomization within biomarker subtypes to evaluate a series of investigational agents or regimens when added to standard neoadjuvant therapy for women with high-risk stage II/III breast cancer - investigational agent (I) +paclitaxel (T) qwk, doxorubicin & cyclophosphamide (AC) q2-3 wk x 4 vs. T+/-HP/AC (control arm(s)). Although the primary endpoint is pathologic complete response (pCR) at surgery, a key secondary aim is to evaluate the toxicity profiles of these investigational agents. Distinct aspects of safety monitoring in a platform trial, as well as the specificities of safety management in a potentially curative population make the experiences from I-SPY 2 valuable to the community.

Methods: Inclusion and exclusion criteria are uniformly applied to all women in I-SPY 2. When a new investigational agent/regimen is planned for the trial, agent specific laboratory/hematologic limits or additional required tests are added, as needed. Eligibility criteria remain in the trial for its duration and apply to all investigational and control arms. Laboratory and adverse event data are collected and monitored in real time. The lead investigator of the investigational agent/regimen who chaperones a specific agent/regimen through the trial (“Agent Chaperone”), Medical Monitor, I-SPY 2 Agents Committee, CRO safety group, and an active DSMB that meets monthly oversee the management of toxicities within each investigational agent/regimen of the trial. Toxicity profiles for an investigational agent/regimen are compared to their relevant control. Safety analyses are intention to treat.

Results: From March 2010-May 2016, eleven (11) investigational agents/regimens have opened (and 6 have completed evaluation) and 973 women have been randomized. These agents/regimens span a variety of mechanisms of action including targeted therapies such as small molecule inhibitors and antibodies, as well as immunotherapies. Additions to the trial's eligibility criteria have been made with new investigational arms. Adverse events of special interest have been monitored for each investigational arm and specific toxicities treated uniformly when applicable. A risk-based monitoring plan has been implemented that focuses on the collection and review of the trial's most critical data elements including serious adverse events and drug specific safety issues, allowing for a more efficient and focused effort. Safety issues have been quickly addressed and requirements updated, when needed, given the importance of limiting (or avoiding) long-term safety complications within this neoadjuvant patient population. Accrual to the trial has (been) maintained over time and the safety of trial participants has been well managed.

Conclusion: A platform trial requires an evolving, and focused safety-monitoring process that adapts as new investigational agents are included. I-SPY 2's infrastructure and team science approach has created a system to manage patients across multiple arms with different risk profiles. These practices will support the safe evaluation of additional new combinations and regimens and serves as a guide for safety management within standing platform trials.