| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| postmenopausal women with hormone receptor positive early breast cancer |
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| MedDRA Classification |
| 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 |
| The primary objective of this study is to compare the frequency of events (i.e., presence of DTC in BM, clinical recurrence and/or death) in patients treated with anastrozole-fulvestrant combination as compared to that in patients treated with anastrozole alone by assessment of the BM status (i.e., the presence or absence of DTC) and the occurrence of clinical recurrences and/or deaths after 12 months (with a diagnostic window of ±3 weeks) of randomised treatment. |
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| E.2.2 | Secondary objectives of the trial |
· To assess the safety of the anastrozole-fulvestrant combination (secondary)
· To assess the frequency of events (presence of DTC, clinical recurrence and / or death) after 24 months of randomised treatment (secondary)
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| E.2.3 | Trial contains a sub-study | Information not present in EudraCT |
| E.3 | Principal inclusion criteria |
1. Provision of written informed consent: signed and dated Informed Consent Form prior to commencement of any specific protocol procedures
2. Histological confirmation (core needle biopsy or tumour excision) of breast can-cer staged (c/p)T1-4a-c N0-3 G1-3 M0
3. No signs of distant metastasis in
· Chest X-ray and liver ultrasound (OR chest and abdomen CT scan)
· Whole body bone scan
· Medical history and physical examination
· Routine laboratory evaluation as outlined in section 4.7.2
4. Documented positive hormone receptor status (ER +ve and/or PgR +ve) of par-affin-embedded primary tumour tissue (core needle biopsy or tumour excision), according to the local laboratory parameters. A positive hormone receptor status in fine needle aspiration may be used for pre-selection of patients for intraopera-tive Screening BM aspiration; a positive hormone receptor status of the tumour excision is required for inclusion in the study.
5. Postmenopausal woman, defined as a woman fulfilling any one of the following criteria:
· Age ³ 60 years;
· Amenorrhoea ³ 12 months with an intact uterus and ≥ 1 intact ovaries;
· Having undergone a bilateral oophorectomy;
· For patients with at least one ovary but without a uterus, FSH and estradiol in the postmenopausal range;
· For patients previously treated with an LHRH antagonist, the last dose must have been 4 months prior to randomisation, menses must not have restarted and FSH and estradiol must be in the postmenopausal range;
· Patients who have received adjuvant or neoadjuvant chemotherapy must have met one of the above criteria for postmenopausal status prior to that chemotherapy (subgroup for which pregnancy testing might be considered).
6. WHO performance status 0, 1 or 2.
7. At Screening Phase (within 28 days prior to randomisation)
· Physical examination without clinically significant abnormalities
· Bone marrow aspiration with”DTC-positive” immunocytochemical result
· Chest X-ray, liver ultrasound, (or CT chest and abdomen) and bone scan without signs of metastatic breast cancer
· Laboratory requirements (at a clinically relevant time point prior to specific protocol procedures; i.e. for example 3-4 weeks after any preceding anti-tumour treatment, including chemotherapy, neoadjuvant Herceptin therapy):
o Neutrophils ≥ 1.5 x 109/l, platelets ≥ 100 x 109/l
o Total bilirubin < 1 x ULN (except patients with confirmed Gilbert’s syn-drome who may be included in the study)
o AST (SGOT) and ALT (SGPT) < 1.5x ULN
o Alkaline phosphatases < 1 x ULN.
In case of abnormal values, the liver function tests have to be repeated and meet above criteria within 3 days before study treatment.
o Creatinine ≤ 1.1 x ULN
8. At randomisation (endocrine treatment should start within the following 7 days)
· Final disease stage of completely resected pT1-4a-c N0-3 G1-3 M0 breast cancer
· Positive (ER +ve and/or PgR +ve) hormone receptor status of the formalin-fixed, paraffin-embedded tumour excision / mastectomy.
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| E.4 | Principal exclusion criteria |
1. Inflammatory (pT4d) and / or metastatic breast cancer (M1)
2. Current or prior malignancy within previous 5 years (other than breast cancer or adequately treated non melanoma skin cancer or in-situ carcinoma of the cervix)
3. Premenopausal women
4. Preceding or concurrent systemic antitumour therapy; EXCEPT:
· Patient had received adjuvant chemotherapy and has a DTC-positive Screening Phase BM aspiration in local anaesthesia up to 8 weeks after but not less than 2 weeks of completion of chemotherapy;
· Patient had received prior neoadjuvant chemotherapy with or without tras-tuzumab with an incomplete response (e.g.PR, SD, PD) for assessment of hormone-receptor expression of the residual tumour and has a DTC-positive Screening Phase BM aspiration at or after definitive primary surgery up to 8 weeks after but not less than 2 weeks of completion of chemotherapy;
5. Immunocytochemical BM screening: ”DTC-negative”
Note: patient is no longer subject of this trial and may enter other clinical trial
6. Treatment with a non-approved, investigational or experimental drug within 28 days before randomisation
7. History of bleeding diathesis (i.e., vW syndrome, disseminated intravascular co-agulation [DIC], clotting factor deficiency) or long-term anticoagulant therapy (other than antiplatelet therapy and low dose warfarin with INR < 2 – see Sec-tion 3.7)
8. History of hypersensitivity to active or inactive excipients of fulvestrant, aroma-tase inhibitors or castor oil
9. Any severe concomitant condition which makes it undesirable for the patient to participate in the trial or which would jeopardize compliance with the trial pro-tocol, e.g., uncontrolled cardiac disease or uncontrolled diabetes mellitus
10. Involvement in the planning and conduct of the study (applies to ABCSG staff, AstraZeneca staff or staff at the study site)
11. Previous enrolment or randomisation of treatment in the present study
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| E.5 End points |
| E.5.1 | Primary end point(s) |
·Frequency of events (DTC-positive BM specimens, clinical recurrence, death) af-ter 12 months of randomised treatment
Frequency of events (DTC-positive BM specimens, clinical recurrence, death) af-ter 24 months of randomised treatment
Frequency of National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE Version 3) grade 3 or 4 Adverse Events (AE), and Serious Ad-verse Events (SAE) after 12 and 24 months of randomised treatment. All adverse events will be recorded. |
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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 | No |
| 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) | Yes |
| E.7.3 | Therapeutic confirmatory (Phase III) | No |
| 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 | No |
| E.8.6.2 | Trial being conducted completely outside of the EEA | Information not present in EudraCT |
| 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 data cut-off for the primary analysis will be approximately 12 months after the last pa-tient has been recruited and this is estimated to be the third quarter of 2008.
After the data cut-off for the primary analysis, patients will be followed until the data cut-off date of 24 months after the last patient has been recruited. The study will then be closed and the date for this is estimated to be approximately the fourth quarter of 2009.
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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 | |
| E.8.9.1 | In the Member State concerned months | |
| E.8.9.1 | In the Member State concerned days | |
| E.8.9.2 | In all countries concerned by the trial years | 3 |
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