Metastatic Breast Cancer
Conditions
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.
Interventions
DRUGLasofoxifene in combination with abemaciclib
5 mg/d of oral lasofoxifene plus oral abemaciclib 150 mg twice a day
DRUGFulvestrant 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
Sponsors
LeonaBio
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Intervention model description
open label, randomized, parallel-group, multicenter study
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
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 at least 1 measurable (according to RECIST 1.1) lesion with or without 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. 23. Subjects with a history of familial hypertriglyceridemia or fasting triglyceride levels \>880 mg/dL at screening. 24. 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). 25. 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).
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| 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 as determined by BICR or death due to any cause. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| 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. |
| 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. |
| 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). |
| Time to cytotoxic chemotherapy | Within approximately 3 years | From the date of randomization to the date of first documented use of cytotoxic chemotherapy. |
| 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 |
Countries
Australia, Belgium, Canada, China, France, Germany, Israel, Italy, Poland, Romania, Singapore, South Korea, Spain, Taiwan, Turkey (Türkiye), United Kingdom, United States
Contacts
CONTACTSimon Daggett - Senior Vice President, Clinical Operations
Outcome results
None listed