Evaluation of Lasofoxifene Combined With Abemaciclib Compared With Fulvestrant Combined With Abemaciclib in Locally Advanced or Metastatic ER+/HER2- Breast Cancer With an ESR1 Mutation

Phase 3

Recruiting

• Conditions: Metastatic Breast Cancer
• Interventions: Drug: Fulvestrant in combination with abemaciclib; Drug: Lasofoxifene in combination with abemaciclib

• Registration Number: NCT05696626
• Lead Sponsor: Sermonix Pharmaceuticals Inc.

Brief Summary

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.

Detailed Description

Not available

Study Timeline

• Study First Submitted: 2023-01-13
• Study First Submitted QC: 2023-01-13
• Study First Posted: 2023-01-25
• Study Start: 2023-10-31
• Status Verified: 2025-09
• Last Update Submitted: 2025-09-08
• Last Update Posted: 2025-09-12
• Primary Completion: 2027-04
• Study Completion: 2028-04-01

Recruitment & Eligibility

• Status: RECRUITING
• Sex: All
• Target Recruitment: 500

Inclusion Criteria

1. Pre- or postmenopausal women or men.

2. 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.

3. Histological or cytological confirmation of ER+/HER2 - disease

4. No evidence of progression for at least 6 months on an AI/CDKi combination for advanced breast cancer.

5. 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.

6. Locally advanced or metastatic breast cancer with either measurable (according to RECIST 1.1) or non-measurable lesions.

7. 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.

8. Eastern Cooperative Oncology Group (ECOG) performance score of 0 or 1

9. Adequate organ function

10. Able to swallow tablets

11. Brain metastases are allowed only if the following 4 parameters hold:

    1. Asymptomatic,
    2. Definitively treated (e.g., radiotherapy, surgery),
    3. Not requiring steroids up to 4 weeks before study treatment initiation, AND
    4. Central nervous system disease stable for >3 months prior to registration as documented by magnetic resonance imagining (MRI).

12. Able to understand and voluntarily sign a written informed consent before any screening procedures.

13. 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 Criteria

1. Lymphangitic carcinomatosis involving the lung.
2. History of Grade 3 or Grade 4 interstitial lung disease (ILD) on previous therapy.
3. Visceral crisis in need of cytotoxic chemotherapy as assessed by the investigator.
4. Prior progression of disease on abemaciclib, fulvestrant, or other selective estrogen receptor degrader (SERD) therapy.
5. Subjects with a known hypersensitivity to fulvestrant or to any of the excipients
6. 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).
7. 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.)
8. History of long QTc (Q-T interval corrected for heart rate) syndrome or a QTc of >480 msec.
9. 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).
10. 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).
11. On concomitant strong CYP3A4 inhibitors.
12. On strong and moderate CYP3A4 inducers.
13. Any significant co-morbidity that would impact the study or the subject's safety, including subjects with significant malabsorption.
14. Active systemic bacterial or fungal infection (requiring intravenous [IV] antibiotics or antifungals at the time of initiating study treatment).
15. Known infection with human immunodeficiency virus (HIV), hepatitis B virus (HBV), or hepatitis C virus (HCV).
16. 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.
17. Positive serum pregnancy test (only if premenopausal).
18. Sexually active premenopausal women and men unwilling to use double-barrier contraception.
19. Women who are breast feeding
20. History of non-compliance to medical regimens.
21. Unwilling or unable to comply with the protocol.
22. Current participation in any clinical research trial involving an investigational drug or device within the last 30 days.

Study & Design

• Study Type: INTERVENTIONAL
• Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
Reference Therapy	Fulvestrant in combination with abemaciclib	Pre- and Postmenopausal Women and Men with locally advanced or metastatic ER+/HER2- breast cancer who have disease progression on an AI in combination with either palbociclib or ribociclib as their first hormonal treatment for metastatic disease and who have an ESR1 mutation.
Treatment	Lasofoxifene in combination with abemaciclib	Pre- and Postmenopausal Women and Men with locally advanced or metastatic ER+/HER2- breast cancer who have disease progression on an AI in combination with either palbociclib or ribociclib as their first hormonal treatment for metastatic disease and who have an ESR1 mutation.

Primary Outcome Measures

Name	Time	Method
Progression free survival (PFS)	Within approximately 3 years	PFS is defined as the time from the date of randomization \[Visit 0 (Day 1)\] to the earliest date of first documented progression per RECIST 1.1 or death due to any cause.

Secondary Outcome Measures

Name	Time	Method
Time to cytotoxic chemotherapy	Within approximately 3 years	From the date of randomization to the date of first documented use of cytotoxic chemotherapy.
Overall survival (OS)	Within approximately 3 years	Overall survival is defined as time from the date of Visit 0 (Day 1) to death due to any cause.
Clinical benefit rate (CBR)	Within approximately 3 years	CBR is defined as the percentage of subjects with best overall response of confirmed CR, confirmed PR, or stable disease (SD) with a duration of 24 weeks or longer according to RECIST 1.1. As used in this calculation, stable disease is defined as stable disease in those subjects with measurable disease plus nonPR/non progressive disease (PD) in subjects with non-measurable disease.
Duration of response (DoR) in subjects with an objective response	Within approximately 3 years	DoR is from the date of first documented confirmed response (CR or PR) to the date of first documented progression of disease or death due to any cause, whichever is earlier.
Objective response rate (ORR)	Within approximately 3 years	ORR is defined as the percentage of subjects with measurable disease at baseline whose best overall response is either a confirmed CR or a confirmed PR according to RECIST 1.1.
Time to response (TTR) in subjects with an objective response	Within approximately 3 years	TTR is from the date of randomization to the date of first documented confirmed response (CR or PR).
Quality of Life (QoL) evaluated using the Functional Assessment of Cancer Therapy-Breast Cancer-Endocrine Subscale (FACT B-ES)	Within approximately 3 years	Scale ranges from 'Not at all' to 'Very much'
Incidence of Adverse Events (AEs) and Serious AEs	Within approximately 3 years	The type, severity (graded by Common Terminology Criteria for Adverse Events \[CTCAE version 5.0\]), course, duration, seriousness, and relationship to study treatment will be assessed at each visit

Trial Locations

Locations (210)

Mayo Clinic - Scottsdale; 🇺🇸 Scottsdale, Arizona, United States

Cancer Care Specialists; 🇺🇸 Reno, Nevada, United States

Rutgers Cancer Institute of New Jersey; 🇺🇸 New Brunswick, New Jersey, United States

Presbyterian Rust Cancer Center; 🇺🇸 Rio Rancho, New Mexico, United States

University Hospitals Seidman Cancer Center; 🇺🇸 Cleveland, Ohio, United States

Swedish Cancer Institute (SCI); 🇺🇸 Seattle, Washington, United States

Anyang Tumour Hospital; 🇨🇳 Anyang, China

Peking Union Medical College Hospital; 🇨🇳 Beijing, China

Sun Yat-sen Memorial Hospital, Sun Yat-sen University; 🇨🇳 Guangzhou, China

The First Affiliated Hospital of Hainan Medical University; 🇨🇳 Haikou, China

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