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

Plain English Summary

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 is a Phase 3 clinical trial sponsored by LeonaBio studying Metastatic Breast Cancer. This trial tests two combinations of drugs: lasofoxifene plus abemaciclib versus fulvestrant plus abemaciclib. It is for pre- and postmenopausal women and men with advanced or metastatic ER+/HER2- breast cancer that has an ESR1 mutation and has progressed on prior hormonal therapy. Participants will receive one of the two treatment combinations. The study is randomized, meaning participants are assigned to a treatment group by chance. Standard treatment options for this type of cancer may include other hormone therapies or chemotherapy, depending on the specific situation and prior treatments. The trial aims to enroll 500 participants.

Official 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.

Who Can Participate

Here is what you need to know about eligibility for this trial. You may be eligible if you are a pre- or postmenopausal woman or man with ER+/HER2- breast cancer that has spread to other parts of the body (metastatic) or is locally advanced. Your cancer must have an ESR1 mutation and have progressed after treatment with an aromatase inhibitor (AI) and a CDK4/6 inhibitor (like palbociclib or ribociclib). You cannot have certain lung conditions, a history of severe interstitial lung disease, or a condition requiring immediate chemotherapy. You must have good organ function and an ECOG performance score of 0 or 1 (meaning you are capable of all self-care and are ambulatory at least 50% of the time). This trial is studying Metastatic Breast Cancer, so participants generally need a confirmed diagnosis. The trial is currently accepting new participants.

What They're Measuring

The primary outcome is progression-free survival, which means the trial will measure how long patients live without their cancer getting worse on either treatment combination. The specific primary outcome measures are: Progression free survival (PFS) (Within approximately 3 years). These endpoints are how researchers determine whether the treatment is effective and will form the basis of any future regulatory submissions.

About This Phase

This trial is in Phase 3, the final and most rigorous stage before seeking FDA approval. Phase 3 trials involve 300-3,000+ patients across multiple sites and compare the new treatment directly against the current standard of care. These pivotal trials generate the evidence needed for regulatory review. About 58% of Phase 3 drugs receive FDA approval. Successful Phase 3 results typically lead to a New Drug Application submission.

Why This Trial Matters

This trial addresses a significant need for new treatment options for patients with ER+/HER2- metastatic breast cancer who have specific ESR1 mutations and have progressed on standard therapies. As a Phase 3 trial, positive results could directly lead to FDA approval, making this treatment available to the broader patient population. This research targets Metastatic Breast Cancer, where improved treatment options are needed.

Investor Insight

This trial targets a specific subtype of breast cancer with a known resistance mechanism, indicating a focused approach to a challenging patient population. Success could lead to a new treatment optio Phase 3 trials have approximately a 50-60% chance of gaining FDA approval if they reach this stage.

Is This Trial Right for Me?

Ask your doctor if your cancer has an ESR1 mutation and if this trial is a good fit for your specific situation. Participation involves receiving one of two investigational drug combinations and regular study visits for monitoring and assessments. Be prepared for potential side effects and the need for regular blood draws and imaging scans. This trial is currently recruiting participants. The trial is being conducted at 20 sites. Always discuss clinical trial participation with your healthcare provider before making any decisions. This information is for educational purposes only and is not medical advice.

AI-generated analysis for educational purposes only. This is not medical advice. Discuss clinical trial participation with your doctor. Data sourced from ClinicalTrials.gov.

Study Design

• Study Type: INTERVENTIONAL
• Allocation: RANDOMIZED
• Model: PARALLEL
• Masking: NONE
• Enrollment: 500 participants

Interventions

• DRUG: Lasofoxifene in combination with abemaciclib — 5 mg/d of oral lasofoxifene plus oral abemaciclib 150 mg twice a day
• DRUG: Fulvestrant in combination with abemaciclib — Fulvestrant 500 mg intramuscular (IM) on Days 1, 15, and 29 and then once monthly thereafter plus oral abemaciclib 150 mg twice a day

Primary Outcomes

• Progression free survival (PFS) (Within approximately 3 years)

Secondary Outcomes

• Objective response rate (ORR) (Within approximately 3 years)
• Overall survival (OS) (Within approximately 3 years)
• Clinical benefit rate (CBR) (Within approximately 3 years)
• Duration of response (DoR) in subjects with an objective response (Within approximately 3 years)
• Time to response (TTR) in subjects with an objective response (Within approximately 3 years)

Full Eligibility Criteria

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.

Trial Locations

• Mayo Clinic - Scottsdale, Scottsdale, Arizona, United States
• University of Arizona - Cancer Center, Tucson, Arizona, United States
• Providence Medical Foundation - Santa Rosa, CA, Santa Rosa, California, United States
• Mayo Clinic - Jacksonville, Jacksonville, Florida, United States
• Miami Cancer Institute, Miami, Florida, United States
• Miami Cancer Institute Plantation, Plantation, Florida, United States
• Emory University School of Medicine, Atlanta, Georgia, United States
• Norton Cancer Institute, Louisville, Kentucky, United States
• Johns Hopkins Kimmel Cancer Center, Baltimore, Maryland, United States
• Massachusetts General Hospital, Boston, Massachusetts, United States
• ...and 10 more locations

Frequently Asked Questions

Related Conditions

• Metastatic Breast Cancer
• ER-positive Breast Cancer
• HER2-negative Breast Cancer
• Hormone Receptor-Positive Breast Cancer
• Advanced Breast Cancer
• ESR1-mutated Breast Cancer
• Endocrine-Resistant Breast Cancer
• Postmenopausal Breast Cancer
• Premenopausal Breast Cancer
• Metastatic Cancer

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