| 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 |
Overall survival
Systemic disease-free survival
Quality of life
Sites of first treatment failure
Late side effects of early menopause
Incidence of second (non-breast) malignancies
Causes of death without cancer event |
|
| 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] 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; the only patients who do not require testing of estradiol (E2) to confirm premenopausal status are those who have been menstruating regularly during the 6 months prior to randomization and have not used any form of hormonal contraception or any other hormonal treatments during the 6 months prior to randomization.
• Patients who received prior adjuvant and/or neoadjuvant chemotherapy should be
randomized after completing chemotherapy and within 8 months of the final dose of
chemotherapy as soon as premenopausal status is confirmed; all such patients should have premenopausal status confirmed by an estradiol (E2) in the premenopausal range between 2 weeks and 8 months after completing chemotherapy.
Adjuvant trastuzumab (Herceptin ®) is allowable, and is not considered to be chemotherapy for eligibility timing determination.
Patients with temporary chemotherapy-induced amenorrhea who regain premenopausal status within eight months of the final dose of chemotherapy are eligible. [Please note that some patients taking tamoxifen or aromatase inhibitors, even without evidence of menses, 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 [34]. Therefore in patients wishing to participate in the study, with postmenopausal hormone levels shortly after chemotherapy, it is recommended to
recheck their estradiol level at a later timepoint within 8 months of completing
chemotherapy, even in the absence of return of menses.
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. If there is more than one breast tumor, each tumor must be hormone receptor positive. 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.
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.
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. If all other margins are clear, a positive posterior (deep) margin is permitted, provided the surgeon documents that the excision was performed down to the pectoral fascia and all tumor has been removed. Likewise, if all other margins are clear, a positive anterior (superficial; abutting skin) margin is permitted provided the surgeon documents that all tumor has been removed. Radiation therapy to the conserved
breast is required; patients may be randomized before, during or after completion of radiation therapy to the breast.
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 negative or microscopically axillary positive sentinel nodes (pN1mi: micrometastasis none >2.0mm) do not require further axillary therapy. Those with positive sentinel nodes must have either an axillary dissection or radiation of axillary 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.
Written informed consent signed and dated.
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 positive final margins (referring to only DCIS and invasive cancer, not
LCIS), except as noted in section 3.1.5. DCIS at a margin is permitted if a complete mastectomy has been performed.
Patients with clinically detectable residual axillary disease.
Patients with a history of prior ipsilateral or contralateral invasive breast cancer. Patients with synchronous bilateral invasive breast cancer (diagnosed histologically within 2 months) are eligible if the bilateral disease meets all other eligibility criteria (see section 8.1.2 for data management for such patients).
Patients with previous or concomitant invasive malignancy are not eligible. The
exceptions are patients with the following (and only the following) malignancies (previous or concomitant) who are eligible if adequately treated:
• basal or squamous cell carcinoma of the skin
• in situ non-breast carcinoma without invasion
• contra- or ipsilateral in situ breast carcinoma
• non-breast invasive malignancy diagnosed at least 5 years ago and without recurrence:
o stage I papillary thyroid cancer
o stage Ia carcinoma of the cervix
o stage Ia or b endometrioid endometrial cancer
o borderline or stage I ovarian cancer
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. Patients who will be recommended to undergo oophorectomy within 5 years (e.g., BRCA1 / 2 gene carriers) and therefore for whom randomization to a treatment arm without OFS is inappropriate.
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. A pregnancy test is recommended for women of child-bearing potential who are sexually active and not using reliable contraceptive methods.
Patients who received endocrine therapy (including neoadjuvant and adjuvant) for more than 8 months after their breast cancer diagnosis. Patients who are receiving endocrine therapy at randomization (and have received it for less than 8 months) may continue such therapy until protocol-specified tamoxifen/exemestane is initiated (see section 5.1).
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 that would prevent compliance with protocol requirements. |
|
| 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 | Yes |
| 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
|
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 |
Print
