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

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ClinicalTrials.gov Identifier: NCT03781063
Recruitment Status : Recruiting
First Posted : December 19, 2018
Last Update Posted : May 29, 2020
Sponsor:
Collaborator:
Linical Accelovance Group
Information provided by (Responsible Party):
Sermonix Pharmaceuticals Inc.

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).

Condition or disease Intervention/treatment Phase
Locally Advanced or Metastatic Breast Cancer Drug: Lasofoxifene Drug: Fulvestrant Phase 2

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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 100 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Intervention Model Description: open label, randomized, parallel-group, multicenter study
Masking: None (Open Label)
Primary Purpose: Treatment
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
Actual Study Start Date : September 20, 2019
Estimated Primary Completion Date : July 2020
Estimated Study Completion Date : September 2020

Resource links provided by the National Library of Medicine

MedlinePlus related topics: Breast Cancer
Drug Information available for: Fulvestrant

Arm Intervention/treatment
Experimental: Lasofoxifene
5 mg/d of oral lasofoxifene
Drug: Lasofoxifene
Estrogen receptor antagonist antineoplastic agent

Active Comparator: Fulvestrant
500 mg fulvestrant intramuscular (IM)
Drug: Fulvestrant
Estrogen receptor antagonist antineoplastic agent




Primary Outcome Measures :
  1. 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


Secondary Outcome Measures :
  1. 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.

  2. 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.

  3. Overall Survival (OS) [ Time Frame: through study completion, an average of 1 year ]
    OS is defined as time from randomization to death due to any cause.

  4. 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



Information from the National Library of Medicine

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Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   Female
Gender Based Eligibility:   Yes
Gender Eligibility Description:   Pre- and Postmenopausal women
Accepts Healthy Volunteers:   No
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.

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT03781063


Contacts
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Contact: Sermonix Pharmaceuticals Study Inquiry 614-864-4919 info@sermonixpharma.com

Locations
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Sponsors and Collaborators
Sermonix Pharmaceuticals Inc.
Linical Accelovance Group
Investigators
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Study Director: Paul V. Plourde, MD Sermonix Pharmaceuticals
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Responsible Party: Sermonix Pharmaceuticals Inc.
ClinicalTrials.gov Identifier: NCT03781063    
Other Study ID Numbers: SMX 18001
First Posted: December 19, 2018    Key Record Dates
Last Update Posted: May 29, 2020
Last Verified: January 2020

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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
Keywords provided by Sermonix Pharmaceuticals Inc.:
Locally Advanced Breast Cancer
Metastatic Breast Cancer
Lasofoxifene
Fulvestrant
ER+/HER2
ESR1 mutation
Additional relevant MeSH terms:
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Breast Neoplasms
Neoplasms by Site
Neoplasms
Breast Diseases
Skin Diseases
Fulvestrant
Antineoplastic Agents, Hormonal
Antineoplastic Agents
Estrogen Receptor Antagonists
Estrogen Antagonists
Hormone Antagonists
Hormones, Hormone Substitutes, and Hormone Antagonists
Physiological Effects of Drugs