Compares two drug combinations for ESR1-mutated advanced ER-positive breast cancer

Trial details

Who runs it

LeonaBio

Trial code

NCT05696626EU 2023-503708-10-00

Record updated

29 October 2026

Original description

The goal of this clinical trial is to assess the efficacy, safety and tolerability of the combination of lasofoxifene and abemaciclib compared to fulvestrant and abemaciclib for the treatment of pre- and postmenopausal women and men who have previously received ribociclib or palbociclib-based treatment and have locally advanced or metastatic estrogen receptor positive (ER+)/human epidermal growth factor 2 negative (HER2-) breast cancer with an estrogen receptor 1 (ESR1) mutation.Read full original descriptionShow less

An Open Label, Randomized, Multicenter Study Comparing the Efficacy and Safety of the Combination of Lasofoxifene and Abemaciclib to the Combination of Fulvestrant and Abemaciclib for the Treatment of Pre- and Postmenopausal Women and Men With Locally Advanced or Metastatic ER+/HER2- Breast Cancer With an ESR1 Mutation

The goal of this clinical trial is to assess the efficacy, safety and tolerability of the combination of lasofoxifene and abemaciclib compared to fulvestrant and abemaciclib for the treatment of pre- and postmenopausal women and men who have previously received ribociclib or palbociclib-based treatment and have locally advanced or metastatic estrogen receptor positive (ER+)/human epidermal growth factor 2 negative (HER2-) breast cancer with an estrogen receptor 1 (ESR1) mutation.

The main question the study aims to answer is:

• To compare the efficacy of the combination of lasofoxifene and abemaciclib with that of fulvestrant and abemaciclib Participants will receive either receive 5 mg/d of oral lasofoxifene plus oral abemaciclib 150 mg twice a day or the combination of fulvestrant 500 mg intramuscular (IM) on Days 1, 15, and 29 and then once monthly thereafter plus oral abemaciclib 150 mg twice a day.

Inclusion: Pre- or postmenopausal women or men; Locally advanced and/or metastatic ER+ breast cancer with radiological or clinical evidence of progression on an AI in combination with either palbociclib or ribociclib as their first hormonal treatment for metastatic disease; Histological or cytological confirmation of ER+/HER2 - disease; No evidence of progression for at least 6 months on an AI/CDKi combination for advanced breast cancer; At least 1 or more ESR1 point mutations in the ESR1 ligand binding domain as assessed in cell- free ctDNA obtained from a blood or breast cancer tissue; Locally advanced or metastatic breast cancer with at least 1 measurable (according to RECIST 1.1) lesion with or without non-measurable lesions; Subjects may have received 1 cytotoxic chemotherapy regimen in the metastatic disease setting prior to study entry, but must have recovered from chemotherapy acute toxicity excluding alopecia and Grade 2 peripheral neuropathy; Eastern Cooperative Oncology Group (ECOG) performance score of 0 or 1; Adequate organ function; Able to swallow tablets; Brain metastases are allowed only if the following 4 parameters hold:; Asymptomatic,; Definitively treated (e.g., radiotherapy, surgery),; Not requiring steroids up to 4 weeks before study treatment initiation, AND; Central nervous system disease stable for >3 months prior to registration as documented by magnetic resonance imagining (MRI); Able to understand and voluntarily sign a written informed consent before any screening procedures; Every attempt should be made to obtain a biopsy of metastatic breast cancer tissue, when safe and feasible, to provide histological or cytological confirmation of ER+/HER2- disease as assessed by a local laboratory, according to American Society of Clinical Oncology/College of American Pathologists guidelines, using slides, paraffin blocks, or paraffin samples. If a biopsy is done, it may undergo genomic testing at some point to assess for ESR1 mutations and correlation with ctDNA results. If a biopsy is not possible or inappropriate from a clinical standpoint, the ER and HER2 status from the subject's most recent biopsy must confirm that the subject is ER+ and HER2.

Exclusion: History of Grade 3 or Grade 4 interstitial lung disease (ILD) on previous therapy; Visceral crisis in need of cytotoxic chemotherapy as assessed by the investigator; Prior progression of disease on abemaciclib, fulvestrant, or other selective estrogen receptor degrader (SERD) therapy; Radiotherapy within 30 days prior to Visit 0 (Day 1) except in case of localized radiotherapy for analgesic purposes or for lytic lesions at risk of fracture, which can then be completed within 7 days prior to Visit 0 (Day 1). Subjects must have recovered from radiotherapy toxicities prior to Visit 0 (Day 1); History of a pulmonary embolus (PE), deep vein thrombosis (DVT), or any known thrombophilia, unless the event occurred greater than 6 months prior to screening and the subject is treated with chronic anticoagulant therapy such as apixaban (Eliquis) or rivaroxaban (Xarelto); On concomitant strong CYP3A4 inhibitors; Current participation in any clinical research trial involving an investigational drug or device within the last 30 days; Subjects with a known hypersensitivity to fulvestrant or to any of the excipients; Lasofoxifene is not recommended for use in subjects with conditions that place them at increased risk for VTEs (such as severe congestive heart failure [CHF] or prolonged immobilization); Active systemic bacterial or fungal infection (requiring intravenous [IV] antibiotics or antifungals at the time of initiating study treatment); Known infection with human immunodeficiency virus (HIV), hepatitis B virus (HBV), or hepatitis C virus (HCV); History of malignancy within the past 5 years (excluding breast cancer), except basal cell or squamous cell carcinoma of the skin curatively treated by surgery; History of non-compliance to medical regimens; History of long QTc (Q-T interval corrected for heart rate) syndrome or a QTc of >480 msec; Positive serum pregnancy test (only if premenopausal); Subjects with a history of familial hypertriglyceridemia or fasting triglyceride levels >880 mg/dL at screening; Fasting triglyceride level >300 mg/dL and ≤880 mg/dL at screening. Subjects may be retested and enrolled if they have a repeat fasting triglyceride level less than or equal to 300 mg/dL prior to enrollment (e.g., after adjustment with diet and/or treatment); Fasting cholesterol level >400 mg/dL at screening. Subjects may be retested and enrolled if they have a repeat fasting cholesterol level less than or equal to 400 mg/dL prior to enrollment (e.g., after adjustment with diet and/or treatment); Lymphangitic carcinomatosis involving the lung; Known RB1 mutations or deletions that in the opinion of the investigator confer resistance to CDK4/6i. (Screening for RB1 mutation is not required for entry.); On strong and moderate CYP3A4 inducers; Any significant co-morbidity that would impact the study or the subject's safety, including subjects with significant malabsorption; Sexually active premenopausal women and men unwilling to use double-barrier contraception; Women who are breast feeding; Unwilling or unable to comply with the protocol.

ClinicalTrials.gov NCT05696626 · EU CTIS 2023-503708-10-00