Abstract No. 
Markers in Cancer: A joint meeting by ASCO, EORTC and NCI
November 7-9

Rationale of the design of the I-SPY trial

DeMichele A, Yee D, Hylton N, Van't Veer L, Symmons WF, Perlmutter J, Lyandres J, Davis S, Buxton M, Berry D, Esserman L

New approaches to drug development are needed to lessen the time, cost and resources to identify and optimize active agents. Strategies to accelerate drug development include testing drugs earlier in the disease process such as the neoadjuvant setting, in which the surrogate short-term endpoint, pathological response (pCR), may identify active agents and shorten the time to approval of both efficacious drugs and biomarkers identifying patients most likely to respond. I-SPY 2 is a multicenter, phase 2 trial using adaptive randomization within biomarker subtypes to evaluate a series of novel agents/combinations when added to standard neoadjuvant weekly paclitaxel (T) ×12 (with trastuzumab if Her2+), followed by doxorubicin & cyclophosphamide (AC) q2–3 wk ×4, for women with high-risk stage II/III breast cancer. The primary endpoint is pathologic complete response (pCR) at surgery. Participation is limited to patients with sufficiently poor prognosis (risk of early recurrence) with standard therapy to justify exposure to investigational agents; thus those with tumors <2.5 cm or hormone receptor (HR)+/MammaPrint (MP) low biomarker profiles are not eligible. Agents selected for inclusion in I-SPY2 must have adequate safety information from phase Ib studies in combination with a taxane at a dose and schedule approximating the I-SPY2 regimen. I-SPY2 safety data are collected electronically through a web-based application (“TRANSCEND”) developed specifically for the trial in collaboration with the NCICB. The I-SPY2 DSMB meets monthly to review safety and outcome data, providing the opportunity to conduct frequent monitoring for unexpected safety signals, and constantly re-evaluate the risk/benefit ratio for a given drug or combination in the trial. The study is designed to identify and “graduate” regimens that have ≥85% Bayesian predictive probability of success (statistical significance) in a 300-patient biomarker-linked Phase 3 neoadjuvant confirmatory trial defined by HR & HER2 status & MP “signature”. Experimental regimens can “graduate” in at least 1 of 10 possible signatures, with a maximum number of 120 patients enrolled per regimen. As of August 2013, over 400 women have been enrolled to the trial and randomized to T/AC with or without one of seven investigational therapies from five different pharmaceutical companies, including veliparib/carboplatin, neratinib, AMG-386, ganitumab/metformin, pertuzumab, pertuzumab/ado-trastuzumab emtansine (T-DM1) or MK-2206. Whether any of these investigational therapies have been graduated or dropped for futility has not been announced. The I-SPY3 TRIAL, currently in development, will provide a platform for drugs graduating from I-SPY2 to be definitively tested in a randomized phase 3 trial with primary endpoints of both pCR and event-free survival.

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