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I-SPY2 +: Evolving the I-SPY 2 TRIAL to include MRI-directed, adaptive sequential treatment to optimize breast cancer outcomes

Award Number: P01CA210961
ORGANIZATION: NATIONAL CANCER INSTITUTE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

Group Awards By Issue Date FY or Funding FY:

View Award Abstract

The overarching goal of this program project is to advance the science of individualizing treatment to improve outcomes on the basis of response to therapy. Neoadjuvant chemotherapy (NAC) provides the opportunity to assess response to systemic therapy prior to surgery in women with high risk early breast cancer. The optimal outcome is the complete eradication of tumor, (pathologic complete response (pCR)), which is strongly associated with improved long-term survival and is a surrogate endpoint for accelerated drug approval. Conversely, women with significant residual cancer burden (RCB 2/3) suffer event free survival of less than 60% at 3-5 years. Redirecting therapy in poor responders could dramatically improve breast cancer survival in the highest risk women and minimize toxicities in early responders. The neoadjuvant I-SPY 2 adaptive clinical trial platform, designed to accelerate phase II development of new agents for stage II/III breast cancer is the ideal setting for this work. MRI will serve as a foundation for an integrated residual cancer burden assessment tool (“iRCB”), optimized by tumor subtype and pathway. Two decades of MRI imaging research in the I-SPY program have provided the necessary technology, bioinformatic and statistical approaches, and validation datasets to optimize the iRCB tool to serve as the trigger to redirect to rationally selected, biologically targeted agents. The advances from each project coalesce in Project 1, where we have developed the mechanics of integrating the pieces to determine whether treatment redirection on the basis of pathway abnormalities and avoiding the additional toxicity of chemotherapeutic agents in the setting of complete or poor response leads to better outcomes. Project 2 contributes the tools for the optimization of the iRCB, using advances in imaging methods (diffusion weighted imaging and breast PET) and a longitudinal model that includes molecular data from diagnosis, and an inter-regimen biopsy to confirm absence or presence of disease and accurately classify excellent and poor response (RCB 0 and RCB 2/3, respectively). Project 3 will provide an understanding of the dynamics of the biology of response and treatment resistance, and Project 4 will delineate the rational selection of `second chance” therapies based on the biology and knowledge of agents already or being developed. We will work closely with the FDA over the course of this Program Project to establish the subtype specific thresholds for iRCB. The final result will be an evolution of the existing I-SPY Trial (into “I-SPY2+”) that employs an innovative Sequential Multiple Assignment Randomization Trial (SMART) design to maximize both clinical impact and knowledge generation, while closely reflecting the realities of current clinical practice. Taken together, these projects leverage an established, successful, efficient, and highly innovative clinical trial platform and an experienced, collaborative research team to address a critical clinical issue in breast cancer. The innovative approach employed will mark a milestone in the implementation of personalized medicine in breast cancer and generate an unprecedented view of the molecular evolution of treatment resistance.


Issue Date FY	Funding FY	Legal Entity Name	Legal Entity Address	Legal Entity City	Legal Entity State	Legal Entity Zip Code	Legal Entity COUNTY	Legal Entity COUNTRY	Assistance Listing	Award Code	Budget Year	Action Date	Action Type	Action Amount

Issue Date FY: 2023 ( Subtotal = $2,689,478 )
2023	2023	REGENTS OF THE UNIVERSITY OF CALIFORNIA, SAN FRANCISCO, THE	1855 FOLSOM ST STE 425	SAN FRANCISCO	CA	94143	SAN FRANCISCO	USA	Cancer Detection and Diagnosis Research	001	6	7/3/2023	COMPETING CONTINUATION	$2,689,478
2023	2021	REGENTS OF THE UNIVERSITY OF CALIFORNIA, SAN FRANCISCO, THE	1855 FOLSOM ST STE 425	SAN FRANCISCO	CA	94143	SAN FRANCISCO	USA	Cancer Detection and Diagnosis Research	000	5	6/26/2023	NON-COMPETING CONTINUATION	$0
														Subtotal = $2,689,478

Issue Date FY: 2021 ( Subtotal = $1,800,771 )
2021	2021	REGENTS OF THE UNIVERSITY OF CALIFORNIA, SAN FRANCISCO, THE	1855 FOLSOM ST STE 425	SAN FRANCISCO	CA	94143	SAN FRANCISCO	USA	Cancer Detection and Diagnosis Research	000	5	8/6/2021	NON-COMPETING CONTINUATION	$1,800,771
														Subtotal = $1,800,771

Issue Date FY: 2020 ( Subtotal = $1,845,433 )
2020	2020	REGENTS OF THE UNIVERSITY OF CALIFORNIA, SAN FRANCISCO, THE	1855 FOLSOM ST STE 425	SAN FRANCISCO	CA	94143	SAN FRANCISCO	USA	Cancer Detection and Diagnosis Research	000	4	8/28/2020	NON-COMPETING CONTINUATION	$1,845,433
														Subtotal = $1,845,433

Issue Date FY: 2019 ( Subtotal = $1,954,475 )
2019	2019	REGENTS OF THE UNIVERSITY OF CALIFORNIA, SAN FRANCISCO, THE	1855 FOLSOM ST STE 425	SAN FRANCISCO	CA	94143	SAN FRANCISCO	USA	Cancer Detection and Diagnosis Research	000	3	9/9/2019	NON-COMPETING CONTINUATION	$1,954,475
														Subtotal = $1,954,475

Issue Date FY: 2018 ( Subtotal = $2,124,555 )
2018	2018	REGENTS OF THE UNIVERSITY OF CALIFORNIA, SAN FRANCISCO, THE	1855 FOLSOM ST STE 425	SAN FRANCISCO	CA	94143	SAN FRANCISCO	USA	Cancer Detection and Diagnosis Research	000	2	9/20/2018	NON-COMPETING CONTINUATION	$2,124,555
														Subtotal = $2,124,555

Issue Date FY: 2017 ( Subtotal = $2,339,503 )
2017	2017	REGENTS OF THE UNIVERSITY OF CALIFORNIA, SAN FRANCISCO, THE	1855 FOLSOM ST STE 420	SAN FRANCISCO	CA	94103	SAN FRANCISCO	USA	Cancer Detection and Diagnosis Research	000	1	9/7/2017	NEW	$2,339,503
														Subtotal = $2,339,503

Grand Total All Awards = $12,754,215

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I-SPY2 +: Evolving the I-SPY 2 TRIAL to include MRI-directed, adaptive sequential treatment to optimize breast cancer outcomes

Award Number: P01CA210961

ORGANIZATION: NATIONAL CANCER INSTITUTE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

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