E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
Operable primary breast cancer with over expression/ amplification of HER2. |
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MedDRA Classification |
E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 9.1 |
E.1.2 | Level | LLT |
E.1.2 | Classification code | 10006187 |
E.1.2 | Term | Breast cancer |
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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 disease-free survival (DFS) in patients with HER2 overexpressing and/or amplified breast cancer randomised to trastuzumab for one year versus lapatinib for one year versus trastuzumab (12 or 18 weeks, according to the assigned ‘design’) followed by a 6-week treatment-free interval followed by lapatinib (28 or 34 weeks, according to assigned ‘design’) versus trastuzumab in combination with lapatinib for one year. |
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E.2.2 | Secondary objectives of the trial |
To compare overall survival (OS) in patients randomised to trastuzumab for one year versus lapatinib for one year versus trastuzumab (12 or 18 weeks, according to the assigned ‘design’) followed by a 6-week treatment-free interval followed by lapatinib (28 or 34 weeks, according to the assigned ‘design’) versus trastuzumab in combination with lapatinib for one year. |
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E.2.3 | Trial contains a sub-study | No |
E.3 | Principal inclusion criteria |
1. Age > or = 18 years;
2. Eastern Cooperative Oncology Group performance status < or = 1;
3. Non-metastatic operable primary invasive adenocarcinoma of the breast fulfilling the following: a. Histologically confirmed; b. Adequately excised (exceptions: patients who have 'non-resectable' deep margin invasion or histologically documented infiltration of the skin (pT4) are eligible provided they have had or will receive radiotherapy); c. Axilla dissected; sentinel node sampling is allowed provided that axillary dissection follows confirmation of a positive sentinel node (sentinel node sampling alone is not acceptable after neo-adjuvant chemotherapy); d. Axillary node positive patient or node negative patient with a tumor of more than 1 cm in greatest diameter (> or = T1c);
4. Known hormone receptor status (ER/PgR or ER alone);
5. For designs 1 and 2 must have received at least four cycles of an approved anthracycline-based (neo-) adjuvant chemotherapy regimen; For design 1: Randomisation must be performed no longer than 12 weeks from day 1 of the last chemotherapy cycle. For design 2: Randomisation must be performed no longer than 6 weeks from day 1 of the last anthracycline-containing chemotherapy cycle. For design 2b: Randomisation must be performed no longer than 8 weeks from definitive surgery. Non-anthracycline platinum containing and study treatment should start concomitantly and no more than 14 days after randomization.
6. Baseline LVEF > or = 50% for design 1 and design 2 after completion of all anthracycline-based (neo-) adjuvant chemotherapy and prior to the targeted therapy(ies); for design 2b prior to targeted therapies and chemotherapy.
7. Confirmed overexpression and/or gene amplification of ErbB2 (HER2) in the invasive component of the primary tumour, according to one of the following definitions: – 3+ overexpression by IHC (>30% of invasive tumour cells); – 2+ or 3+ (in 30% or less neoplastic cells) overexpression by IHC and positive in situ hybridisation (FISH/CISH) test; – ErbB2 (HER2) gene amplification by FISH/CISH; - Patients with a negative or equivocal overall result for overexpression and/or gene amplification are not eligible for participation in the trial; - Equivocal local results may be submitted for a final determination by the central laboratory.
8. Completion of all necessary baseline laboratory and radiological investigations;
9. Signed written informed consent prior to any study specific screening procedures. |
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E.4 | Principal exclusion criteria |
Patients meeting any of the following criteria are not eligible for this study:
1. History of any prior (ipsi- and/or contralateral) invasive breast carcinoma;
2. Past or current history of malignant neoplasms, unless curatively treated;
3. Any clinically staged T4 tumour, including inflammatory breast cancer;
4. Bilateral tumours;
5. Multifocal tumor - this exclusion criterion has been removed as of protocol am 1
6. Maximum cumulative dose of doxorubicin >360mg/m2 or maximum cumulative dose of epirubicin >720mg/m2 or any prior anthracyclines unrelated to the present breast cancer;
7. Previous (neo-) adjuvant chemotherapy with peripheral stem cell or bone marrow stem cell support;
8. Any prior mediastinal irradiation except internal mammary node irradiation for the present breast cancer;
9. Patients with positive or suspicious internal mammary nodes identified by sentinel node technique which have not been irradiated or will not be irradiated, or patients with supraclavicular lymph node involvement;
10. Prior anti-ErbB2 (HER2) therapy for any reason, or other prior biologic or immunotherapy for breast cancer;
11. Concurrent anti-cancer treatment, except hormonal therapy;
12. Concurrent anti-cancer treatment in another investigational trial with hormone therapy or immunotherapy;
13. Serious cardiac illness or medical conditions including but not confined to: – History of documented congestive heart failure (CHF) or systolic dysfunction (LVEF < 50%) ; – High-risk uncontrolled arrhythmias (ventricular tachycardia, high-grade AV-block, supraventricular arrhythmias which are not adequately rate-controlled); – Angina pectoris requiring antianginal medication; – Clinically significant valvular heart disease; – Evidence of transmural infarction on ECG; – Poorly controlled hypertension (e.g. systolic >180mm Hg or diastolic >100mm Hg);
14. Other concurrent serious diseases that may interfere with planned treatment including severe pulmonary conditions/illness;
15. Any of the following abnormal laboratory tests immediately prior to randomisation: – serum total bilirubin; – alanine amino transferase (ALAT) or aspartate amino transferase (ASAT); – alkaline phosphatase (ALP); – serum creatinine; – total white blood cell count (WBC); – absolute neutrophil count; – platelets;
16. Unresolved or unstable serious toxicity from prior adjuvant chemotherapy or radiotherapy;
17. Malabsorption syndrome, disease significantly affecting gastrointestinal function, or resection of the stomach or small bowel, or persons unable to swallow oral medication. Subjects with ulcerative colitis are also excluded;
18. Pregnant or lactating women (women of childbearing potential must have a negative pregnancy test - urine or serum - within 7 days prior to randomisation);
19. Women of childbearing potential including women whose last menstrual period was <1 year ago (unless surgically sterile) who are unable or unwilling to use adequate contraceptive measures during study treatment as defined in the protocol;
20. Concomitant use of CYP3A4 inhibitors or inducers.
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E.5 End points |
E.5.1 | Primary end point(s) |
The primary endpoint for analysis is disease-free survival (DFS) which will be defined as the time from randomisation until the first occurrence of: 1. Breast cancer recurrence at any site; 2. A second primary cancer (invasive contralateral breast or non-breast malignancy); 3. Death from any cause as first event. |
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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 | Yes |
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.8.4.1 | Number of sites anticipated in Member State concerned | 2 |
E.8.5 | The trial involves multiple Member States | Yes |
E.8.5.1 | Number of sites anticipated in the EEA | 549 |
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 |
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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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E.8.9 Initial estimate of the duration of the trial |
E.8.9.1 | In the Member State concerned years | 13 |
E.8.9.1 | In the Member State concerned months | 10 |
E.8.9.1 | In the Member State concerned days | 0 |
E.8.9.2 | In all countries concerned by the trial years | 13 |
E.8.9.2 | In all countries concerned by the trial months | 10 |
E.8.9.2 | In all countries concerned by the trial days | 0 |