<clinical_study>
  <!-- This xml conforms to an XML Schema at:
    https://clinicaltrials.gov/ct2/html/images/info/public.xsd -->
  <required_header>
    <download_date>ClinicalTrials.gov processed this data on September 20, 2023</download_date>
    <link_text>Link to the current ClinicalTrials.gov record.</link_text>
    <url>https://clinicaltrials.gov/ct2/show/NCT03781063</url>
  </required_header>
  <id_info>
    <org_study_id>SMX 18001</org_study_id>
    <nct_id>NCT03781063</nct_id>
  </id_info>
  <brief_title>Evaluation of Lasofoxifene Versus Fulvestrant in Advanced or Metastatic ER+/HER2- Breast Cancer With an ESR1 Mutation</brief_title>
  <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</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>Sermonix Pharmaceuticals Inc.</agency>
      <agency_class>Industry</agency_class>
    </lead_sponsor>
    <collaborator>
      <agency>Linical Accelovance Group</agency>
      <agency_class>Other</agency_class>
    </collaborator>
  </sponsors>
  <source>Sermonix Pharmaceuticals Inc.</source>
  <oversight_info>
    <has_dmc>No</has_dmc>
    <is_fda_regulated_drug>Yes</is_fda_regulated_drug>
    <is_fda_regulated_device>No</is_fda_regulated_device>
    <is_us_export>No</is_us_export>
  </oversight_info>
  <brief_summary>
    <textblock>
      This is an open label, randomized, multicenter study evaluating the activity of lasofoxifene&#xD;
      relative to fulvestrant for the treatment of pre- and postmenopausal women with locally&#xD;
      advanced or metastatic ER+/HER2- breast cancer with an acquired ESR1 mutation and who have&#xD;
      disease progression on an aromatase inhibitor (AI) in combination with a cyclin dependent&#xD;
      kinase (CDK) 4/6 inhibitor.&#xD;
&#xD;
      The primary objective is to evaluate the progression free survival (PFS) of 5 mg lasofoxifene&#xD;
      relative to fulvestrant for the treatment of pre- and postmenopausal women with locally&#xD;
      advanced or metastatic estrogen receptor positive (ER+)/human epidermal growth factor 2&#xD;
      negative (HER2-) breast cancer with an estrogen receptor 1 (ESR1) mutation.&#xD;
&#xD;
      The secondary objectives are to evaluate:&#xD;
&#xD;
        1. Clinical benefit rate (CBR) and Objective Response Rate (ORR)&#xD;
&#xD;
        2. Duration of response&#xD;
&#xD;
        3. Time to response&#xD;
&#xD;
        4. Overall Survival (OS)&#xD;
&#xD;
        5. Pharmacokinetics of lasofoxifene&#xD;
&#xD;
        6. Quality of life (QoL): Quality of Life (QoL): vaginal assessment scale (VAS) and vulvar&#xD;
           assessment scale (VuAS) questionnaires&#xD;
&#xD;
        7. Safety of lasofoxifene&#xD;
&#xD;
        8. Response to various ESR1 mutation (Y537S, Y537C, D538G, E380Q, S463P, V534E, P535H,&#xD;
           L536H, L536P, L536R, L536Q, or Y537N).&#xD;
    </textblock>
  </brief_summary>
  <detailed_description>
    <textblock>
      Lasofoxifene is a potent SERM that has demonstrated in non-clinical models to prevent and&#xD;
      treat breast cancer. In a large clinical osteoporosis trial, lasofoxifene reduced the&#xD;
      incidence of ER+ breast cancer, which most likely represents a beneficial effect on&#xD;
      clinically undetectable breast cancer. The clinical and non-clinical results are not&#xD;
      unexpected based on the results seen with tamoxifen and fulvestrant as the mechanisms of&#xD;
      action are similar. Moreover, the safety profile of lasofoxifene is well established in&#xD;
      postmenopausal women and therefore a clinical trial investigating lasofoxifene for the&#xD;
      treatment of breast cancer is scientifically justifiable.&#xD;
&#xD;
      Subjects with ESR1 mutations have endocrine resistance and shorter time to progression when&#xD;
      treated with currently approved endocrine therapy. There is an unmet medical need for&#xD;
      endocrine agents that can provide greater efficacy in this population. Non-clinical in vitro&#xD;
      and in vivo studies with lasofoxifene have demonstrated efficacy. If this benefit translates&#xD;
      to subjects with ESR1 mutated breast cancer cells, an important treatment option beyond&#xD;
      fulvestrant will be available. The population being recruited in this trial are subjects with&#xD;
      advanced breast cancer who have been treated with an AI in combination with a&#xD;
      cyclin-dependent kinase (CDK) 4/6 inhibitor and who have an ESR1 mutation. The efficacy of&#xD;
      endocrine agents in this population has never been prospectively studied. For this reason,&#xD;
      this study will evaluate lasofoxifene in a randomized Phase 2 trial against a comparator to&#xD;
      better evaluate the magnitude of the effect as well as to provide data to estimate the Phase&#xD;
      3 sample size.&#xD;
&#xD;
      In both non-clinical and clinical studies, fulvestrant has shown activity in ESR1 mutated&#xD;
      breast cancer cells and will be used as the comparator in this Phase 2 study to better&#xD;
      determine the relative clinical efficacy of lasofoxifene. The FDA approved fulvestrant dose&#xD;
      will be used.&#xD;
&#xD;
      A major limiting factor in the administration of fulvestrant is its poor solubility requiring&#xD;
      IM injection. The volume of administration limits the dose that can be administered. Initial&#xD;
      clinical trials administered 250 mg of fulvestrant in 5 cc of castor oil as a single&#xD;
      injection once monthly. Because the IM injections were well tolerated, loading and higher&#xD;
      doses were investigated. This was found to have acceptable tolerability and resulted in&#xD;
      greater efficacy. Limited by the volume of administration higher doses of fulvestrant cannot&#xD;
      be investigated further.&#xD;
&#xD;
      Once the subject has consented to participate in the study, screening tests will be performed&#xD;
      within 30 days of enrollment.&#xD;
&#xD;
      All subjects meeting the eligibility criteria will be first stratified into those with&#xD;
      visceral metastasis and those without visceral metastasis. Each of these stratified groups&#xD;
      will then be further stratified into those with the Y537S ESR1 mutation and those without&#xD;
      this particular mutation. Each of the stratified groups will then be randomized 1:1 to&#xD;
      receive either 5 mg/d of oral lasofoxifene or fulvestrant 500 mg intramuscular (IM) on Days&#xD;
      1, 15, and 29, then every 4 weeks thereafter. Treatment will continue until radiographic or&#xD;
      clinical evidence of disease progression. Enrolled subjects will be seen every 2 weeks for&#xD;
      the first month of treatment and then monthly until progression. Efficacy assessments will be&#xD;
      done every 8 weeks.&#xD;
&#xD;
      For subjects randomized to lasofoxifene, blood samples will be drawn to assess the population&#xD;
      PK. Serum samples will be collected at each visit starting at Visit 0 (Day 1) through&#xD;
      Final/ET visit to measure serum lasofoxifene concentration at time points outlined below.&#xD;
      Serum samples for PK analysis will be collected before the time that the next lasofoxifene&#xD;
      dose is ingested. The actual time and date of dosing on the previous day as well as dosing on&#xD;
      the visit day, and the PK blood sampling time/date must be recorded for all subjects.&#xD;
      Pharmacokinetic samples are to be collected before clinical lab blood sampling.&#xD;
&#xD;
      A maximum of 100 subjects will be randomized and it is expected that all subjects enrolled in&#xD;
      the study will be treated until documented disease progression. It is estimated that full&#xD;
      recruitment into the study will occur within 12 to 18 months with another 12 months of follow&#xD;
      up before the primary outcome measure is analyzed.&#xD;
    </textblock>
  </detailed_description>
  <overall_status>Active, not recruiting</overall_status>
  <start_date type="Actual">September 20, 2019</start_date>
  <completion_date type="Anticipated">February 2024</completion_date>
  <primary_completion_date type="Anticipated">February 2024</primary_completion_date>
  <phase>Phase 2</phase>
  <study_type>Interventional</study_type>
  <has_expanded_access>No</has_expanded_access>
  <study_design_info>
    <allocation>Randomized</allocation>
    <intervention_model>Parallel Assignment</intervention_model>
    <intervention_model_description>open label, randomized, parallel-group, multicenter study</intervention_model_description>
    <primary_purpose>Treatment</primary_purpose>
    <masking>None (Open Label)</masking>
  </study_design_info>
  <primary_outcome>
    <measure>Progression-Free Survival (PFS)</measure>
    <time_frame>through study completion, an average of 1 year</time_frame>
    <description>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</description>
  </primary_outcome>
  <secondary_outcome>
    <measure>Clinical Benefit Rate (CBR)</measure>
    <time_frame>through study completion, an average of 1 year</time_frame>
    <description>CBR is defined as the percentage of all subjects with a complete or partial response; or stable disease for &gt;/=24 weeks.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Objective Response Rate (ORR)</measure>
    <time_frame>through study completion, an average of 1 year</time_frame>
    <description>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.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Overall Survival (OS)</measure>
    <time_frame>through study completion, an average of 1 year</time_frame>
    <description>OS is defined as time from randomization to death due to any cause.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Incidence of Adverse Events (AEs) and Serious AEs</measure>
    <time_frame>through study completion, an average of 1 year</time_frame>
    <description>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</description>
  </secondary_outcome>
  <number_of_arms>2</number_of_arms>
  <enrollment type="Anticipated">100</enrollment>
  <condition>Locally Advanced or Metastatic Breast Cancer</condition>
  <arm_group>
    <arm_group_label>Lasofoxifene</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>5 mg/d of oral lasofoxifene</description>
  </arm_group>
  <arm_group>
    <arm_group_label>Fulvestrant</arm_group_label>
    <arm_group_type>Active Comparator</arm_group_type>
    <description>500 mg fulvestrant intramuscular (IM)</description>
  </arm_group>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Lasofoxifene</intervention_name>
    <description>Estrogen receptor antagonist antineoplastic agent</description>
    <arm_group_label>Lasofoxifene</arm_group_label>
  </intervention>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Fulvestrant</intervention_name>
    <description>Estrogen receptor antagonist antineoplastic agent</description>
    <arm_group_label>Fulvestrant</arm_group_label>
  </intervention>
  <eligibility>
    <criteria>
      <textblock>
        Inclusion Criteria:&#xD;
&#xD;
          1. Pre- or postmenopausal.&#xD;
&#xD;
             Postmenopausal women are defined as:&#xD;
&#xD;
               1. ≥60 years of age with no vaginal bleeding over the prior year, or&#xD;
&#xD;
               2. &lt;60 years with &quot;premature menopause&quot; or &quot;premature ovarian failure&quot; manifest&#xD;
                  itself with secondary amenorrhea for at least 1 year and follicle stimulating&#xD;
                  hormone (FSH) and estradiol levels in the postmenopausal range according to&#xD;
                  institutional standards, or&#xD;
&#xD;
               3. surgical menopause with bilateral oophorectomy. Note: premenopausal women who&#xD;
                  meet all of the other entry criteria must be maintained on ovarian suppression&#xD;
                  (such as Lupron) during the study and subjects counseled to use appropriate&#xD;
                  contraception to prevent pregnancy.&#xD;
&#xD;
          2. If possible, a biopsy of metastatic breast cancer tissue will be obtained to provide&#xD;
             histological or cytological confirmation of ER+ and HER2- disease as assessed by a&#xD;
             local laboratory, according to the American Society of Clinical Oncology/College of&#xD;
             American Pathologists (ASCO/CAP) guidelines, using slides, paraffin blocks, or&#xD;
             paraffin samples. If a biopsy is not possible, the ER and HER2 status from the tissue&#xD;
             obtained at the time of the original diagnosis must confirm that the subject's cancer&#xD;
             is ER+ and HER2-.&#xD;
&#xD;
          3. Locally advanced or metastatic breast cancer with radiological or clinical evidence of&#xD;
             progression on an AI in combination with a CDK 4/6 inhibitor for advanced breast&#xD;
             cancer with demonstrated prior sensitivity to endocrine therapy (recurrence or&#xD;
             progression after at least 12 months of treatment in the metastatic setting).&#xD;
&#xD;
          4. Locally advanced or metastatic breast cancer with either measurable (according to&#xD;
             RECIST 1.1) or non-measurable lesions.&#xD;
&#xD;
          5. At least one or more of the following point ESR1 mutations as assessed in cell-free&#xD;
             circulating tumor DNA (ctDNA) obtained from a blood (plasma) or tissue sample: Y537S,&#xD;
             Y537C, D538G, E380Q, S463P, V534E, P535H, L536H, L536P, L536R, L536Q, or Y537N. The&#xD;
             ctDNA sample collection must be obtained within 30 days prior to randomization to&#xD;
             determine eligibility and baseline. Note: a prior genomic test confirming that the&#xD;
             subject has an ESR1 mutation can be used to determine eligibility; however, an ESR1&#xD;
             sample must also be collected within 30 days of randomization.&#xD;
&#xD;
          6. Subjects who have not received cytotoxic chemotherapy or those who have received one&#xD;
             cytotoxic chemotherapy regimen in the neo-adjuvant or adjuvant setting prior to entry&#xD;
             into the trial and/or no more than one chemotherapy regimen for metastatic breast&#xD;
             cancer. Subjects must be free of all chemotherapy acute toxicity excluding alopecia&#xD;
             and Grade II peripheral neuropathy before study entry.&#xD;
&#xD;
          7. ECOG performance score of 0 or 1.&#xD;
&#xD;
          8. Adequate organ function as shown by:&#xD;
&#xD;
               1. absolute neutrophil count (ANC) &gt;/=1,500 cells/mm3&#xD;
&#xD;
               2. platelet count ≤100,000 cells/mm3&#xD;
&#xD;
               3. hemoglobin &gt;/=9.0 g/dl&#xD;
&#xD;
               4. ALT and AST levels ≤2.5 upper limit of normal (ULN) or ≤5 in the presence of&#xD;
                  visceral metastasis&#xD;
&#xD;
               5. total serum bilirubin ≤1.5 X ULN (≤ 3 X ULN for subjects known to have Gilbert&#xD;
                  Syndrome)&#xD;
&#xD;
               6. alkaline phosphatase level ≤ 2.5 X ULN&#xD;
&#xD;
               7. creatinine clearance of 40 ml/min or greater as calculated by the Cockcroft-Gault&#xD;
                  formula&#xD;
&#xD;
               8. International normalized ratio (INR), activated partial thromboplastin (aPTT), or&#xD;
                  partial thromboplastin time (PTT) &lt;2.0 X ULN.&#xD;
&#xD;
          9. Able to swallow tablets.&#xD;
&#xD;
         10. Able to understand and voluntarily sign a written informed consent before any&#xD;
             screening procedures.&#xD;
&#xD;
        Exclusion Criteria:&#xD;
&#xD;
          1. Prior use of everolimus or other mammalian target of rapamycin (mTOR) inhibitor or&#xD;
             phosphoinositide 3-kinase inhibitor (PI3K) inhibitors is excluded unless discontinued&#xD;
             to reasons other than disease progression.&#xD;
&#xD;
          2. Presence of brain metastasis.&#xD;
&#xD;
          3. Lymphangitic carcinomatosis involving the lung.&#xD;
&#xD;
          4. Impending visceral crisis in need of cytotoxic chemotherapy as assessed by the&#xD;
             investigator.&#xD;
&#xD;
          5. Radiotherapy within 30 days prior to randomization except in case of localized&#xD;
             radiotherapy for analgesic purposes or for lytic lesions at risk of fracture, which&#xD;
             can then be completed within 7 days prior to randomization. Subjects must have&#xD;
             recovered from radiotherapy toxicities prior to randomization.&#xD;
&#xD;
          6. History of long QTC syndrome or a QTC of &gt;480 ms.&#xD;
&#xD;
          7. History of a pulmonary embolus (PE) or deep vein thrombosis (DVT) within the last 6&#xD;
             months or any known thrombophilia. Subjects stable on anti-coagulants for maintenance&#xD;
             are eligible as long as the DVT and/or PE occurred &gt;6 months prior to enrollment and&#xD;
             there is no evidence for active thrombosis. The use of low dose ASA is permitted.&#xD;
&#xD;
          8. Any significant co-morbidity that would impact the study or the subject's safety.&#xD;
&#xD;
          9. History of a positive human immunodeficiency virus (HIV), hepatitis B virus (HBV) or&#xD;
             hepatitis C virus (HCV) at Screening. Subjects cured of hepatitis C (no viral load)&#xD;
             are eligible.&#xD;
&#xD;
         10. History of malignancy within the past 5 years (excluding breast cancer), except basal&#xD;
             cell or squamous cell carcinoma of the skin curatively treated by surgery, or early&#xD;
             stage cervical cancer.&#xD;
&#xD;
         11. History of vaginal bleeding over the last year unless it is documented that the&#xD;
             bleeding was due to non-uterine causes (e.g. vaginal atrophy).&#xD;
&#xD;
         12. Uncontrolled hypertension defined as sitting systolic pressure &gt;160 mm Hg or diastolic&#xD;
             pressure &gt;100 mm Hg at Screening.&#xD;
&#xD;
         13. History of non-compliance to medical regimens.&#xD;
&#xD;
         14. Unwilling or unable to comply with the protocol.&#xD;
&#xD;
         15. Current participation in any clinical research trial involving an investigational drug&#xD;
             or device within the last 30 days.&#xD;
      </textblock>
    </criteria>
    <gender>Female</gender>
    <gender_based>Yes</gender_based>
    <gender_description>Pre- and Postmenopausal women</gender_description>
    <minimum_age>18 Years</minimum_age>
    <maximum_age>N/A</maximum_age>
    <healthy_volunteers>No</healthy_volunteers>
  </eligibility>
  <overall_official>
    <last_name>Paul V. Plourde, MD</last_name>
    <role>Study Director</role>
    <affiliation>Sermonix Pharmaceuticals</affiliation>
  </overall_official>
  <location>
    <facility>
      <name>Mayo Clinic Arizona</name>
      <address>
        <city>Phoenix</city>
        <state>Arizona</state>
        <zip>85054</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Yuma Regional Medical Center (JIT)</name>
      <address>
        <city>Yuma</city>
        <state>Arizona</state>
        <zip>85364</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>City of Hope Comprehensive Cancer</name>
      <address>
        <city>Duarte</city>
        <state>California</state>
        <zip>91010</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Compassionate Care Research Group</name>
      <address>
        <city>Fountain Valley</city>
        <state>California</state>
        <zip>92708</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>UCSF Cancer Center</name>
      <address>
        <city>San Francisco</city>
        <state>California</state>
        <zip>94115</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Rocky Mountain Cancer Centers</name>
      <address>
        <city>Longmont</city>
        <state>Colorado</state>
        <zip>80501</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Mayo Clinic Florida</name>
      <address>
        <city>Jacksonville</city>
        <state>Florida</state>
        <zip>32224</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Miami Cancer Institute</name>
      <address>
        <city>Miami</city>
        <state>Florida</state>
        <zip>33176</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Ocala Oncology Center (JIT)</name>
      <address>
        <city>Ocala</city>
        <state>Florida</state>
        <zip>34474</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Florida Cancer Specialists</name>
      <address>
        <city>Tallahassee</city>
        <state>Florida</state>
        <zip>32308</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>The Bond Clinic Cancer &amp; Research Center.</name>
      <address>
        <city>Winter Haven</city>
        <state>Florida</state>
        <zip>33880</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Emory University</name>
      <address>
        <city>Atlanta</city>
        <state>Georgia</state>
        <zip>30322</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Hawaii Cancer Care (JIT)</name>
      <address>
        <city>Honolulu</city>
        <state>Hawaii</state>
        <zip>96813</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Robert H. Lurie Comprehensive Cancer Center of Northwestern University</name>
      <address>
        <city>Chicago</city>
        <state>Illinois</state>
        <zip>60611</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>University of Chicago</name>
      <address>
        <city>Chicago</city>
        <state>Illinois</state>
        <zip>60637</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Illinois Cancer Care (JIT)</name>
      <address>
        <city>Peoria</city>
        <state>Illinois</state>
        <zip>61615</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Carle Cancer Center</name>
      <address>
        <city>Urbana</city>
        <state>Illinois</state>
        <zip>61801</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Beacon Health (JIT)</name>
      <address>
        <city>South Bend</city>
        <state>Indiana</state>
        <zip>46601</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>University of Louisville / James Graham Brown Cancer Center</name>
      <address>
        <city>Louisville</city>
        <state>Kentucky</state>
        <zip>40202</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>FMH James M Stockman Cancer Institute (JIT)</name>
      <address>
        <city>Frederick</city>
        <state>Maryland</state>
        <zip>21702</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Mayo Clinic</name>
      <address>
        <city>Rochester</city>
        <state>Minnesota</state>
        <zip>55902</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Hattiesburg Clinic Hematology/Oncology</name>
      <address>
        <city>Hattiesburg</city>
        <state>Mississippi</state>
        <zip>39401</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Saint Luke's Cancer Institute</name>
      <address>
        <city>Kansas City</city>
        <state>Missouri</state>
        <zip>64111</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>HCA Midwest Health</name>
      <address>
        <city>Kansas City</city>
        <state>Missouri</state>
        <zip>64132</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Washington University School of Medicine</name>
      <address>
        <city>Saint Louis</city>
        <state>Missouri</state>
        <zip>63110</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Comprehensive Cancer Centers of Nevada (JIT)</name>
      <address>
        <city>Las Vegas</city>
        <state>Nevada</state>
        <zip>89128</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>New Jersey Cancer Care and Blood Disorders (JIT)</name>
      <address>
        <city>Belleville</city>
        <state>New Jersey</state>
        <zip>07203</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Summit Medical Group (JIT)</name>
      <address>
        <city>Florham Park</city>
        <state>New Jersey</state>
        <zip>07932</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Roswell Park Comprehensive Cancer Center</name>
      <address>
        <city>Buffalo</city>
        <state>New York</state>
        <zip>14263</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Duke University Medical Center</name>
      <address>
        <city>Durham</city>
        <state>North Carolina</state>
        <zip>27710</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>TriHealth Cancer Institute</name>
      <address>
        <city>Cincinnati</city>
        <state>Ohio</state>
        <zip>45220</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>The Ohio State University - Comprehensive Cancer Center</name>
      <address>
        <city>Columbus</city>
        <state>Ohio</state>
        <zip>43210</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Ohio Health (JIT)</name>
      <address>
        <city>Columbus</city>
        <state>Ohio</state>
        <zip>43221</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>UPMC Hillman Cancer Center</name>
      <address>
        <city>Pittsburgh</city>
        <state>Pennsylvania</state>
        <zip>15232</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Sanford Cancer Center (JIT)</name>
      <address>
        <city>Sioux Falls</city>
        <state>South Dakota</state>
        <zip>57104</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Tennessee Oncology Chattanooga</name>
      <address>
        <city>Chattanooga</city>
        <state>Tennessee</state>
        <zip>37404</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>West Cancer Center</name>
      <address>
        <city>Germantown</city>
        <state>Tennessee</state>
        <zip>38138</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Tennessee Oncology/SCRI</name>
      <address>
        <city>Nashville</city>
        <state>Tennessee</state>
        <zip>37203</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Mary Crowley Cancer Research (JIT)</name>
      <address>
        <city>Dallas</city>
        <state>Texas</state>
        <zip>75230</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Oncology Consultants (JIT)</name>
      <address>
        <city>Houston</city>
        <state>Texas</state>
        <zip>77024</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Utah Cancer Specialists (JIT)</name>
      <address>
        <city>Salt Lake City</city>
        <state>Utah</state>
        <zip>84102</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Peninsula Cancer Institute</name>
      <address>
        <city>Newport News</city>
        <state>Virginia</state>
        <zip>23601</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>The Ottawa Hospital</name>
      <address>
        <city>Ottawa</city>
        <state>Ontario</state>
        <zip>K1H8L6</zip>
        <country>Canada</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Sunnybrook Health Sciences Center</name>
      <address>
        <city>Toronto</city>
        <state>Ontario</state>
        <zip>M4N3M5</zip>
        <country>Canada</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>CIUSSS de Saguenay-Lac-Saint Jean</name>
      <address>
        <city>Chicoutimi</city>
        <state>Quebec</state>
        <zip>G7H5H6</zip>
        <country>Canada</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Jewish General Hospital</name>
      <address>
        <city>Montréal</city>
        <state>Quebec</state>
        <zip>H3T1E2</zip>
        <country>Canada</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>McGill University Health Centre</name>
      <address>
        <city>Montréal</city>
        <state>Quebec</state>
        <zip>H4A3J1</zip>
        <country>Canada</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Soroka University Medical Center</name>
      <address>
        <city>Be'er Sheva</city>
        <zip>84101</zip>
        <country>Israel</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Hadassah Ein Kerem Medical Center</name>
      <address>
        <city>Jerusalem</city>
        <zip>9112001</zip>
        <country>Israel</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Rabin Medical Center</name>
      <address>
        <city>Petah tikva</city>
        <zip>49100</zip>
        <country>Israel</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Sheba Medical Center</name>
      <address>
        <city>Ramat Gan</city>
        <zip>52656021</zip>
        <country>Israel</country>
      </address>
    </facility>
  </location>
  <location_countries>
    <country>Canada</country>
    <country>Israel</country>
    <country>United States</country>
  </location_countries>
  <verification_date>April 2023</verification_date>
  <study_first_submitted>December 14, 2018</study_first_submitted>
  <study_first_submitted_qc>December 17, 2018</study_first_submitted_qc>
  <study_first_posted type="Actual">December 19, 2018</study_first_posted>
  <last_update_submitted>April 10, 2023</last_update_submitted>
  <last_update_submitted_qc>April 10, 2023</last_update_submitted_qc>
  <last_update_posted type="Actual">April 11, 2023</last_update_posted>
  <responsible_party>
    <responsible_party_type>Sponsor</responsible_party_type>
  </responsible_party>
  <keyword>Locally Advanced Breast Cancer</keyword>
  <keyword>Metastatic Breast Cancer</keyword>
  <keyword>Lasofoxifene</keyword>
  <keyword>Fulvestrant</keyword>
  <keyword>ER+/HER2</keyword>
  <keyword>ESR1 mutation</keyword>
  <condition_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Breast Neoplasms</mesh_term>
  </condition_browse>
  <intervention_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Fulvestrant</mesh_term>
  </intervention_browse>
  <!-- Results have not yet been posted for this study                                          -->
</clinical_study>


download date: ClinicalTrials.gov processed this data on September 20, 2023
link text: Link to the current ClinicalTrials.gov record.
url: https://clinicaltrials.gov/ct2/show/NCT03781063
org study id: SMX 18001
nct id: NCT03781063
lead sponsor: 
collaborator: 
has dmc: No
is fda regulated drug: Yes
is fda regulated device: No
is us export: No
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).
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.
allocation: Randomized
intervention model: Parallel Assignment
intervention model description: open label, randomized, parallel-group, multicenter study
primary purpose: Treatment
masking: None (Open Label)
measure: Progression-Free Survival (PFS)
time frame: through study completion, an average of 1 year
description: 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
measure: Clinical Benefit Rate (CBR)
time frame: through study completion, an average of 1 year
description: CBR is defined as the percentage of all subjects with a complete or partial response; or stable disease for >/=24 weeks.
measure: Objective Response Rate (ORR)
time frame: through study completion, an average of 1 year
description: 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.
measure: Overall Survival (OS)
time frame: through study completion, an average of 1 year
description: OS is defined as time from randomization to death due to any cause.
measure: Incidence of Adverse Events (AEs) and Serious AEs
time frame: through study completion, an average of 1 year
description: 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
arm group label: Lasofoxifene
arm group type: Experimental
description: 5 mg/d of oral lasofoxifene
arm group label: Fulvestrant
arm group type: Active Comparator
description: 500 mg fulvestrant intramuscular (IM)
intervention type: Drug
intervention name: Lasofoxifene
description: Estrogen receptor antagonist antineoplastic agent
arm group label: Lasofoxifene
intervention type: Drug
intervention name: Fulvestrant
description: Estrogen receptor antagonist antineoplastic agent
arm group label: Fulvestrant
criteria: 
gender: Female
gender based: Yes
gender description: Pre- and Postmenopausal women
minimum age: 18 Years
maximum age: N/A
healthy volunteers: No
last name: Paul V. Plourde, MD
role: Study Director
affiliation: Sermonix Pharmaceuticals
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country: Canada
country: Israel
country: United States
responsible party type: Sponsor
mesh term: Breast Neoplasms
mesh term: Fulvestrant