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A Phase III Trial Evaluating The Role Of Exemestane Plus GnRH Analogue As Adjuvant Therapy For Premenopausal Women With Endocrine Responsive Breast Cancer

Phase 3
Open (Enrolling)
Estrogen Receptor-positive Breast Cancer, Progesterone Receptor-positive Breast Cancer, Stage IA Breast Cancer, Stage IB Breast Cancer, Stage II Breast Cancer, Stage IIIA Breast Cancer

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Trial Information

A Phase III Trial Evaluating The Role Of Exemestane Plus GnRH Analogue As Adjuvant Therapy For Premenopausal Women With Endocrine Responsive Breast Cancer


I. Compare the disease-free and overall survival of premenopausal women with
endocrine-responsive breast cancer when treated with triptorelin and exemestane vs
triptorelin and tamoxifen.

II. Compare the quality of life, including late side effects of early menopause, of patients
treated with these regimens.

III. Compare the sites of first treatment failure in patients treated with these regimens.

IV. Compare the incidence of second (non-breast) malignancies in patients treated with these

OUTLINE: This is a randomized, multicenter study. Patients are stratified according to
participating center, concurrent adjuvant chemotherapy (yes vs no), and number of positive
axillary and/or internal mammary lymph nodes (0 vs 1 or more). Patients are randomized to 1
of 2 treatment arms.

ARM I: Patients receive triptorelin intramuscularly on day 1 every 28 days. Patients in the
adjuvant chemotherapy stratum receive chemotherapy concurrently with triptorelin for at
least 2 months (if anthracycline is included) or at least 4 months (if no anthracycline is
included). Beginning after the completion of chemotherapy or approximately 6-8 weeks after
the initiation of triptorelin, patients receive oral tamoxifen daily.

ARM II: Patients receive triptorelin as in arm I. Beginning after the completion of adjuvant
chemotherapy or approximately 6-8 weeks after the initiation of triptorelin, patients also
receive oral exemestane daily.

In both arms, treatment continues for 5 years in the absence of disease progression or
unacceptable toxicity. Quality of life is assessed at baseline, every 6 months for 2 years,
and annually for 3 years.

Patients are followed every 3 months for 1 year, every 6 months for 5 years, and then
annually thereafter.

Inclusion Criteria:

- Histologically confirmed breast cancer

- Completely resected disease

- No clinically detectable residual loco-regional axillary disease

- Prior surgery for primary breast cancer of 1 of the following types:

- Total mastectomy with or without adjuvant radiotherapy

- Breast-conserving procedure (e.g., lumpectomy, quadrantectomy, or partial
mastectomy with margins negative* for invasive disease and ductal carcinoma
in situ) with planned radiotherapy

- Tumor confined to the breast and axillary nodes

- Tumor detected in internal mammary chain nodes by sentinel node procedure and is
not enlarged is allowed

- Axillary lymph node dissection or a negative axillary sentinel node biopsy required

- Patients with negative or microscopically positive axillary sentinel nodes are

- Positive sentinel nodes must have either axillary dissection or radiation of
axillary nodes

- No distant metastases

- No locally advanced inoperable breast cancer, including any of the following:

- Inflammatory breast cancer

- Supraclavicular node involvement

- Enlarged internal mammary nodes (unless pathologically negative)

- Bilateral synchronous invasive breast cancer allowed if disease meets all other
eligibility criteria

- No prior ipsilateral or contralateral invasive breast cancer

- Hormone receptor status:

- Estrogen and/or progesterone receptor positive

- At least 10% of the tumor cells positive by immunohistochemistry

- If > 1 breast tumor, each tumor must be hormone receptor positive

- Female

- Premenopausal

- Estradiol in the premenopausal range after prior surgery OR meets the following

- Menstruating regularly for the past 6 months

- Has not used any form of hormonal treatment (including hormonal
contraception) within the past 6 months

- No systemic hepatic disease that would preclude prolonged follow-up

- No systemic renal disease that would preclude prolonged follow-up

- No systemic cardiovascular disease that would preclude prolonged follow-up

- No prior thrombosis (e.g., deep vein thrombosis) and/or embolism unless patient is
medically suitable

- No systemic pulmonary disease that would preclude prolonged follow-up

- Not pregnant or nursing

- Fertile patients must use effective nonhormonal contraception

- No history of noncompliance to medical regimens

- No other nonmalignant systemic disease that would preclude prolonged follow-up

- No other malignancy within the past 5 years except adequately treated basal cell or
squamous cell skin cancer, non-breast carcinoma in situ, contralateral or ipsilateral
carcinoma in situ of the breast, or other non recurrent invasive non-breast
malignancy, including any of the following:

- Stage I papillary thyroid cancer

- Stage IA carcinoma of the cervix

- Stage IA or B endometrioid endometrial cancer

- Borderline or stage I ovarian cancer

- No psychiatric, addictive, or other disorder that would preclude study compliance

- Prior or concurrent neoadjuvant or adjuvant trastuzumab allowed

- No prior neoadjuvant or adjuvant chemotherapy

- No prior tamoxifen, other selective estrogen-receptor modulators (SERMs) (e.g.,
raloxifene), or hormone replacement therapy for more than 1 year before breast cancer

- No prior neoadjuvant or adjuvant endocrine therapy since diagnosis of breast cancer

- No concurrent oral or transdermal hormonal therapy

- No other concurrent estrogen, progesterone, or androgens

- No other concurrent aromatase inhibitors

- No concurrent oral or other hormonal contraceptives (i.e., implants or depot

- No concurrent bisphosphonates, except in the following cases:

- Bone density is at least 1.5 standard deviations below the young adult normal

- Participation in a randomized clinical study testing bisphosphonates in the
adjuvant breast cancer setting

- No prior ovarian radiotherapy

- No other concurrent investigational agents

- No prior bilateral oophorectomy

Type of Study:


Study Design:

Allocation: Randomized, Endpoint Classification: Efficacy Study, Intervention Model: Parallel Assignment, Masking: Open Label, Primary Purpose: Treatment

Outcome Measure:

Disease-free survival (DFS)

Outcome Description:

Using two-sided stratified logrank tests to determine if the treatment groups are different, with an alpha level of 0.05. Kaplan-Meier estimates of the DFS distributions will be calculated for each of the two arms. Cox proportional hazards regression models will be used to investigate whether the treatment comparison is modified by adjustments for various covariates.

Outcome Time Frame:

From randomization to local, regional or distant relapse, contralateral breast cancer, appearance of a second (non-breast) primary tumor, or death from any cause, whichever occurs first, assessed up to 6 years

Safety Issue:


Principal Investigator

Barbara Walley

Investigator Role:

Principal Investigator

Investigator Affiliation:

International Breast Cancer Study Group


United States: Food and Drug Administration

Study ID:




Start Date:

August 2003

Completion Date:

Related Keywords:

  • Estrogen Receptor-positive Breast Cancer
  • Progesterone Receptor-positive Breast Cancer
  • Stage IA Breast Cancer
  • Stage IB Breast Cancer
  • Stage II Breast Cancer
  • Stage IIIA Breast Cancer
  • Breast Neoplasms



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