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What is I-SPY and I-SPY Trials?

The I-SPY series of trials are changing the way new treatments are developed for breast cancer, helping make available new, better and more personalized treatments, faster. At the heart of the I-SPY program is the ground-breaking I-SPY 2 platform trial for neoadjuvant treatment of locally advanced breast cancer.

>2500

Patients Enrolled

25

Agents completed evaluation

3

Agents received accelerated approval

The Clinical Trial, Re-Imagined

The ground-breaking I-SPY 2 trial of neoadjuvant treatment for locally advanced breast cancer established a new benchmark for efficiency of phase II clinical trials. Widely regarded as a pioneer of the ‘platform’ trial, I-SPY 2’s success continues to be a major influence on the development of next-generation trial designs in oncology and beyond.

Efficiency Bred From Innovation

The success of the I-SPY 2 trial is not simply the result of a single innovation in trial design.It is the result of a pain-staking deconstruction and re-engineering of the entire clinical trial enterprise, from protocol development through registration.

Early Endpoint

I-SPY 2’s early surrogate efficacy endpoint (pCR) gets results faster

Adaptive Design

Adaptive randomization makes the most of every patient enrolled

Real-World Control

A common control arm as comparator, with a decade of historical data

Curable Population

A breast cancer population where standard of care has much room to improve

Neoadjuvant Model

Systemic therapy first lets you see how tumors respond to treatment

Multiple Agents

Up to 6 agents can be efficiently, independently evaluated in parallel

Biological Targeting

Randomization targets agents to more responsive molecular subtypes

Master Protocol

Less paperwork means vastly compressed start-up times by 3-4 months

Serial MRI

Optimized imaging protocols quantify tumor response over time

Biomarker Discovery

Integrated platform forcompanion biomarker discovery

Active QC

Enterprise-wide process standardization with frequent re-certification

How I-SPY 2 Works

I-SPY 2 breaks from the traditional randomized clinical trial model, employing an ‘adaptive’ clinical trial model designed to increase trial efficiency by minimizing the number of participants and time required to evaluated an experimental agent.

At consent, a new participant’s breast cancer is classified into one of 10 molecular subtypes. Then, for each participant in the trial:

1

Randomize to Expt’l or Control Arm

I-SPY 2’s adaptive randomization engine assigns a participant to a study arm; it gives greater weight to arms that have been successful in the participant’s tumor subtype.

5

Update Randomization Probabilities

The participant’s serial MRI measures, RCB scores and tumor subtype are used to update the prior probabilities of the randomization engine — over time this refines the targeting of subsequent participants..

2

Patient Outcome (RCB/pCR)

I-SPY 2’s adaptive randomization engine assigns a participant to a study arm; it gives greater weight to arms that have been successful in the participant’s tumor subtype.

3

Update Predictive Probabilities

Based on the participant’s tumor subtype, outcome (i.e. MRI volume, pCR) and treatment received, the predictive probabilities of the agent in the various subtypes are updated in real time.

4

Apply Termination Rules (Per Arm)

If predictive probabilities for an experimental agent reach a pre-determined level of efficacy in one or more molecular subtypes, it is declared a success (“graduates”). Alternatively, it may be stopped for futility after reaching a maximum number of participants. At any point new agents can enter the trial through a protocol amendment.

Study Schema

I-SPY 2 was one of the first, and is now the longest-running ‘platform’ trial ever. As a platform trial, I-SPY 2 uses a master protocol that provides a regulatory framework to study multiple treatments in the same study. It also allows new agents to enter and leave the study without having to halt enrollment or resubmit the entire clinical trial protocol for regulatory review.

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