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

Study Overview
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Brief Summary
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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.

Official Title
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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

Conditions
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Metastatic Breast Cancer

Intervention / Treatment
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* Drug: Lasofoxifene in combination with abemaciclib
* Drug: Fulvestrant in combination with abemaciclib


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: 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 either measurable (according to RECIST 1.1) or 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. Exclusion Criteria: Lymphangitic carcinomatosis involving the lung. 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. Subjects with a known hypersensitivity to fulvestrant or to any of the excipients 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). 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.) History of long QTc (Q-T interval corrected for heart rate) syndrome or a QTc of >480 msec. History of a pulmonary embolus (PE), deep vein thrombosis (DVT), or any known thrombophilia. 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). On concomitant strong CYP3A4 inhibitors. 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. 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. Positive serum pregnancy test (only if premenopausal). Sexually active premenopausal women and men unwilling to use double-barrier contraception. Women who are breast feeding History of non-compliance to medical regimens. Unwilling or unable to comply with the protocol. Current participation in any clinical research trial involving an investigational drug or device within the last 30 days.

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Interventional Model Description: open label, randomized, parallel-group, multicenter study
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Treatment<br>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. | Drug: Lasofoxifene in combination with abemaciclib<br>* 5 mg/d of oral lasofoxifene plus oral abemaciclib 150 mg twice a day<br>|
| Active Comparator: Reference Therapy<br>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. | Drug: Fulvestrant in combination with abemaciclib<br>* Fulvestrant 500 mg intramuscular (IM) on Days 1, 15, and 29 and then once monthly thereafter plus oral abemaciclib 150 mg twice a day<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Progression free survival (PFS) | 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. | Within approximately 3 years | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Objective response rate (ORR) | 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. | Within approximately 3 years | 
| Overall survival (OS) | Overall survival is defined as time from the date of Visit 0 (Day 1) to death due to any cause. | Within approximately 3 years | 
| Clinical benefit rate (CBR) | 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. | Within approximately 3 years | 
| Duration of response (DoR) in subjects with an objective response | 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. | Within approximately 3 years | 
| Time to response (TTR) in subjects with an objective response | TTR is from the date of randomization to the date of first documented confirmed response (CR or PR). | Within approximately 3 years | 
| Time to cytotoxic chemotherapy | From the date of randomization to the date of first documented use of cytotoxic chemotherapy. | Within approximately 3 years | 
| Quality of Life (QoL) evaluated using the Functional Assessment of Cancer Therapy-Breast Cancer-Endocrine Subscale (FACT B-ES) | Scale ranges from 'Not at all' to 'Very much' | Within approximately 3 years | 
| Incidence of Adverse Events (AEs) and Serious AEs | 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 | Within approximately 3 years |