Evolutionary Clinical Trial for Novel Biomarker-Driven Therapies (EVOLVE-BDT)

TBCRC Evolutionary Clinical Trial for Novel Biomarker-Driven Therapies (EVOLVE-BDT)

This is a multicenter, multi-arm, biomarker-stratified trial designed to evaluate biomarker-directed therapies in patients with estrogen receptor-positive/hormone receptor-negative (ER+/HR-) and triple-negative (TN) metastatic breast cancer (MBC). The trial integrates both retrospective and prospective data collection, including archival tumor tissue, medical record abstraction, and prospective tumor and blood sampling prior to initiation of protocol directed treatment. Based on biomarker subtype, participants will receive standard of care therapy. Liquid biopsy will be collected on Cycle 2 Day 1, and then liquid biopsy, imaging and clinical data will be collected at each re-staging. Treatment will continue until discontinuation for progression, toxicity or at the discretion of the treating physician.

Study Overview

• Status: Recruiting
• Conditions: Breast Cancer; Metastatic Breast Cancer; Triple Negative Breast Cancer; Estrogen-receptor-positive Breast Cancer; Hormone Receptor Negative Breast Carcinoma
• Intervention / Treatment: Drug: SERD* + abemaciclib; Drug: SERD* + everolimus; Drug: SERD* + everolimus or capecitabine; Drug: SOC; Drug: Antiandrogen

Detailed Description

The platform design makes it easy to assess multiple targeted therapies at the same time, focusing on patient groups identified by specific biomarkers. Patients who experience disease progression may be reassigned to additional eligible sub trials evaluating alternative therapeutic options. The primary endpoint for each arm is progression-free survival (PFS). This adaptive framework enables continuous learning and rapid translation of biomarker discoveries into therapeutic evaluation, promoting an agile and data-driven approach to treatment optimization in advanced breast cancer.

Beyond ER and HER2, there are few biomarkers to drive treatment decisions in metastatic and primary breast cancer, leaving a gap in effective treatments for other subtypes. To address this, triple-negative (TNBC) is pioneering an adaptive, evolutionary trial focusing on women with metastatic breast cancer (MBC) in the second-line (2L) setting. The adaptive trial infrastructure is designed to serve as an integrated parent study, enabling coordinated acquisition of clinical and translational data, as well as training and testing activities. Within this framework, individual biomarker-driven sub-trials (based on biomarker development) can be created and conducted.

Eligible participants include patients with ER+/HER2- or triple-negative (TNBC) metastatic breast cancer (MBC) who have progressed on first line (1L) therapy but have not yet initiated second-line (2L) treatment. HER2+ patients will be excluded due to the availability of established effective therapies.

This Sub Protocol #1 will enroll subjects based on biomarker subtype. Participants will receive a standard of care therapy. Liquid biopsy will be collected on Cycle 2 Day 1, and then liquid biopsy, imaging and clinical data will be collected at each re-staging. Treatment will continue until discontinuation for progression, toxicity or at the discretion of the treating physician. In order to participate in Sub Protocol #1 subjects must have consented to the Parent protocol.

• Study Type: Interventional
• Enrollment (Estimated): 700
• Phase: Phase 2

Contacts and Locations

• Study Contact: Name: Emily L Schworer; Phone Number: 919-984-0000; Email: emily_lane@med.unc.edu
• Study Contact Backup: Name: Ana Gallegos; Email: ana_gallegos@med.unc.edu

Study Locations

• United States
  • Minnesota
    • Rochester, Minnesota, United States, 55905
      • Not yet recruiting
      • Mayo Clinic
      • Principal Investigator: Karthik Giridhar, MD
      • Contact: Jen Hager; Email: hager.jennifer@mayo.edu
  • North Carolina
    • Chapel Hill, North Carolina, United States, 27599-7305
      • Recruiting
      • Lineberger Comprehensive Cancer Center at University of North Carolina - Chapel Hill
      • Principal Investigator: Lisa A Carey, MD
      • Contact: Lisa A. Carey, MD; Phone Number: 919-966-4431

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Adult; Older Adult
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

• Written informed consent obtained to participate in the study and HIPAA authorization for release of personal health information.
• Subject is willing and able to comply with study procedures based on the judgement of the investigator.
• Age ≥ 18 years of age at the time of consent
• ECOG Performance Status of 0-2 (see APPENDIX A: ECOG Performance Status Scale).
• Patients must fulfill all eligibility criteria outlined in the LCCC2521 Parent Protocol and consented to LCCC2521 Parent Protocol

Exclusion Criteria:

• Inaccessible metastatic lesion to research biopsy
• Subject has already initiated 2nd line therapy
• Concurrent disease or condition that in the opinion of the treating oncologist renders the patient inappropriate for study participation

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Non-Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

6

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Cohort 1 Arm A; ER+ (Estrogen Receptor Positive) and HER2- (Human Epidermal Growth Factor Receptor 2 Negative). ESR1 mutant positive or negative and Phosphatidylinositol 3-kinase catalytic subunit alpha / AKT serine/threonine kinase / PTEN loss or deletion negative.	Drug: SERD* + abemaciclib; Investigators choice Selective Estrogen Receptor Degrader + abemaciclib therapy.
Experimental: Cohort 1- Arm B; ER+ (Estrogen Receptor Positive) and HER2- (Human Epidermal Growth Factor Receptor 2 Negative). ESR1 mutant positive or negative and Phosphatidylinositol 3-kinase catalytic subunit alpha / AKT serine/threonine kinase / PTEN loss or deletion negative.	Drug: SERD* + everolimus; Investigators choice Selective Estrogen Receptor Degrader + everolimus therapy.
Experimental: Cohort 2 Arm A; ER+ (Estrogen Receptor Positive) and HER2- (Human Epidermal Growth Factor Receptor 2 Negative). ESR1 mutant negative or positive, and Phosphatidylinositol 3-kinase catalytic subunit alpha / AKT serine/threonine kinase / PTEN loss or deletion positive.	Drug: SERD* + abemaciclib; Investigators choice Selective Estrogen Receptor Degrader + abemaciclib therapy.
Experimental: Cohort 2 Arm B; ER+ (Estrogen Receptor Positive) and HER2- (Human Epidermal Growth Factor Receptor 2 Negative). ESR1 mutant negative or positive, and Phosphatidylinositol 3-kinase catalytic subunit alpha / AKT serine/threonine kinase / PTEN loss or deletion positive.	Drug: SERD* + everolimus or capecitabine; Investigators choice Selective Estrogen Receptor Degrader + everolimus or capecitabine therapy.
Active Comparator: Cohort 3; Triple-Negative Breast Cancer (TNBC): ER- (Estrogen receptor negative), PR- (Progesterone receptor negative), HER2- HER2 negative. AR - = Androgen Receptor negative, PD-L1 (Programmed Death-Ligand 1) positive or negative.	Drug: SOC; standard-of-care (SOC) chemotherapy in breast cancer
Experimental: Cohort 4; Triple-Negative Breast Cancer (TNBC): ER- (Estrogen receptor negative), PR- (Progesterone receptor negative), HER2- HER2 negative. AR + = Androgen Receptor positive, PD-L1 (Programmed Death-Ligand 1) positive or negative.	Drug: Antiandrogen; Antiandrogen therapy

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Intra-Individual Progression-Free Survival (PFS)	Progression-Free Survival (PFS) is defined as the time from initiation of study therapy until documented disease progression per Response Evaluation Criteria In Solid Tumors Criteria (RECIST) v1.1 or death from any cause, whichever occurs first. For intra-individual comparisons across successive therapy lines, a PFS ratio will be calculated by dividing the PFS of the current line (nth line, PFSₙ) by the PFS of the preceding line ((n-1)th line, PFSn-1). This allows each patient to serve as their own control, reducing between-patient variability and normalizing for the expected decline in PFS with later lines. RECIST v1.1 defines Complete Response (CR) as disappearance of all target lesions, Partial Response (PR) as ≥30% decrease, Stable Disease (SD) as insufficient change for PR or PD, and Progressive Disease (PD) as ≥20% increase, measurable growth in non-target lesions, or new lesions.	Up to 5 years

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Progression free survival (PFS) -Within Arm Evaluation	This endpoint assesses PFS in a specific treatment arm compared with a prespecified historical control derived from contemporary real-world data or prior clinical trials. Progression-Free Survival (PFS) is defined as the time from initiation of study therapy until documented disease progression per Response Evaluation Criteria In Solid Tumors Criteria (RECIST) v1.1 or death from any cause, whichever occurs first. RECIST v1.1 defines Complete Response (CR) as disappearance of all target lesions, Partial Response (PR) as ≥30% decrease, Stable Disease (SD) as insufficient change for PR or PD, and Progressive Disease (PD) as ≥20% increase, measurable growth in non-target lesions, or new lesions.	Up to 5 years
Progression free survival (PFS) - Between-Arm Evaluation	This endpoint assesses between two or more concurrently accruing arms, typically an investigational or biomarker-driven regimen versus a shared control or reference arm. Progression-Free Survival (PFS) is defined as the time from initiation of study therapy until documented disease progression per Response Evaluation Criteria In Solid Tumors Criteria (RECIST) v1.1 or death from any cause, whichever occurs first. RECIST v1.1 defines Complete Response (CR) as disappearance of all target lesions, Partial Response (PR) as ≥30% decrease, Stable Disease (SD) as insufficient change for PR or PD, and Progressive Disease (PD) as ≥20% increase, measurable growth in non-target lesions, or new lesions.	Up to 3 months
Tissue- and blood-based biomarkers on response rate	Tissue- and blood-based biomarkers predictive of response or resistance to standard-of-care first- and second-line therapies will be investigated. Response Evaluation Criteria In Solid Tumors Criteria (RECIST) v1.1 will be used for tumor response assessment. RECIST v1.1 defines Complete Response (CR) as disappearance of all target lesions, Partial Response (PR) as ≥30% decrease, Stable Disease (SD) as insufficient change for PR or PD, and Progressive Disease (PD) as ≥20% increase, measurable growth in non-target lesions, or new lesions.	Up to 3 months
Overall survival (OS)	Overall survival (OS) is defined as the time from initiation of study therapy to death from any cause.	Up to 12 months
Objective response rate (ORR)	Objective response rate (ORR) is defined as the proportion of subjects with a complete response or partial response to treatment according to Response Evaluation Criteria in Solid Tumors (RECIST)v1.1. RECIST v1.1 defines Complete Response (CR) as disappearance of all target lesions, Partial Response (PR) as ≥30% decrease, Stable Disease (SD) as insufficient change for PR or PD, and Progressive Disease (PD) as ≥20% increase, measurable growth in non-target lesions, or new lesions.	Up to 3 months
Duration of response (DoR)	DOR is defined as the time from documentation of PR or better to progressive disease (PD) and will be assessed according to Response Evaluation Criteria in Solid Tumors (RECIST) v1.1 for each investigational regimen. RECIST v1.1 defines Complete Response (CR) as disappearance of all target lesions, Partial Response (PR) as ≥30% decrease, Stable Disease (SD) as insufficient change for PR or PD, and Progressive Disease (PD) as ≥20% increase, measurable growth in non-target lesions, or new lesions.	Up to 12 months
Clinical benefit rate (CBR)	Clinical benefit rate (CBR) is defined as the proportion of patients who achieve a complete response (CR), partial response (PR), or stable disease (SD) per Response Evaluation Criteria in Solid Tumors (RECIST) v1.1. RECIST v1.1 defines Complete Response (CR) as disappearance of all target lesions, Partial Response (PR) as ≥30% decrease, Stable Disease (SD) as insufficient change for PR or PD, and Progressive Disease (PD) as ≥20% increase, measurable growth in non-target lesions, or new lesions. C	Up to 12 months
Grade 2 or above Adverse Events per NCI Common Terminology Criteria for Adverse Events (CTCAE)	Grade 2 or above treatment attributed Adverse Events per NCI CTCAE will be reported. The NCI CTCAE is a descriptive terminology which can be utilized for Adverse Event (AE) reporting. A grading (severity) scale is provided for each AE term. Grade 1 Mild; asymptomatic or mild symptoms; clinical or diagnostic observations only; intervention not indicated. Grade 2 Moderate; minimal, local or noninvasive intervention indicated; limiting age-appropriate instrumental Activities of Daily Living (ADL). Grade 3 Severe or medically significant but not immediately life-threatening; hospitalization or prolongation of hospitalization indicated; disabling; limiting self-care ADL. Grade 4 Life-threatening consequences; urgent intervention indicated. Grade 5 Death related to AE.	Up to 12 months
Changes in circulating tumor DNA (ctDNA) levels	Changes in circulating tumor DNA (ctDNA) levels and mutation profiles under therapeutic pressure over time will be assessed. Circulating tumor DNA (ctDNA) mutation profiles during treatment will be assessed via blood draws using the Tempus Xf assay. Detected set of oncogenic drivers, resistance mutations, single nucleotide variants (SNVs), insertions and deletions (INDELs), copy number gains (CNGs) and gene rearrangements will be reported.	Up to 12 months
Changes in transcriptomic data - tissue	Changes in transcriptomic profiles under therapeutic pressure will be assessed over time. Transcriptomic data from baseline and post-baseline primary or metastatic tumor tissue will be generated using the Tempus XR platform, providing quantitative gene expression levels for each panel gene per sample.	Up to 12 months
Changes in transcriptomic data - blood	Transcriptomic changes under therapeutic pressure will be assessed over time using evRNA-seq expression levels obtained from blood-derived extracellular vesicles, in patient blood will provide quantitative estimates of gene transcript levels transcriptome-wide.	Up to 12 months
Changes in Circulating tumor DNA (ctDNA) and tumor response relation	Changes in ctDNA and tumor response relation over time will be assessed. ctDNA will be assessed via blood draws using the Tempus Xf assay and gene rearrangements will be reported. Tumor response will be evaluated at corresponding time points using RECIST v1.1 criteria. RECIST v1.1 defines Complete Response (CR) as disappearance of all target lesions, Partial Response (PR) as ≥30% decrease, Stable Disease (SD) as insufficient change for PR or PD, and Progressive Disease (PD) as ≥20% increase, measurable growth in non-target lesions, or new lesions.	Up to 12 months

Collaborators and Investigators

• Sponsor: UNC Lineberger Comprehensive Cancer Center
• Collaborators: Translational Breast Cancer Research Consortium; Breast Cancer Research Foundation; Advanced Research Projects Agency for Health (ARPA-H)
• Investigators: Principal Investigator: Lisa A Carey, MD, UNC Lineberger Comprehensive Cancer Center; Study Chair: Eric Winer, MD, Yale University

Publications and helpful links

Helpful Links

• University of North Carolina Lineberger Comprehensive Cancer Center Clinical Trials

Study record dates

Study Major Dates

• Study Start (Actual): February 16, 2026
• Primary Completion (Estimated): June 2, 2031
• Study Completion (Estimated): June 2, 2031

Study Registration Dates

• First Submitted: January 12, 2026
• First Submitted That Met QC Criteria: January 13, 2026
• First Posted (Actual): January 14, 2026

Study Record Updates

• Last Update Posted (Actual): May 20, 2026
• Last Update Submitted That Met QC Criteria: May 19, 2026
• Last Verified: May 1, 2026

More Information

Terms related to this study

• Keywords: biomarker directed therapies; biomarker stratified trial
• Additional Relevant MeSH Terms: Neoplasms by Site; Neoplasms; Skin Diseases; Breast Diseases; Skin and Connective Tissue Diseases; Breast Neoplasms; Triple Negative Breast Neoplasms; Physiological Effects of Drugs; Hormones, Hormone Substitutes, and Hormone Antagonists; Hormone Antagonists; Organic Chemicals; Heterocyclic Compounds, 1-Ring; Heterocyclic Compounds; Nucleic Acids, Nucleotides, and Nucleosides; Pharmacologic Actions; Chemical Actions and Uses; Deoxycytidine; Cytidine; Pyrimidine Nucleosides; Pyrimidines; Macrolides; Lactones; Nucleosides; Uracil; Pyrimidinones; Deoxyribonucleosides; Fluorouracil; Sirolimus; Capecitabine; Everolimus; Androgen Antagonists; abemaciclib
• Other Study ID Numbers: LCCC2521-TBCRC-073(EVOLVE-BDT); 140D042590009 (Other Identifier: ARPA-H)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No