A Synthetic Lethality-Focused Algorithm to Identify Therapeutic Options in Advanced Metastatic Breast Cancer (SYNTHESIS-Breast)

NCT07067138 | Recruiting

• 2 other identifiers: 10001891001891-C
• Study Type: interventional
• Target: 175
• Locations: 1 country
• Sites: 1

Brief Summary

Background: Breast cancer is the most common cancer in US women. There are different types of breast cancers; some are aggressive and difficult to treat. Researchers want to know if an algorithm (ENLIGHT) can help choose approved drugs that will treat these cancers more effectively. Objective: To test whether ENLIGHT can find better treatments for aggressive breast cancers. Eligibility: People aged 18 years and older with triple-negative or endocrine therapy resistant breast cancer; the cancer must have either failed to respond to treatment or come back after treatment. Design: Participants will be screened. A sample of tissue taken from the tumor will be tested using ENLIGHT as well as another method (TruSight Oncology 500). Participants will be assigned to 1 of 3 groups based on the algorithm search results: Group 1: No drug option was recommended. Participants will continue with their standard treatment with their local doctors. Group 2: A drug already approved for the participant's disease was recommended, but the participant has not yet received it. These results will be sent to the participant's local doctors. Participants may return to the NIH if their disease gets worse after using the suggested drugs. Group 3: A drug approved for other uses was recommended. Participants will be treated with the recommended drugs at the NIH; their care will be managed by an NIH doctor. They will continue to receive treatment as long as the drugs are helping them. They will have follow-up visits for 2 years after treatment ends. Participants who are not treated at the NIH will be contacted for a check on their health every 3 months for 2 years.

Conditions

Breast Carcinoma; Breast Cancer; Cancer of the Breast; Malignant Neoplasm of Breast

Keywords

ENLIGHT; Triple Negative Breast Cancer (TNBC); Her2; NSR device

Outcome Measures

Primary Outcomes (2)

• Part A: To assess the feasibility of using the ENLIGHT algorithm to match heavily pretreated participants with metastatic breast cancer to off-label therapies

  The number of participants of the first 20 enrolled overall having a match via ENLIGHT and being assigned to Arm 3.

  Assessed after the Reporting Visit of the 20th participant to the study, and to be completed before Part B

• Part B: (If feasibility lead-in met) To assess the objective response rate (ORR) of participants with advanced breast cancer using treatment recommended by the ENLIGHT algorithm

  ORR is reported as a single endpoint measure (percentage) at time of interim analysis and at time of study completion and will be accompanied by a 95% confidence interval.

  Every 2 cycles until progression of disease, completion of treatment, or 2 years after treatment initiation (whichever comes first)

Secondary Outcomes (5)

• To determine the overall frequency of the ENLIGHT algorithm in recommending matches of targeted therapy or immunotherapy for participants who would otherwise be ineligible per existing biomarkers associated with FDA-approved, on-label treatments

  Every 2 cycles until progression of disease, completion of treatment, or 2 years after treatment initiation (whichever comes first)

• To assess the duration of clinical benefit for treatments recommended by the ENLIGHT algorithm

  Every 2 cycles until progression of disease, completion of treatment, or 2 years after treatment initiation (whichever comes first)

• To determine the specific agents for which ENLIGHT demonstrates the best predictive performance in the context of breast cancer

  Ongoing

• To determine extent of therapy associated toxicity burden and related outcomes for participants who are matched to a therapy through the ENLIGHT algorithm

  At least Day 1 of each cycle, throughout treatment, and at the end-of treatment visit; then every 3 months for up to 2 years.

• To assess the ORR/duration of clinical benefit for participants undergoing an additional iteration of treatment as recommended by the ENLIGHT algorithm

  Every 2 cycles until progression of disease, completion of treatment, or 2 years after treatment initiation (whichever comes first)

Study Arms (3)

1/No Recommended Match

ACTIVE COMPARATOR

Treatment per physician's choice

Device: Expression Networks for highLIGHting Tumor vulnerabilities (ENLIGHT); Device: TruSight(R) Oncology 500; Device: TruSeq Matched Tumor Normal Whole Exome Sequencing Assay

2/Genomic Marker Associated with FDA-Approved On-Label Treatment

EXPERIMENTAL

Treatment in accordance with genomic marker; treatment to be directed locally by referring/treating physician

Device: Expression Networks for highLIGHting Tumor vulnerabilities (ENLIGHT); Device: TruSight(R) Oncology 500; Device: TruSeq Matched Tumor Normal Whole Exome Sequencing Assay

3/Transcriptomic Match

EXPERIMENTAL

Treatment regimen as selected by transcriptomic algorithm; treatment to be directed by NIH study team with requirement for treatment at NIH

Device: Expression Networks for highLIGHting Tumor vulnerabilities (ENLIGHT); Device: TruSight(R) Oncology 500; Device: TruSeq Matched Tumor Normal Whole Exome Sequencing Assay

Interventions

Expression Networks for highLIGHting Tumor vulnerabilities (ENLIGHT) DEVICE

This is a computational algorithm that takes RNA-seq data from tumor FFPE blocks and, given a list of pre-specified treatments, generates as output the predicted responses to those treatments.

1/No Recommended Match; 2/Genomic Marker Associated with FDA-Approved On-Label Treatment; 3/Transcriptomic Match

TruSight(R) Oncology 500 DEVICE

TSO500 uses formalin-fixed, paraffin-embedded (FFPE) tumor blocks to generate a 523-gene DNA panel (with tumor mutational burden and microsatellite instability) to assess for biomarkers linked to FDA-approved, on-label therapies as well as whole-exome RNA-seq that can be used with the ENLIGHT algorithm.

1/No Recommended Match; 2/Genomic Marker Associated with FDA-Approved On-Label Treatment; 3/Transcriptomic Match

TruSeq Matched Tumor Normal Whole Exome Sequencing Assay DEVICE

The TruSeq Matched Tumor-Normal Whole Exome Sequencing assay is a next-generation sequencing assay that uses tumor DNA from formalin-fixed, paraffin-embedded (FFPE) tumor blocks and germline DNA drawn from blood to provide extended sequencing information on the tumor as well as any pathogenic variants, likely pathogenic variants, and variants of uncertain significance in 156 genes from the normal blood sample.

1/No Recommended Match; 2/Genomic Marker Associated with FDA-Approved On-Label Treatment; 3/Transcriptomic Match

Eligibility Criteria

• Age: 18 Years - 120 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• Participants must have a histologically confirmed diagnosis of metastatic breast cancer. Note: Pathology testing outside NIH will be accepted for eligibility purposes.
• Participant tumor subtypes will be enrolled as follows:
• TNBC Cohort: TNBC will be defined as ER \< 10% or PR \< 10% by immunohistochemistry (IHC).
• Endocrine-Refractory Cohort: HR+ (ER+ and/or PR+) will be defined as ER \>= 10% or PR \>= 10% by IHC.
• For both cohorts, HER2 will be considered negative if not amplified as per ASCOCAP guidelines per IHC/FISH. Note: HER2-low status will be regarded in accordance with NCCN guidelines (in which this designation serves as a predictive marker for trastuzumab deruxtecan, but participants are otherwise not considered eligible for other HER2-directed therapies).
• Participants must have been treated with at least one (1) line of systemic therapy after diagnosis of metastatic disease, have progressive disease or adverse events requiring discontinuation of their current regimen, and must not be able to transition to another approved systemic therapy shown to improve overall survival.
• Participants with HR+ disease must be deemed refractory to endocrine therapy per their clinical team, with concordance by study team.
• Note: Participants who cannot receive standard therapy that has been shown to prolong overall survival due to concurrent medical issues versus progression of disease will be eligible, if other eligibility criteria are met. If appropriate, participants may remain on treatment during biopsy, screening and initial tissue review/testing for this study. However, their clinical team must confirm that the current line of treatment no longer offers benefit prior to the time of reporting and treatment assignment.
• Participants must have measurable disease per RECIST v1.1. Note: Palliative radiotherapy to site(s) of disease may be completed during screening as long as disease outside of the planned sites of radiation is available for response assessment.
• Archival tumor (preserved via FFPE) must be available from a biopsy performed within the past 6 months. The timeframe of 6 months is required to optimize reliability of ENLIGHT results. It is assumed that a participant has had no more than one (1) line of systemic treatment since the last biopsy. Participants who have had multiple intervening lines of therapy since biopsy was obtained will be reviewed by the study team to determine if another biopsy may be needed. Note: If archival tissue is not available within that timeframe, tissue from the next scheduled biopsy can be sent to NIH for testing. If it is not possible for a biopsy to be scheduled, the study team will evaluate the possibility of a biopsy being performed at the NIH for enrollment purposes.
• Age \>=18 years.
• ECOG performance status \<2 (Karnofsky \>60%)
• Participants must have organ and marrow function as defined below:
• Leukocytes \>= 3,000/mcL
• Hemoglobin \>= 8g/dL

You may not qualify if:

• Participants in active visceral crisis, symptomatic brain metastases requiring local therapy, or active leptomeningeal disease given the time required for testing and therapy selection.
• Participants with uncontrolled intercurrent illness evaluated by physical exam and chemistries or situations that would limit compliance with study requirements, interpretation of results or that could increase risk to the participant.
• Participants with the following active cardiac conditions: symptomatic congestive heart failure, unstable angina pectoris or cardiac arrhythmia (per medical record).
• Participants with lung disease requiring continuous oxygen supplementation.
• Participants with decompensated cirrhosis and/or end-stage kidney disease on dialysis.
• Participants with positive serum or urine beta-HCG pregnancy test performed at screening.
• Participants who are unable to provide tissue specimens of sufficient quality for use in this study. Quality of DNA and RNA is determined during screening. This may be due to issues with biopsy sample collection, inadequate RNA extraction, or quality control failure. Participants may be re-screened if initial specimens are not adequate, if they are amenable to re-biopsy, and additional site(s) of disease for adequate re-sampling are available.

Sponsors & Collaborators

• National Cancer Institute (NCI): lead

Study Sites (1)

National Institutes of Health Clinical Center

Bethesda, Maryland, 20892, United States

RECRUITING

Related Links

• NIH Clinical Center Detailed Web Page

MeSH Terms

Conditions

Breast Neoplasms; Triple Negative Breast Neoplasms

Condition Hierarchy (Ancestors)

Neoplasms by Site; Neoplasms; Breast Diseases; Skin Diseases; Skin and Connective Tissue Diseases

Study Officials

• Padma S Rajagopal, M.D.

  National Cancer Institute (NCI)

  PRINCIPAL INVESTIGATOR

Central Study Contacts

Ann C McCoy, R.N.

CONTACT

(240) 760-6021; ann.mccoy@nih.gov

Padma S Rajagopal, M.D.

CONTACT

(240) 858-3169; sheila.rajagopal@nih.gov

Study Design

• Study Type: interventional
• Phase: not applicable
• Allocation: NON RANDOMIZED
• Masking: NONE
• Purpose: DEVICE FEASIBILITY
• Intervention Model: PARALLEL
• Sponsor Type: NIH
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: July 12, 2025
• First Posted: July 16, 2025
• Study Start: February 23, 2026
• Primary Completion (Estimated): August 4, 2027
• Study Completion (Estimated): August 4, 2029
• Last Updated: April 30, 2026

Record last verified: 2026-04-27

Data Sharing

• IPD Sharing: Will share
• Shared Documents: STUDY PROTOCOL, SAP, ICF
• Time Frame: Data will be made available as soon as possible or at the time of associated publication. Data not published in a manuscript will be shared via public source once the data set completes QC. Clinical data will be made available during the study and indefinitely via BTRIS.
• Access Criteria: Clinical data will be made available upon request and with the permission of the study PI. Genomic data are made available via dbGAP through requests to the data custodians. Clinical data will be made available via subscription to BTRIS and with the permission of the study PI.

Locations

US (1)