An Open Label Phase II Trial of BIBW 2992 in Patients With HER2-negative Metastatic Breast Cancer

Study Overview
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Brief Summary
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The purpose of this trial is to evaluate the efficacy, safety and pharmacokinetics of BIBW 2992, a dual, irreversible EGFR- and HER2-inhibitor, in two cohorts of patients with HER2-negative breast cancer after failure of no more than three regimen of prior chemotherapy.

Official Title
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An Open Label Phase II Trial to Assess the Efficacy and Safety of a Once Daily Oral Dose of 50 mg BIBW 2992 in Two Cohorts of Patients With HER2-negative Metastatic Breast Cancer After Failure of no More Than Two Chemotherapy Regimen

Conditions
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Breast Neoplasms

Intervention / Treatment
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* Drug: BIBW 2992


Participation Criteria
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Eligibility Criteria
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Inclusion criteria: Inclusion Criteria: Female patients age 18 years or older Histologically proven breast cancer after failure or relapse of no more than three lines of chemotherapy including adjuvant, irrespective of prior hormone therapy metastatic disease (stage IV); HER2-negative patients (HER2 1+ or negative, or HER2 2+ and FISH negative) At least one measurable tumour lesion (RECIST); Availability of tumour samples Written informed consent that is consistent with ICH-GCP guidelines and local law Eastern Cooperative Oncology Group (ECOG, R01-0787) performance score 0 - 2. Exclusion criteria: Exclusion Criteria: Active infectious disease Gastrointestinal disorders that may interfere with the absorption of the study drug or chronic diarrhoea Serious illness, concomitant non-oncological disease or mental problems considered by the investigator to be incompatible with the protocol Active/symptomatic brain metastases Cardiac left ventricular function with resting ejection fraction < 50% (below upper limit of normal) ANC less than 1500/mm3 platelet count less than 100 000/mm3 Bilirubin greater than 1.5 mg /dl (>26 and#61549 mol /L, SI unit equivalent) AST and ALT greater than 2.5 times the upper limit of normal or greater 5 times the upper limit of normal in case of known liver metastases Serum creatinine greater than 1.5 mg/dl (>132 and#61549 mol/L, SI unit equivalent) Patients who are sexually active and unwilling to use a medically acceptable method of contraception Pregnancy or breast-feeding Concomitant treatment with other investigational drugs or other anti-cancer-therapy during this study and/or during the past two/four weeks, prior to the first treatment with the trial drug. Concurrent treatment with biphosphonates is allowed Previous treatment with trastuzumab, EGFR-, or EGFR/HER2-inhibitors patients unable to comply with the protocol Active alcohol or drug abuse Other malignancy within the past 5 years

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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Female

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Diagnostic
Allocation: Non-Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: BIBW 2992<br>high dose once daily | Drug: BIBW 2992<br>* high dose once daily<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Objective Response (OR) | OR is defined as complete response (CR) and partial response (PR) and was assessed according to the Response Evaluation Criteria in Solid Tumours version 1.0 (RECIST). OR was primary endpoint only for Cohort B. | Tumour assessments were performed at screening, week 8, week 16, week 24, and every 8 weeks thereafter. | 
| Clinical Benefit (CB) | CB was defined as CR, PR or stable disease (SD) for a minimum of 4 months (modified CB) and was assessed according to RECIST 1.0 criteria. CB was primary endpoint only for Cohort A. | Tumour assessments were performed at screening, week 8, week 16, week 24, and every 8 weeks thereafter. | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Clinical Benefit (CB) | CB was defined as CR, PR or stable disease (SD) for a minimum of 4 months (modified CB) and was assessed according to RECIST 1.0 criteria. CB was secondary endpoint only for Cohort B as it was primary endpoint for Cohort A. | Tumour assessments were performed at screening, week 8, week 16, week 24, and every 8 weeks thereafter. | 
| Time to OR | The time to OR was the duration from the first treatment to the time when the measurement criteria for CR and/or PR were met according to RECIST 1.0 criteria. | Tumour assessments were performed at screening, week 8, week 16, week 24, and every 8 weeks thereafter. | 
| Duration of OR | Duration of OR was measured from the time the criteria for CR or PR (whichever was documented first) were first met until the first date that progressive disease or death was objectively documented. | Tumour assessments were performed at screening, week 8, week 16, week 24, and every 8 weeks thereafter. | 
| Progression-free Survival (PFS) | PFS was defined as the time from the first treatment to the occurrence of tumour progression or death, whichever came first. It was assessed according to RECIST 1.0 criteria as well as by the investigators assessment. Median time results from unstratified Kaplan-Meier estimates. | Tumour assessments were performed at screening, week 8, week 16, week 24, and every 8 weeks thereafter. | 
| Overall Survival (OS) | OS is defined as time from randomisation to death. | From randomisation to end of follow-up. | 
| Significant Change in Cardiac Left Ventricular Ejection Fraction (LVEF) | LVEF as measured by echocardiography or Multiple Gated Acquisition (MUGA) scan. MUGA scan is an useful noninvasive tool for assessing the function of the heart. Significant change in LVEF values was defined as >=20 percent decrease from baseline or to below lower limit of normal, which was defined as 50 percent. | Baseline and last assessment | 
| Best Change From Baseline in ECOG Performance Status | Best change from baseline in ECOG (Eastern Cooperative Oncology Group) performance status. ECOG is measured as score between 0 (fully active) and 5 (dead). | baseline till end of treatment | 
| Pre-dose Concentration of Afatinib in Plasma at Steady State on Day 29 (Cpre,ss,29) | Cpre,ss,29 represents the pre-dose concentration of afatinib in plasma at steady state on day 29. | day 29 |