Biomarker-Driven Therapies for the Treatment of Metastatic Estrogen Receptor Positive, HER2 Negative and Triple-Negative Breast Cancer, EVOLVE-BDT Trial
This phase II trial evaluates the effect of using biomarkers to guide treatment decisions in patients with estrogen receptor positive (ER+), HER2 negative and triple negative breast cancer (TNBC) that has spread from where it first started (primary site) to other places in the body (metastatic) who have progressed on first line (1L) therapy. Studying samples of blood and tissue may help researchers identify specific features, called biomarkers, that may help match patients to the treatment that is most likely to help them. This information may also help doctors better understand why some tumors respond to treatment and others do not, so that future patients can receive more personalized care.
Inclusion Criteria
- EVOLVE-BDT PARENT PROTOCOL: Written informed consent obtained to participate in the study and Health Insurance Portability and Accountability Act (HIPAA) authorization for release of personal health information
- EVOLVE-BDT PARENT PROTOCOL: Subject is willing and able to comply with study procedures based on the judgement of the investigator
- EVOLVE-BDT PARENT PROTOCOL: Age ≥ 18 years of age at the time of consent
- EVOLVE-BDT PARENT PROTOCOL: Eastern Cooperative Oncology Group (ECOG) performance status of 0-2
- EVOLVE-BDT PARENT PROTOCOL: Prior diagnosis of ER+/HER2- or triple negative (TNBC) MBC
- EVOLVE-BDT PARENT PROTOCOL: ER+/HER2- subjects must have received endocrine therapy + CDK4/6 inhibitor (CDK4/6i) in the first line setting or relapsed while receiving adjuvant endocrine therapy (ET) + CDK4/6i
- EVOLVE-BDT PARENT PROTOCOL: Willing to undergo mandatory research biopsy prior to beginning sub protocol biomarker directed therapy * Baseline biopsy requirement can be waived if a patient had a biopsy completed within a 4-month window prior to the date of consent AND has sufficient tissue remaining to fulfill the Tempus assay requirements; details can be found in the lab manual
- EVOLVE-BDT PARENT PROTOCOL: Subjects must either be appropriate or CT staging or, for those that cannot have contrasted CT, may have PET/CT with the CT component without contrast at conventional diagnostic resolution (3-5 mm slide thickness). For subjects undergoing PET/CT in lieu of contrast-enhanced diagnostic CT (e.g., due to contraindication to iodinated contrast), the CT component of the PET/CT must match standard diagnostic CT image quality to the extent feasible. Low-dose CT performed solely for attenuation correction is not sufficient to meet protocol imaging requirements
- EVOLVE-BDT PARENT PROTOCOL: Willing to provide archival tumor tissue from the primary and/or metastatic lesion
- EVOLVE-BDT PARENT PROTOCOL: Must have RECIST v1.1-defined disease, meeting at least one of the following criteria: * (a) Measurable disease per RECIST v1.1, at least one target lesion that can be accurately measured in at least one dimension, with longest diameter >= 10 mm by spiral CT, MRI, or clinical exam (or >= 15 mm short axis for pathological lymph nodes by spiral CT or MRI) * (b) Non-measurable but RECIST-evaluable disease per RECIST 1.1, disease that does not meet measurable-disease criteria but is qualitatively trackable for unequivocal progression at protocol-defined imaging time points ** Eligible non-measurable evaluable categories include: bone disease with at least one lytic lesion or mixed lytic-sclerotic lesion (sclerotic-only lesions are excluded); pleural or pericardial effusion; ascites; lymphangitic disease (pulmonary or cutaneous); inflammatory breast disease with cutaneous component; lymphangitis cutis / pulmonitis; and abdominal masses not followed by CT or MRI but otherwise qualitatively trackable on imaging. . Patients enrolled under (b) are reported separately for response endpoints per RECIST 1.1 ** Patients whose disease does not meet either (a) or (b), that is, whose disease is neither measurable nor RECIST evaluable, are not eligible * Sub-protocol inheritance. Sub-protocols whose eligibility matches this parent protocol inherit the measurable and non-measurable evaluable definitions above. A sub-protocol that applies more restrictive eligibility (for example, restricting enrollment to patients with measurable disease only) states the deviation explicitly in its own eligibility criteria and describes how it differs from the parent
- EVOLVE-BDT PARENT PROTOCOL: Agree to consent onto an LCCC2521 subprotocol if applicable
- SUBPROTOCOL #1: Written informed consent obtained to participate in the study and HIPAA authorization for release of personal health information
- SUBPROTOCOL #1: Participant is willing and able to comply with study procedures based on the judgement of the investigator
- SUBPROTOCOL #1: Age ≥ 18 years of age at the time of consent
- SUBPROTOCOL #1: ECOG performance status of 0-2
- SUBPROTOCOL #1: Participants must fulfill all eligibility criteria outlined in the LCCC2521 Parent Protocol and consented to LCCC2521 Parent Protocol
- SUBPROTOCOL #1: For all cohorts, patients must be planned to receive treatment as outlined in standard of care (SOC) therapy
Exclusion Criteria
- EVOLVE-BDT PARENT PROTOCOL: Concurrent disease or condition that in the opinion of the treating oncologist renders the patient inappropriate for study participation
- EVOLVE-BDT PARENT PROTOCOL: Patients with no evidence of disease (NED)
- EVOLVE-BDT PARENT PROTOCOL: Patients who only have sclerotic lesions
- EVOLVE-BDT PARENT PROTOCOL: Patients whose disease cannot be assessed for progression by imaging, that is, disease that is neither measurable nor RECIST-evaluable per RECIST 1.1 (truly non-evaluable disease, including patients with metastatic disease detectable only by tumor markers or circulating tumor DNA without an imaging correlate), are not eligible
- SUBPROTOCOL #1: Participant has already initiated 2^nd line therapy
- SUBPROTOCOL #1: Concurrent disease or condition that in the opinion of the treating oncologist renders the participant inappropriate for study participation
Study sponsor and potential other locations can be found on ClinicalTrials.gov for NCT07340541.
Locations matching your search criteria
United States
Connecticut
New Haven
Maryland
Baltimore
Minnesota
Rochester
North Carolina
Chapel Hill
PRIMARY OBJECTIVES (PARENT PROTOCOL):
I. To establish a prospective, biomarker-adaptive clinical trial framework that enables seamless integration of emerging biomarker discoveries into sub-trials testing novel, biomarker-driven therapeutic approaches for patients with metastatic breast cancer (MBC).
Ia. To determine whether a particular treatment arm yields a clinically meaningful improvement in progression-free survival (PFS) relative to a prespecified historical control benchmark within a sub protocol, derived from contemporary real-world or prior clinical trial data; (Category A-Within-Arm Evaluation)
Ib. To compare PFS between two or more concurrently accruing arms within the same sub-protocol, typically an investigational biomarker-driven regimen versus a sub-protocol-specific reference arm. No reference arm is shared across subprotocols. (Category B-Between-Arm Evaluation)
Ic. To evaluate proposed novel biomarker targets and associated targeted therapies for initial efficacy and signal in a sequential monitoring framework. (Feasibility Pilot)
PRIMARY OBJECTIVES (SUBPROTOCOL #1)
I. To evaluate the efficacy of second-line (2L) endocrine therapy (ET) combined with resistance-targeting drugs, with participants in each ER+/HER2- cohort randomized 1:1 between a CDK4/6 inhibitor arm and an mTOR or PI3-kinase/AKT inhibitor arm (PIK3CA/AKT/PTEN wild-type cohort: CDK4/6 inhibitor versus mTOR inhibitor; PIK3CA/AKT/PTEN aberrant cohort: CDK4/6 inhibitor versus mTOR or PI3-kinase/AKT inhibitor), in patients with ER+/HER2- metastatic breast cancer (MBC), as measured by median progression-free survival (PFS) compared to historical control benchmarks.
II. To evaluate the median progression-free survival (PFS) with standard-of-care therapy in second-line (2L) triple-negative breast cancer (TNBC), relative to prespecified historical control benchmarks, with results reported stratified by PD-L1 status.
SECONDARY OBJECTIVES (PARENT PROTOCOL):
I. To use tissue- and blood-based biomarkers to identify and validate predictive biomarkers associated with response or resistance to standard-of-care (SOC) first- and second-line therapies.
II. To evaluate overall survival (OS), objective response rate (ORR), duration of response (DoR), and clinical benefit rate (CBR) for each investigational regimen.
III. To assess safety and tolerability, using harmonized adverse event (AE)/serious AE (SAE) definitions and Common Terminology Criteria for Adverse Events (CTCAE)-based toxicity grading.
IV. To characterize tumor evolution under therapeutic pressure, integrating serial circulating tumor deoxyribonucleic acid (ctDNA), imaging, and transcriptomic data.
SECONDARY OBJECTIVE (SUBPROTOCOL #1)
I. To evaluate secondary efficacy endpoints including best overall response rate (ORR) per Response Evaluation Criteria in Solid Tumors (RECIST) 1.1, clinical benefit rate (complete response [CR] + partial response [PR] + stable disease [SD] ≥ 24 weeks in measurable patients, or the RECIST 1.1 equivalent non-CR/non-progressive disease (PD) ≥ 24 weeks in non-target-only patients), overall survival (OS), and duration of response (DOR) among responders.
EXPLORATORY OBJECTIVES (PARENT PROTOCOL):
I. To identify frequency of acquisition of targetable biomarker-positivity by liquid biopsy after 1L, 2L, third line (3L)+ therapy.
II. To identify proportion of patients after 2L therapy (on conventional therapy or biomarker-driven novel approach) who enroll on 3L and greater sub-trials.
III. To identify the association between ctDNA and RECIST at each timepoint relative to response, progression and other relevant clinical endpoints.
EXPLORATORY OBJECTIVE (SUBPROTOCOL #1)
I. To provide serial biomarker imaging, and clinical data for identification of resistance and sensitivity biomarkers.
OUTLINE:
EVOLVE-BIOMARKER DRIVEN THERAPIES (BDT) PARENT PROTOCOL: Patients undergo computed tomography (CT) or positron emission tomography (PET)/CT, tumor biopsy and blood sample collection prior to beginning next therapy. Patients are then assigned to an available subtrial based on biomarkers identified during testing. Patients who experience disease progression may be reassigned to additional eligible subtrials evaluating alternative therapeutic options.
SUBPROTOCOL #1:
ER+/HER2- PATIENTS: Patients without PI3KCA, AKT, or PTEN changes and with or without ESR1 mutations are assigned to Cohort 1. Patients with PI3KCA, AKT, or PTEN changes and with or without ESR1 mutations are assigned to Cohort 2.
COHORT 1: Patients are randomized to 1 of 2 arms.
ARM A: Patients receive fulvestrant or another selective estrogen receptor down regulator (SERD) orally (PO) per investigators choice and abemaciclib per SOC in the absence of disease progression or unacceptable toxicity. Patients also undergo CT or PET/CT and blood sample collection throughout the study as well as a tumor biopsy sample collection with biopsy for clinical purposes after progression.
ARM B: Patients receive fulvestrant or other SERD PO per investigators choice and everolimus per SOC in the absence of disease progression or unacceptable toxicity. Patients also undergo CT or PET/CT and blood sample collection throughout the study as well as a tumor biopsy sample collection with biopsy for clinical purposes after progression.
COHORT 2: Patients are randomized to 1 of 2 arms.
ARM A: Patients receive fulvestrant or other SERD PO per investigators choice and abemaciclib per SOC in the absence of disease progression or unacceptable toxicity. Patients also undergo CT or PET/CT and blood sample collection throughout the study as well as a tumor biopsy sample collection with biopsy for clinical purposes after progression.
ARM B: Patients receive fulvestrant or other SERD PO per investigators choice and everolimus or capivasertib per SOC in the absence of disease progression or unacceptable toxicity. Patients also undergo CT or PET/CT and blood sample collection throughout the study as well as a tumor biopsy sample collection with biopsy for clinical purposes after progression.
TNBC PATIENTS: Patients with or without PD-L1 and without AR are assigned to Cohort 1. Patients with or without PD-L1 and with AR are assigned to Cohort 2.
COHORT 1: Patients receive SOC chemotherapy in the absence of disease progression or unacceptable toxicity. Patients also undergo CT or PET/CT and blood sample collection throughout the study as well as a tumor biopsy sample collection with biopsy for clinical purposes after progression.
COHORT 2: Patients receive antiandrogen therapy in the absence of disease progression or unacceptable toxicity. Patients also undergo CT or PET/CT and blood sample collection throughout the study as well as a tumor biopsy sample collection with biopsy for clinical purposes after progression.
After completion of study treatment, patients are followed for up to 5 years.
Trial PhasePhase II
Trial Typetreatment
Lead OrganizationUNC Lineberger Comprehensive Cancer Center
Principal InvestigatorLisa A. Carey
- Primary IDLCCC2521-PARENT
- Secondary IDsNCI-2026-03903, 25-2830
- ClinicalTrials.gov IDNCT07340541