Clinical trial NCT03781063: Evaluation of Lasofoxifene Versus Fulvestrant in Advanced or Metastatic ER+/HER2- Breast Cancer With an ESR1 Mutation
Official title: 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
Study type: INTERVENTIONAL
Overall status: ACTIVE_NOT_RECRUITING
Phase: PHASE2
Conditions: Locally Advanced or Metastatic Breast Cancer
Keywords: Locally Advanced Breast Cancer
Metastatic Breast Cancer
Lasofoxifene
Fulvestrant
ER+/HER2
ESR1 mutation
Lead sponsor: Sermonix Pharmaceuticals Inc.
Sponsor class: INDUSTRY
Collaborators: name: Linical Accelovance Group
First posted: 2018-12-19
Enrollment: 100
Sex: FEMALE
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Intervention model description: open label, randomized, parallel-group, multicenter study
Primary purpose: TREATMENT

Brief summary: 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).

Detailed description: 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.

Eligibility criteria: Inclusion Criteria:

1. Pre- or postmenopausal.

   Postmenopausal women are defined as:
   1. ≥60 years of age with no vaginal bleeding over the prior year, or
   2. \<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
   3. 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.
2. 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-.
3. 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).
4. Locally advanced or metastatic breast cancer with either measurable (according to RECIST 1.1) or non-measurable lesions.
5. 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.
6. 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.
7. ECOG performance score of 0 or 1.
8. Adequate organ function as shown by:

   1. absolute neutrophil count (ANC) \>/=1,500 cells/mm3
   2. platelet count ≤100,000 cells/mm3
   3. hemoglobin \>/=9.0 g/dl
   4. ALT and AST levels ≤2.5 upper limit of normal (ULN) or ≤5 in the presence of visceral metastasis
   5. total serum bilirubin ≤1.5 X ULN (≤ 3 X ULN for subjects known to have Gilbert Syndrome)
   6. alkaline phosphatase level ≤ 2.5 X ULN
   7. creatinine clearance of 40 ml/min or greater as calculated by the Cockcroft-Gault formula
   8. International normalized ratio (INR), activated partial thromboplastin (aPTT), or partial thromboplastin time (PTT) \<2.0 X ULN.
9. Able to swallow tablets.
10. Able to understand and voluntarily sign a written informed consent before any screening procedures.

Exclusion Criteria:

1. 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.
2. Presence of brain metastasis.
3. Lymphangitic carcinomatosis involving the lung.
4. Impending visceral crisis in need of cytotoxic chemotherapy as assessed by the investigator.
5. 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.
6. History of long QTC syndrome or a QTC of \>480 ms.
7. 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.
8. Any significant co-morbidity that would impact the study or the subject's safety.
9. 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.
10. 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.
11. 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).
12. Uncontrolled hypertension defined as sitting systolic pressure \>160 mm Hg or diastolic pressure \>100 mm Hg at Screening.
13. History of non-compliance to medical regimens.
14. Unwilling or unable to comply with the protocol.
15. Current participation in any clinical research trial involving an investigational drug or device within the last 30 days.

Primary outcomes:
measure: Progression-Free Survival (PFS)
timeFrame: through study completion, an average of 1 year
Secondary outcomes:
measure: Clinical Benefit Rate (CBR)
timeFrame: through study completion, an average of 1 year
measure: Objective Response Rate (ORR)
timeFrame: through study completion, an average of 1 year
measure: Overall Survival (OS)
timeFrame: through study completion, an average of 1 year
measure: Incidence of Adverse Events (AEs) and Serious AEs
timeFrame: through study completion, an average of 1 year
Other outcomes:
Locations:
city: Phoenix
country: United States
facility: Mayo Clinic Arizona
state: Arizona
city: Yuma
country: United States
facility: Yuma Regional Medical Center (JIT)
state: Arizona
city: Duarte
country: United States
facility: City of Hope Comprehensive Cancer
state: California
city: Fountain Valley
country: United States
facility: Compassionate Care Research Group
state: California
city: San Francisco
country: United States
facility: UCSF Cancer Center
state: California
city: Longmont
country: United States
facility: Rocky Mountain Cancer Centers
state: Colorado
city: Jacksonville
country: United States
facility: Mayo Clinic Florida
state: Florida
city: Miami
country: United States
facility: Miami Cancer Institute
state: Florida
city: Ocala
country: United States
facility: Ocala Oncology Center (JIT)
state: Florida
city: Tallahassee
country: United States
facility: Florida Cancer Specialists
state: Florida
city: Winter Haven
country: United States
facility: The Bond Clinic Cancer & Research Center.
state: Florida
city: Atlanta
country: United States
facility: Emory University
state: Georgia
city: Honolulu
country: United States
facility: Hawaii Cancer Care (JIT)
state: Hawaii
city: Chicago
country: United States
facility: Robert H. Lurie Comprehensive Cancer Center of Northwestern University
state: Illinois
city: Chicago
country: United States
facility: University of Chicago
state: Illinois
city: Peoria
country: United States
facility: Illinois Cancer Care (JIT)
state: Illinois
city: Urbana
country: United States
facility: Carle Cancer Center
state: Illinois
city: South Bend
country: United States
facility: Beacon Health (JIT)
state: Indiana
city: Louisville
country: United States
facility: University of Louisville / James Graham Brown Cancer Center
state: Kentucky
city: Frederick
country: United States
facility: FMH James M Stockman Cancer Institute (JIT)
state: Maryland
city: Rochester
country: United States
facility: Mayo Clinic
state: Minnesota
city: Hattiesburg
country: United States
facility: Hattiesburg Clinic Hematology/Oncology
state: Mississippi
city: Kansas City
country: United States
facility: Saint Luke's Cancer Institute
state: Missouri
city: Kansas City
country: United States
facility: HCA Midwest Health
state: Missouri
city: Saint Louis
country: United States
facility: Washington University School of Medicine
state: Missouri
city: Las Vegas
country: United States
facility: Comprehensive Cancer Centers of Nevada (JIT)
state: Nevada
city: Belleville
country: United States
facility: New Jersey Cancer Care and Blood Disorders (JIT)
state: New Jersey
city: Florham Park
country: United States
facility: Summit Medical Group (JIT)
state: New Jersey
city: Buffalo
country: United States
facility: Roswell Park Comprehensive Cancer Center
state: New York
city: Durham
country: United States
facility: Duke University Medical Center
state: North Carolina
city: Cincinnati
country: United States
facility: TriHealth Cancer Institute
state: Ohio
city: Columbus
country: United States
facility: The Ohio State University - Comprehensive Cancer Center
state: Ohio
city: Columbus
country: United States
facility: Ohio Health (JIT)
state: Ohio
city: Pittsburgh
country: United States
facility: UPMC Hillman Cancer Center
state: Pennsylvania
city: Sioux Falls
country: United States
facility: Sanford Cancer Center (JIT)
state: South Dakota
city: Chattanooga
country: United States
facility: Tennessee Oncology Chattanooga
state: Tennessee
city: Germantown
country: United States
facility: West Cancer Center
state: Tennessee
city: Nashville
country: United States
facility: Tennessee Oncology/SCRI
state: Tennessee
city: Dallas
country: United States
facility: Mary Crowley Cancer Research (JIT)
state: Texas
city: Houston
country: United States
facility: Oncology Consultants (JIT)
state: Texas
city: Salt Lake City
country: United States
facility: Utah Cancer Specialists (JIT)
state: Utah
city: Newport News
country: United States
facility: Peninsula Cancer Institute
state: Virginia
city: Ottawa
country: Canada
facility: The Ottawa Hospital
state: Ontario
city: Toronto
country: Canada
facility: Sunnybrook Health Sciences Center
state: Ontario
city: Chicoutimi
country: Canada
facility: CIUSSS de Saguenay-Lac-Saint Jean
state: Quebec
city: Montréal
country: Canada
facility: Jewish General Hospital
state: Quebec
city: Montréal
country: Canada
facility: McGill University Health Centre
state: Quebec
city: Be'er Sheva
country: Israel
facility: Soroka University Medical Center
city: Jerusalem
country: Israel
facility: Hadassah Ein Kerem Medical Center
city: Petah tikva
country: Israel
facility: Rabin Medical Center
city: Ramat Gan
country: Israel
facility: Sheba Medical Center
Study officials:
affiliation: Sermonix Pharmaceuticals
name: Paul V. Plourde, MD
role: STUDY_DIRECTOR
References: