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

Phase 2

Completed

Conditions: Stage 0 Breast Cancer AJCC v6 and 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 I Breast Cancer AJCC v7
Stage IIB Breast Cancer AJCC v6 and v7

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

Registration Number: NCT02598557

Lead Sponsor: National Cancer Institute (NCI)

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: 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.

Recruitment & Eligibility

Status: COMPLETED

Sex: Female

Target Recruitment: 180

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)

Study & Design

Study Type: INTERVENTIONAL

Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
Arm I: Exemestane 25 mg QD	Pharmacological Study	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.
Arm I: Exemestane 25 mg QD	Quality-of-Life Assessment	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.
Arm III: Exemestane 25 mg QW (exemestane, placebo)	Laboratory Biomarker Analysis	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.
Arm I: Exemestane 25 mg QD	Therapeutic Conventional Surgery	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.
Arm I: Exemestane 25 mg QD	Laboratory Biomarker Analysis	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.
Arm II: Exemestane 25 TIW (exemestane, placebo)	Laboratory Biomarker Analysis	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.
Arm II: Exemestane 25 TIW (exemestane, placebo)	Pharmacological Study	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.
Arm III: Exemestane 25 mg QW (exemestane, placebo)	Pharmacological Study	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.
Arm III: Exemestane 25 mg QW (exemestane, placebo)	Therapeutic Conventional Surgery	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.
Arm II: Exemestane 25 TIW (exemestane, placebo)	Questionnaire Administration	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.
Arm II: Exemestane 25 TIW (exemestane, placebo)	Therapeutic Conventional Surgery	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.
Arm III: Exemestane 25 mg QW (exemestane, placebo)	Placebo Administration	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.
Arm III: Exemestane 25 mg QW (exemestane, placebo)	Questionnaire Administration	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.
Arm I: Exemestane 25 mg QD	Questionnaire Administration	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.
Arm II: Exemestane 25 TIW (exemestane, placebo)	Placebo Administration	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.
Arm II: Exemestane 25 TIW (exemestane, placebo)	Quality-of-Life Assessment	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.
Arm III: Exemestane 25 mg QW (exemestane, placebo)	Quality-of-Life Assessment	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.
Arm I: Exemestane 25 mg QD	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.
Arm II: Exemestane 25 TIW (exemestane, placebo)	Exemestane	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.
Arm III: Exemestane 25 mg QW (exemestane, placebo)	Exemestane	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.

Primary Outcome Measures

Name	Time	Method
Percent Change in Time of Circulating Estradiol SPE in Each Arm	baseline and 4-6 weeks	LS means of percent change

Secondary Outcome Measures

Name	Time	Method
Percent Change of Circulating Estrone SPE	baseline and 4-6 weeks	\[(Final levels-baseline levels)/baseline levels\]\*100
Percent Change of Circulating SHBG	baseline and 4-6 weeks	\[(Final levels-baseline levels)/baseline levels\]\*100
Percent Change of Circulating Testosterone	baseline and 4-6 weeks	\[(Final levels-baseline levels)/baseline levels\]\*100
Percent Change of Circulating LDL Cholesterol	baseline and 4-6 weeks	\[(Final levels-baseline levels)/baseline levels\]\*100
Percent Change of Serum Glucose	baseline and 4-6 weeks	\[(Final levels-baseline levels)/baseline levels\]\*100
17 OH Exemestane Tissue Concentration at Surgery	4-6 weeks	Final drug concentration
Percent Change of Circulating Androstenedione	baseline and 4-6 weeks	\[(Final levels-baseline levels)/baseline levels\]\*100
Percent Change in Time of Circulating Estradiol LLE in Each Arm	baseline and 4-6 weeks	LS means of percent change
Percent Change of Circulating Estrone Sulfate	baseline and 4-6 weeks	\[(Final levels-baseline levels)/baseline levels\]\*100
Percent Change of Circulating Total Cholesterol	baseline and 4-6 weeks	\[(Final levels-baseline levels)/baseline levels\]\*100
Percent Change of Circulating Insulin	baseline and 4-6 weeks	\[(Final levels-baseline levels)/baseline levels\]\*100
Change of PgR Expression (Cancer Tissue), Central Review	4-6 weeks	Surgery level-biopsy level.
Change of Ki67% Expression (Adjacent Non Cancer Tissue), Central Review	4-6 weeks	Surgery level-biopsy level.
Percent Change of Circulating Total Estrone	baseline and 4-6 weeks	\[(Final levels-baseline levels)/baseline levels\]\*100
Percent Change of Circulating Testosterone CLIA	baseline and 4-6 weeks	\[(Final levels-baseline levels)/baseline levels\]\*100
Percent Change of Circulating Leptin	baseline and 4-6 weeks	\[(Final levels-baseline levels)/baseline levels\]\*100
Estradiol Tissue Concentration at Surgery	4-6 weeks	Final biomarker concentration
Testosterone Tissue Concentration at Surgery	4-6 weeks	Final biomarker concentration
Percent Change of Circulating Estrone LLE	baseline and 4-6 weeks	\[(Final levels-baseline levels)/baseline levels\]\*100
Percent Change of Circulating HDL Cholesterol	baseline and 4-6 weeks	\[(Final levels-baseline levels)/baseline levels\]\*100
Percent Change of Circulating Triglycerides	baseline and 4-6 weeks	\[(Final levels-baseline levels)/baseline levels\]\*100
17-OH Exemestane Blood Concentration at Surgery	at surgery	Final drug concentration
Estrone Tissue Concentration at Surgery	4-6 weeks	Final biomarker concentration
Androstenedione Tissue Concentration at Surgery	4-6 weeks	Final biomarker concentration.
Percent Change of HOMA IR	baseline and 4-6 weeks	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.
Percent Change of Circulating Adiponectin	baseline and 4-6 weeks	\[(Final levels-baseline levels)/baseline levels\]\*100
Exemestane Blood Concentration at Surgery	at surgery	Final drug concentration
Change of ER Expression (Cancer Tissue), Central Review	4-6 weeks	Surgery level-biopsy level.
Change of Ki67% Expression (Cancer Tissue), Central Review	4-6 weeks	Surgery level-biopsy level.
Exemestane Tissue Concentration at Surgery	4-6 weeks	Final drug concentration
Change in MenQoL Questionnaire Score	baseline and 4-6 weeks	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

Trial Locations

Locations (5): European Institute of Oncology
🇮🇹
Milano, Italy
Moffitt Cancer Center
🇺🇸
Tampa, Florida, United States
Galliera Hospital
🇮🇹
Genoa, Italy
M D Anderson Cancer Center
🇺🇸
Houston, Texas, United States
NYP/Columbia University Medical Center/Herbert Irving Comprehensive Cancer Center
🇺🇸
New York, New York, United States