| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| patients with metastatic HER2 over-expressing breast cancer |
|
| E.1.1.1 | Medical condition in easily understood language |
| patients with breast cancer that is spreading in the body ant that is over-expressing HER2 receptor on tumour cells |
|
| 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 | 17.0 |
| 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) |
|
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 17.0 |
| E.1.2 | Level | PT |
| E.1.2 | Classification code | 10065430 |
| E.1.2 | Term | HER-2 positive breast cancer |
| E.1.2 | System Organ Class | 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps) |
|
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 17.0 |
| E.1.2 | Level | LLT |
| E.1.2 | Classification code | 10027475 |
| E.1.2 | Term | Metastatic 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 |
| The primary objective is to determine whether BIBW 2992 and vinorelbine i.v. prolongs progression-free survival (PFS) in comparison to trastuzumab and vinorelbine i.v. |
|
| E.2.2 | Secondary objectives of the trial |
Secondary objectives are:
- further evaluation of efficacy (best RECIST assessment, overall survival, tumour shrinkage),
- health status (ECOG, weight)
- quality of life (no longer applicable after June 8th, 2013)
- safety (adverse events, laboratory)
- pharmacokinetics |
|
| 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 |
Initial Plan: At selected sites and on patient consent: Exploratory biomarkers sub-study on fresh biopsies.
date and version: same as main protocol
The objective is to investigate the rationale of EGFR/HER1 and HER2 inhibition by BIBW 2992 over only HER2-inhibition by trastuzumab.
The drug impact on a certain biomarkers must be investigated in fresh tissue, as up-or down-regulation of certain target proteins and EGFR-phosphorylation are transient processes
Due to premature discontinuation of this trial: the requested number of samples cannot be reached and the above described investigation cannot be performed |
|
| E.3 | Principal inclusion criteria |
•patients with metastatic HER2-positive breast cancer
•no prior HER2-targeted treatment other than trastuzumab allowed
•no prior vinorelbine treatment allowed
•patients should have received prior taxane and/or anthracycline containing chemotherapy
•patients must have progressed on one prior trastuzumab treatment, i.e. patients with:
- First-line metastatic breast cancer failing on adjuvant trastuzumab or within 12 months of completion of adjuvant trastuzumab treatment; prior trastuzumab treatment must have been at least 9 weeks
- Second-line metastatic breast cancer failing on first-line trastuzumab or within 6 months of completion of first-line trastuzumab treatment; prior trastuzumab treatment must have been at least 6 weeks
•Must have (archived) tumour tissue sample available for central re-assessment of HER2-status and prove HER2-positive. HER2 status must be confirmed by sponsor contracted laboratory prior to randomisation.
•At least one measurable lesion according to RECIST 1.1
|
|
| E.4 | Principal exclusion criteria |
1.Prior treatment with EGFR/HER2-targeted small molecules or antibodies other than trastuzumab
2.Prior treatment with vinorelbine
3.Known pre-existing interstitial lung disease
4.Radiotherapy, chemotherapy, hormone therapy, immunotherapy or surgery (other than biopsy) within 4 weeks (2 weeks for hormone therapy, 3 weeks for trastuzumab) prior to randomisation.
5.Active brain metastases (defined as stable for <4 weeks and/or symptomatic and/or requiring changes of treatment with anticonvulsants or steroids within the past 4 weeks and/or leptomeningeal disease). Patients with known history of brain metastases should undergo a baseline brain image to ensure that the disease is stable
6.Any other current malignancy or malignancy diagnosed within the past five (5) years (other than than bilateral primary breast cancer, metastases to the contralateral breast, non-melanomatous skin cancer and in situ cervical cancer).
7.Significant or recent acute gastrointestinal disorders with diarrhoea as a major symptom e.g. Crohn's disease, malabsorption or CTC grade ≥2 diarrhoea of any aetiology.
8.History or presence of clinically relevant cardiovascular abnormalities such as uncontrolled hypertension, congestive heart failure NYHA classification of 3, unstable angina or poorly controlled arrhythmia. Myocardial infarction within 6 months prior to randomisation.
9.Cardiac left ventricular function with resting ejection fraction of less than 50%.
10.Any other concomitant serious illness or organ system dysfunction which in the opinion of the investigator would either compromise patient safety or interfere with the evaluation of the safety of the test drug.
11.Absolute neutrophil count (ANC) < 1500 / mm³.
12.Platelet count < 100,000 / mm³
13.Calculated creatinine clearance < 60 ml / min (using preferably Cockcroft-Gault formula for GFR estimate, see appendix 1) or serum creatinine > 1.5 times upper limit of normal.
14.Bilirubin > 1.5 times upper limit of normal.
15.Aspartate amino transferase (AST) or alanine amino transferase (ALT) > 2.5 times the upper limit of normal (ULN) (if related to liver metastases > 5 times ULN).
16.Women of childbearing potential, unwilling to use a medically acceptable method of contraception during the trial, see Section 5.2.2.4.
17.Pregnancy or breast-feeding.
18.Patients unable to comply with the protocol.
19.Known hepatitis B infection, known hepatitis C infection or known HIV carrier.
20.Known or suspected active drug or alcohol abuse.
21.Requirement for treatment with any of the prohibited concomitant medications listed in section 4.2.2.1.
22.Any contraindications for therapy with vinorelbine or trastuzumab.
23.Known hypersensitivity to BIBW 2992 or the excipients of any of the trial drugs.
24.Use of any investigational drug within 4 weeks of randomisation.
|
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
Initial plan: The primary endpoint of this study is progression-free survival, defined as the time from the date of randomisation to the date of disease progression, or to the date of death if a patient died earlier. The analysis will be based upon the evaluation of tumour imaging as reviewed by an independent central unit, blinded to treatment assignments.
Due to premature discontinuation of this trial: The analysis will be based upon the evaluation of tumour imaging performed by investigators review utilizing RECIST version 1.1
|
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
Initial plan: The primary analysis of PFS will be conducted when at least 484 patients have progressed (based on central review) or died.
Due to premature discontinuation of this trial: The primary analysis of PFS will be conducted based on data obtained from the assessments scheduled until June 8th, 2013. |
|
| E.5.2 | Secondary end point(s) |
- Best RECIST assessment
- Overall survival
- Objective response (clarified in CTP v7.0) |
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
Initial plan: The first analysis will be performed at same timepoint than primary analysis
A second overall survival analysis should be performed approximately 42 months after the start of recruitment.
Due to premature discontinuation of this trial: Analyses of other RECIST based endpoints will utilise data obtained until June 8th, 2013. For OS all available data will be used. Patients who have discontinued the active parts of the study at the time recruitment into the study was suspended will also be shown in a separate analysis.
The final report will not be updated with new data. Descriptive summaries will be provided for these patients for RECIST based endpoints separately. For overall survival the same approach as for the primary report will be used |
|
| 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 | Yes |
| 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 | Yes |
| E.6.13 | Others | Yes |
| E.6.13.1 | Other scope of the trial description |
exploratory biomarkers in sub-study
Due to premature discontinuation of this trial, the exploratory biomarker sub-study will not be further proceeded |
|
| 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 | 2 |
| E.8.3 |
The trial involves single site in the Member State concerned
| Yes |
| E.8.4 | The trial involves multiple sites in the Member State concerned | No |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 100 |
| 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 |
| Austria |
| Belarus |
| Belgium |
| Brazil |
| Canada |
| Chile |
| China |
| Colombia |
| Czech Republic |
| Egypt |
| France |
| Germany |
| India |
| Ireland |
| Israel |
| Italy |
| Japan |
| Korea, Republic of |
| Latvia |
| Lebanon |
| Lithuania |
| Mexico |
| Netherlands |
| Norway |
| Peru |
| Poland |
| Portugal |
| Russian Federation |
| Saudi Arabia |
| Singapore |
| Slovakia |
| Slovenia |
| South Africa |
| Spain |
| Sri Lanka |
| Taiwan |
| Turkey |
| United Arab Emirates |
| United Kingdom |
| United States |
| Jordan |
|
| 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
|
The active treatment phase will end when the last patient has completed the EOT visit and the 1st follow-up visit (28 days after EOT), i.e. LPLV.
A premature recruitment stop required a primary analysis and 1st report thereof to be produced by 8-June-2014.
An updated (2nd) report will be produced within 12 months after LPLV and the clinical trial summary report will be provided to Health Authorities and IRB in accordance with respective EC guidance on CTA 2010/C 82/01
|
|
| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 4 |
| E.8.9.1 | In the Member State concerned months | 0 |
| E.8.9.1 | In the Member State concerned days | 0 |
| E.8.9.2 | In all countries concerned by the trial years | 4 |
| 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 |
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