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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 : Recruiting
First Posted : November 6, 2015
Last Update Posted : October 25, 2018
Sponsor:
Information provided by (Responsible Party):
National Cancer Institute (NCI)

Brief Summary:
This randomized 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.

Condition or disease Intervention/treatment Phase
Estrogen Receptor Positive Postmenopausal 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 Drug: Exemestane Other: Laboratory Biomarker Analysis Other: Pharmacological Study Other: Placebo Other: Quality-of-Life Assessment Other: Questionnaire Administration Procedure: Therapeutic Conventional Surgery Phase 2

Detailed Description:

PRIMARY OBJECTIVES:

I. Non-inferiority of percent change in time of serum 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 and circulating 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, courses 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 : Interventional  (Clinical Trial)
Estimated Enrollment : 300 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Double (Participant, Investigator)
Primary Purpose: Prevention
Official Title: Alternative Dosing of Exemestane in Postmenopausal Women With Stage 0-II ER-Positive Breast Cancer: A Randomized Presurgical Trial
Actual Study Start Date : December 6, 2016
Estimated Primary Completion Date : January 31, 2019

Resource links provided by the National Library of Medicine

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

Arm Intervention/treatment
Experimental: Arm I (exemestane)
Patients receive exemestane PO QD on days 1-7. Courses 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.
Drug: Exemestane
Given PO
Other Names:
  • Aromasin
  • FCE-24304

Other: Laboratory Biomarker Analysis
Correlative studies

Other: Pharmacological Study
Correlative studies

Other: Quality-of-Life Assessment
Ancillary studies
Other Name: Quality of Life Assessment

Other: Questionnaire Administration
Ancillary studies

Procedure: Therapeutic Conventional Surgery
Undergo 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. Courses 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.
Drug: Exemestane
Given PO
Other Names:
  • Aromasin
  • FCE-24304

Other: Laboratory Biomarker Analysis
Correlative studies

Other: Pharmacological Study
Correlative studies

Other: Placebo
Given PO
Other Names:
  • placebo therapy
  • PLCB
  • sham therapy

Other: Quality-of-Life Assessment
Ancillary studies
Other Name: Quality of Life Assessment

Other: Questionnaire Administration
Ancillary studies

Procedure: Therapeutic Conventional Surgery
Undergo surgery

Experimental: Arm III (exemestane, placebo)
Patients receive exemestane PO QD on day 1 and placebo PO QD on days 2-7. Courses 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.
Drug: Exemestane
Given PO
Other Names:
  • Aromasin
  • FCE-24304

Other: Laboratory Biomarker Analysis
Correlative studies

Other: Pharmacological Study
Correlative studies

Other: Placebo
Given PO
Other Names:
  • placebo therapy
  • PLCB
  • sham therapy

Other: Quality-of-Life Assessment
Ancillary studies
Other Name: Quality of Life Assessment

Other: Questionnaire Administration
Ancillary studies

Procedure: Therapeutic Conventional Surgery
Undergo surgery




Primary Outcome Measures :
  1. 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, 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 :
  1. 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 ]
  2. 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.

  3. 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.

  4. Additional validated method of estradiol measurement [ Time Frame: Up to day 43 ]
  5. Serum concentrations of estrone and estrone sulfate measured by liquid chromatography coupled with tandem mass spectrometry [ Time Frame: Up to day 43 ]
  6. Androstenedione and testosterone expression measured by radioimmunoassay [ Time Frame: Up to day 43 ]
  7. Sex hormone binding globulin serum levels measured by a chemiluminescent microparticle immunoassay [ Time Frame: Up to day 43 ]
  8. 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 ]
  9. 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.

  10. Breast estradiol concentration in tumor and normal breast tissue [ Time Frame: At time of surgery ]
  11. Changes in estrogen receptor, progesterone receptor, human epidermal growth factor receptor 2, and Ki67 expression levels [ Time Frame: Baseline to up to day 43 ]
  12. Ki67 in adjacent intraepithelial neoplasia and or grossly benign tissue [ Time Frame: Up to day 43 ]
  13. Proteomic analysis [ Time Frame: Up to day 43 ]
  14. UGT2B17 gene analysis assessed by the Taqman copy number variation assay [ Time Frame: Up to day 43 ]
  15. Changes in the occurrence of crown like structures in mammary fat tissue by immunohistochemistry [ Time Frame: Baseline to up to day 43 ]


Information from the National Library of Medicine

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Ages Eligible for Study:   up to 75 Years   (Child, Adult, Older Adult)
Sexes Eligible for Study:   Female
Accepts Healthy Volunteers:   No
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)

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): NCT02598557


Locations
United States, Florida
Moffitt Cancer Center Recruiting
Tampa, Florida, United States, 33612
Contact: Nagi B. Kumar    813-745-6885    nagi.kumar@moffitt.org   
Principal Investigator: Nagi B. Kumar         
United States, New York
Columbia University/Herbert Irving Cancer Center Recruiting
New York, New York, United States, 10032
Contact: Katherine D. Crew    212-305-1732    kd59@cumc.columbia.edu   
Principal Investigator: Katherine D. Crew         
United States, Texas
M D Anderson Cancer Center Recruiting
Houston, Texas, United States, 77030
Contact: Powel H. Brown    713-792-4509    phbrown@mdanderson.org   
Principal Investigator: Powel H. Brown         
Italy
Galliera Hospital Recruiting
Genoa, Italy, 16128
Contact: Andrea Decensi    39-010 5634501    andrea.decensi@galliera.it   
Principal Investigator: Andrea Decensi         
European Institute of Oncology Recruiting
Milano, Italy, 20141
Contact: Bernardo Bonanni    39-0257489022    bernardo.bonanni@ieo.it   
Principal Investigator: Bernardo Bonanni         
Sponsors and Collaborators
National Cancer Institute (NCI)
Investigators
Principal Investigator: Bernardo Bonanni M.D. Anderson Cancer Center

Responsible Party: National Cancer Institute (NCI)
ClinicalTrials.gov Identifier: NCT02598557     History of Changes
Other Study ID Numbers: NCI-2015-01821
NCI-2015-01821 ( Registry Identifier: CTRP (Clinical Trial Reporting Program) )
N01-CN-2012-00034
HHSN26120120034I
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 )
First Posted: November 6, 2015    Key Record Dates
Last Update Posted: October 25, 2018
Last Verified: October 2018

Additional relevant MeSH terms:
Physiological Effects of Drugs
Breast Neoplasms
Breast Carcinoma In Situ
Neoplasms by Site
Neoplasms
Breast Diseases
Skin Diseases
Carcinoma in Situ
Carcinoma
Neoplasms, Glandular and Epithelial
Neoplasms by Histologic Type
Exemestane
Antineoplastic Agents
Aromatase Inhibitors
Steroid Synthesis Inhibitors
Enzyme Inhibitors
Molecular Mechanisms of Pharmacological Action
Estrogen Antagonists
Hormone Antagonists
Hormones, Hormone Substitutes, and Hormone Antagonists