| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Histologically proven, resected breast cancer with ER and/or PgR positive tumors |
|
| MedDRA Classification |
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 7.0 |
| E.1.2 | Level | LLT |
| E.1.2 | Classification code | 10057654 |
|
| E.1.3 | Condition being studied is a rare disease | No |
| E.2 Objective of the trial |
| E.2.1 | Main objective of the trial |
To compare ovarian function suppression (OFS: GnRH analogue or oophorectomy or
ovarian irradiation) plus tamoxifen vs. tamoxifen alone
To compare OFS plus exemestane vs. tamoxifen alone
To compare OFS plus exemestane vs. OFS plus tamoxifen
|
|
| E.2.2 | Secondary objectives of the trial | |
| E.2.3 | Trial contains a sub-study | Information not present in EudraCT |
| E.3 | Principal inclusion criteria |
Premenopausal women [estradiol (E2) in the premenopausal range (according to
institution parameters)] who meet the following criteria:
• Patients who did not receive chemotherapy should be randomized within 12 weeks after definitive surgery; such patients should have estradiol (E2) in the premenopausal range following surgery.
• Patients who received prior adjuvant and/or neoadjuvant chemotherapy should be
randomized after completing chemotherapy and within 6 months of the final dose of
chemotherapy as soon as premenopausal status is confirmed; such patients should have estradiol (E2) in the premenopausal range between 2 weeks and 6 months after completing chemotherapy.
Patients with temporary chemotherapy-induced amenorrhea who regain premenopausal status within six months of the final dose of chemotherapy are eligible. [Attention: under tamoxifen or aromatase inhibitors, even without evidence of menses, some women may have ovarian function recovery following chemotherapy and resume estradiol secretion.]
Premenopausal levels of serum estradiol may persist after chemotherapy-induced amenorrhea despite prolonged amenorrhea.
Histologically proven, resected breast cancer. Pathology material should be available for submission for central review as part of the quality control measures for this protocol.
Patients must have hormone receptor positive tumors. Hormone receptors must be
determined using immunohistochemistry. ER and/or PgR must be greater than or equal to 10% of the tumor cells positive by immunohistochemical evaluation. Biochemical determination alone is not acceptable. Detailed guidelines for assessments of ER and PgR are given in the Appendix III.
The tumor must be confined to the breast and axillary nodes without detected metastases elsewhere, with the exception of tumor detected in internal mammary chain nodes by sentinel node procedure. Patients who received neoadjuvant therapy must have had operable disease prior to neoadjuvant treatment to be eligible. Patients who had a pathological evaluation with tru cut or core biopsy of invasive breast cancer prior to neoadjuvant therapy and were found to have
no invasive tumor in the pathological specimen from definitive surgery are eligible. For these patients, pre-neoadjuvant tumor characteristics will be used for defining eligibility. In case of persistent disease, pathology findings from the definitive surgery should be used.
Patients must have had proper surgery for primary breast cancer with no known clinical residual loco-regional disease.
• A total mastectomy. Radiotherapy is optional after mastectomy.
OR
• A breast-conserving procedure (lumpectomy, quadrantectomy or partial mastectomy with margins clear of invasive cancer and DCIS). The local pathologist must document negative margins of resection in the pathology report. Radiation therapy to the conserved breast is required.
Either axillary lymph node dissection (pathological examination of at least 6 nodes
recommended) or a negative axillary sentinel node biopsy [pN0(sn)] is required. Patients with positive axillary nodes require axillary dissection, except for patients with microscopically positive (pN1mi: micrometastasis > 0.2mm, none > 2.0mm) axillary sentinel nodes who are randomized in a clinical trial evaluating microscopically positive lymph nodes.
For IBCSG centers, patients must have completed baseline Quality of Life (QL) Forms
prior to randomization. The only exceptions are cognitive or physical impairment that interferes with QL assessment or inability to read any of the languages available on IBCSG QL forms. For non-IBCSG centers, extent of participation in the QL study is to be determined at the activation of the trial for each cooperative group (see Appendix VII for Group-specific guidelines).
Written informed consent must be signed and dated by the patient and the investigator prior to randomization.
Patients must be accessible for follow-up.
Patients must be informed of and agree to data and tissue material transfer and handling, in accordance with national data protection guidelines.
|
|
| E.4 | Principal exclusion criteria |
Patients who are postmenopausal (i.e., do not have an estradiol (E2) level in the premenopausal range) after surgery or after chemotherapy, whichever is later.
Patients with distant metastatic disease.
Patients with locally advanced inoperable breast cancer including inflammatory breast
cancer or supraclavicular node involvement or with enlarged internal mammary nodes (unless pathologically negative) are not eligible. Patients with involved internal mammary nodes detected by sentinel node biopsy that are not enlarged are eligible.
Patients with bilateral invasive breast cancer.
Patients with positive final margins (referring to only DCIS and invasive cancer, not
LCIS).
Patients with clinically detectable residual axillary disease.
Patients with a history of prior ipsilateral or contralateral invasive breast cancer.
Patients with previous or concomitant malignancy EXCEPT adequately treated: basal or squamous cell carcinoma of the skin in situ carcinoma of the cervix or bladder,
contra- or ipsilateral in situ breast carcinoma.
Patients with other non-malignant systemic diseases (cardiovascular, renal, hepatic, lung, etc.) that would prevent prolonged follow-up. Patients with previous thrombosis (e.g., DVT) and/or embolism can be included only if medically suitable.
Patients who have had a bilateral oophorectomy or ovarian irradiation or are planning oophorectomy within 5 years.
Patients with a history of noncompliance to medical regimens and patients who are
considered potentially unreliable.
Patients who are pregnant or lactating at the time of randomization or who desire a
pregnancy within 5 years. Patients planning to use additional hormonal therapy apart from the randomized treatment (see Section 5.3.1) during the next five years including all types of hormonal contraception.
Patients who received endocrine therapy (including neoadjuvant and adjuvant) for more than 6 months after their breast cancer diagnosis.
Patients who were taking tamoxifen or other SERM (e.g. Raloxifene) or hormone
replacement therapy (HRT) within one year prior to their breast cancer diagnosis. Prior oral contraceptives are allowed.
Patients who have received GnRH analogues as part of their breast cancer treatment prior to randomization.
Patients with psychiatric, addictive, or any disorder, which compromises ability to give
informed consent for participation in this study.
|
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
|
| E.6 and E.7 Scope of the trial |
| E.6 | Scope of the trial |
| E.6.1 | Diagnosis | No |
| E.6.2 | Prophylaxis | No |
| E.6.3 | Therapy | Yes |
| E.6.4 | Safety | Yes |
| E.6.5 | Efficacy | Yes |
| E.6.6 | Pharmacokinetic | No |
| E.6.7 | Pharmacodynamic | No |
| E.6.8 | Bioequivalence | No |
| E.6.9 | Dose response | No |
| E.6.10 | Pharmacogenetic | Information not present in EudraCT |
| E.6.11 | Pharmacogenomic | No |
| E.6.12 | Pharmacoeconomic | No |
| E.6.13 | Others | No |
| E.7 | Trial type and phase |
| E.7.1 | Human pharmacology (Phase I) | No |
| E.7.1.1 | First administration to humans | No |
| E.7.1.2 | Bioequivalence study | No |
| E.7.1.3 | Other | No |
| E.7.1.3.1 | Other trial type description | |
| E.7.2 | Therapeutic exploratory (Phase II) | No |
| E.7.3 | Therapeutic confirmatory (Phase III) | Yes |
| E.7.4 | Therapeutic use (Phase IV) | No |
| E.8 Design of the trial |
| E.8.1 | Controlled | Yes |
| E.8.1.1 | Randomised | Yes |
| E.8.1.2 | Open | Yes |
| E.8.1.3 | Single blind | No |
| E.8.1.4 | Double blind | No |
| E.8.1.5 | Parallel group | No |
| E.8.1.6 | Cross over | No |
| E.8.1.7 | Other | No |
| E.8.2 | Comparator of controlled trial |
| E.8.2.1 | Other medicinal product(s) | Yes |
| E.8.2.2 | Placebo | No |
| E.8.2.3 | Other | No |
| E.8.3 |
The trial involves single site in the Member State concerned
| No |
| E.8.4 | The trial involves multiple sites in the Member State concerned | Yes |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.6 Trial involving sites outside the EEA |
| E.8.6.1 | Trial being conducted both within and outside the EEA | Yes |
| E.8.6.2 | Trial being conducted completely outside of the EEA | Information not present in EudraCT |
| E.8.6.3 | If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned |
|
| E.8.7 | Trial has a data monitoring committee | Information not present in EudraCT |
| E.8.8 |
Definition of the end of the trial and justification where it is not the last
visit of the last subject undergoing the trial
|
There are two possible answers to this question depending on the context and reason for asking the question:
1. The trial will continue indefinitely as patients are to be followed life-long.
2. The primary analysis will be conducted when the target number of events described in the protocol are observed. Follow-up of patients is to continue indefinitely (life-long) to assess treatment effects on long-term outcome and to evaluate late occurring events.
|
|
| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 6 |
| E.8.9.1 | In the Member State concerned months | 11 |
| E.8.9.1 | In the Member State concerned days | |
| E.8.9.2 | In all countries concerned by the trial years | 6 |
| E.8.9.2 | In all countries concerned by the trial months | 11 |
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