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

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ClinicalTrials.gov Identifier: NCT02598557
Recruitment Status : Active, not recruiting
First Posted : November 6, 2015
Last Update Posted : September 30, 2021
Sponsor:
Information provided by (Responsible Party):
National Cancer Institute (NCI)

Tracking Information
First Submitted Date  ICMJE November 5, 2015
First Posted Date  ICMJE November 6, 2015
Last Update Posted Date September 30, 2021
Actual Study Start Date  ICMJE December 6, 2016
Actual Primary Completion Date October 3, 2019   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: June 25, 2020)
Percentage change of serum unconjugated estradiol concentration [ Time Frame: Baseline to up to day 43 ]
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.
Original Primary Outcome Measures  ICMJE
 (submitted: November 5, 2015)
Percentage change of serum estradiol concentration [ Time Frame: Baseline to up to day 43 ]
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, i
Change History
Current Secondary Outcome Measures  ICMJE
 (submitted: June 24, 2021)
  • 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 ]
  • Change in Ki67 expression [ Time Frame: Baseline to up to day 43 ]
    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.
  • Change in serum drug measurements of exemestane and 17-dihydroxyexemestane at the end of treatment [ Time Frame: Baseline to up to day 43 ]
    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.
  • Serum concentrations of unconjugated and total estrone and estrone sulfate measured by liquid chromatography coupled with tandem mass spectrometry [ Time Frame: Up to day 43 ]
  • Serum concentrations of androstenedione and testosterone measured by liquid chromatography coupled with tandem mass spectrometry [ Time Frame: Up to day 43 ]
  • Serum testosterone determined by a chemiluminescent immunoassay [ Time Frame: Up to day 43 ]
  • Sex hormone binding globulin serum levels measured by a chemiluminescent microparticle immunoassay [ Time Frame: Up to day 43 ]
  • 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 ]
  • Change in leptin and adiponectin serum concentrations measured by enzyme linked immunoassays [ Time Frame: Baseline to up to day 43 ]
    The change in leptin and adiponectin serum concentrations will be analyzed and compared among the different treatment arms.
  • Measurement exemestane and 17-dihydroxyexemestane [ Time Frame: Up to day 43 ]
    Will be performed on frozen tissue samples (normal breast and breast cancer tissue).
  • Breast estradiol and estrone concentration in tumor and normal breast tissue [ Time Frame: At time of surgery ]
  • Changes in estrogen receptor, progesterone receptor, human epidermal growth factor receptor 2, and Ki67 expression levels [ Time Frame: Baseline to up to day 43 ]
  • Ki67 in adjacent intraepithelial neoplasia and or grossly benign tissue [ Time Frame: Up to day 43 ]
  • Proteomic analysis [ Time Frame: Up to day 43 ]
  • UGT2B17 gene analysis assessed by the Taqman copy number variation assay [ Time Frame: Up to day 43 ]
  • Changes in the occurrence of crown like structures in mammary fat tissue by immunohistochemistry [ Time Frame: Baseline to up to day 43 ]
Original Secondary Outcome Measures  ICMJE
 (submitted: November 5, 2015)
  • Additional validated method of estradiol measurement [ Time Frame: Up to day 43 ]
  • Androstenedione and testosterone expression measured by radioimmunoassay [ Time Frame: Up to day 43 ]
  • Breast tissue estradiol concentration in tumor and breast fat [ Time Frame: At time of surgery ]
  • Change in Ki67 expression [ Time Frame: Baseline to up to day 43 ]
    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.
  • Change in leptin and adiponectin serum concentrations measured by enzyme linked immunoassays [ Time Frame: Baseline to up to day 43 ]
    The change in leptin and adiponectin serum concentrations will be analyzed and compared among the different treatments arms.
  • Change in serum drug measurements of exemestane and 17-dihydroxyexemestane at the end of treatment [ Time Frame: Baseline to up to day 43 ]
    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 consider
  • Changes in estrogen receptor, progesterone receptor, and human epidermal growth factor receptor 2 expression levels [ Time Frame: Baseline to up to day 43 ]
  • Changes in the occurrence of crown like structures in mammary fat tissue by immunohistochemistry [ Time Frame: Baseline to up to day 43 ]
  • 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 ]
  • Insulin and glucose concentrations measured with the Architect Immunoassay analyzer [ Time Frame: Up to day 43 ]
  • Ki67 in adjacent intraepithelial neoplasia and or grossly benign tissue [ Time Frame: Up to day 43 ]
  • Proteomic analysis [ Time Frame: Up to day 43 ]
  • Serum concentrations of estrone and estrone sulfate measured by liquid chromatography coupled with tandem mass spectrometry [ Time Frame: Up to day 43 ]
  • Sex hormone binding globulin serum levels measured by a chemiluminescent microparticle immunoassay [ Time Frame: Up to day 43 ]
  • UDP glucuronosyltransferase 2 family, polypeptide B17 gene analysis assessed by the Taqman copy number variation assay [ Time Frame: Up to day 43 ]
Current Other Pre-specified Outcome Measures Not Provided
Original Other Pre-specified Outcome Measures Not Provided
 
Descriptive Information
Brief Title  ICMJE Alternative Dosing of Exemestane Before Surgery in Treating Postmenopausal Patients With Stage 0-II Estrogen Positive Breast Cancer
Official Title  ICMJE Alternative Dosing of Exemestane in Postmenopausal Women With Stage 0-II ER-Positive Breast Cancer: A Randomized Presurgical Trial
Brief Summary 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.

Study Type  ICMJE Interventional
Study Phase  ICMJE Phase 2
Study Design  ICMJE Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Double (Participant, Investigator)
Primary Purpose: Prevention
Condition  ICMJE
  • 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
Intervention  ICMJE
  • Drug: Exemestane
    Given PO
    Other Names:
    • Aromasin
    • FCE-24304
  • Other: Laboratory Biomarker Analysis
    Correlative studies
  • Other: Pharmacological Study
    Correlative studies
  • Other: Placebo Administration
    Given PO
  • Other: Quality-of-Life Assessment
    Ancillary studies
    Other Name: Quality of Life Assessment
  • Other: Questionnaire Administration
    Ancillary studies
  • Procedure: Therapeutic Conventional Surgery
    Undergo surgery
Study Arms  ICMJE
  • Experimental: Arm I (exemestane)
    Patients 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.
    Interventions:
    • Drug: Exemestane
    • Other: Laboratory Biomarker Analysis
    • Other: Pharmacological Study
    • Other: Quality-of-Life Assessment
    • Other: Questionnaire Administration
    • Procedure: Therapeutic Conventional Surgery
  • Experimental: Arm II (exemestane, placebo)
    Patients 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.
    Interventions:
    • Drug: Exemestane
    • Other: Laboratory Biomarker Analysis
    • Other: Pharmacological Study
    • Other: Placebo Administration
    • Other: Quality-of-Life Assessment
    • Other: Questionnaire Administration
    • Procedure: Therapeutic Conventional Surgery
  • Experimental: Arm III (exemestane, placebo)
    Patients 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.
    Interventions:
    • Drug: Exemestane
    • Other: Laboratory Biomarker Analysis
    • Other: Pharmacological Study
    • Other: Placebo Administration
    • Other: Quality-of-Life Assessment
    • Other: Questionnaire Administration
    • Procedure: Therapeutic Conventional Surgery
Publications * Not Provided

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruitment Information
Recruitment Status  ICMJE Active, not recruiting
Actual Enrollment  ICMJE
 (submitted: November 19, 2020)
180
Original Estimated Enrollment  ICMJE
 (submitted: November 5, 2015)
300
Study Completion Date  ICMJE Not Provided
Actual Primary Completion Date October 3, 2019   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

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)
Sex/Gender  ICMJE
Sexes Eligible for Study: Female
Ages  ICMJE up to 75 Years   (Child, Adult, Older Adult)
Accepts Healthy Volunteers  ICMJE No
Contacts  ICMJE Contact information is only displayed when the study is recruiting subjects
Listed Location Countries  ICMJE Italy,   United States
Removed Location Countries Norway
 
Administrative Information
NCT Number  ICMJE NCT02598557
Other Study ID Numbers  ICMJE NCI-2015-01821
NCI-2015-01821 ( Registry Identifier: CTRP (Clinical Trial Reporting Program) )
HHSN26120120034I
N01-CN-2012-00034
2016-0276 ( Other Identifier: M D Anderson Cancer Center )
MDA2014-04-01 ( Other Identifier: DCP )
N01CN00034 ( U.S. NIH Grant/Contract )
P30CA016672 ( U.S. NIH Grant/Contract )
Has Data Monitoring Committee Yes
U.S. FDA-regulated Product Not Provided
IPD Sharing Statement  ICMJE Not Provided
Responsible Party National Cancer Institute (NCI)
Study Sponsor  ICMJE National Cancer Institute (NCI)
Collaborators  ICMJE Not Provided
Investigators  ICMJE
Principal Investigator: Bernardo Bonanni M.D. Anderson Cancer Center
PRS Account National Cancer Institute (NCI)
Verification Date June 2021

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