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Evaluation of Lasofoxifene Versus Fulvestrant in Advanced or Metastatic ER+ / HER2- Breast Cancer With an ESR1 Mutation

Trial Status: Active

This is 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 acquired ESR1 mutation and who have disease progression on an aromatase inhibitor (AI) in combination with a cyclin dependent kinase (CDK) 4 / 6 inhibitor. The primary objective is to evaluate the progression free survival (PFS) of 5 mg lasofoxifene relative to fulvestrant for the treatment of pre- and postmenopausal women 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. The secondary objectives are to evaluate: 1. Clinical benefit rate (CBR) and Objective Response Rate (ORR) 2. Duration of response 3. Time to response 4. Overall Survival (OS) 5. Pharmacokinetics of lasofoxifene 6. Quality of life (QoL): Quality of Life (QoL): vaginal assessment scale (VAS) and vulvar assessment scale (VuAS) questionnaires 7. Safety of lasofoxifene 8. Response to various ESR1 mutation (Y537S, Y537C, D538G, E380Q, S463P, V534E, P535H, L536H, L536P, L536R, L536Q, or Y537N).

Inclusion Criteria

  • 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 on an AI in combination with a CDK 4/6 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 either measurable (according to RECIST 1.1) or non-measurable lesions.
  • At least one or more of the following point ESR1 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 30 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 or those who have received one cytotoxic chemotherapy regimen in the neo-adjuvant or adjuvant setting prior to entry into the trial and/or no more than one chemotherapy regimen for metastatic breast cancer. 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 ≤1.5 X ULN (≤ 3 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), activated partial thromboplastin (aPTT), or partial thromboplastin time (PTT) <2.0 X ULN.
  • Able to swallow tablets.
  • Able to understand and voluntarily sign a written informed consent before any screening procedures.

Exclusion Criteria

  • Prior use of everolimus or other mammalian target of rapamycin (mTOR) inhibitor or phosphoinositide 3-kinase inhibitor (PI3K) inhibitors is excluded unless discontinued 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 ms.
  • 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.
  • 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.


Mayo Clinic in Arizona
Status: ACTIVE


City of Hope Comprehensive Cancer Center
Status: ACTIVE
San Francisco
UCSF Medical Center-Mount Zion
Status: ACTIVE
Contact: Helen Diller Family Comprehensive Cancer Center
Phone: 877-827-3222


Mayo Clinic in Florida
Status: ACTIVE


Emory University Hospital / Winship Cancer Institute
Status: ACTIVE


Northwestern University
Status: ACTIVE
University of Chicago Comprehensive Cancer Center
Status: ACTIVE


Mayo Clinic in Rochester
Status: ACTIVE


Saint Louis
Siteman Cancer Center at Washington University
Status: ACTIVE

New York

Roswell Park Cancer Institute
Status: ACTIVE

North Carolina

Duke University Medical Center
Status: ACTIVE


Ohio State University Comprehensive Cancer Center
Status: ACTIVE


University of Pittsburgh Cancer Institute (UPCI)
Status: ACTIVE

Lasofoxifene is a potent SERM that has demonstrated in non-clinical models to prevent and

treat breast cancer. In a large clinical osteoporosis trial, lasofoxifene reduced the

incidence of ER+ breast cancer, which most likely represents a beneficial effect on

clinically undetectable breast cancer. The clinical and non-clinical results are not

unexpected based on the results seen with tamoxifen and fulvestrant as the mechanisms of

action are similar. Moreover, the safety profile of lasofoxifene is well established in

postmenopausal women and therefore a clinical trial investigating lasofoxifene for the

treatment of breast cancer is scientifically justifiable.

Subjects with ESR1 mutations have endocrine resistance and shorter time to progression when

treated with currently approved endocrine therapy. There is an unmet medical need for

endocrine agents that can provide greater efficacy in this population. Non-clinical in vitro

and in vivo studies with lasofoxifene have demonstrated efficacy. If this benefit translates

to subjects with ESR1 mutated breast cancer cells, an important treatment option beyond

fulvestrant will be available. The population being recruited in this trial are subjects with

advanced breast cancer who have been treated with an AI in combination with a

cyclin-dependent kinase (CDK) 4/6 inhibitor and who have an ESR1 mutation. The efficacy of

endocrine agents in this population has never been prospectively studied. For this reason,

this study will evaluate lasofoxifene in a randomized Phase 2 trial against a comparator to

better evaluate the magnitude of the effect as well as to provide data to estimate the Phase

3 sample size.

In both non-clinical and clinical studies, fulvestrant has shown activity in ESR1 mutated

breast cancer cells and will be used as the comparator in this Phase 2 study to better

determine the relative clinical efficacy of lasofoxifene. The FDA approved fulvestrant dose

will be used.

A major limiting factor in the administration of fulvestrant is its poor solubility requiring

IM injection. The volume of administration limits the dose that can be administered. Initial

clinical trials administered 250 mg of fulvestrant in 5 cc of castor oil as a single

injection once monthly. Because the IM injections were well tolerated, loading and higher

doses were investigated. This was found to have acceptable tolerability and resulted in

greater efficacy. Limited by the volume of administration higher doses of fulvestrant cannot

be investigated further.

Once the subject has consented to participate in the study, screening tests will be performed

within 30 days of enrollment.

All subjects meeting the eligibility criteria will be first stratified into those with

visceral metastasis and those without visceral metastasis. Each of these stratified groups

will then be further stratified into those with the Y537S ESR1 mutation and those without

this particular mutation. Each of the stratified groups will then be randomized 1:1 to

receive either 5 mg/d of oral lasofoxifene or fulvestrant 500 mg intramuscular (IM) on Days

1, 15, and 29, then every 4 weeks thereafter. Treatment will continue until radiographic or

clinical evidence of disease progression. Enrolled subjects will be seen every 2 weeks for

the first month of treatment and then monthly until progression. Efficacy assessments will be

done every 8 weeks.

For subjects randomized to lasofoxifene, blood samples will be drawn to assess the population

PK. Serum samples will be collected at each visit starting at Visit 0 (Day 1) through

Final/ET visit to measure serum lasofoxifene concentration at time points outlined below.

Serum samples for PK analysis will be collected before the time that the next lasofoxifene

dose is ingested. The actual time and date of dosing on the previous day as well as dosing on

the visit day, and the PK blood sampling time/date must be recorded for all subjects.

Pharmacokinetic samples are to be collected before clinical lab blood sampling.

A maximum of 100 subjects will be randomized and it is expected that all subjects enrolled in

the study will be treated until documented disease progression. It is estimated that full

recruitment into the study will occur within 12 to 18 months with another 12 months of follow

up before the primary outcome measure is analyzed.

Trial Phase Phase II

Trial Type Treatment

Lead Organization
Sermonix Pharmaceuticals Inc.

  • Primary ID SMX 18001
  • Secondary IDs NCI-2019-02318
  • ID NCT03781063