| 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. |
|
| E.1.1.1 | Medical condition in easily understood language |
| Operable primary breast cancer with over expression/ amplification of HER2. |
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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 | 20.0 |
| E.1.2 | Level | PT |
| E.1.2 | Classification code | 10006187 |
| E.1.2 | Term | Breast cancer |
| E.1.2 | System Organ Class | 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps) |
|
| 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 ErbB2 (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 six-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. |
|
| E.2.2 | Secondary objectives of the trial |
The secondary objectives of the study are to evaluate and compare the following criteria between treatment arms: Overall survival (OS), time to recurrence (TTR), time to distant recurrence (TTDR), cumulative incidence of brain metastases as the first site of breast cancer recurrance. In addition the safety and tolerability of all four treatment groups will be evaluated.
Exploraty Translational Research Objective:
To evaluate the quantitiva HER2 protein and/or HER2 domain levels (e.g. presence or absence of p95 HER2 domain or ration of intracellular and extracellular HER2 expression levels) and determine the relationship with response to HER2 targeted agents and clinical outcome. |
|
| 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. 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 1 & 2: Study treatment should start no more than 14 days after randomisation;
6. Baseline LVEF > or = 50% after completion of all anthracycline-based (neo-) adjuvant chemotherapy and prior to the targeted therapy(ies);
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. |
|
| 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 (less than 10 years) or current history of malignant neoplasms, unless curatively treated basal and squamous cell carcinoma of the skin or carcinoma in situ of the cervix;
NOTE: Patients with a prior malignancy diagnosed greater than 10 years in the past who have been curatively treated with surgery ONLY, WITHOUT radiation therapy or systemic therapy (chemotherapy or
endocrine) are eligible for the study. Patients with any prior diagnosis of breast cancer or melanoma, at any time, are excluded from this study.
3. Any clinically staged T4 tumour, including inflammatory breast cancer;
4. Bilateral tumours;
5. 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;
6. Previous (neo-) adjuvant chemotherapy with peripheral stem cell or bone marrow stem cell support;
7. Any prior mediastinal irradiation except internal mammary node irradiation for the present breast cancer;
8. 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;
9. Prior anti-ErbB2 (HER2) therapy for any reason, or other prior biologic or immunotherapy for breast cancer;
10. Concurrent anti-cancer treatment, except hormonal therapy or radiotherapy for the present breast cancer;
11. Concurrent anti-cancer treatment in another investigational trial with hormone therapy or immunotherapy unless approved by the Executive Committee;
12. 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);
13. Other concurrent serious diseases that may interfere with planned treatment including severe pulmonary conditions/illness;
14. 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;
15. Unresolved or unstable serious toxicity from prior adjuvant chemotherapy or radiotherapy;
16. Malabsorption syndrome, disease significantly affecting gastrointestinal function, or resection of the stomach or small bowel, or persons unable to swallow oral medication. Patients with ulcerative colitis are also excluded;
17. Pregnant, lactating (women of childbearing potential must have a negative pregnancy test - urine or serum - within 7 days prior to randomisation);
18. 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 study protocol;
19. Concomitant use of CYP3A4 inhibitors or inducers.
|
|
| 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. |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
|
| E.5.2 | Secondary end point(s) |
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
|
| 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.8.2.4 | Number of treatment arms in the trial | 4 |
| 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 | 3 |
| 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 | 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 |
| Argentina |
| Australia |
| Belgium |
| Brazil |
| Bulgaria |
| Canada |
| Chile |
| China |
| Croatia |
| Czech Republic |
| Denmark |
| Estonia |
| France |
| Germany |
| Greece |
| Hong Kong |
| Hungary |
| India |
| Ireland |
| Israel |
| Italy |
| Japan |
| Korea, Republic of |
| Mexico |
| Netherlands |
| New Zealand |
| Norway |
| Pakistan |
| Peru |
| Philippines |
| Poland |
| Romania |
| Russian Federation |
| Singapore |
| Slovakia |
| Slovenia |
| South Africa |
| Spain |
| Switzerland |
| Taiwan |
| Thailand |
| Ukraine |
| United Kingdom |
| United States |
|
| 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
|
| Ten years from the date of last randomized patient |
|
| 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 |
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