Quantum Leap Healthcare Collaborative

The I-SPY 2 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-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 for
companion 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) 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.

2) The endpoint 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 (i.e. MRI volume, pCR) and treatment received, the predictive probabilities of the agent in the various subtypes are updated in real time.

4) 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.

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-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 enrolment or resubmit the entire clinical trial protocol for regulatory review.

I-SPY 2 Substudies