Carcinoma, Non-Small-Cell Lung
Conditions
Brief summary
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.
Interventions
DRUGBiBW 2992
BIBW 2992 in EGFR FISH positive NSCLC patients
Sponsors
Boehringer Ingelheim
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
1. Male and female patients aged \>18 years. 2. Patients with pathologically confirmed diagnosis of NSCLC Stage IIIB (with pleural effusion) or Stage IV and histopathological classification of adeno- or bronchoalveolar carcinoma (BAC). 3. 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. 4. 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. 5. 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). 6. Life expectancy of at least three (3) months. 7. Eastern Cooperative Oncology Group (ECOG, R01-0787) performance score 0, 1 or 2. 8. Written informed consent that is consistent with ICH-GCP guidelines.
Exclusion criteria
1. 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 2. Previous treatment with erlotinib (Tarceva®), gefitinib (Iressa®) or any other EGFR inhibiting small molecule or antibody. 3. 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. 4. 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. 5. 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 6. 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. 7. Other malignancies diagnosed within the past five (5) years (other than non melanomatous skin cancer and in situ cervical cancer). 8. Radiotherapy within the past 2 weeks prior to treatment with the trial drug. 9. Patients with any serious active infection (i.e., requiring an IV antibiotic, antifungal, or antiviral agents). 10. Patients with known HIV, active hepatitis B or active hepatitis C. 11. Known or suspected active drug or alcohol abuse. 12. 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. 13. Pregnancy or breast feeding. 14. Patients unable to comply with the protocol.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Percentage of Participants With Best Objective Response | 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 best objective response: confirmed complete response (CR) or confirmed partial response (PR) according to RECIST version 1.0. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Duration of Confirmed Objective Response (OR) | 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 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). |
| Percentage of Participants With Disease Control (DC) | Every 8 weeks until last response assessment 28NOV12 | Percentage of participants with Objective response (OR) or stable disease (SD) as determined by RECIST version 1.0. |
| Duration of Confirmed Disease Control | Every 8 weeks until last response assessment 28NOV12 | 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. |
| Progression Free Survival (PFS) Time | Every 8 weeks until last response assessment 28NOV12 | 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. |
| Number of Participants With Objective Response (OR) Categorized by Time | 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. | Cumulative number of participants with objective response by time points with responders. |
| Pre-dose Concentration of Afatinib in Plasma at Steady State on Day 15 (Cpre,ss,15) | Day 15 | Cpre,ss,15 represents the pre-dose concentration of afatinib in plasma at steady state on day 15. |
| Number of Participants With Clinical Relevant Finding in Gastrointestinal and Skin Disorder | First administration of trial medication until 28 days after last administration of trial medication, up until 194 weeks | 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. |
| Number of Participants With Clinical Relevant Findings in Laboratory Safety Parameters, Vital Signs and Left Ventricular Ejection Fraction | 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 . 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). |
| Assessment of Eastern Cooperative Oncology Group (ECOG) Performance Status | End Of Treatment, up until 190 weeks | 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. 1. : 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. 2. : Ambulatory and capable of all selfcare but unable to carry out any work activities. Up and about more than 50% of waking hours. 3. : Capable of only limited selfcare, confined to bed or chair more than 50% of waking hours. 4. : Completely disabled. Cannot carry on any selfcare. Totally confined to bed or chair. 5. : Dead. Note: The ECOG scores presented are assessed at the end of treatment not at baseline, hence the patients having ECOGs\>2 are included. |
| Overall Survival (OS) Time | Baseline until last vital status assessment 17JUN13 | Overall survival time is defined as time from the date of start of treatment to the date of death. |
Countries
Italy
Participant flow
Recruitment details
First patient enrolled on December 23rd 2008 . Last patient enrolled on September 1st 2011. Patients were recruited in Oncology departments of Italian investigational sites
Participants by arm
| Arm | Count |
|---|---|
| Afatinib 50mg Afatinib 50mg film coated tablets was administered once daily as long as they were tolerated by patients, until disease progression (according to the response evaluation criteria in solid tumors) | 69 |
| Total | 69 |
Withdrawals & dropouts
| Period | Reason | FG000 |
|---|---|---|
| Overall Study | Adverse Event | 11 |
| Overall Study | not entered | 149 |
| Overall Study | Other | 2 |
| Overall Study | Progressive disease | 56 |
Baseline characteristics
| Characteristic | Afatinib 50mg |
|---|---|
| Age, Continuous | 63.8 years STANDARD_DEVIATION 11.3 |
| Sex: Female, Male Female | 34 Participants |
| Sex: Female, Male Male | 35 Participants |
Adverse events
| Event type | EG000 affected / at risk |
|---|---|
| deaths Total, all-cause mortality | — / — |
| other Total, other adverse events | 66 / 69 |
| serious Total, serious adverse events | 35 / 69 |
Outcome results
Primary
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.
Time frame: 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.
Population: Treated set (TS). TS consisted of all patients who were dispensed study medication and have taken at least 1 dose of Afatinib.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Afatinib 50mg | Percentage of Participants With Best Objective Response | 13.0 percentage of participants |
Secondary
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. 1. : 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. 2. : Ambulatory and capable of all selfcare but unable to carry out any work activities. Up and about more than 50% of waking hours. 3. : Capable of only limited selfcare, confined to bed or chair more than 50% of waking hours. 4. : Completely disabled. Cannot carry on any selfcare. Totally confined to bed or chair. 5. : Dead. Note: The ECOG scores presented are assessed at the end of treatment not at baseline, hence the patients having ECOGs\>2 are included.
Time frame: End Of Treatment, up until 190 weeks
Population: Treated set (TS).
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Afatinib 50mg | Assessment of Eastern Cooperative Oncology Group (ECOG) Performance Status | 2 | 7.2 percentage of participants |
| Afatinib 50mg | Assessment of Eastern Cooperative Oncology Group (ECOG) Performance Status | 0 | 23.2 percentage of participants |
| Afatinib 50mg | Assessment of Eastern Cooperative Oncology Group (ECOG) Performance Status | 1 | 40.6 percentage of participants |
| Afatinib 50mg | Assessment of Eastern Cooperative Oncology Group (ECOG) Performance Status | 3 | 1.4 percentage of participants |
| Afatinib 50mg | Assessment of Eastern Cooperative Oncology Group (ECOG) Performance Status | 4 | 1.4 percentage of participants |
| Afatinib 50mg | Assessment of Eastern Cooperative Oncology Group (ECOG) Performance Status | Missing | 26.1 percentage of participants |
Secondary
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.
Time frame: Every 8 weeks until last response assessment 28NOV12
Population: Treated set (TS).
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Afatinib 50mg | Duration of Confirmed Disease Control | 37.4 Weeks | Standard Deviation 35.6 |
Secondary
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).
Time frame: 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.
Population: Treated set (TS).
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Afatinib 50mg | Duration of Confirmed Objective Response (OR) | 45.5 Weeks | Standard Deviation 36.5 |
Secondary
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.
Time frame: First administration of trial medication until 28 days after last administration of trial medication, up until 194 weeks
Population: Treated Set (TS).
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Afatinib 50mg | Number of Participants With Clinical Relevant Finding in Gastrointestinal and Skin Disorder | Odynophagia | 1.4 Percentage of participants |
| Afatinib 50mg | Number of Participants With Clinical Relevant Finding in Gastrointestinal and Skin Disorder | Peritoneal haemorrhage | 1.4 Percentage of participants |
| Afatinib 50mg | Number of Participants With Clinical Relevant Finding in Gastrointestinal and Skin Disorder | Rash | 73.9 Percentage of participants |
| Afatinib 50mg | Number of Participants With Clinical Relevant Finding in Gastrointestinal and Skin Disorder | Skin exfoliation | 15.9 Percentage of participants |
| Afatinib 50mg | Number of Participants With Clinical Relevant Finding in Gastrointestinal and Skin Disorder | Vomiting | 13.0 Percentage of participants |
| Afatinib 50mg | Number of Participants With Clinical Relevant Finding in Gastrointestinal and Skin Disorder | Diarrhoea | 82.6 Percentage of participants |
| Afatinib 50mg | Number of Participants With Clinical Relevant Finding in Gastrointestinal and Skin Disorder | Stomatitis | 13.0 Percentage of participants |
| Afatinib 50mg | Number of Participants With Clinical Relevant Finding in Gastrointestinal and Skin Disorder | Nausea | 14.5 Percentage of participants |
| Afatinib 50mg | Number of Participants With Clinical Relevant Finding in Gastrointestinal and Skin Disorder | Constipation | 7.2 Percentage of participants |
| Afatinib 50mg | Number of Participants With Clinical Relevant Finding in Gastrointestinal and Skin Disorder | Abdominal pain | 5.8 Percentage of participants |
| Afatinib 50mg | Number of Participants With Clinical Relevant Finding in Gastrointestinal and Skin Disorder | Abdominal pain upper | 2.9 Percentage of participants |
| Afatinib 50mg | Number of Participants With Clinical Relevant Finding in Gastrointestinal and Skin Disorder | Cheilitis | 2.9 Percentage of participants |
| Afatinib 50mg | Number of Participants With Clinical Relevant Finding in Gastrointestinal and Skin Disorder | Dyspepsia | 2.9 Percentage of participants |
| Afatinib 50mg | Number of Participants With Clinical Relevant Finding in Gastrointestinal and Skin Disorder | Dysphagia | 2.9 Percentage of participants |
| Afatinib 50mg | Number of Participants With Clinical Relevant Finding in Gastrointestinal and Skin Disorder | Abdominal distension | 1.4 Percentage of participants |
| Afatinib 50mg | Number of Participants With Clinical Relevant Finding in Gastrointestinal and Skin Disorder | Dry mouth | 1.4 Percentage of participants |
| Afatinib 50mg | Number of Participants With Clinical Relevant Finding in Gastrointestinal and Skin Disorder | Flatulence | 1.4 Percentage of participants |
| Afatinib 50mg | Number of Participants With Clinical Relevant Finding in Gastrointestinal and Skin Disorder | Gastritis erosive | 1.4 Percentage of participants |
| Afatinib 50mg | Number of Participants With Clinical Relevant Finding in Gastrointestinal and Skin Disorder | Rectal haemorrahage | 1.4 Percentage of participants |
| Afatinib 50mg | Number of Participants With Clinical Relevant Finding in Gastrointestinal and Skin Disorder | Tongue Ulceration | 1.4 Percentage of participants |
| Afatinib 50mg | Number of Participants With Clinical Relevant Finding in Gastrointestinal and Skin Disorder | Dry skin | 14.5 Percentage of participants |
| Afatinib 50mg | Number of Participants With Clinical Relevant Finding in Gastrointestinal and Skin Disorder | Nail disorder | 13.0 Percentage of participants |
| Afatinib 50mg | Number of Participants With Clinical Relevant Finding in Gastrointestinal and Skin Disorder | Pruritus | 13.0 Percentage of participants |
| Afatinib 50mg | Number of Participants With Clinical Relevant Finding in Gastrointestinal and Skin Disorder | Dermatitis acneiform | 5.8 Percentage of participants |
| Afatinib 50mg | Number of Participants With Clinical Relevant Finding in Gastrointestinal and Skin Disorder | Alopecia | 1.4 Percentage of participants |
| Afatinib 50mg | Number of Participants With Clinical Relevant Finding in Gastrointestinal and Skin Disorder | Granuloma skin | 1.4 Percentage of participants |
| Afatinib 50mg | Number of Participants With Clinical Relevant Finding in Gastrointestinal and Skin Disorder | Hirsutism | 1.4 Percentage of participants |
| Afatinib 50mg | Number of Participants With Clinical Relevant Finding in Gastrointestinal and Skin Disorder | Hypertrichosis | 1.4 Percentage of participants |
| Afatinib 50mg | Number of Participants With Clinical Relevant Finding in Gastrointestinal and Skin Disorder | Nail discolouration | 1.4 Percentage of participants |
| Afatinib 50mg | Number of Participants With Clinical Relevant Finding in Gastrointestinal and Skin Disorder | Night sweats | 1.4 Percentage of participants |
| Afatinib 50mg | Number of Participants With Clinical Relevant Finding in Gastrointestinal and Skin Disorder | palmar-plantar erythrodysaesthesia syndrome | 1.4 Percentage of participants |
| Afatinib 50mg | Number of Participants With Clinical Relevant Finding in Gastrointestinal and Skin Disorder | Skin fissures | 1.4 Percentage of participants |
| Afatinib 50mg | Number of Participants With Clinical Relevant Finding in Gastrointestinal and Skin Disorder | Skin reaction | 1.4 Percentage of participants |
Secondary
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).
Time frame: First administration of trial medication until 28 days after last administration of trial medication, up until 194 weeks
Population: Treated Set (TS).
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Afatinib 50mg | Number of Participants With Clinical Relevant Findings in Laboratory Safety Parameters, Vital Signs and Left Ventricular Ejection Fraction | Alanine aminotransferase increased | 2.9 percentage of participants |
| Afatinib 50mg | Number of Participants With Clinical Relevant Findings in Laboratory Safety Parameters, Vital Signs and Left Ventricular Ejection Fraction | Aspartate aminotransferase increased | 2.9 percentage of participants |
| Afatinib 50mg | Number of Participants With Clinical Relevant Findings in Laboratory Safety Parameters, Vital Signs and Left Ventricular Ejection Fraction | Blood alkaline phosphatase increased | 2.9 percentage of participants |
| Afatinib 50mg | Number of Participants With Clinical Relevant Findings in Laboratory Safety Parameters, Vital Signs and Left Ventricular Ejection Fraction | Blood bilirubin increased | 1.4 percentage of participants |
| Afatinib 50mg | Number of Participants With Clinical Relevant Findings in Laboratory Safety Parameters, Vital Signs and Left Ventricular Ejection Fraction | Blood Creatine phosphokinase increased | 1.4 percentage of participants |
| Afatinib 50mg | Number of Participants With Clinical Relevant Findings in Laboratory Safety Parameters, Vital Signs and Left Ventricular Ejection Fraction | Blood lactate dehydrogenase increased | 1.4 percentage of participants |
| Afatinib 50mg | Number of Participants With Clinical Relevant Findings in Laboratory Safety Parameters, Vital Signs and Left Ventricular Ejection Fraction | Ejection fraction decreased | 1.4 percentage of participants |
| Afatinib 50mg | Number of Participants With Clinical Relevant Findings in Laboratory Safety Parameters, Vital Signs and Left Ventricular Ejection Fraction | Gamma-glutamyltransferase increased | 1.4 percentage of participants |
| Afatinib 50mg | Number of Participants With Clinical Relevant Findings in Laboratory Safety Parameters, Vital Signs and Left Ventricular Ejection Fraction | International normalised ratio increased | 1.4 percentage of participants |
| Afatinib 50mg | Number of Participants With Clinical Relevant Findings in Laboratory Safety Parameters, Vital Signs and Left Ventricular Ejection Fraction | Transaminases increased | 2.9 percentage of participants |
| Afatinib 50mg | Number of Participants With Clinical Relevant Findings in Laboratory Safety Parameters, Vital Signs and Left Ventricular Ejection Fraction | Weight decreased | 7.2 percentage of participants |
Secondary
Number of Participants With Objective Response (OR) Categorized by Time
Cumulative number of participants with objective response by time points with responders.
Time frame: 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.
Population: Treated set (TS).
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Afatinib 50mg | Number of Participants With Objective Response (OR) Categorized by Time | by week 8 | 11.6 percentage of participants |
| Afatinib 50mg | Number of Participants With Objective Response (OR) Categorized by Time | by week 96 | 13.0 percentage of participants |
Secondary
Overall Survival (OS) Time
Overall survival time is defined as time from the date of start of treatment to the date of death.
Time frame: Baseline until last vital status assessment 17JUN13
Population: Treated set (TS).
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Afatinib 50mg | Overall Survival (OS) Time | 50.43 Weeks |
Secondary
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.
Time frame: Every 8 weeks until last response assessment 28NOV12
Population: Treated set (TS).
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Afatinib 50mg | Percentage of Participants With Disease Control (DC) | 50.7 percentage of participants |
Secondary
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.
Time frame: Day 15
Population: Pharmacokinetic set (PK set) contains all patients who received study medication and have evaluable pharmacokinetic parameter data.~Data from patients who received the starting dose of 50 mg afatinib and were still on treatment and not dose-reduced on Day 15 are presented.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Afatinib 50mg | Pre-dose Concentration of Afatinib in Plasma at Steady State on Day 15 (Cpre,ss,15) | 37.9 ng/mL | Geometric Coefficient of Variation 64.5 |
| Afatinib 50mg 2nd Line | Pre-dose Concentration of Afatinib in Plasma at Steady State on Day 15 (Cpre,ss,15) | 29.7 ng/mL | Geometric Coefficient of Variation 61.6 |
Secondary
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.
Time frame: Every 8 weeks until last response assessment 28NOV12
Population: Treated set (TS).
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Afatinib 50mg | Progression Free Survival (PFS) Time | 8.43 Weeks |