BIBW2992 (Afatinib) in Advanced (EGFR-FISH +) NSCLC (Non Small Cell Lung Cancer) Patients

Study Overview
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Brief Summary
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The primary objective of this open-label, single arm Phase II trial is to explore the efficacy of BIBW 2992 defined by the objective response rate (CR, PR) as determined by the RECIST criteria in patients with EGFR FISH positive advanced NSCLC Stage IIIB or IV, selected according to the following scheme: Forty (40) 1st line patients Thirty (30) 2nd line patients Patients entered into the trial will be treated and followed until death or lost to follow-up. Additional information will be obtained on the safety profile and PK analysis of BIBW 2992.

Official Title
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A Phase II Single-arm Trial of BIBW 2992 in EGFR FISH Positive Non-small Cell Lung Cancer Patients

Conditions
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Carcinoma, Non-Small-Cell Lung

Intervention / Treatment
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* Drug: BiBW 2992


Participation Criteria
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Eligibility Criteria
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Inclusion criteria: Male and female patients aged >18 years. Patients with pathologically confirmed diagnosis of NSCLC Stage IIIB (with pleural effusion) or Stage IV and histopathological classification of adeno- or bronchoalveolar carcinoma (BAC). Increased EGFR gene copy number assessed by FISH analysis. After signed informed consent, positive result to EGFR FISH determination is mandatory to proceed to other screening assessments. At least one tumour lesion that can accurately be measured by computed tomography (CT) or magnetic resonance imaging (MRI) in at least one dimension with longest diameter to be recorded as more or same 20 mm using conventional techniques or moro or same 10 mm with spiral CT scan. Patients not previously exposed to chemotherapy for NSCLC (1st line patients, 40 in total; for these subjects adjuvant chemotherapy is allowed if at least 12 months elapsed since last course of treatment), or patients with relapse after one systemic treatment (2nd line patients, 30 in total; if less than 12 months elapsed since adjuvant chemotherapy, patients are 2nd line ones, as adjuvant chemotherapy must be considered a line of treatment). Life expectancy of at least three (3) months. Eastern Cooperative Oncology Group (ECOG, R01-0787) performance score 0, 1 or 2. Written informed consent that is consistent with ICH-GCP guidelines. Exclusion criteria: More than two (2) prior cytotoxic chemotherapy treatment regimens for relapsed or metastatic NSCLC, included adjuvant chemotherapy if relapse occurred less than 12 months before Previous treatment with erlotinib (Tarceva®), gefitinib (Iressa®) or any other EGFR inhibiting small molecule or antibody. Active brain metastases (stable <4 weeks, symptomatic, requiring treatment with anticonvulsants, or leptomeningeal disease). Dexamethasone therapy will be allowed if administered as a stable dose for at least one month before randomization. Chemo-, hormone- (other than megestrol acetate or steroids required for maintenance non-cancer therapy) or immunotherapy within the past 4 weeks before first drug administration. Significant or recent acute gastrointestinal disorders with diarrhea as a major symptom e.g., Crohn disease, malabsorption, or CTCAE Grade >2 diarrhea of any etiology at baseline Patients who have any other life-threatening 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. Other malignancies diagnosed within the past five (5) years (other than non melanomatous skin cancer and in situ cervical cancer). Radiotherapy within the past 2 weeks prior to treatment with the trial drug. Patients with any serious active infection (i.e., requiring an IV antibiotic, antifungal, or antiviral agents). Patients with known HIV, active hepatitis B or active hepatitis C. Known or suspected active drug or alcohol abuse. Women of child-bearing potential or men who are able to father a child unwilling to use a medically acceptable method of contraception during the trial. Pregnancy or breast feeding. Patients unable to comply with the protocol.

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

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: Treatment
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: BIBW 2992<br>BIBW 2992 in EGFR FISH positive NSCLC patients | Drug: BiBW 2992<br>* BIBW 2992 in EGFR FISH positive NSCLC patients<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percentage of Participants With Best Objective Response | Percentage of participants with best objective response: confirmed complete response (CR) or confirmed partial response (PR) according to RECIST version 1.0. | Tumour assessments were performed at baseline (tumour assessment obtained within 4 weeks prior to beginning of treatment), week 8, and every 8 weeks until last response assessment 28NOV12. | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Participants With Objective Response (OR) Categorized by Time | Cumulative number of participants with objective response by time points with responders. | Tumour assessments were performed at baseline (tumour assessment obtained within 4 weeks prior to beginning of treatment), week 8, and every 8 weeks until last response assessment 28NOV12. | 
| Duration of Confirmed Objective Response (OR) | Duration of confirmed Objective Response is measured from the time of first Objective Response (OR) to the time of progression or death (or date of censoring for progression free survival). | Tumour assessments were performed at baseline (tumour assessment obtained within 4 weeks prior to beginning of treatment), week 8, and every 8 weeks until last response assessment 28NOV12. | 
| Percentage of Participants With Disease Control (DC) | Percentage of participants with Objective response (OR) or stable disease (SD) as determined by RECIST version 1.0. | Every 8 weeks until last response assessment 28NOV12 | 
| Duration of Confirmed Disease Control | Duration of Disease Control is measured from the time of first Objective Response to the time of progression or death (or date of censoring for progression free survival) or respectively for SD as the time from date of randomization to date that disease progression. | Every 8 weeks until last response assessment 28NOV12 | 
| Progression Free Survival (PFS) Time | Progression Free Survival time defined as time from the start of treatment to the earliest of progression (RECIST), clinical progression (investigator), start of new anti-cancer treatment or death. | Every 8 weeks until last response assessment 28NOV12 | 
| Overall Survival (OS) Time | Overall survival time is defined as time from the date of start of treatment to the date of death. | Baseline until last vital status assessment 17JUN13 | 
| Pre-dose Concentration of Afatinib in Plasma at Steady State on Day 15 (Cpre,ss,15) | Cpre,ss,15 represents the pre-dose concentration of afatinib in plasma at steady state on day 15. | Day 15 | 
| Number of Participants With Clinical Relevant Finding in Gastrointestinal and Skin Disorder | The safety of patients was overall assessed in terms of adverse events (AEs), graded according to US NCI CTCAE version 3.0 [R04-0474], including skin reactions and gastrointestinal AEs. | First administration of trial medication until 28 days after last administration of trial medication, up until 194 weeks | 
| Number of Participants With Clinical Relevant Findings in Laboratory Safety Parameters, Vital Signs and Left Ventricular Ejection Fraction | Number of participants with clinical relevant findings in Laboratory safety parameters, vital signs and Left ventricular ejection fraction . Relevant findings or worsenings of baseline conditions were reported as Adverse Events. There were no clinically relevant finding reported for Vital signs and Left ventricular ejection fraction (LVEF). | First administration of trial medication until 28 days after last administration of trial medication, up until 194 weeks | 
| Assessment of Eastern Cooperative Oncology Group (ECOG) Performance Status | Performance status assessed according to Eastern Cooperative Oncology Group (ECOG) performance status based on categories defined below : 0 : Fully active, able to carry on all pre-disease performance without restriction. : Restricted in physically strenuous activity but ambulatory and able to carry out work of a light or sedentary nature, e.g., light house work, office work. : Ambulatory and capable of all selfcare but unable to carry out any work activities. Up and about more than 50% of waking hours. : Capable of only limited selfcare, confined to bed or chair more than 50% of waking hours. : Completely disabled. Cannot carry on any selfcare. Totally confined to bed or chair. : Dead. Note: The ECOG scores presented are assessed at the end of treatment not at baseline, hence the patients having ECOGs>2 are included. | End Of Treatment, up until 190 weeks |