Efficacy and Safety of Lasofoxifene and Abemaciclib vs. Fulvestrant and Abemaciclib in ER+/HER2- Advanced Breast Cancer with ESR1 Mutation
- Trial ID
- 2023-503708-10-00
- Protocol
- SMX 22-002
- Sponsor
- Leonabio Inc.
Trial statistics
Diseases & Conditions
Objectives
The primary objective of this study is to evaluate the **progression free survival** (PFS) of the combination of lasofoxifene and abemaciclib compared to fulvestrant and abemaciclib. This is specifically for the treatment of pre- and postmenopausal women and men with locally advanced or metastatic estrogen receptor positive (ER+)/human epidermal growth factor 2 negative (HER2−) breast cancer with an estrogen receptor 1 (ESR1) mutation, who have previously received ribociclib or palbociclib-based treatment. The clinical relevance of this objective lies in determining the efficacy of the lasofoxifene and abemaciclib combination in extending the time patients live without disease progression, which is crucial for improving patient outcomes in this population.
Secondary objectives include:
- Evaluating the antitumor response of each drug regimen, characterized by objective response rate (ORR), overall survival (OS), clinical benefit rate (CBR), duration of response (DoR) in subjects with an objective response, and time to response (TTR) in subjects with an objective response.
- Determining the time to cytotoxic chemotherapy for the study population.
- Assessing quality of life (QoL) using the Functional Assessment of Cancer Therapy Breast Cancer-Endocrine Subscale (FACT B-ES) and evaluating safety.
Participants
The clinical trial involves a total of **193 participants** diagnosed with **locally advanced or metastatic breast cancer**. The study population includes both pre- and postmenopausal women and men, with an age range starting from 18 years and above. Participants were selected based on their previous treatment history, specifically those who have received ribociclib or palbociclib-based treatment and have estrogen receptor-positive (ER+)/human epidermal growth factor receptor 2 negative (HER2-) breast cancer with an estrogen receptor 1 (ESR1) mutation. The trial includes individuals who may have received one cytotoxic chemotherapy regimen in the metastatic disease setting, provided they have recovered from acute toxicity. Participants are required to have an Eastern Cooperative Oncology Group (ECOG) performance score of 0 or 1, indicating they are fully active or restricted in physically strenuous activity but ambulatory. The trial population is diverse, including both genders and vulnerable populations, with no specific lifestyle considerations such as diet or physical activity mentioned. Key inclusion criteria include adequate organ function and the ability to swallow tablets, while brain metastases are permissible under certain conditions. The trial aims to evaluate the progression-free survival of a combination therapy involving lasofoxifene and abemaciclib compared to fulvestrant and abemaciclib.
Plans and Procedures
The clinical trial is designed as an **open-label**, randomized, multicenter study to evaluate the efficacy and safety of the combination of **lasofoxifene** and **abemaciclib** compared to **fulvestrant** and abemaciclib in treating pre- and postmenopausal women and men with locally advanced or metastatic **breast cancer** with an **ESR1 mutation**. The trial aims to assess progression-free survival (PFS) as the primary endpoint, with secondary endpoints including objective response rate (ORR) and overall survival (OS). The study is expected to run from October 2023 to October 2026, with a maximum treatment period of 27 months for participants.
Participants will undergo a series of study visits, beginning with an inclusion (screening) visit to confirm eligibility based on criteria such as age, disease status, and previous treatments. The trial will include regular follow-up visits to monitor treatment efficacy and safety, with assessments conducted according to **RECIST 1.1** guidelines. The end-of-study visit will occur upon completion of the treatment period or earlier if disease progression or unacceptable toxicity is observed. Participants are expected to be involved in the study for the full duration unless they meet conditions for early termination, such as withdrawal of consent, non-compliance with study procedures, or adverse events that necessitate discontinuation.
The trial involves the administration of lasofoxifene and abemaciclib in tablet form, taken orally, and fulvestrant as a solution for injection, administered intramuscularly. The study will ensure that participants have adequate organ function and meet other health criteria before enrollment. The trial's design and procedures are structured to provide robust data on the comparative efficacy and safety of the treatment regimens, contributing valuable insights into the management of advanced breast cancer with ESR1 mutations.
Treatment
The clinical trial involves the administration of **Lasofoxifene**, a chemical entity provided in the form of a tablet. The active substance, lasofoxifene, is administered orally. The maximum daily dose is 5 mg, with a total maximum dose of 5475 mg over a treatment period of 27 weeks. The medication is produced by Sermonix Pharmaceuticals Inc. and is not formulated for pediatric use. Participant compliance with the dosing schedule will be monitored throughout the trial.
**Fulvestrant** is utilized as a comparator treatment in this study. It is a chemical entity available as a solution for injection. The active substance, fulvestrant, is administered intramuscularly. The maximum daily dose is 500 mg, with a total maximum dose of 14.5 g over the same 27-week treatment period. This medication is also manufactured by Sermonix Pharmaceuticals Inc. and is not intended for pediatric patients. Compliance with the administration schedule will be closely monitored.
**Abemaciclib** is another experimental medication used in combination with both lasofoxifene and fulvestrant. It is provided in tablet form and is administered orally. The maximum daily dose is 300 mg, with a total maximum dose of 328.5 g over the 27-week treatment period. Abemaciclib is produced by Sermonix Pharmaceuticals Inc. and is not a pediatric formulation. Participant adherence to the dosing regimen will be assessed regularly to ensure compliance.
Efficacy
The efficacy of the clinical trial will be assessed primarily through **Progression Free Survival (PFS)**, which is defined as the time from the date of randomization to the earliest date of first documented progression or death due to any cause. This endpoint will provide a measure of how long patients remain free from disease progression while on the treatment regimen. Secondary efficacy endpoints include the **Objective Response Rate (ORR)**, which is the percentage of subjects with measurable disease at baseline whose best overall response is either a confirmed complete response (CR) or a confirmed partial response (PR) according to RECIST 1.1 criteria. Additionally, **Overall Survival (OS)** will be evaluated, defined as the time from the date of randomization to death due to any cause.
The trial will involve the administration of Lasofoxifene and Abemaciclib in combination, compared to Fulvestrant and Abemaciclib, for the treatment of pre- and postmenopausal women and men with locally advanced or metastatic estrogen receptor-positive (ER+)/human epidermal growth factor receptor 2-negative (HER2-) breast cancer with an ESR1 mutation. The study is designed to compare the efficacy and safety of these combinations in patients who have previously received ribociclib or palbociclib-based treatment. The trial is open-label and randomized, ensuring that the allocation of treatments is unbiased and that the results are scientifically valid.
Inclusion and Exclusion Criteria
Inclusion Criteria
- Age ≥18 years of age or a country's minimal age of maturity or greater.
- Adequate organ function as shown by: a. absolute neutrophil count (ANC) ≥1,000 cells/mm3 (≥1 g/L) b. platelet count ≥100,000 cells/mm3 (≥100 g/L) c. hemoglobin ≥8.0 g/dl (80 g/L) d. ALT and AST levels ≤3 upper limit of normal (ULN) or ≤5 in the presence of liver metastasis e. total serum bilirubin ≤1.5 X ULN (≤3 X ULN for subjects known to have Gilbert Syndrome) f. alkaline phosphatase level ≤3 ULN g. creatinine clearance of 40 mL/min or greater as calculated by the Cockcroft-Gault formula or by a standard method used by the investigational site.
- Able to swallow tablets
- Able to understand and voluntarily sign a written informed consent before any screening procedures.
- Pre- or postmenopausal women or men. Postmenopausal women are defined as: a. ≥60 years of age with no vaginal bleeding over the prior year, or b. <60 years with "premature menopause" or "premature ovarian failure,” which manifests itself with secondary amenorrhea for at least 1 year and follicle stimulating hormone (FSH) and estradiol levels in the postmenopausal range according to institutional standards, or c. surgical menopause with bilateral oophorectomy.
- 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−.
- Locally advanced and/or metastatic 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 locally advanced or metastatic disease. Before starting study treatment, subjects should have stopped any CDKi for at least 14 days. The subject may have received hormonal treatment in the adjuvant setting and up to 2 prior lines of endocrine therapy for metastatic disease. No prior adjuvant CDK4/6 inhibitor is allowed.
- 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. Examples may include, but not be limited to, the mutations Y537S, Y537C, D538G, E380Q, S463P, V534E, P535H, L536H, L536P, L536R, L536Q, and Y537N or other ESR1 missense mutation(s) between codons 310 and 547 known to induce protein changes to the ESR1 binding domain. The ctDNA sample collection or tissue must be obtained within 90 days prior to Screening to determine eligibility and baseline
- Locally advanced or metastatic breast cancer with either measurable (according to RECIST 1.1 [Eisenhauer, et al, 2009]) 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. A washout period of at least 14 days is required between last chemotherapy dose and entry into the study. (Antibody drug conjugates [ADC] and poly (ADP-ribose) polymerase [PARP] inhibitors are considered systemic chemotherapy.)
- Eastern Cooperative Oncology Group (ECOG) performance score of 0 or 1
- Brain metastases are allowed only if the following 4 parameters hold: a. Asymptomatic, b. Definitively treated (e.g., radiotherapy, surgery), c. Not requiring steroids up to 4 weeks before study treatment initiation, AND d. Central nervous system disease stable for >3 months prior to registration as documented by magnetic resonance imagining (MRI).
Exclusion Criteria
- Lymphangitic carcinomatosis involving the lung.
- Positive serum pregnancy test (only if premenopausal).
- 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).
- 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
- 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
- Any significant co-morbidity that would impact the study or the subject’s safety, including subjects with significant malabsorption. Since the occurrence of ILD has been reported with CDKi, subjects with a history of ILD and those with severe dyspnea at rest or requiring oxygen therapy should not enter the study.
- Active systemic bacterial or fungal infection (requiring intravenous [IV] antibiotics or antifungal drugs at the time of initiating study treatment).
- History of a PE, 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 such as clarithromycin, telithromycin, nefazodone, itraconazole, ketoconazole, atazanavir, darunavir, indinavir, lopinavir, nelfinavir, ritonavir, saquinavir, or tipranavir.
- Sexually active premenopausal women and men unwilling to use contraception
- On strong and moderate CYP3A4 inducers such as amprenavir, barbiturates, carbamazepine, clotrimazole, dexamethasone, efavirenz, ethosuximide, griseofulvin, modafinil, nevirapine, oxcarbazepine, phenobarbital, phenytoin, chronic prednisone treatment, primidone, rifabutin, rifampin, rifapentine, ritonavir, or topiramate.
- History of Grade 3 or Grade 4 interstitial lung disease (ILD) on previous therapy.
- History of non-compliance to medical regimens.
- 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).
- 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.
- Known infection with HIV, Hepatitis B virus (HBV), or Hepatitis C virus (HCV). Patients with resolved HBV infection (defined as having a negative hepatitis B surface antigen [HbsAg] test and a positive hepatitis B core antibody {HbcAb] test, accompanied by a negative HBV DNA test) are eligible. Patients positive for HCV antibody are eligible only if polymerase chain reaction (PCR) is negative for HCV RNA.
- 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. For history of other cancers considered to have a low risk of recurrence, discussion with the Medical Monitor is required
- Women who are breast feeding
Trial Status by Country
| Country | Status | Start of Recruitment | Planned Patients |
|---|---|---|---|
 Belgium | Recruiting | 13 Oct 2023 | 20 |
 France | Recruiting | 13 Oct 2023 | 52 |
 Germany | Not Yet Recruiting | 13 Oct 2023 | 11 |
 Hungary | Not Recruiting | 13 Oct 2023 | 1 |
 Italy | Recruiting | 13 Oct 2023 | 70 |
 Poland | Recruiting | 13 Oct 2023 | 26 |
 Romania | Recruiting | 13 Oct 2023 | 24 |
 Spain | Recruiting | 13 Oct 2023 | 86 |
Sites & Investigators
Investigational Products
Details about the medicinal products being studied in this clinical trial.
| Product Name | Role in Trial | Formulation | Administration | Max Daily Dose | Treatment Duration | EU MP Number |
|---|---|---|---|---|---|---|
Abemaciclib | Test | TABLET | ORAL | 300 | 27 | PRD10375240 |
Lasofoxifene | Test | TABLET | ORAL | 5 | 27 | PRD10370082 |
Fulvestrant | Comparator | SOLUTION FOR INJECTION | INTRAMUSCULAR | 500 | 27 | PRD10375182 |