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

Study Overview
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Brief Summary
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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
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We have conducted an international, multicenter, pre-surgical double-blind non-inferiority phase IIb study in which a total of 180 participants have been randomized to receive either exemestane 25 mg/day (Exemestane 25 mg QD) or 25 mg/ three times a week (Exemestane 25 mg TIW) or a single dose of 25 mg/week (Exemestane 25 mg QW) for a minimum of 4 up to 6 weeks. Participants were stratified by center and BMI (<25 kg/m2 vs >25 kg/m2). Participants were histologically confirmed ER-positive (ER >10%) primary breast cancer patients who were candidates for breast surgery. Postmenopausal women younger than 76 years of age with cT0-2, cN0-1, Mx or women with larger tumors who refuse neo-adjuvant therapy before surgery were eligible. No previous treatment for breast cancer was allowed. Complete physical exam and safety lab tests have been performed at baseline and at the end of treatment (28+1, 35+1, 42+1 days). Phone contact occurred on day 1 and a week before surgery (+3 days). Participants experiencing persistent adverse events (certainly, probably, and possibly treatment-related) have been monitored 20-30 days after study completion. Biomarkers: blood samples were collected at baseline and the end of treatment (fasting blood for biomarkers collected prior to randomization and either on the day of surgery or the day before; fasting strongly recommended but not mandated), tissue samples collected from the diagnostic or research biopsy and at the time of surgery.

Official Title
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Alternative Dosing of Exemestane in Postmenopausal Women With Stage 0-II ER-Positive Breast Cancer: A Randomized Presurgical Trial

Conditions
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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 / Treatment
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* Drug: Exemestane
* Other: Laboratory Biomarker Analysis
* Other: Pharmacological Study
* Other: Placebo Administration
* Other: Quality-of-Life Assessment
* Other: Questionnaire Administration
* Procedure: Therapeutic Conventional Surgery


Participation Criteria
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Eligibility Criteria
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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)

Ages Eligible for Study
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Maximum Age: 75 Years

Sexes Eligible for Study
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Female

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Prevention
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Arm I: Exemestane 25 mg QD<br>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. | Drug: Exemestane<br>* Given PO<br>* Other names: FCE-24304;Other: Laboratory Biomarker Analysis<br>* Correlative studies<br>Other: Pharmacological Study<br>* Correlative studies<br>Other: Quality-of-Life Assessment<br>* Ancillary studies<br>* Other names: Quality of Life Assessment;Other: Questionnaire Administration<br>* Ancillary studies<br>Procedure: Therapeutic Conventional Surgery<br>* Undergo surgery<br>|
| Experimental: Arm II: Exemestane 25 TIW (exemestane, placebo)<br>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. | Drug: Exemestane<br>* Given PO<br>* Other names: FCE-24304;Other: Laboratory Biomarker Analysis<br>* Correlative studies<br>Other: Pharmacological Study<br>* Correlative studies<br>Other: Placebo Administration<br>* Given PO<br>Other: Quality-of-Life Assessment<br>* Ancillary studies<br>* Other names: Quality of Life Assessment;Other: Questionnaire Administration<br>* Ancillary studies<br>Procedure: Therapeutic Conventional Surgery<br>* Undergo surgery<br>|
| Experimental: Arm III: Exemestane 25 mg QW (exemestane, placebo)<br>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. | Drug: Exemestane<br>* Given PO<br>* Other names: FCE-24304;Other: Laboratory Biomarker Analysis<br>* Correlative studies<br>Other: Pharmacological Study<br>* Correlative studies<br>Other: Placebo Administration<br>* Given PO<br>Other: Quality-of-Life Assessment<br>* Ancillary studies<br>* Other names: Quality of Life Assessment;Other: Questionnaire Administration<br>* Ancillary studies<br>Procedure: Therapeutic Conventional Surgery<br>* Undergo surgery<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percent Change in Time of Circulating Estradiol SPE in Each Arm | LS means of percent change | baseline and 4-6 weeks | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percent Change in Time of Circulating Estradiol LLE in Each Arm | LS means of percent change | baseline and 4-6 weeks | 
| Percent Change of Circulating Estrone SPE | [(Final levels-baseline levels)/baseline levels]*100 | baseline and 4-6 weeks | 
| Percent Change of Circulating Estrone LLE | [(Final levels-baseline levels)/baseline levels]*100 | baseline and 4-6 weeks | 
| Percent Change of Circulating Total Estrone | [(Final levels-baseline levels)/baseline levels]*100 | baseline and 4-6 weeks | 
| Percent Change of Circulating Estrone Sulfate | [(Final levels-baseline levels)/baseline levels]*100 | baseline and 4-6 weeks | 
| Percent Change of Circulating Androstenedione | [(Final levels-baseline levels)/baseline levels]*100 | baseline and 4-6 weeks | 
| Percent Change of Circulating Testosterone | [(Final levels-baseline levels)/baseline levels]*100 | baseline and 4-6 weeks | 
| Percent Change of Circulating Testosterone CLIA | [(Final levels-baseline levels)/baseline levels]*100 | baseline and 4-6 weeks | 
| Percent Change of Circulating SHBG | [(Final levels-baseline levels)/baseline levels]*100 | baseline and 4-6 weeks | 
| Percent Change of Circulating Total Cholesterol | [(Final levels-baseline levels)/baseline levels]*100 | baseline and 4-6 weeks | 
| Percent Change of Circulating HDL Cholesterol | [(Final levels-baseline levels)/baseline levels]*100 | baseline and 4-6 weeks | 
| Percent Change of Circulating LDL Cholesterol | [(Final levels-baseline levels)/baseline levels]*100 | baseline and 4-6 weeks | 
| Percent Change of Circulating Triglycerides | [(Final levels-baseline levels)/baseline levels]*100 | baseline and 4-6 weeks | 
| Percent Change of Circulating Insulin | [(Final levels-baseline levels)/baseline levels]*100 | baseline and 4-6 weeks | 
| Percent Change of Serum Glucose | [(Final levels-baseline levels)/baseline levels]*100 | baseline and 4-6 weeks | 
| Percent Change of HOMA IR | Insulin Resistance Index (HOMA-IR) measures insulin resistance, calculated by fasting insulin (mU/L) multiplied by fasting glucose (mmol/L), and divided by a constant (22.5). A higher score indicates higher insulin resistance. | baseline and 4-6 weeks | 
| Percent Change of Circulating Adiponectin | [(Final levels-baseline levels)/baseline levels]*100 | baseline and 4-6 weeks | 
| Percent Change of Circulating Leptin | [(Final levels-baseline levels)/baseline levels]*100 | baseline and 4-6 weeks | 
| Exemestane Blood Concentration at Surgery | Final drug concentration | at surgery | 
| 17-OH Exemestane Blood Concentration at Surgery | Final drug concentration | at surgery | 
| Change of ER Expression (Cancer Tissue), Central Review | Surgery level-biopsy level. | 4-6 weeks | 
| Change of PgR Expression (Cancer Tissue), Central Review | Surgery level-biopsy level. | 4-6 weeks | 
| Change of Ki67% Expression (Cancer Tissue), Central Review | Surgery level-biopsy level. | 4-6 weeks | 
| Change of Ki67% Expression (Adjacent Non Cancer Tissue), Central Review | Surgery level-biopsy level. | 4-6 weeks | 
| Estradiol Tissue Concentration at Surgery | Final biomarker concentration | 4-6 weeks | 
| Estrone Tissue Concentration at Surgery | Final biomarker concentration | 4-6 weeks | 
| Androstenedione Tissue Concentration at Surgery | Final biomarker concentration. | 4-6 weeks | 
| Testosterone Tissue Concentration at Surgery | Final biomarker concentration | 4-6 weeks | 
| Exemestane Tissue Concentration at Surgery | Final drug concentration | 4-6 weeks | 
| 17 OH Exemestane Tissue Concentration at Surgery | Final drug concentration | 4-6 weeks | 
| Change in MenQoL Questionnaire Score | MenQOL questionnaire assessed how bothered participants were with 31 symptoms. It contains domains: vasomotor (items 1-3); psychosocial (items 4-10); physical (items 11-26); sexual (items 27-29); in addition to nausea and indigestion. 31 individual symptoms are rated on a scale of 0 (not at all bothered) to 6 (extremely bothered). Total possible score ranged from 0 to 186. MenQOL summary score was calculated as mean of four domain scores (Physical function, Psychosocial function, Sexual function and Vasomotor function) ranging from 1 to 8, with higher scores indicating worse quality of life. Final score-baseline score | baseline and 4-6 weeks |