Biomarker-Driven Therapies for the Treatment of Metastatic Estrogen Receptor Positive, HER2 Negative and Triple-Negative Breast Cancer, EVOLVE-BDT Trial

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, 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, typically an investigational or biomarker-driven regimen versus a shared control or reference arm. (Category B-Between-Arm Evaluation)

PRIMARY OBJECTIVES (SUBPROTOCOL #1)

I. To evaluate the efficacy of second-line (2L) endocrine therapy (ET) combined with resistance targeting drugs (tumors without PIK3CA/AKT/PTEN aberrations: CDK4/6 inhibitor or mTOR inhibitor; tumors with PIK3CA/AKT/PTEN aberrations: CDK4/6 inhibitor or PI3-kinase/mTOR pathway 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 chemotherapy-based regimens (including antibody-drug conjugates) or antiandrogen therapy in second-line (2L) triple-negative breast cancer (TNBC), stratified by PDL1 status, relative to prespecified historical control benchmarks.

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), 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.

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.