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

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Know the risks and potential benefits of clinical studies and talk to your health care provider before participating. Read our disclaimer for details. Identifier: NCT03781063
Recruitment Status : Recruiting
First Posted : December 19, 2018
Last Update Posted : September 10, 2019
Linical Accelovance Group
Information provided by (Responsible Party):
Sermonix Pharmaceuticals LLC

Tracking Information
First Submitted Date  ICMJE December 14, 2018
First Posted Date  ICMJE December 19, 2018
Last Update Posted Date September 10, 2019
Estimated Study Start Date  ICMJE September 2019
Estimated Primary Completion Date July 2020   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: December 17, 2018)
Progression-Free Survival (PFS) [ Time Frame: through study completion, an average of 1 year ]
PFS is defined as the interval from the date of randomization to the earlier date of first documented radiographic progression or death due to any cause
Original Primary Outcome Measures  ICMJE Same as current
Change History Complete list of historical versions of study NCT03781063 on Archive Site
Current Secondary Outcome Measures  ICMJE
 (submitted: December 17, 2018)
  • Clinical Benefit Rate (CBR) [ Time Frame: through study completion, an average of 1 year ]
    CBR is defined as the percentage of all subjects with a complete or partial response; or stable disease for >/=24 weeks.
  • Objective Response Rate (ORR) [ Time Frame: through study completion, an average of 1 year ]
    ORR is defined as the percentage of subjects with either a complete response (CR) or a partial response (PR) as assessed by the RECIST 1.1 criteria.
  • Incidence of Adverse Events (AEs) and Serious AEs [ Time Frame: through study completion, an average of 1 year ]
    The type, severity (graded by Common Terminology Criteria for Adverse Events [CTCAE version 5.0]), course, duration, seriousness, and relationship to study treatment will be assess at each visit
Original Secondary Outcome Measures  ICMJE Same as current
Current Other Pre-specified Outcome Measures Not Provided
Original Other Pre-specified Outcome Measures Not Provided
Descriptive Information
Brief Title  ICMJE Evaluation of Lasofoxifene Versus Fulvestrant in Advanced or Metastatic ER+/HER2− Breast Cancer With an ESR1 Mutation
Official Title  ICMJE An Open-Label, Randomized, Multicenter Study Evaluating the Activity of Lasofoxifene Relative to Fulvestrant for the Treatment of Postmenopausal Women With Locally Advanced or Metastatic ER+/HER2− Breast Cancer With an ESR1 Mutation
Brief Summary

This is an open label, randomized, multicenter study evaluating the activity of lasofoxifene relative to fulvestrant for the treatment of 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 postmenopausal women with locally advanced or metastatic estrogen receptor positive (ER+)/human epidermal growth factor 2 negative (HER2−) breast cancer with an 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)
  9. The presence of the following mutations from tumor free DNA will be documented and part of an exploratory analysis:

    1. erbb2 extracellular domain mutation 5310;
    2. erbb2 kinase domain mutations V777, L755, and Exon 20 insertion;
    3. all NF1 mutations that are truncating, frame shifting and nonsense or homozygous deletions; and
    4. KRAS (Kirsten RAt Sarcoma).
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 cycline 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) Day 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. Serum samples for PK analysis will be collected ±15 minutes before the time that the 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.

Study Type  ICMJE Interventional
Study Phase  ICMJE Phase 2
Study Design  ICMJE Allocation: Randomized
Intervention Model: Parallel Assignment
Intervention Model Description:
open label, randomized, parallel-group, multicenter study
Masking: None (Open Label)
Primary Purpose: Treatment
Condition  ICMJE Locally Advanced or Metastatic Breast Cancer
Intervention  ICMJE
  • Drug: Lasofoxifene
    Estrogen receptor antagonist antineoplastic agent
  • Drug: Fulvestrant
    Estrogen receptor antagonist antineoplastic agent
Study Arms  ICMJE
  • Experimental: Lasofoxifene
    5 mg/d of oral lasofoxifene
    Intervention: Drug: Lasofoxifene
  • Active Comparator: Fulvestrant
    500 mg fulvestrant intramuscular (IM)
    Intervention: Drug: Fulvestrant
Publications * Not Provided

*   Includes publications given by the data provider as well as publications identified by Identifier (NCT Number) in Medline.
Recruitment Information
Recruitment Status  ICMJE Recruiting
Estimated Enrollment  ICMJE
 (submitted: December 17, 2018)
Original Estimated Enrollment  ICMJE Same as current
Estimated Study Completion Date  ICMJE September 2020
Estimated Primary Completion Date July 2020   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

Inclusion Criteria:

  1. Postmenopausal women 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.
  2. If possible, a biopsy of metastatic breast cancer tissue will be obtained to provide histological or cytological confirmation of ER+/HER2− disease as assessed by a local laboratory, according to 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 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. A pre-study assessment, however, may be used to determine eligibility if done within 30 days prior to Screening but a screening sample will be collected to confirm eligibility.
  6. Received one chemotherapy regimen in the neo-adjuvant or adjuvant setting prior to entry into the trial but must be free of all chemotherapy toxicity 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 any SERM (eg, tamoxifen, raloxifene, ospemifene, droloxifene, toremifene, bazedoxifene, endoxifen, etc.) in the adjuvant or metastatic setting except for subjects who completed adjuvant tamoxifen treatment and relapsed at least 1 year after stopping tamoxifen and were then given an AI in combination with a CDK 4/6 inhibitor. Prior use of raloxifene for osteoporosis, ospemifene for vulvo- vaginal atrophy, or conjugated estrogens/bazedoxifene for hot flashes is allowed as long as the medication had been stopped at the time of the subject being diagnosed with breast cancer.
  2. Prior use of everolimus or phosphoinositide 3-kinase inhibitor (PI3K) inhibitors.
  3. Presence of brain metastasis.
  4. Lymphangitic carcinomatosis involving the lung.
  5. Impending visceral crisis in need of cytotoxic chemotherapy as assessed by the investigator.
  6. 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.
  7. History of long QTC syndrome or a QTC of >480 ms.
  8. 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.
  9. Any significant co-morbidity that would impact the study or the subject's safety.
  10. History of a positive human immunodeficiency virus (HIV), hepatitis B virus (HBV) or hepatitis C virus (HCV) at Screening.
  11. 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.
  12. History of vaginal bleeding over the last year.
  13. Uncontrolled hypertension defined as sitting systolic pressure >160 mm Hg or diastolic pressure >100 mm Hg at Screening.
  14. History of non-compliance to medical regimens.
  15. Unwilling or unable to comply with the protocol.
  16. Current participation in any clinical research trial involving an investigational drug or device within the last 30 days.
Sex/Gender  ICMJE
Sexes Eligible for Study: Female
Gender Based Eligibility: Yes
Gender Eligibility Description: Postmenopausal women
Ages  ICMJE 18 Years and older   (Adult, Older Adult)
Accepts Healthy Volunteers  ICMJE No
Contacts  ICMJE
Contact: Sermonix Pharmaceuticals Study Inquiry 614-864-4919
Listed Location Countries  ICMJE United States
Removed Location Countries  
Administrative Information
NCT Number  ICMJE NCT03781063
Other Study ID Numbers  ICMJE SMX 18001
Has Data Monitoring Committee No
U.S. FDA-regulated Product
Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
Product Manufactured in and Exported from the U.S.: No
IPD Sharing Statement  ICMJE Not Provided
Responsible Party Sermonix Pharmaceuticals LLC
Study Sponsor  ICMJE Sermonix Pharmaceuticals LLC
Collaborators  ICMJE Linical Accelovance Group
Investigators  ICMJE
Study Director: Sermonix Pharmaceuticals Study Inquiry Sermonix Pharmaceuticals
PRS Account Sermonix Pharmaceuticals LLC
Verification Date September 2019

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP