MC# 20-22 - An Open-label, Randomized, Multicenter Study Evaluating the Activity of Lasofoxifene Relative to Fulvestrant for the Treatment of Pre- and Postmenopausal Women with Locally Advanced or Metastatic ER+/HER2− Breast Cancer with an ESR1 Mutation
Agent(s): Lasofoxifene tartrate
Disease Type(s): Breast
Drug Classification(s): Small Molecule
Molecular Target(s): ERα and mutated ERα
Mechanism of Action
Lasofoxifene is a non-steroidal 3rd generation selective estrogen receptor modulator (SERM) that selectively binds to both ERα and mutated ERα (ESR1 mutation) with high affinity.
In this study, the sponsor and investigators want to learn:
- Compare the effects of a drug called fulvestrant to the effects of a drug called lasofoxifene on your breast cancer
- Determine if the time to progression while receiving lasofoxifene improves compared to fulvestrant without increasing side effects
- The effects of fulvestrant and lasofoxifene on certain aspects on the quality of your life
- Pre- or postmenopausal. Postmenopausal women are defined as:
- ≥60 years of age with no vaginal bleeding over the prior year, or
- <60 years with "premature menopause" or "premature ovarian failure” manifest 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
- surgical menopause with bilateral oophorectomy
Note: Premenopausal women who meet all of the other entry criteria must be maintained on ovarian suppression (such as Lupron) during the study and subjects counseled to use appropriate contraception to prevent pregnancy
- If possible, a biopsy of metastatic breast cancer tissue will be obtained to provide histological or cytological confirmation of ER+ and HER2− disease as assessed by a local laboratory, according to the American Society of Clinical Oncology/College of American Pathologists (ASCO/CAP) guidelines, using slides, paraffin blocks, or paraffin samples. If a biopsy is not possible, the ER and HER2 status from the tissue obtained at the time of the original diagnosis must confirm that the subject’s cancer is ER+ and HER2−.
- Locally advanced or metastatic breast cancer with radiological or clinical evidence of progression while on an AI in combination with a CDK4/6 inhibitor for advanced breast cancer with demonstrated prior sensitivity to endocrine therapy (recurrence or progression after at least 12 months of treatment in the metastatic setting)
- Locally advanced or metastatic breast cancer with measurable (according to RECIST 1.1) and/or non-measurable lesions
- At least one or more of the following ESR1 point mutations as assessed in cell-free circulating tumor DNA (ctDNA) obtained from a blood (plasma) or tissue sample: Y537S, Y537C, D538G, E380Q, S463P, V534E, P535H, L536H, L536P, L536R, L536Q, or Y537N. The ctDNA sample collection must be obtained within 90 days prior to randomization to determine eligibility and baseline.
Note: a prior genomic test confirming that the subject has an ESR1 mutation can be used to determine eligibility; however, an ESR1 sample must also be collected within 30 days of randomization
- Subjects who have not received cytotoxic chemotherapy as well as those who have received one cytotoxic chemotherapy regimen in the neo-adjuvant or adjuvant setting prior to entry into the trial. Subjects must be free of all chemotherapy acute toxicity excluding alopecia and Grade II peripheral neuropathy before study entry.
- ECOG performance score of 0 or 1
- Adequate organ function as shown by:
- absolute neutrophil count (ANC) ≥1,500 cells/mm3
- platelet count ≥100,000 cells/mm3
- hemoglobin ≥9.0 g/dl
- ALT and AST levels ≤2.5 upper limit of normal (ULN) or <5 in the presence of visceral metastasis
- total serum bilirubin ≤0.5 X ULN (≤3.0 X ULN for subjects known to have Gilbert Syndrome)
- alkaline phosphatase level ≤2.5 X ULN
- creatinine clearance of 40 ml/min or greater as calculated by the Cockcroft-Gault formula
- international normalized ratio (INR) and activated partial thromboplastin (aPTT) <2.0 X ULN
- Able to swallow tablets
- Able to understand and voluntarily sign a written informed consent before any screening procedures
- Prior use of everolimus or other mammalian target of rapamycin (mTOR) inhibitor or phosphoinositide 3-kinase inhibitor (PI3K) inhibitors are excluded unless discontinued due to reasons other than disease progression
- Presence of brain metastasis
- Lymphangitic carcinomatosis involving the lung
- Impending visceral crisis in need of cytotoxic chemotherapy as assessed by the investigator
- Radiotherapy within 30 days prior to randomization 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 randomization. Subjects must have recovered from radiotherapy toxicities prior to randomization.
- History of long QTC syndrome or a QTC of >480 msec
- History of a pulmonary embolus (PE) or deep vein thrombosis (DVT) within the last 6 months or any known thrombophilia. Subjects stable on anti-coagulants for maintenance are eligible as long as the DVT and/or PE occurred >6 months prior to enrollment and there is no evidence for active thrombosis. The use of low dose acetylsalicylic acid (ASA) is permitted.
- Any significant co-morbidity that would impact the study or the subject’s safety
- History of a positive human immunodeficiency virus (HIV), hepatitis B virus (HBV) or hepatitis C virus (HCV) at Screening. Subjects cured of hepatitis C (no viral load) are eligible.
- 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, or early stage cervical cancer
- History of vaginal bleeding over the last year unless it is documented that the bleeding was due to non-uterine causes (e.g. vaginal atrophy)
- Uncontrolled hypertension defined as sitting systolic pressure >160 mm Hg or diastolic pressure >100 mm Hg at Screening
- 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
- Dallas, TX - Mary Crowley Cancer Research - Medical City