I-SPY 2 Innovations

I-SPY 2 represents an unprecedented reengineering of the clinical trial design process. Incorporating a number of highly innovative and unique features, the I-SPY 2 TRIAL rapidly tests emerging and promising new agents. The goal is to significantly reduce the cost, time and number of patients required for efficiently bringing new drug therapies to breast cancer patients who need them urgently.

The I-SPY 2 TRIAL represents a significant departure from conventional clinical trial models. Five critical components contribute to the I-SPY 2 groundbreaking approach:

1.   I-SPY 2 uses tissue and imaging markers (biomarkers) from individual cancer patients’ tumors to determine eligibility, guide/screen promising new treatments and identify which treatments are most effective in specific tumor subtypes.

2.   The trial’s adaptive design allows the I-SPY 2 Team to “learn as we go,” enabling researchers to use data from patients early in the trial to guide decisions about which treatments might be more useful for patients who enter the trial later. I-SPY 2 provides a scientific basis for researchers to eliminate ineffective treatments and graduate effective treatments more quickly.

3.   The I-SPY 2 neoadjuvant treatment approach—in which chemotherapy is given to patients prior to surgery—allows the team to evaluate tumor response with MRI before removing the “evidence.” This approach is as safe as treating after surgery, allowing tumors to shrink, and most importantly, it enables critical learning early on about how well treatments work.

4.  Key to the trial’s destinctive design, the team will screen multiple drug candidates developed by multiple companies—up to 12 different investigational drugs over the course of the trial. New agents will be selected and added as those used initially either graduate to Phase III or are dropped, based on their efficacy in targeted patients. Not only does this enable an enormous improvement in efficiency but, by using only one standard arm for comparison throughout the trial, it also immediately saves 35% of the costs of standard Phase III trials.

5.   The trial incorporates a robust informatics system that allows data to be collected, verified and shared real-time and to be accessed early and in an integrated fashion—enhancing and encouraging pre-competitive collaboration.

I-SPY 2 trial model

Industry Collaboration

As with its predecessor, I-SPY 2 is focused on collaboration across institutions. Collaboration in I-SPY 2 includes the Food and Drug Administration (FDA),  the National Cancer Institute (NCI), the Foundation for the National Institutes of Health (FNIH), Biomarker’s Consortium, at least 11 leading academic centers (researchers and physicians), major pharmaceutical companies and breast cancer patient advocates. It involves investigators sharing data, tissue and tools as well as common information management platforms and repositories. A sophisticated informatics portal has been built to integrate and interpret the complex and disparate data (genomics, proteomics, pathology and imaging) from many investigators, providing real-time access to study data for effective adaptation in the trial.

I-SPY 2 Technical Highlights

Biomarkers to be used in I-SPY 2 are of three classes:

  • • Standard biomarkers, in clinical use or FDA-approved, will be used to determine patient eligibility and randomization.
  • • Qualifying biomarkers (hypothesis-testing), showing promise for predicting which patients will respond to which agents, but not yet FDA approved, will be evaluated under Clinical Laboratory Improvement Amendment (CLIA) quality standards.
  • • Exploratory biomarkers (hypothesis-generating) of predictive or prognostic value for breast cancer treatment will also be investigated. Importantly, emerging platforms of the future can also be tested to prevent technology obsolescence even many years from now.

We know from whole-genome molecular analysis of solid tumors that cancer is a disease at the level of dysregulation of cellular pathways. These pathways provide the targets for “targeted” therapies. In I-SPY 2, this vital pathway information forms the basis for rationalized therapeutic guidance for patient selection, stratification and further exploration to find response-predictive biomarkers.

I-SPY 2 investigators use new state-of-the-art technologies to provide a comprehensive overview of gene mutation, gene copy number, gene expression (at mRNA and protein level) and protein phosphorylation of both tumor and normal background tissue and blood. The net impact should be more targeted therapies, developed, tested and approved for the appropriate patient or tumor subgroup. The process and collaborative framework of the trial will allow testing in greatly accelerated time frames and at significantly lower cost, benefiting an ever-growing number of patients across an ever-increasing diversity of cancer types and subtypes.

I-SPY 2 Benefits

I-SPY 2 provides significant benefits for the breast cancer patient, for the FDA and for industry, and it responds to critical problems in clinical research. The goal is to create a new paradigm to:

I-SPY 2 provides significant benefits for the breast cancer patient, for the FDA and for industry, and it responds to critical problems in clinical research. The goal is to create a new paradigm to:

• Dramatically reduce the cost of bringing a drug from discovery to market (or from compound to approval);

• Dramatically reduce the time to conclusive results;

• Dramatically reduce the number of patients needed to enroll in trials—a tenfold reduction for Phase III trials;

• Significantly improve the pace of innovation;

• Significantly improve the success rate of Phase III trials—as high as 85% vs 25-30% historically

• Significantly improve pre-competitive collaboration for applying molecular and protein pathway profiling and imaging in clinical trials;

• Significantly improve the efficiency of drug evaluation and approval in concert with the FDA, and provide support for innovation in regulatory decision-making.

Looking Ahead

I-SPY 2 is a great beginning, and with additional funding the approach can be further expanded. The I-SPY 2 model holds tremendous promise for many  cancers and diseases in addition to breast cancer. It also poses the possibility of moving the adaptive trial concept even further, to the point of adapting within patients once we have identified successful new agent/biomarker pairs.

Given the highly motivated and expert I-SPY 2 Team, existing infrastructure from the original I-SPY 1 TRIAL, adaptive trial design, existing and developing biomarkers, promising investigational cancer drugs and the use of early endpoints to learn what works within months rather than years, this initiative promises to be transformational for women with breast cancer.