MC# 20-42 - An Open-label, Multicenter Study Evaluating the Safety of Lasofoxifene in Combination with Abemaciclib for the Treatment of Pre- and Postmenopausal Women with Locally Advanced or Metastatic ER+/HER2− Breast Cancer and have an ESR1 Mutation

  • Agent(s): Lasofoxifene
  • Disease Type(s): Breast
  • Phase(s): II
  • 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 ERα (ESR1 mutation) receptors with high affinity.


In this study, the sponsor and investigators want to learn:

  • If the combination of lasofoxifene and abemaciclib is safe and effective enough to conduct further research in a larger number of subjects with breast cancer
Inclusion Criteria
  • Age ≥18 years of age
  • 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 American Society of Clinical Oncology/College of American Pathologists 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 is ER+ and HER2−.
  • Locally advanced or metastatic breast cancer with radiological or clinical evidence of progression on first and/or 2nd line of hormonal therapy for metastatic disease.  Progression may have occurred on no more than 2 of the following endocrine treatments for metastatic breast cancer: an aromatase inhibitor (AI) and/or fulvestrant either as monotherapy or in combination with any commercially approved CDKi; and/or the combination of fulvestrant and everolimus; and/or the combination of fulvestrant and alpelisib; and/or tamoxifen; and/or the combination of exemestane/everolimus. (Note: Before starting study treatment, subjects should have stopped any CDKi for at least 21 days)
  • Subjects must have had no evidence of progression for at least 6 months during their first hormonal treatment for advanced breast cancer
  • At least one or more of the following ESR1 point mutations as assessed in cell-free circulating tumor DNA (ctDNA) obtained from a blood or tissue sample: Y537S, Y537C, D538G, E380Q, S463P, V534E, P535H, L536H, L536P, L536R, L536Q, or Y537N.  Note: the Sponsor’s blood ctDNA assay must be used but tissue sequencing (if done) may be done by a validated commercial assay.
    • Note: A positive ESR1 mutation in tissue or ctDNA using a validated commercial assay if done prior or at the time of disease progression is acceptable to meet this entry criteria.  However, blood for ctDNA must still be obtained for genomic analyses using the sponsor’s ctDNA assay.
  • Locally advanced or metastatic breast cancer with either measurable (according to RECIST 1.1) or non-measurable lesions
  • Subjects who may have received one cytotoxic chemotherapy regime for metatastic disease, as well as those who received one cytotoxic chemotherapy regimen in the neo-adjuvant or adjuvant setting prior to entry into the trial, can be enrolled but must be free of all chemotherapy acute toxicity, excluding alopecia and Grade 2 peripheral neuropathy, before study entry.  A washout period of at least 21 days is required between last chemotherapy dose and entry into the study.
  • Stable breast cancer metastasis to the brain is allowed as long as the subject has received radiotherapy and not demonstrated any evidence of brain metastasis progression for at least 3 months after the completion of radiotherapy
  • 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 ≥8.0 g/dl
    • ALT and AST levels ≤3 upper limit of normal (ULN) or ≤5 in the presence of liver metastasis
    • total serum bilirubin ≤0.5 X ULN (≤3.0 X ULN for subjects known to have Gilbert Syndrome)
    • alkaline phosphatase level ≤3 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 time (aPTT) <2.0 X ULN
  • Able to swallow tablets
  • Able to understand and voluntarily sign a written informed consent before any screening procedures
Exclusion Criteria
  • Lymphangitic carcinomatosis involving the lung
  • Visceral crisis in need of cytotoxic chemotherapy as assessed by the investigator
  • Radiotherapy within 30 days prior to entry into the trial 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 entry into the trial. Subjects must have recovered from radiotherapy toxicities prior entry
  • Subjects with known inactivating RB1 mutations or deletions (Screening for RB1 mutation is not required for entry)
  • 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 ASA is permitted.
  • Subjects on concomitant strong CYP3A4 inhibitors such as clarithromycin, telithromycin, nefazodone, itraconazole, ketoconazole, atazanavir, darunavir, indinavir, lopinavir, nelfinavir, ritonavir, saquinavir, tipranavir
  • Subjects on strong and moderate CYP3A4 inducers such as amprenavir, barbituates, carbamazepine, clotrimazole, dexamethasone, efavirenz, ethosuximide, griseofulvin, modafinil, nevirapine, oxcarbazepine, phenobarbital, phenytoin, chronic prednisone treatment, primidone, rifabutin, rifampin, rifapentine, ritonavir, topiramate
  • Any significant co-morbidity that would impact the study or the subject’s safety.  Since CDKi have reported the occurrence of interstial lung disease (ILD), subjects who have a history of ILD or have severe dyspnea at rest or require oxygen therapy should not enter the study.
  • Subject has an active systemic bacterial or fungal infection (requiring intravenous [IV] antibiotics at the time of initiating treatment)
  • History of a positive human immunodeficiency virus (HIV) or hepatitis B virus (HBV) test [Screening is not required for enrollment]
  • Subjects with hepatitis C virus (HCV) at Screening who still have a viral load.  Subjects previously treated and achieved a HCV cure (no viral load) can be entered into the study.
  • 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
  • A positive serum pregnancy test (only if premenopausal)
  • 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
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Re: MC# 20-42