# Project 1: Imaging, pathology, and molecular biomarkers to Optimize Treatment Switching within a SMART adaptive Framework

> **NIH NIH P01** · UNIVERSITY OF CALIFORNIA, SAN FRANCISCO · 2023 · $343,192

## Abstract

The I-SPY2 Trial accelerated development of novel therapies for breast cancer in the neoadjuvant setting through its
design as a phase II, multicenter platform trial. Since launching in 2010, 24 new therapies or combinations have been
tested, and 7 were found to significantly improve pathologic complete response (pCR), leading to several definitive phase
III trials. However, with this success came the realization that not every patient benefited, and the serial addition of drugs
to the standard regimen came at a cost in terms of increased toxicity. In 2015, the I-SPY P01 led to further development of
tools that address these issues, including tools to better evaluate individual patient responses to therapy and subsequent
event-free survival outcomes, that have enabled escalation for poor responders and de-escalation for exceptional
responders. This has led to some patients receiving additional therapies such as immune checkpoint inhibitors or
platinums and others being able to forego the toxicity of agents such as anthracyclines, key initial steps toward treatment
individualization and precision medicine. These innovations have led to shared decision-making over the course of
neoadjuvant therapy and necessitated the expansion of the number of sites to participate in the trial. Project 1 was
instrumental in coordinating the efforts of the other projects in developing these tools, implementing and validating them
within the I-SPY2 trial as well as galvanizing the I-SPY Trial team in designing the next generation trial, I-SPY2.2. We
now hypothesize that by further refining the process of escalation and de-escalation in the I-SPY2.2 Trial, including the
integration of circulating tumor DNA (ctDNA) and our novel Response Predictive Subtype schema into key decision
processes and timepoints, we can improve the proportion of patients who achieve pCR across the entire trial population
and reduce recurrence, through better matching patients to drugs that maximize an individual’s chance for pCR while
concurrently reducing toxicity of treatment and improving patient well-being. Project 1 will test this hypothesis in the
process of cyclical improvements in the real-time, biomarker-based decision making along the course of the trial, with the
goal of further optimizing outcomes for individual patients in the context of drug development for early breast cancer. In
Project 1, we will further leverage the work of Projects 2-4 to implement refinements to the sequential randomization
(escalation strategy) to best-in-class rescue therapies for poor responders and de-escalation to minimize unnecessary
therapy in exceptional responders. We will develop novel measures to compare tested agents, such as changes in the RCB
distribution (as trial arm level proximate outcome) and composite measures of efficacy and toxicity (including patient-
reported outcomes (PRO)). PRO and a return of results process will also be used to evaluate impacts on patient
perception, shared dec...

## Key facts

- **NIH application ID:** 10628609
- **Project number:** 2P01CA210961-06A1
- **Recipient organization:** UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
- **Principal Investigator:** ANGELA DEMICHELE
- **Activity code:** P01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2023
- **Award amount:** $343,192
- **Award type:** 2
- **Project period:** 2017-09-08 → 2028-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10628609

## Citation

> US National Institutes of Health, RePORTER application 10628609, Project 1: Imaging, pathology, and molecular biomarkers to Optimize Treatment Switching within a SMART adaptive Framework (2P01CA210961-06A1). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10628609. Licensed CC0.

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