E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
Premenopausal women (estradiol (E2) levels in the premenopausal range) with histologically proven, resected breast cancer with ER and/or PgR positive tumors who have received either no chemotherapy or remain premenopausal following completion of adjuvant and/or neoadjuvant chemotherapy. |
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E.1.1.1 | Medical condition in easily understood language |
Hormone (estrogen & progesterone) receptor positive breast cancer |
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E.1.1.2 | Therapeutic area | Diseases [C] - Cancer [C04] |
MedDRA Classification |
E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 14.0 |
E.1.2 | Level | PT |
E.1.2 | Classification code | 10057654 |
E.1.2 | Term | Breast cancer female |
E.1.2 | System Organ Class | 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps) |
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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. OFS plus tamoxifen (This comparison will combine data with the IBCSG 25-02 TEXT trial as the primary analysis for the TEXT trial) |
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E.2.2 | Secondary objectives of the trial |
To compare OFS plus exemestane vs. tamoxifen alone |
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E.2.3 | Trial contains a sub-study | Yes |
E.2.3.1 | Full title, date and version of each sub-study and their related objectives |
There are two substudies:
SOFT-EST Substudy & Cognitive Function Substudy (Co-SOFT)
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SOFT-EST (SOLTI 0801): SOFT Estrogen Suppression Substudy, V1.0 15Oct08, Substudy of SOFT (IBCSG 24-02 / BIG 2-02)
The primary objectives:
- to describe estrogen levels (E2, E1 and E1S) at different timepoints during the first 4 years of protocol treatment among patients receiving triptorelin (GnRH analogue) plus either tamoxifen (arm B) or exemestane (arm C).
- to assess whether there is a suboptimally estrogen-suppressed subgroup of patients who receive exemestane (arm C).
Secondary objectives:
- to compare levels of estrogens (E2, E1, E1S) at different timepoints between triptorelin + tamoxifen vs. triptorelin + exemestane (arm B vs. C).
- to examine potential predictive factors of ineffective estrogen suppression such as: age, chemotherapy (yes/no), type of chemotherapy received, smoking history, BMI and evidence of menses at entry.
- to investigate the predictive value of optimal estrogen suppression during the first 6 and 12 months with regard to long term suppression (48-month period).
- to compare outcome (disease-free survival) in the suboptimally suppressed group in arm C with that of patients with optimal suppression (exploratory analysis).
- to examine related endocrine function (FSH, LH) to further elucidate causes of suboptimal estrogen suppression.
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IBCSG 24-02 / BIG 2-02 / ANZ 0701 Cognitive Function Substudy (Co-SOFT)
Version 2.1 (11 June 2007)
The primary objective is to evaluate and compare changes in cognitive function over 1 year in premenopausal BC patients who receive adjuvant tamoxifen (T) with or without ovarian function suppression (OFS). We hypothesise that women who receive T + OFS will show greater deterioration in cognitive function than those who receive T alone.
Secondary Objectives
To compare the effect of T + OFS versus exemestane (E) + OFS on cognitive function over 1year. We hypothesise that women who receive E + OFS will have a similar degree of deterioration in cognitive function to those who receive T + OFS, because of the overwhelming effect on cognitive function of profound hypoestrogenism from OFS.
To compare the effect of T alone versus E + OFS on cognitive function over 1 year.
We hypothesise that women who receive E + OFS will show greater deterioration in
cognitive function than those who receive T alone.
To evaluate and compare changes in cognitive function over 5 years and 6 years between the 3 treatment groups (pending funding becoming available for the year 5 and 6 measures).
To explore:
the impact of receiving prior chemotherapy or not on changes in cognitive function,
the relationship between subjective and objective cognitive function, and
the relationship between cognitive function, psychological distress, fatigue, insomnia and quality of life.
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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. 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; such patients should have 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. Premenopausal levels of serum estradiol may persist after chemotherapy-induced amenorrhea despite prolonged amenorrhea. 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. Biochemical determination alone is not acceptable.
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. 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 or a negative axillary sentinel node biopsy is required. Patients with negative or microscopically axillary positive sentinel nodes 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 must be signed and dated by the patient and the investigator prior to randomization.
Patients must be accessible for follow-up. |
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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.
Patients with previous or concomitant invasive malignancy EXCEPT 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 recurrrence: stage I papillary thyroid cancer, stage Ia carcinoma of the cervix, stage Ia or b endometrioid endometrial cancer, 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. Apregnancy 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.
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.
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E.5 End points |
E.5.1 | Primary end point(s) |
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E.5.1.1 | Timepoint(s) of evaluation of this end point |
2013 Q3 at a median follow up of approximately 5 years |
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E.5.2 | Secondary end point(s) |
- Overall survival
- Breast cancer-free interval and distant recurrence-free interval
- 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 |
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E.5.2.1 | Timepoint(s) of evaluation of this end point |
2013 Q3 at a median follow up of approximately 5 years |
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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 | No |
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.8.2.4 | Number of treatment arms in the trial | 3 |
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.8.4.1 | Number of sites anticipated in Member State concerned | 9 |
E.8.5 | The trial involves multiple Member States | Yes |
E.8.5.1 | Number of sites anticipated in the EEA | 107 |
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 | No |
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 |
Australia |
Belgium |
Brazil |
Canada |
Chile |
France |
Germany |
Hungary |
India |
Ireland |
Israel |
Italy |
Montenegro |
Netherlands |
New Zealand |
Peru |
Poland |
Portugal |
Serbia |
South Africa |
Spain |
Sweden |
Switzerland |
Turkey |
United Kingdom |
United States |
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E.8.7 | Trial has a data monitoring committee | Yes |
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
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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 time-driven analysis plan defines the cut-off date to be in fall 2013 at a median follow up of approximately 5 years.
Follow-up of patients is to continue indefinitely (life-long) to assess treatment effects on long-term outcome and to evaluate late occurring events.
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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 | 0 |
E.8.9.2 | In all countries concerned by the trial years | 10 |
E.8.9.2 | In all countries concerned by the trial months | 0 |
E.8.9.2 | In all countries concerned by the trial days | 0 |