Clinical Trials /

Alternative Dosing of Exemestane Before Surgery in Treating Postmenopausal Patients With Stage 0-II Estrogen Positive Breast Cancer

NCT02598557

Description:

This phase IIb trial studies how well alternative dosing of exemestane before surgery works in treating in postmenopausal patients with stage 0-II estrogen positive breast cancer. Chemoprevention is the use of drugs to keep breast cancer from forming or coming back. The use of exemestane may treat early stage (stage 0-II) breast cancer. Comparing the exemestane standard dose regimen versus two alternative, less frequent dose regimens may decrease undesirable symptoms and have similar efficacy in reducing serum estradiol.

Related Conditions:
  • Breast Carcinoma
Recruiting Status:

Active, not recruiting

Phase:

Phase 2

Trial Eligibility

Document

Title

  • Brief Title: Alternative Dosing of Exemestane Before Surgery in Treating Postmenopausal Patients With Stage 0-II Estrogen Positive Breast Cancer
  • Official Title: Alternative Dosing of Exemestane in Postmenopausal Women With Stage 0-II ER-Positive Breast Cancer: A Randomized Presurgical Trial

Clinical Trial IDs

  • ORG STUDY ID: NCI-2015-01821
  • SECONDARY ID: NCI-2015-01821
  • SECONDARY ID: HHSN26120120034I
  • SECONDARY ID: N01-CN-2012-00034
  • SECONDARY ID: 2016-0276
  • SECONDARY ID: MDA2014-04-01
  • SECONDARY ID: N01CN00034
  • SECONDARY ID: P30CA016672
  • NCT ID: NCT02598557

Conditions

  • Stage 0 Breast Cancer AJCC v6 and v7
  • Stage I Breast Cancer AJCC v7
  • Stage IA Breast Cancer AJCC v7
  • Stage IB Breast Cancer AJCC v7
  • Stage II Breast Cancer AJCC v6 and v7
  • Stage IIA Breast Cancer AJCC v6 and v7
  • Stage IIB Breast Cancer AJCC v6 and v7

Interventions

DrugSynonymsArms
ExemestaneAromasin, FCE-24304Arm I (exemestane)

Purpose

This phase IIb trial studies how well alternative dosing of exemestane before surgery works in treating in postmenopausal patients with stage 0-II estrogen positive breast cancer. Chemoprevention is the use of drugs to keep breast cancer from forming or coming back. The use of exemestane may treat early stage (stage 0-II) breast cancer. Comparing the exemestane standard dose regimen versus two alternative, less frequent dose regimens may decrease undesirable symptoms and have similar efficacy in reducing serum estradiol.

Detailed Description

      PRIMARY OBJECTIVE:

      I. Non-inferiority of percent change in time of serum unconjugated estradiol levels, adjusted
      for baseline levels, following four up to six weeks of exemestane 25 mg given three times per
      week or one time per week compared with exemestane 25 mg daily dosing.

      SECONDARY OBJECTIVES:

      I. To assess safety and toxicity. II. To support the preventive activity of exemestane we
      will investigate the change in Ki-67 and progesterone receptor (PgR) levels in tumor cells
      and the adjacent intraepithelial neoplasia or benign histologic structures.

      III. To assess possible association of estradiol level with tissue and circulating
      biomarkers.

      IV. To investigate possible pharmacogenetic markers. V. To assess drug levels on tissue
      samples. VI. To investigate tissue proteomics profiling.

      OUTLINE: Patients are randomized to 1 of 3 treatment arms.

      ARM I: Patients receive exemestane orally (PO) once daily (QD) on days 1-7.

      ARM II: Patients receive exemestane PO QD on days 1, 3, and 5. Patients also receive placebo
      PO QD on days 2, 4, 6, and 7.

      ARM III: Patients receive exemestane PO QD on day 1 and placebo PO QD on days 2-7.

      In all arms, cycles repeat every 7 days for 4-6 weeks in the absence of disease progression
      or unacceptable toxicity. Patients then undergo surgery on days 29, 36, or 43.

      After completion of study treatment, patients are followed up at 20-30 days.
    

Trial Arms

NameTypeDescriptionInterventions
Arm I (exemestane)ExperimentalPatients receive exemestane PO QD on days 1-7. Cycles repeat every 7 days for 4-6 weeks in the absence of disease progression or unacceptable toxicity. Patients then undergo surgery on days 29, 36, or 43.
  • Exemestane
Arm II (exemestane, placebo)ExperimentalPatients receive exemestane PO QD on days 1, 3, and 5. Patients also receive placebo PO QD on days 2, 4, 6, and 7. Cycles repeat every 7 days for 4-6 weeks in the absence of disease progression or unacceptable toxicity. Patients then undergo surgery on days 29, 36, or 43.
  • Exemestane
Arm III (exemestane, placebo)ExperimentalPatients receive exemestane PO QD on day 1 and placebo PO QD on days 2-7. Cycles repeat every 7 days for 4-6 weeks in the absence of disease progression or unacceptable toxicity. Patients then undergo surgery on days 29, 36, or 43.
  • Exemestane

Eligibility Criteria

        Inclusion Criteria:

          -  Postmenopausal women (postmenopausal: age >= 60 years, or amenorrhea >= 12 months, or
             bilateral oophorectomy, or - in women with hysterectomy only - follicle stimulating
             hormone [FSH] in the menopausal levels as per local institutional guidelines if < 60
             years old) with histologically-confirmed estrogen receptor (ER)-positive (>= 10%)
             primary breast cancer stage cT0-2, cN0-1, Mx; women with larger tumors who refuse
             chemotherapy (chemo) and/or endocrine neoadjuvant therapy can be eligible

          -  Eastern Cooperative Oncology Group (ECOG) performance status =< 1 (Karnofsky >= 70%)

          -  Leukocytes >= 3,000/microliter

          -  Absolute neutrophil count >= 1,500/microliter

          -  Platelets >= 100,000/microliter

          -  Total bilirubin =< 2 x institutional upper limit of normal (ULN)

          -  Aspartate aminotransferase (AST) (serum glutamic oxaloacetic transaminase
             [SGOT])/alanine aminotransferase (ALT) (serum glutamate pyruvate transaminase [SGPT])
             =< 1.5 x institutional ULN

          -  Serum creatinine =< 1.5 times institutional ULN

          -  Ability to understand and the willingness to sign a written informed consent document

        Exclusion Criteria:

          -  Body mass index (BMI) < 18.5 Kg/m^2

          -  Previous treatment for breast cancer including chemotherapy, endocrine therapy and
             radiotherapy; women with prior ductal breast carcinoma in situ (DCIS) who were treated
             with surgery only and whose treatment ended >= 2 years prior to enrollment are
             eligible for the trial

          -  Women who are planned to receive neoadjuvant therapy

          -  Participants may not be receiving investigational agents

          -  History of allergic reactions attributed to compounds of similar chemical or biologic
             composition to exemestane

          -  Uncontrolled intercurrent illness including, but not limited to, ongoing or active
             infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac
             arrhythmia, or psychiatric illness/social situations that would limit compliance with
             study requirements

          -  Other co-existing invasive malignancies (with the exclusion of basal cell carcinoma or
             skin squamous cell carcinoma) diagnosed during the last 2 years before randomization

          -  History of severe osteoporosis (T score =< -4 either spine or hip), or presence of
             vertebral fracture

          -  Use of systemic hormone replacement therapy (HRT) in the last 30 days prior to the
             randomization; the use of non-systemic estrogen (such as vaginal estrogen use) is
             allowed

          -  Use of any chemopreventive agents (selective estrogen receptor modulators [SERM]) in
             the last 3 months

          -  Concomitant use of CYP3A4 inducer medication (rifampicin, phenytoin, carbamazepine,
             phenobarbital, and St. John's wort)
      
Maximum Eligible Age:75 Years
Minimum Eligible Age:N/A
Eligible Gender:Female
Healthy Volunteers:No

Primary Outcome Measures

Measure:Percentage change of serum unconjugated estradiol concentration
Time Frame:Baseline to up to day 43
Safety Issue:
Description:Full distribution and median values of estradiol at baseline (before treatment), at post (after treatment) will be presented, and changes and percentage changes (with interquartile ranges) of estradiol level, from baseline to post, by arms. Differences by arms of percent change, change and final values will be tested considering t-test and analysis of covariance (ANCOVA) models. Estradiol at baseline will be included as explanatory variable together with other possible confounders such as BMI, age and time since last dose. Normal distribution of residuals from full model will be checked and, if needed, a transformation will be considered. Percentages of patients with final values of estradiol below the detectable level will be compared by arms with Chi-square tests and logistic models.

Secondary Outcome Measures

Measure:Incidence of toxicity graded according to the Common Terminology Criteria for Adverse Events version 4.0 and Menopause-Specific Quality of Life Questionnaire
Time Frame:Up to day 43
Safety Issue:
Description:
Measure:Change in Ki67 expression
Time Frame:Baseline to up to day 43
Safety Issue:
Description:Full distributions and median values of circulating biomarkers, Ki67, in tissue at baseline, after treatment and also of changes and percentage changes (with interquartile ranges) of all continuous variable, will be presented by arms. ANCOVA models will evaluate the associations of post values (after treatment) and changes from baseline by study arms adjusting for baseline values, explanatory variables and possible confounders (such as age and BMI). Normal distribution of residuals from full models will be checked and, if needed, a transformation will be considered.
Measure:Change in serum drug measurements of exemestane and 17-dihydroxyexemestane at the end of treatment
Time Frame:Baseline to up to day 43
Safety Issue:
Description:Full distributions and median values of circulating biomarkers, exemestane and 17dihydroxyexemestane in tissue at baseline, after treatment and also of changes and percentage changes (with interquartile ranges) of all continuous variable, will be presented by arms. ANCOVA models will evaluate the associations of post values (after treatment) and changes from baseline by study arms adjusting for baseline values, explanatory variables and possible confounders (such as age and BMI). Normal distribution of residuals from full models will be checked and, if needed, a transformation will be considered.
Measure:Serum concentrations of unconjugated and total estrone measured by liquid chromatography coupled with tandem mass spectrometry
Time Frame:Up to day 43
Safety Issue:
Description:
Measure:Serum concentrations of androstenedione and testosterone measured by liquid chromatography coupled with tandem mass spectrometry
Time Frame:Up to day 43
Safety Issue:
Description:
Measure:Serum testosterone determined by a chemiluminescent immunoassay
Time Frame:Up to day 43
Safety Issue:
Description:
Measure:Sex hormone binding globulin serum levels measured by a chemiluminescent microparticle immunoassay
Time Frame:Up to day 43
Safety Issue:
Description:
Measure:Change in concentrations of insulin, glucose (homeostatic model assessment index), and lipid profile (total cholesterol, high-density lipoprotein cholesterol and triglycerides
Time Frame:Baseline up to day 43
Safety Issue:
Description:
Measure:Change in leptin and adiponectin serum concentrations measured by enzyme linked immunoassays
Time Frame:Baseline to up to day 43
Safety Issue:
Description:The change in leptin and adiponectin serum concentrations will be analyzed and compared among the different treatment arms.
Measure:Breast estradiol and estrone concentration in tumor and normal breast tissue
Time Frame:At time of surgery
Safety Issue:
Description:
Measure:Changes in estrogen receptor, progesterone receptor, human epidermal growth factor receptor 2, and Ki67 expression levels
Time Frame:Baseline to up to day 43
Safety Issue:
Description:
Measure:Ki67 in adjacent intraepithelial neoplasia and or grossly benign tissue
Time Frame:Up to day 43
Safety Issue:
Description:
Measure:Proteomic analysis
Time Frame:Up to day 43
Safety Issue:
Description:
Measure:UGT2B17 gene analysis assessed by the Taqman copy number variation assay
Time Frame:Up to day 43
Safety Issue:
Description:
Measure:Changes in the occurrence of crown like structures in mammary fat tissue by immunohistochemistry
Time Frame:Baseline to up to day 43
Safety Issue:
Description:

Details

Phase:Phase 2
Primary Purpose:Interventional
Overall Status:Active, not recruiting
Lead Sponsor:National Cancer Institute (NCI)

Last Updated

January 5, 2021