An Exploratory Study Using a Synthetic Lethality-Focused Algorithm to Identify Therapeutic Options in Advanced Metastatic Breast Cancer (SYNTHESIS-Breast)

Plain English Summary

A Synthetic Lethality-Focused Algorithm to Identify Therapeutic Options in Advanced Metastatic Breast Cancer (SYNTHESIS-Breast) is a Not Applicable clinical trial sponsored by National Cancer Institute (NCI) studying Breast Cancer, Breast Carcinoma, Cancer of the Breast, Malignant Neoplasm of Breast. This study tests a computer program called ENLIGHT to see if it can help doctors choose the best approved drugs for patients with advanced breast cancer that has not responded to treatment. It is for individuals aged 18 and older who have triple-negative or endocrine-resistant metastatic breast cancer that has stopped responding to or returned after treatment. Participation involves providing a tumor tissue sample for testing, and based on the results, patients may receive standard care, a previously unused approved drug, or a drug approved for a different condition, potentially at the NIH. Alternative options include continuing standard treatment with local doctors or seeking other approved therapies based on current medical guidelines. The trial aims to enroll 175 participants.

Official 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.

Who Can Participate

Here is what you need to know about eligibility for this trial. You can join if you are 18 or older and have metastatic breast cancer that is either triple-negative or resistant to hormone therapy, and has not responded to or has returned after treatment. You cannot join if your cancer has not met specific subtype criteria or if you have not had at least one prior treatment for metastatic disease, unless other conditions are met. You need to have measurable disease and a recent tumor tissue sample (within the last 6 months) available for testing. Good organ and blood cell function are required, and you must be able to take oral medications. This trial is studying Breast Cancer, Breast Carcinoma, Cancer of the Breast, Malignant Neoplasm of Breast, so participants generally need a confirmed diagnosis. The trial is currently accepting new participants.

What They're Measuring

The primary outcome measures will determine if the ENLIGHT algorithm can successfully identify potential treatments for patients with advanced breast cancer, and if those treatments lead to a response The specific primary outcome measures are: Part A: To assess the feasibility of using the ENLIGHT algorithm to match heavily pretreated participants with metastatic breast cancer to off-label therapies (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 (Every 2 cycles until progression of disease, completion of treatment, or 2 years after treatment initiation (whichever comes first)). These endpoints are how researchers determine whether the treatment is effective and will form the basis of any future regulatory submissions.

About This Phase

This study does not have a traditional clinical phase designation. It may be an observational study that follows patients without intervening in their care, an expanded access or compassionate use program, or other non-interventional research. These studies contribute valuable data about disease progression, treatment patterns, and patient outcomes.

Why This Trial Matters

This trial matters because it explores a new computational approach to identify personalized treatment options for aggressive breast cancers that are difficult to treat, potentially filling a gap for This research targets Breast Cancer, Breast Carcinoma, Cancer of the Breast, Malignant Neoplasm of Breast, where improved treatment options are needed.

Investor Insight

This trial represents an investment in precision medicine for breast cancer, leveraging advanced algorithms to repurpose existing drugs, which could lead to more efficient drug development and a large

Is This Trial Right for Me?

Ask your doctor if your specific type of breast cancer might be suitable for this study and what the ENLIGHT algorithm does. Be prepared for initial screening, providing a tumor tissue sample, and potentially traveling to the NIH for treatment and follow-up visits. If treated at the NIH, your care will be managed by an NIH doctor, and you will have regular follow-up appointments for up to two years after treatment ends. This trial is currently recruiting participants. The trial is being conducted at 1 site. Always discuss clinical trial participation with your healthcare provider before making any decisions. This information is for educational purposes only and is not medical advice.

AI-generated analysis for educational purposes only. This is not medical advice. Discuss clinical trial participation with your doctor. Data sourced from ClinicalTrials.gov.

Study Design

• Study Type: INTERVENTIONAL
• Allocation: NON_RANDOMIZED
• Model: PARALLEL
• Masking: NONE
• Enrollment: 175 participants

Interventions

• DEVICE: Expression Networks for highLIGHting Tumor vulnerabilities (ENLIGHT) — 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.
• DEVICE: TruSight(R) Oncology 500 — 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.
• DEVICE: TruSeq Matched Tumor Normal Whole Exome Sequencing Assay — 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.

Primary Outcomes

• Part A: To assess the feasibility of using the ENLIGHT algorithm to match heavily pretreated participants with metastatic breast cancer to off-label therapies (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 (Every 2 cycles until progression of disease, completion of treatment, or 2 years after treatment initiation (whichever comes first))

Secondary Outcomes

• 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))

Full Eligibility Criteria

-INCLUSION CRITERIA:

1. Participants must have a histologically confirmed diagnosis of metastatic breast cancer. Note: Pathology testing outside NIH will be accepted for eligibility purposes.
2. 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).
3. 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.
4. 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.
5. 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.
6. Age \>=18 years.
7. ECOG performance status \<2 (Karnofsky \>60%)
8. Participants must have organ and marrow function as defined below:

   * Leukocytes \>= 3,000/mcL
   * Hemoglobin \>= 8g/dL
   * Absolute neutrophil count \>= 1,200/mcL
   * Platelets \>=75,000/mcL
   * Total bilirubin \<= 1.5 x institutional upper limit of normal (In the case of known Gilbert's Disease, total bili \>1.5 may be considered.)
   * AST(SGOT)/ALT(SGPT) \<= 3x institutional upper limit of normal
   * Creatinine \< 1.5 x normal institutional limits OR Creatinine clearance \>=60 mL/min/1.73 m2
9. Ability to take oral medications.
10. Participants with an existing diagnosis of diabetes or hypertension, must have disease well-controlled with at least annual physician follow-up.
11. Women of child-bearing potential and men with a partner of child-bearing potential must be willing to use appropriate contraception in the event that they match to a therapy that requires such. The duration of contraception use will depend on the therapy assigned.
12. Willingness to comply with required study procedures and visits for the duration of study.
13. Participants with asymptomatic brain metastases may be included if metastases have been previously treated with local therapy including radiation at least 4 weeks prior to first dose of treatment and there is no indication for additional local therapy (including active progression).
14. Participants with human immunodeficiency virus (HIV) must be on an effective antiretroviral therapy with undetectable viral load for at least the last 6 months.
15. Participants with evidence of chronic hepatitis B virus (HBV) infection, must have HBV viral load that is undetectable on suppressive therapy, if indicated.
16. Participants with a history of hepatitis C virus (HCV) infection must have been treated and cured. Participants with HCV infection must be currently on treatment, with undetectable HCV viral load.
17. Participants with a prior or concurrent malignancy are eligible if the natural history or treatment does not have the potential to interfere with the safety or efficacy assessment of the off-label therapies offered on this study in the 

Trial Locations

• National Institutes of Health Clinical Center, Bethesda, Maryland, United States

Frequently Asked Questions

Related Conditions

• Breast Cancer
• Metastatic Breast Cancer
• Triple-Negative Breast Cancer
• Hormone Receptor-Positive Breast Cancer
• Endocrine-Resistant Breast Cancer
• Metastatic Cancer
• Oncology
• Cancer Therapy
• Precision Medicine
• Drug Repurposing

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