Project 01 - Sequential Multiple Assignment Randomization using imaging and molecular biomarkers in I-SPY 2 non-responders

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PROJECT 1 SUMMARY Women with aggressive breast cancer who achieve a pathologic complete response (pCR) to preoperative (“neoadjuvant”) therapy have excellent outcomes, despite presentation with stage II or III disease. In contrast, women with substantial residual cancer burden (“RCB 2/3”) after exposure to chemotherapy have poor outcomes, with event free survival below 60% at 3-5 years. Numerous studies and an FDA meta-analysis confirm the strong prognostic effect of pCR as a surrogate for long-term survival. The overarching goal of Project 1 is to exploit the pCR or RCB0 and RCB 2/3 surrogate to allow the successful I-SPY2 trial to evolve and test a new treatment paradigm where there are more opportunities for patients to reach a pCR. The I- SPY 2 TRIAL is already an innovative, adaptive clinical trial framework designed to accelerate new drug development tied to biomarkers of treatment response. To date, over 1000 patients (250 per year) have been randomized to one of 12 investigational treatment arms, 5 of which have successfully graduated from the trial. But we have observed that many women still fail to reach pCR, while others have excellent early response to therapy, and likely could be spared additional toxicity. We hypothesize that by utilizing an MRI-based tool to assess residual cancer burden (called the “Integrated RCB, or iRCB) midway through the course of neoadjuvant therapy, we will be able to effectively redirect treatment in those with either exceptional or poor response sparing the former (in whom iRCB predicts early pCR) additional toxic therapy by allowing them to go to surgery sooner, while providing the latter (in whom iRCB predicts RCB 2/3) with alternative novel, “personalized” therapies based upon their own tumor biology, in effect offering a `second chance' at achieving pCR. To optimize response, we will leverage insights into the mechanisms and markers of treatment resistance emerging from the I-SPY2 TRIAL, We have selected a Sequential Multiple Assignment Randomized Trial (SMART) model that permits us to incorporate these innovations within the I-SPY framework, ultimately enabling `serial' treatment modifications for women who continue to exhibit poor response. Project 1 will leverage knowledge and tools generated across all projects and cores: refinement of iRCB as the `trigger' for treatment re-direction (Project 2); an enhanced library of potential subsequent agents/combinations and probability of response based on the presence of tumor biomarkers, both known and newly identified (Projects 3, 4); and a clinical decision tool to assign substitute therapy based on the presence of multiple biomarkers of response. The end result will be the evolution of I-SPY 2 into I-SPY 2+.Our Admin core will oversee regulatory requirements as per our discussions with the FDA. Our Bioinformatics Core has leading expertise on the design of SMART and adaptive trials. This novel and innovative approach will evaluate both pathway and individualized treatment strategies critical to realizing the potential of precision medicine.