Project Overview

I-SPY 2 TRIAL (I-SPY 2) uses a novel process for rapid, focused clinical development of paired oncologic therapies and biomarkers. I-SPY 2 will be performed as a neoadjuvant (pre-operative) treatment trial for women with large primary breast cancers where the endpoint for response to treatment will be the measurement of pathologic complete response (pCR). I-SPY 2 will test, analytically validate, and qualify biomarkers in conjunction with new drug testing; employ an adaptive trial design to enable efficient learning about the efficacy of each drug with each biomarker signature; and utilize organizational management principles and sophisticated bioinformatics to eliminate inefficiencies that often typify current clinical trials. I-SPY 2 builds on the earlier I-SPY 1 project, which employed sophisticated biomarker testing but did not explore new drugs.

Classic randomized clinical trials evaluate one drug at a time for a set number of individuals over a long period of time, a design that is inefficient and does not allow for rapid learning regarding which investigational agents are most effective for which patients. To address this problem, the I-SPY 2 Team, in a broad-based collaboration under the auspices of the Foundation for the National Institutes of Health (FNIH) Biomarkers Consortium, has designed an adaptive randomized Phase II trial based on biomarker signatures where multiple drug classes can be evaluated simultaneously on the backbone of molecularly profiled patients.

Project Goals

- Core Hypothesis

The core hypothesis of I-SPY 2 is that the clinical trial process can be significantly improved by the introduction of a biomarker-based approach to target the correct therapy to the most appropriate individual patients, and an adaptive trial design to accelerate decision-making about candidate new agents.

I-SPY 2 is intended to improve the clinical trial process by pairing novel oncologic therapies with biomarkers (both molecular and imaging) in an adaptive setting that will accelerate the advancement of Phase II drug evaluation to Phase III confirmation of efficacy. The proposed assignment of Phase II investigational drugs to cohorts of patients whose disease characteristics suggest they might benefit from this “personalized” therapy is based on an understanding of the fundamental regulatory pathways that control breast cancer pathology, as well as development of validated assay methods that can reproducibly identify tissue or serum markers that predict response. There are a large number of Phase II biologically targeted therapies that need to be efficiently evaluated. Fortunately, most of them do not appear to be toxic, even in combination with chemotherapy. Further, emerging data suggests that these agents will be most efficacious in combination with chemotherapy.

It is absolutely critical that the knowledge turns and lifecycle for evaluating new agents be shortened and that the most promising agents be given to those most likely to benefit. Introducing these agents in the neoadjuvant setting, where there is a short-term (six-month) intermediate endpoint to approximate efficacy, will provide the proper time horizon for agent evaluation. Furthermore, the introduction of these agents to women with curable high-risk disease carries the promise of improving survival rates in women most at risk of death due to their disease.

- Primary Objectives

1)  I-SPY 2 will test, analytically validate, and qualify biomarkers in conjunction with the new drug testing; employ an adaptive trial design to enable efficient learning about the activity of each drug with each biomarker signature; and utilize organizational management principles and sophisticated bioinformatics to eliminate inefficiencies that often typify current clinical trials.

The primary objectives of I-SPY 2 are to determine whether adding experimental agents to standard neoadjuvant paclitaxel and AC therapy increases the probability of pCR (pathologic complete response) over standard neoadjuvant chemotherapy for each biomarker signature established at trial entry, and to determine for each experimental drug used the predictive probability of success in a subsequent Phase III trial for each possible biomarker signature.

Additional objectives:

2)  To build predictive and prognostic indices based on qualification and exploratory markers to predict pCR and residual cancer burden (RCB);

3)  To initiate the creation of a biological specimen repository, consisting of tumor tissue, RNA, DNA, serum and cells, as well as corresponding MR and pathology images of these specimens for ongoing translational studies in genomics, proteomics and imaging, for establishing their relationship to overall survival;

4)  To determine three- and five-year RFS (recurrence-free survival) and OS (overall survival) among the treatment arms;

5)  To encourage pre-competitive collaboration among cancer researchers, pharmaceutical industry and regulatory agencies to collaborate and share information to accelerate the pace of drug development and approval while enriching patient lives.

Potential Application of I-SPY 2 Research

If the trial is successful, it will enable a new approach to “personalized medicine” in the development of new agents in breast cancer.  In addition, it will demonstrate a streamlined model for trials that could result in earlier/more precise “pass-fail” of novel agents; identify agents that are more precisely targeted to be efficacious in particular populations; and enable dramatically smaller, faster trials in both Phase II and Phase III trial settings.  Given the continuous involvement of FDA throughout the process of planning I-SPY 2, the I-SPY 2 Team believes the trial will have particularly strong value in informing new approaches to regulatory decision-making in the field.

I-SPY 2 provides an infrastructure and process for the efficient evaluation of new drugs and biomarker profiles. Thus, the deliverables from the successful conduct of I-SPY 2 will be 1) an efficient process for evaluating new drugs and biomarkers, and 2) information on the response of locally advanced breast cancer with specific biomarker profiles to drugs representing several mechanistic classes.

Regulatory decision-making with regard to breast cancer drugs will be facilitated. The results will be applicable to design of larger multi-center trials in the short term, and will eventually be extendable to modify patient clinical care in the community.