The I-SPY2 Trial

Widely hailed as the future of phase II drug development, the adaptive I-SPY 2 platform trial has set a new benchmark for efficiency, through innovation in trial design and clinical operations.

The clinical trial, re-imagined

The ground-breaking I-SPY2 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-SPY2’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-SPY2 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-SPY2’s early surrogate efficacy endpoint (pCR) gets results faster
Multiple Agents
Up to 6 agents can be efficiently, independently evaluated in parallel
Adaptive Design
Adaptive randomization makes the most of every patient enrolled
Master Protocol
Less paperwork means vastly compressed start-up times – 3-4 months
Neoadjuvant Model
Systemic therapy first lets you see how tumors respond to treatment
Real-world control
A common control arm as comparator, with a decade of historical data
Biololgical targeting
Randomization targets agents to more responsive molecular subtypes
Active QC
Enterprise-wide process standardization with frequent re-certification
Serial MRI
Optimized imaging protocols quantify tumor response over time
Biomarker Discovery
Integrated platform for
companion biomarker discovery
Curable Population
A breast cancer population where standard of care has much room to improve

How I-SPY2 Works

I-SPY2 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) I-SPY2’s adaptive randomization engine assigns a participant to a study arm with the higher Bayesian prior probability of efficacy. 

2) The is assessed at time of surgery. Primary endpoint is RCB 0 or pathologic complete response meaning the tumor has disappeared completely.

3) Based on the participant's tumor subtype, outcome (ie. MRI volume, pCR) and treatment received, the predictive probabilities of the agent in the various subtypes are updated in real time, and affects the next participant to enter the arm.

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

5) 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.

Study Schema

I-SPY2 was one of the first, and is now the longest running 'platform' trial ever. As a platform trial, I-SPY2 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 enrolment or resubmit the entire clinical trial protocol for regulatory review.

I-SPY2 Substudies