An Exploratory Study Using a Synthetic Lethality-Focused Algorithm to Identify Therapeutic Options in Advanced Metastatic Breast Cancer (SYNTHESIS-Breast)
试验速览
- 阶段
- 不适用
- 状态
- 招募中
- 入组人数
- 175
- 试验地点
- 2
- 主要终点
- Part A: To assess the feasibility of using the ENLIGHT algorithm to match heavily pretreated participants with metastatic breast cancer to off-label therapies
研究概览
简要总结
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.
详细描述
Background:
- While 10-20% of breast cancers diagnosed in the U.S. are "triple-negative" (TNBC), the 5-year survival rate among TNBC patients with metastatic disease at diagnosis is 12%, and median survival after recurrence is approximately 24 months, demonstrating clear need for additional therapeutic options.
- Patients with metastatic hormone-receptor positive (HR+) breast cancer who develop endocrine-refractory disease (that is, no longer responsive to combinations including endocrine therapy) also suffer from a dearth of therapeutic options beyond cytotoxic chemotherapy, with overall survival after standard of care treatment (as seen across recent trials) often less than 1 year.
- Personalized oncology strategies have the potential to identify therapies across multiple cancer types. However, such strategies (which currently use patient DNA sequencing) only select a small subgroup of candidate patients by targeting direct matches in their cancers necessitating approaches that can broaden the pool of patients who may benefit from targeted therapies.
- Recent computational approaches are able to leverage additional -omics data, such as whole-transcriptome RNA-seq, and relationships between genes, such as synthetic lethality, to better predict responses to off-label targeted therapy or immunotherapy treatments compared to single-target strategies in retrospective clinical trial data.
- This study will apply the use of one such published computational transcriptomics algorithm, ENLIGHT, to prospectively identify therapeutic options for participants with metastatic breast cancer who currently experience limited treatment options.
Objectives:
- Part A: To assess the feasibility of using the ENLIGHT algorithm to match heavily pretreated participants with metastatic breast cancer to off-label therapies
- Part B (If feasibility-run in is met): To assess the objective response rate (ORR) of participants with advanced breast cancer using treatment recommended by the computational transcriptomics algorithm ENLIGHT
Eligibility:
研究设计
- 研究类型
- Interventional
- 分配方式
- Non Randomized
- 干预模型
- Parallel
- 主要目的
- Device Feasibility
- 盲法
- None
入排标准
- 年龄范围
- 18 Years 至 120 Years（Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •INCLUSION CRITERIA:
- •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, anticipate or 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 or decline to receive standard therapy that has been shown to prolong overall survival, or if such therapy is not deemed in the participant s best interest, 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.
- •Participants must have measurable disease per RECIST v1.
- •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:
- •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.)
- •(For participants with known liver involvement, <=3x institutional upper limit of normal)
- •AST(SGOT)/ALT(SGPT) <= 3x institutional upper limit of normal
- •(For participants with known liver involvement, <=5x institutional upper limit of normal)
- •Creatinine < 1.5 x normal institutional limits OR Creatinine clearance >=30 mL/min/1.73 m2
- •Ability to take oral medications.
- •Participants with an existing diagnosis of diabetes or hypertension, must have disease well-controlled with at least annual physician follow-up.
- •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.
- •Willingness to comply with required study procedures and visits for the duration of study.
- •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).
- •Participants with human immunodeficiency virus (HIV) must be on an effective anti-retroviral therapy with undetectable viral load for at least the last 6 months.
- •Participants with evidence of chronic hepatitis B virus (HBV) infection, must have HBV viral load that is undetectable on suppressive therapy, if indicated.
- •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.
- •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 opinion of the Principal Investigator (PI) and are otherwise eligible for this trial.
- •Participants with current symptoms of cardiac disease, or history of treatment with cardiotoxic agents, should have a clinical risk assessment of cardiac function using the New York Heart Association Functional Classification. Note: To be eligible for this trial, participants should be class 2B or better.
- •Ability of participant to understand and the willingness to sign a written informed consent document.
排除标准
- •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.
研究组 & 干预措施
1/No Recommended Match
Treatment per physician's choice
干预措施: Expression Networks for highLIGHting Tumor vulnerabilities (ENLIGHT) (Device)
2/Genomic Marker Associated with FDA-Approved On-Label Treatment
Treatment in accordance with genomic marker; treatment to be directed locally by referring/treating physician
干预措施: TruSight(R) Oncology 500 (Device)
1/No Recommended Match
Treatment per physician's choice
干预措施: TruSight(R) Oncology 500 (Device)
2/Genomic Marker Associated with FDA-Approved On-Label Treatment
Treatment in accordance with genomic marker; treatment to be directed locally by referring/treating physician
干预措施: TruSeq Matched Tumor Normal Whole Exome Sequencing Assay (Device)
3/Transcriptomic Match
Treatment regimen as selected by transcriptomic algorithm; treatment to be directed by NIH study team with requirement for treatment at NIH
干预措施: Expression Networks for highLIGHting Tumor vulnerabilities (ENLIGHT) (Device)
3/Transcriptomic Match
Treatment regimen as selected by transcriptomic algorithm; treatment to be directed by NIH study team with requirement for treatment at NIH
干预措施: TruSight(R) Oncology 500 (Device)
3/Transcriptomic Match
Treatment regimen as selected by transcriptomic algorithm; treatment to be directed by NIH study team with requirement for treatment at NIH
干预措施: TruSeq Matched Tumor Normal Whole Exome Sequencing Assay (Device)
1/No Recommended Match
Treatment per physician's choice
干预措施: TruSeq Matched Tumor Normal Whole Exome Sequencing Assay (Device)
2/Genomic Marker Associated with FDA-Approved On-Label Treatment
Treatment in accordance with genomic marker; treatment to be directed locally by referring/treating physician
干预措施: Expression Networks for highLIGHting Tumor vulnerabilities (ENLIGHT) (Device)
结局指标
主要结局
Part A: To assess the feasibility of using the ENLIGHT algorithm to match heavily pretreated participants with metastatic breast cancer to off-label therapies
时间窗: Assessed after the Reporting Visit of the 20th participant to the study, and to be completed before Part B
The number of participants of the first 20 enrolled overall having a match via ENLIGHT and being assigned to Arm 3.
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
时间窗: Every 2 cycles until progression of disease, completion of treatment, or 2 years after treatment initiation (whichever comes first)
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.
次要结局
- 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))
- 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.)