Afatinib (BIBW 2992) in HER2 Overexpressing Metastatic Breast Cancer Patients

Phase 1

Conditions: patients with metastatic HER2 over-expressing breast cancer
MedDRA version: 14.1Level: PTClassification code 10057654Term: Breast cancer femaleSystem Organ Class: 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps)
MedDRA version: 14.1Level: PTClassification code 10065430Term: HER-2 positive breast cancerSystem Organ Class: 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps)
MedDRA version: 14.1Level: LLTClassification code 10027475Term: Metastatic breast cancerSystem Organ Class: 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Therapeutic area: Diseases [C] - Cancer [C04]

Registration Number: EUCTR2009-015476-98-AT

Lead Sponsor: Boehringer Ingelheim RCV GmbH & Co. KG

Brief Summary: Not available

Detailed Description: Not available

Recruitment & Eligibility

Status: ot Recruiting

Sex: Female

Target Recruitment: 780

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

Are the trial subjects under 18? no
Number of subjects for this age range: 0
F.1.2 Adults (18-64 years) yes
F.1.2.1 Number of subjects for this age range 680
F.1.3 Elderly (>=65 years) yes
F.1.3.1 Number of subjects for this age range 100

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.

Study & Design

Study Type: Interventional clinical trial of medicinal product

Study Design: Not specified

Primary Outcome Measures

Name	Time	Method
Secondary Objective: Secondary objectives are:<br>- further evaluation of efficacy (best RECIST assessment, overall survival, tumour shrinkage),<br>- health status (ECOG, weight) <br>- quality of life<br>- safety (adverse events, laboratory)<br>- pharmacokinetics;Primary end point(s): 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.<br><br>;Timepoint(s) of evaluation of this end point: The primary analysis of PFS will be conducted when at least 484 patients have progressed (based on central review) or died.;Main Objective: 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.

Secondary Outcome Measures

Name	Time	Method
Secondary end point(s): - Best RECIST assessment<br>- Overall survival;Timepoint(s) of evaluation of this end point: The first analysis will be performed at same timepoint than primary analysis<br>A second overall survival analysis should be performed approximately 42 months after the start of recruitment.