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BIBW 2992 (Afatinib) in Head & Neck Cancer

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ClinicalTrials.gov Identifier: NCT00514943
Recruitment Status : Completed
First Posted : August 10, 2007
Results First Posted : December 25, 2013
Last Update Posted : July 26, 2016
Sponsor:
Information provided by (Responsible Party):
Boehringer Ingelheim

Study Type Interventional
Study Design Allocation: Randomized;   Intervention Model: Crossover Assignment;   Masking: None (Open Label);   Primary Purpose: Treatment
Conditions Head and Neck Neoplasms
Carcinoma, Squamous Cell
Interventions Drug: BIBW 2992
Drug: Cetuximab
Enrollment 124

Recruitment Details  
Pre-assignment Details Open-label randomized, cross-over study. 124 patients were randomised. 3 patients were not treated, 1 in Afatinib arm and 2 in Cetuximab arm.
Arm/Group Title Afatinib 50 mg / Cetuximab 250mg/m2 Cetuximab 250 mg/m2 / Afatinib 50 mg
Hide Arm/Group Description Patients were randomized to Afatinib monotherapy 50mg once daily (q.d.) in Stage 1 and if the patients had disease progression or intolerable AEs were crossed over to Cetuximab 250 mg/m2 given as 400mg/m2 once in the first week (load) followed by 250mg/m2 weekly thereafter in Stage 2. Patients were randomized to Cetuximab 250 mg/m2 received 400mg/m2 once in the first week followed by 250 mg/m2 weekly thereafter in Stage 1 and if the patients had disease progression or intolerable AEs were crossed over to Afatinib 50 mg once daily (q.d.) for Stage 2
Period Title: Stage 1
Started 62 [1] 62 [2]
Completed 32 36
Not Completed 30 26
Reason Not Completed
Progressive disease             4             8
Other Adverse Event             16             6
Not treated             1             2
Patient refused to continue study meds             8             3
Other than stated above             1             7
[1]
1 randomized patient was not treated
[2]
2 randomized patients were not treated
Period Title: Stage 2
Started 32 36
Completed 0 0
Not Completed 32 36
Reason Not Completed
Progressive disease             27             24
Other Adverse Event             3             10
Patient refused to continue study meds             2             0
Other than stated above             0             2
Arm/Group Title Afatinib 50 mg / Cetuximab 250mg/m2 Cetuximab 250 mg/m2 / Afatinib 50 mg Total
Hide Arm/Group Description Patients were randomized to Afatinib monotherapy 50mg once daily (q.d.) in Stage 1 and if the patients had disease progression or intolerable AEs were crossed over to Cetuximab 250 mg/m2 given as 400mg/m2 once in the first week (load) followed by 250mg/m2 weekly thereafter in Stage 2. Patients were randomized to Cetuximab 250 mg/m2 received 400mg/m2 once in the first week followed by 250 mg/m2 weekly thereafter in Stage 1 and if the patients had disease progression or intolerable AEs were crossed over to Afatinib 50 mg once daily (q.d.) for Stage 2 Total of all reporting groups
Overall Number of Baseline Participants 62 62 124
Hide Baseline Analysis Population Description
[Not Specified]
Age, Continuous  
Mean (Standard Deviation)
Unit of measure:  Years
Number Analyzed 62 participants 62 participants 124 participants
57.9  (9.4) 58.8  (8.7) 58.3  (9.0)
Sex: Female, Male  
Measure Type: Count of Participants
Unit of measure:  Participants
Number Analyzed 62 participants 62 participants 124 participants
Female
7
  11.3%
10
  16.1%
17
  13.7%
Male
55
  88.7%
52
  83.9%
107
  86.3%
Prior chemotherapies (CT)for recurrent/metastatic disease (R/M)  
Measure Type: Number
Unit of measure:  Number of participants
Number Analyzed 62 participants 62 participants 124 participants
Yes 42 41 83
No 20 21 41
Baseline sum of longest diameters (SLD) of target lesions by investigator assessments   [1] 
Mean (Standard Deviation)
Unit of measure:  Millimeters
Number Analyzed 62 participants 62 participants 124 participants
71.4  (44.6) 65.4  (44.2) 68.4  (44.3)
[1]
Measure Description: Baseline measures were available for only 61 patients in the Afatinib/Cetuximab group and only 60 patients in the Cetuximab/Afatinib group
1.Primary Outcome
Title Tumor Shrinkage Before Crossover (Stage 1) of the Trial as Per Investigator Assessment
Hide Description

Tumor shrinkage before crossover was defined as the change from baseline in the smallest post-randomisation sum of the longest diameters of target lesions (SLD), calculated as the smallest SLD after randomisation but before crossover minus SLD at baseline. Baseline was the SLD measured before randomisation. A negative value means the smallest post-randomisation SLD was smaller than baseline (decreased since baseline); a positive value means tumor size increased since baseline.

Mean calculated is actually the Adjusted mean. Adjusted mean is obtained from fitting an ANCOVA model including treatment, stratification factor prior chemotherapy for recurrent/metastatic disease and the baseline sum of longest distance of target lesions as covariates.

Time Frame From randomization until start of Stage 2 treatment, or within 28 days after the termination of Stage 1.
Show Outcome Measure DataHide Outcome Measure Data
Hide Analysis Population Description
Randomised Set (RS). The randomised set includes all patients who were randomised to receive treatment, whether treated or not. However, patients without baseline or post-baseline tumor measurements were excluded.
Arm/Group Title Afatinib 50 mg - Stage 1 Cetuximab 250 mg/m2 - Stage 1
Hide Arm/Group Description:
Patients were randomised to receive Afatinib 50 mg once daily (q.d.) in Stage 1.
Patients were randomized to Cetuximab 250 mg/m2 given as 400mg/m2 once in the first week followed by 250 mg/m2 weekly thereafter in Stage 1.
Overall Number of Participants Analyzed 50 55
Mean (Standard Error)
Unit of Measure: millimeter
-3.86  (3.62) -2.37  (3.47)
Show Statistical Analysis 1 Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Afatinib 50 mg - Stage 1, Cetuximab 250 mg/m2 - Stage 1
Comments [Not Specified]
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.7606
Comments P-value obtained from fitting an ANCOVA model including treatment, stratification factor prior chemotherapy for recurrent/metastatic disease and the baseline sum of longest distance of target lesions.
Method ANCOVA
Comments Receipt of prior chemotherapy for recurrent/metastatic disease and the baseline sum of longest distance for target lesions are covariates
Method of Estimation Estimation Parameter Mean Difference (Final Values)
Estimated Value -1.49
Confidence Interval (2-Sided) 95%
-11.188 to 8.202
Estimation Comments Mean difference calculated is actually the adjusted mean difference.
2.Secondary Outcome
Title Tumor Shrinkage After Crossover (Stage 2) as Per Investigator Assessments
Hide Description Tumor shrinkage after crossover was defined as the change from baseline in the smallest post-crossover sum of the longest diameters of target lesions (SLD), calculated as the smallest SLD after crossover minus SLD at baseline. Baseline was the SLD measured at the time of crossover, or the closest measurement before the patient started stage 2 treatment. A negative value means the smallest post-crossover SLD was smaller than baseline (decreased after crossover), a positive value means tumor size increased after crossover.
Time Frame From baseline assessed prior to first dose of Stage 2 study medication to 28 days after termination of Stage 2 treatment.
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Hide Analysis Population Description
Patients treated in stage 2 : This analysis set included all patients who received treatment: 36 patients in the afatinib and 32 patients in the cetuximab arm.
Arm/Group Title Afatinib 50 mg - Stage 2 Cetuximab 250 mg/m2 - Stage 2
Hide Arm/Group Description:
Patients were randomized to Cetuximab 250 mg/m2 given as 400mg/m2 once in the first week followed by 250 mg/m2 weekly thereafter in Stage 1 and if the patients had disease progression or intolerable AEs were crossed over to Afatinib 50 mg once daily (q.d.) for Stage 2
Patients were randomized to Afatinib monotherapy 50mg once daily (q.d.) in Stage 1 and if the patients had disease progression or intolerable AEs were crossed over to Cetuximab 250 mg/m2 given as 400mg/m2 once in the first week (load) followed by 250mg/m2 weekly thereafter in Stage 2.
Overall Number of Participants Analyzed 29 27
Mean (Standard Deviation)
Unit of Measure: millimeters
2  (15) 16  (30)
3.Secondary Outcome
Title Best RECIST Assessment as Per Investigator Assessment for Stage 1 (as Confirmed Disease Control (Clinical Benefit) and Objective Response Are Simply Categories of RECIST Assessment).
Hide Description Best RECIST Assessment is defined as confirmed Disease control (complete response (CR), partial response (PR) and Stable disease (SD)), Objective response ( complete response (CR) or partial response (PR)) assessed by the investigator according to the RECIST 1.0 criteria.
Time Frame Response determined from randomization until patient started Stage 2 or within 28 days after termination of Stage 1 treatment
Show Outcome Measure DataHide Outcome Measure Data
Hide Analysis Population Description
Randomised set (RS).
Arm/Group Title Afatinib 50 mg - Stage 1 Cetuximab 250 mg/m2 - Stage 1
Hide Arm/Group Description:
Patients were randomised to receive Afatinib 50 mg once daily (q.d.) in Stage 1.
Patients were randomized to Cetuximab 250 mg/m2 given as 400mg/m2 once in the first week followed by 250 mg/m2 weekly thereafter in Stage 1.
Overall Number of Participants Analyzed 62 62
Measure Type: Number
Unit of Measure: Number of participants
Disease control (CR, PR, SD) 31 35
Objective response (CR, PR) 10 4
Complete response (CR) 0 2
Partial response (PR) 10 2
Stable disease (SD) 21 31
Progressive disease (PD) 16 19
Not evaluable 5 1
Missing 10 7
4.Secondary Outcome
Title Best RECIST Assessment as Per ICR for Stage 1 (as Confirmed Disease Control (Clinical Benefit) and Objective Response Are Simply Categories of RECIST Assessment).
Hide Description Best RECIST Assessment is defined as confirmed Disease control (complete response (CR), partial response (PR) and Stable disease (SD)), Best objective response ( complete response (CR) or partial response (PR)) as assessed by the independent central review (ICR) according to the RECIST 1.0 criteria.
Time Frame Response determined from randomization until patient started Stage 2 or within 28 days after termination of Stage 1 treatment
Show Outcome Measure DataHide Outcome Measure Data
Hide Analysis Population Description
Randomised set (RS).
Arm/Group Title Afatinib 50 mg - Stage 1 Cetuximab 250 mg/m2 - Stage 1
Hide Arm/Group Description:
Patients were randomised to receive Afatinib 50 mg once daily (q.d.) in Stage 1.
Patients were randomized to Cetuximab 250 mg/m2 given as 400mg/m2 once in the first week followed by 250 mg/m2 weekly thereafter in Stage 1.
Overall Number of Participants Analyzed 62 62
Measure Type: Number
Unit of Measure: Number of participants
Disease control (CR, PR, SD) 29 30
Objective response (CR,PR) 5 6
Complete response (CR) 0 0
Partial response (PR) 5 6
Stable disease (SD) 24 24
Progressive disease (PD) 21 21
Not evaluable 2 3
Missing 10 8
5.Secondary Outcome
Title Best RECIST Assessment as Per Investigator Assessment for Stage 2 (as as Confirmed Disease Control (Clinical Benefit) and Objective Response Are Simply Categories of RECIST Assessment)
Hide Description Best RECIST Assessment is defined as confirmed Disease control (complete response (CR), partial response (PR) and Stable disease (SD)), Objective response ( complete response (CR) or partial response (PR)) assessed by the investigator according to the RECIST 1.0 criteria.
Time Frame Response determined during Stage 2 or within 28 days after termination of Stage 2 treatment
Show Outcome Measure DataHide Outcome Measure Data
Hide Analysis Population Description
Patients treated in Stage 2
Arm/Group Title Afatinib 50 mg - Stage 2 Cetuximab 250 mg/m2 - Stage 2
Hide Arm/Group Description:
Patients were randomized to Cetuximab 250 mg/m2 given as 400mg/m2 once in the first week followed by 250 mg/m2 weekly thereafter in Stage 1 and if the patients had disease progression or intolerable AEs were crossed over to Afatinib 50 mg once daily (q.d.) for Stage 2
Patients were randomized to Afatinib monotherapy 50mg once daily (q.d.) in Stage 1 and if the patients had disease progression or intolerable AEs were crossed over to Cetuximab 250 mg/m2 given as 400mg/m2 once in the first week (load) followed by 250mg/m2 weekly thereafter in Stage 2.
Overall Number of Participants Analyzed 36 32
Measure Type: Number
Unit of Measure: Number of participants
Disease control (CR, PR, SD) 14 6
Objective response (CR,PR) 1 2
Complete response (CR) 1 0
Partial response (PR) 0 2
Stable disease (SD) 13 4
Progressive disease (PD) 16 20
Not evaluable 1 4
Missing 5 2
6.Secondary Outcome
Title Best RECIST Assessment as Per ICR for Stage2 (as Confirmed Disease Control (Clinical Benefit) and Objective Response Are Simply Categories of RECIST Assessment)
Hide Description Best RECIST Assessment is defined as confirmed Disease control (complete response (CR), partial response (PR) and Stable disease (SD)), Best objective response ( complete response (CR) or partial response (PR)) as assessed by the independent central review (ICR) according to the RECIST 1.0 criteria.
Time Frame Response determined during Stage 2 or within 28 days after termination of Stage 2 treatment
Show Outcome Measure DataHide Outcome Measure Data
Hide Analysis Population Description
Patients treated in Stage 2
Arm/Group Title Afatinib 50 mg - Stage 2 Cetuximab 250 mg/m2 - Stage 2
Hide Arm/Group Description:
Patients were randomized to Cetuximab 250 mg/m2 given as 400mg/m2 once in the first week followed by 250 mg/m2 weekly thereafter in Stage 1 and if the patients had disease progression or intolerable AEs were crossed over to Afatinib 50 mg once daily (q.d.) for Stage 2.
Patients were randomized to Afatinib monotherapy 50mg once daily (q.d.) in Stage 1 and if the patients had disease progression or intolerable AEs were crossed over to Cetuximab 250 mg/m2 given as 400mg/m2 once in the first week (load) followed by 250mg/m2 weekly thereafter in Stage 2.
Overall Number of Participants Analyzed 36 32
Measure Type: Number
Unit of Measure: Number of participants
Disease control (CR, PR, SD) 12 6
Objective response 0 0
Complete response (CR) 0 0
Partial response (PR) 0 0
Stable disease (SD) 12 6
Progressive disease (PD) 18 21
Not evaluable 1 4
Missing 5 1
7.Secondary Outcome
Title Best RECIST Assessment as Onset of Confirmed Objective Response as Per Investigator Assessment for Stage 1
Hide Description Best RECIST Assessment as onset of confirmed objective response as per Investigator assessment for Stage 1.
Time Frame Response determined from randomization until patient started Stage 2 or within 28 days after termination of Stage 1 treatment
Show Outcome Measure DataHide Outcome Measure Data
Hide Analysis Population Description
Randomised set (RS).
Arm/Group Title Afatinib 50 mg - Stage 1 Cetuximab 250 mg/m2 - Stage 1
Hide Arm/Group Description:
Patients were randomised to receive Afatinib 50 mg once daily (q.d.) in Stage 1.
Patients were randomized to Cetuximab 250 mg/m2 given as 400mg/m2 once in the first week followed by 250 mg/m2 weekly thereafter in Stage 1.
Overall Number of Participants Analyzed 10 4
Measure Type: Number
Unit of Measure: Number of participants
Week 4 (Day 1 − 42) 3 0
Week 8 (Day 43 − 84) 1 3
Week 16 (Day 85 − 140) 4 1
Week 24 (Day 141 − 196) 2 0
8.Secondary Outcome
Title Best RECIST Assessment as Onset of Confirmed Objective Response as as Per ICR for Stage 1
Hide Description Best RECIST Assessment as onset of confirmed objective response as per the independent central review (ICR) according to the RECIST 1.0 criteria.
Time Frame Response determined from randomization until patient started Stage 2 or within 28 days after termination of Stage 1 treatment
Show Outcome Measure DataHide Outcome Measure Data
Hide Analysis Population Description
Randomised set (RS).
Arm/Group Title Afatinib 50 mg - Stage 1 Cetuximab 250 mg/m2 - Stage 1
Hide Arm/Group Description:
Patients were randomised to receive Afatinib 50 mg once daily (q.d.) in Stage 1.
Patients were randomized to Cetuximab 250 mg/m2 given as 400mg/m2 once in the first week followed by 250 mg/m2 weekly thereafter in Stage 1.
Overall Number of Participants Analyzed 5 6
Measure Type: Number
Unit of Measure: Number of participants
Week 4 (Day 1 − 42) 1 0
Week 8 (Day 43 − 84) 2 3
Week 16 (Day 85 − 140) 2 2
Week 24 (Day 141 − 196) 0 1
9.Secondary Outcome
Title Best RECIST Assessment as Onset of Confirmed Objective Response as Per Investigator Assessment for Stage 2
Hide Description Best RECIST Assessment as onset of confirmed objective response as per Investigator assessment according to the RECIST 1.0 criteria.
Time Frame Response determined during Stage 2 or within 28 days after termination of Stage 2 treatment
Show Outcome Measure DataHide Outcome Measure Data
Hide Analysis Population Description
Patients treated in Stage 2
Arm/Group Title Afatinib 50 mg - Stage 2 Cetuximab 250 mg/m2 - Stage 2
Hide Arm/Group Description:
Patients were randomized to Cetuximab 250 mg/m2 given as 400mg/m2 once in the first week followed by 250 mg/m2 weekly thereafter in Stage 1 and if the patients had disease progression or intolerable AEs were crossed over to Afatinib 50 mg once daily (q.d.) for Stage 2
Patients were randomized to Afatinib monotherapy 50mg once daily (q.d.) in Stage 1 and if the patients had disease progression or intolerable AEs were crossed over to Cetuximab 250 mg/m2 given as 400mg/m2 once in the first week (load) followed by 250mg/m2 weekly thereafter in Stage 2.
Overall Number of Participants Analyzed 1 2
Measure Type: Number
Unit of Measure: Number of participants
Week 2 (Day 1 − 14) 0 0
Week 4 (Day 15 − 56) 1 1
Week 12 (Day 57 − 112) 0 1
10.Secondary Outcome
Title Best RECIST Assessment as Confirmed Duration of Objective Response and Disease Control as Per Investigator Assessment for Stage 1
Hide Description Best RECIST Assessment as duration of confirmed objective response and disease control as per Investigator assessment according to the RECIST 1.0 criteria.
Time Frame Response determined from randomization until patient started Stage 2 or within 28 days after termination of Stage 1 treatment
Show Outcome Measure DataHide Outcome Measure Data
Hide Analysis Population Description
Randomised Set (RS)
Arm/Group Title Afatinib 50 mg - Stage 1 Cetuximab 250 mg/m2 - Stage 1
Hide Arm/Group Description:
Patients were randomised to receive Afatinib 50 mg once daily (q.d.) in Stage 1.
Patients were randomized to Cetuximab 250 mg/m2 given as 400mg/m2 once in the first week followed by 250 mg/m2 weekly thereafter in Stage 1.
Overall Number of Participants Analyzed 62 62
Mean (Standard Deviation)
Unit of Measure: Weeks
Duration of objective response (N=10; N=4) 21.4  (12.2) 58.9  (98.1)
Duration of disease control(N=31; N=35) 25.1  (13.9) 30.3  (35.8)
11.Secondary Outcome
Title Best RECIST Assessment as Confirmed Duration of Confirmed Objective Response and Disease Control as Per ICR for Stage 1
Hide Description Best RECIST Assessment as duration of confirmed objective response and disease control as per the independent central review (ICR) according to the RECIST 1.0 criteria.
Time Frame Response determined from randomization until patient started Stage 2 or within 28 days after termination of Stage 1 treatment
Show Outcome Measure DataHide Outcome Measure Data
Hide Analysis Population Description
Randomised Set (RS)
Arm/Group Title Afatinib 50 mg - Stage 1 Cetuximab 250 mg/m2 - Stage 1
Hide Arm/Group Description:
Patients were randomised to receive Afatinib 50 mg once daily (q.d.) in Stage 1.
Patients were randomized to Cetuximab 250 mg/m2 given as 400mg/m2 once in the first week followed by 250 mg/m2 weekly thereafter in Stage 1.
Overall Number of Participants Analyzed 62 62
Mean (Standard Deviation)
Unit of Measure: Weeks
Duration of objective response (N=5; N=6) 28.0  (12.6) 55.1  (76.6)
Duration of disease control(N=29; N=30) 22.8  (11.0) 28.8  (38.1)
12.Secondary Outcome
Title Best RECIST Assessment as Confirmed Duration of Objective Response and Disease Control as Per Investigator Assessment for Stage 2
Hide Description Best RECIST Assessment as confirmed duration of objective response and disease control as per Investigator assessment according to the RECIST 1.0 criteria.
Time Frame Response determined during Stage 2 or within 28 days after termination of Stage 2 treatment
Show Outcome Measure DataHide Outcome Measure Data
Hide Analysis Population Description
patients treated in stage 2
Arm/Group Title Afatinib 50 mg - Stage 2 Cetuximab 250 mg/m2 - Stage 2
Hide Arm/Group Description:
Patients were randomized to Cetuximab 250 mg/m2 given as 400mg/m2 once in the first week followed by 250 mg/m2 weekly thereafter in Stage 1 and if the patients had disease progression or intolerable AEs were crossed over to Afatinib 50 mg once daily (q.d.) for Stage 2
Patients were randomized to Afatinib monotherapy 50mg once daily (q.d.) in Stage 1 and if the patients had disease progression or intolerable AEs were crossed over to Cetuximab 250 mg/m2 given as 400mg/m2 once in the first week (load) followed by 250mg/m2 weekly thereafter in Stage 2.
Overall Number of Participants Analyzed 36 32
Mean (Standard Deviation)
Unit of Measure: Weeks
Duration of objective response (N=1; N=2) 24.7  (0.0) 19.4  (21.1)
Duration of disease control(N=14; N=6) 21.8  (6.1) 21.5  (12.3)
13.Secondary Outcome
Title Best RECIST Assessment as Confirmed Duration of Disease Control as Per ICR for Stage 2
Hide Description Best RECIST Assessment as confirmed duration of disease control as per the independent central review (ICR) assessment according to the RECIST 1.0 criteria.
Time Frame Response determined during Stage 2 or within 28 days after termination of Stage 2 treatment
Show Outcome Measure DataHide Outcome Measure Data
Hide Analysis Population Description
patients treated in stage 2
Arm/Group Title Afatinib 50 mg - Stage 2 Cetuximab 250 mg/m2 - Stage 2
Hide Arm/Group Description:
Patients were randomized to Cetuximab 250 mg/m2 given as 400mg/m2 once in the first week followed by 250 mg/m2 weekly thereafter in Stage 1 and if the patients had disease progression or intolerable AEs were crossed over to Afatinib 50 mg once daily (q.d.) for Stage 2
Patients were randomized to Afatinib monotherapy 50mg once daily (q.d.) in Stage 1 and if the patients had disease progression or intolerable AEs were crossed over to Cetuximab 250 mg/m2 given as 400mg/m2 once in the first week (load) followed by 250mg/m2 weekly thereafter in Stage 2.
Overall Number of Participants Analyzed 36 32
Mean (Standard Deviation)
Unit of Measure: Weeks
17.4  (5.0) 18.4  (10.0)
14.Secondary Outcome
Title Progression Free Survival (PFS) Before Crossover Based on Investigator Assessment
Hide Description

PFS is defined as time from randomisation to until the occurrence of tumor progression or death, whichever occurred first, during Stage 1 of the trial.

Median is calculated from the Kaplan−Meier curve for each treatment group.

Time Frame From randomisation to disease progression in Stage 1 or death whichever occurred first before crossover.
Show Outcome Measure DataHide Outcome Measure Data
Hide Analysis Population Description
Randomised set (RS).
Arm/Group Title Afatinib 50 mg - Stage 1 Cetuximab 250 mg/m2 - Stage 1
Hide Arm/Group Description:
Patients were randomised to receive Afatinib 50 mg once daily (q.d.) in Stage 1.
Patients were randomized to Cetuximab 250 mg/m2 given as 400mg/m2 once in the first week followed by 250 mg/m2 weekly thereafter in Stage 1.
Overall Number of Participants Analyzed 62 62
Median (95% Confidence Interval)
Unit of Measure: weeks
15.86
(10.29 to 17.14)
15.14
(8.29 to 19.29)
Show Statistical Analysis 1 Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Afatinib 50 mg - Stage 1, Cetuximab 250 mg/m2 - Stage 1
Comments [Not Specified]
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.764
Comments [Not Specified]
Method Regression, Cox
Comments [Not Specified]
Method of Estimation Estimation Parameter Hazard Ratio (HR)
Estimated Value 0.942
Confidence Interval (2-Sided) 95%
0.640 to 1.387
Estimation Comments Hazard ratio, 95% CI and p−value are calculated from the Cox proportional hazards model stratified by the number of prior chemotherapies for R/M setting (0 or >=1)
15.Secondary Outcome
Title Progression Free Survival (PFS) After Crossover Based on Investigator Assessment
Hide Description

PFS is defined as time from first administration study medication after cross over until the occurrence of tumor progression or death, whichever came first, during Stage 2 of the trial.

Median is calculated from the Kaplan−Meier curve for each treatment group.

Time Frame From first administration of study medication after cross over to disease progression in Stage 2 or death whichever came first after crossover.
Show Outcome Measure DataHide Outcome Measure Data
Hide Analysis Population Description
Patients treated in stage 2
Arm/Group Title Afatinib 50 mg - Stage 2 Cetuximab mg/m2 - Stage 2
Hide Arm/Group Description:
Patients were randomized to Cetuximab 250 mg/m2 given as 400mg/m2 once in the first week followed by 250 mg/m2 weekly thereafter in Stage 1 and if the patients had disease progression or intolerable AEs were crossed over to Afatinib 50 mg once daily (q.d.) for Stage 2
Patients were randomized to Afatinib monotherapy 50mg once daily (q.d.) in Stage 1 and if the patients had disease progression or intolerable AEs were crossed over to Cetuximab 250 mg/m2 given as 400mg/m2 once in the first week (load) followed by 250mg/m2 weekly thereafter in Stage 2.
Overall Number of Participants Analyzed 36 32
Median (95% Confidence Interval)
Unit of Measure: weeks
7.93
(4.29 to 14.43)
6.43
(4.14 to 8.29)
Show Statistical Analysis 1 Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Afatinib 50 mg - Stage 2, Cetuximab mg/m2 - Stage 2
Comments [Not Specified]
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.219
Comments [Not Specified]
Method Regression, Cox
Comments [Not Specified]
Method of Estimation Estimation Parameter Hazard Ratio (HR)
Estimated Value 0.725
Confidence Interval (2-Sided) 95%
0.434 to 1.212
Estimation Comments Hazard ratio, 95% CI and p−value are calculated from the Cox proportional hazards model stratified by the number of prior chemotherapies for R/M setting (0 or >=1)
16.Secondary Outcome
Title Overall Survival (OS)
Hide Description

OS is defined as time from randomisation to death.

Median is calculated from the Kaplan−Meier curve for each treatment group.

Time Frame From randomisation to data cut-off date.
Show Outcome Measure DataHide Outcome Measure Data
Hide Analysis Population Description
Randomised set (RS).
Arm/Group Title Afatinib 50 mg / Cetuximab 250mg/m2 Cetuximab 250 mg/m2 / Afatinib 50 mg
Hide Arm/Group Description:
Patients were randomized to Afatinib monotherapy 50mg once daily (q.d.) in Stage 1 and if the patients had disease progression or intolerable AEs were crossed over to Cetuximab 250 mg/m2 given as 400mg/m2 once in the first week (load) followed by 250mg/m2 weekly thereafter in Stage 2.
Patients were randomized to Cetuximab 250 mg/m2 received 400mg/m2 once in the first week followed by 250 mg/m2 weekly thereafter in Stage 1 and if the patients had disease progression or intolerable AEs were crossed over to Afatinib 50 mg once daily (q.d.) for Stage 2
Overall Number of Participants Analyzed 62 62
Median (95% Confidence Interval)
Unit of Measure: Weeks
35.86
(25.71 to 45.00)
47.14
(24.14 to 64.71)
Show Statistical Analysis 1 Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Afatinib 50 mg / Cetuximab 250mg/m2, Cetuximab 250 mg/m2 / Afatinib 50 mg
Comments [Not Specified]
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.758
Comments [Not Specified]
Method Regression, Cox
Comments [Not Specified]
Method of Estimation Estimation Parameter Hazard Ratio (HR)
Estimated Value 1.067
Confidence Interval (2-Sided) 95%
0.708 to 1.608
Estimation Comments Hazard ratio, 95% CI and p−value are calculated from the Cox proportional hazards model stratified by the number of prior chemotherapies for R/M setting (0 or >=1)
17.Secondary Outcome
Title Time to Deterioration in HRQoL - Stage 1
Hide Description

Health related Quality of Life (HRQoL) for Time to deterioration was assessed using the the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire (EORTC QLQ-C30) and the Head and Neck Cancer Module (H&N35).

Time to deterioration in HRQoL (defined as a 10-point change towards worsening from the baseline score on a 0-100 point scale) was determined for:

  • global health status (Questions 29 and 30 in EORTC QLQ C30)
  • pain (Questions 9 and 19 in EORTC QLQ C30)
  • swallowing (Questions 35 to 38 in EORTC QLQ-H&N35)
Time Frame From randomisation to deterioration in HRQoL scores before crossover.
Show Outcome Measure DataHide Outcome Measure Data
Hide Analysis Population Description
Randomised Set (RS)
Arm/Group Title Afatinib 50 mg - Stage 1 Cetuximab mg/m2 - Stage 1
Hide Arm/Group Description:
Patients were randomised to receive Afatinib 50 mg in stage 1
Patients were randomized to Cetuximab 250 mg/m2 received 400mg/m2 once in the first week followed by 250 mg/m2 weekly thereafter in Stage 1
Overall Number of Participants Analyzed 62 62
Median (95% Confidence Interval)
Unit of Measure: months
global health status (N=37; N=38)
2.83
(1.91 to 5.85)
3.94
(2.96 to 7.39)
pain (N=34; N=33)
2.73
(1.48 to 5.88)
4.63
(2.92 to 8.61)
swallowing (N=33; N=34)
5.59
(2.07 to 7.36)
6.60
(2.92 to 8.48)
18.Secondary Outcome
Title Patients With AEs Resulting in Diarrhea, Skin Rash, Dose Reduction, Treatment Discontinuation and Decreased Cardiac Left Ventricular Function
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Patients with adverse events (AEs) resulting in Diarrhea, Skin Rash, dose reduction, treatment discontinuation and decreased cardiac left ventricular function

Note: To asses the Decreased Cardiac left ventricular function, Left ventricular ejection fraction (LVEF) was assessed in patients treated with afatinib in Stage 1 and Stage 2 . And no patients in either group had a significant change in LVEF during Stage 1 or Stage 2 of the trial.

Time Frame First administration of trial medication until 28 days after last drug administration
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Treated Set in Stage 1 : This analysis set included the randomized patients who took at least 1 dose of the randomized treatment (61 afatinib and 60 cetuximab patients. Treated set in Stage 2: This analysis set included all patients who received treatment: 36 patients in the afatinib and 32 patients in the cetuximab arm.
Arm/Group Title Afatinib 50 mg - Stage 1 Cetuximab mg/m2 - Stage 1 Afatinib 50 mg - Stage 2 Cetuximab mg/m2 - Stage 2
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Patients were randomised to receive Afatinib 50 mg in stage 1
Patients were randomized to Cetuximab 250 mg/m2 received 400mg/m2 once in the first week followed by 250 mg/m2 weekly thereafter in Stage 1
Patients were randomized to Cetuximab 250 mg/m2 received 400mg/m2 once in the first week followed by 250 mg/m2 weekly thereafter in Stage 1 and if the patients had disease progression or intolerable AEs were crossed over to Afatinib 50 mg once daily (q.d.) for Stage 2
Patients were randomized to Afatinib monotherapy 50mg once daily (q.d.) in Stage 1 and if the patients had disease progression or intolerable AEs were crossed over to Cetuximab 250 mg/m2 given as 400mg/m2 once in the first week (load) followed by 250mg/m2 weekly thereafter in Stage 2.
Overall Number of Participants Analyzed 61 60 36 32
Measure Type: Number
Unit of Measure: number of participants
With AE leading to Diarrhea 49 15 22 2
With AE leading to skin rash 48 46 23 14
With AE leading to dose reduction 18 2 11 0
With AE leading to treatment discontinuation 23 11 8 6
19.Secondary Outcome
Title Incidence and Intensity of Adverse Events With Grading According CTCAE
Hide Description Incidence and intensity of Adverse Events with grading according to the Common Terminology Criteria for Adverse Events (CTCAE version 3.0).
Time Frame First administration of trial medication until 28 days after last drug administration
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Treated Set in Stage 1 : This analysis set included the randomized patients who took at least 1 dose of the randomized treatment (61 afatinib and 60 cetuximab patients. Treated set in Stage 2: This analysis set included all patients who received treatment: 36 patients in the afatinib and 32 patients in the cetuximab arm.
Arm/Group Title Afatinib 50 mg - Stage 1 Cetuximab mg/m2 - Stage 1 Afatinib 50 mg - Stage 2 Cetuximab mg/m2 - Stage 2
Hide Arm/Group Description:
Patients were randomised to receive Afatinib 50 mg in stage 1
Patients were randomized to Cetuximab 250 mg/m2 received 400mg/m2 once in the first week followed by 250 mg/m2 weekly thereafter in Stage 1
Patients were randomized to Cetuximab 250 mg/m2 received 400mg/m2 once in the first week followed by 250 mg/m2 weekly thereafter in Stage 1 and if the patients had disease progression or intolerable AEs were crossed over to Afatinib 50 mg once daily (q.d.) for Stage 2
Patients were randomized to Afatinib monotherapy 50mg once daily (q.d.) in Stage 1 and if the patients had disease progression or intolerable AEs were crossed over to Cetuximab 250 mg/m2 given as 400mg/m2 once in the first week (load) followed by 250mg/m2 weekly thereafter in Stage 2.
Overall Number of Participants Analyzed 61 60 36 32
Measure Type: Number
Unit of Measure: percentage of participants
CTCAE grade 1 3.3 5.0 5.6 9.4
CTCAE grade 2 24.6 41.7 25.0 37.5
CTCAE grade 3 39.3 28.3 25.0 25.0
CTCAE grade 4 8.2 6.7 13.9 9.4
CTCAE grade 5 24.6 16.7 30.6 15.6
20.Secondary Outcome
Title Pre-dose Concentration of Afatinib in Plasma for Dose 40mg and 50mg at Steady State on Day 15 (Cpre,ss,15)
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Cpre,ss,15 represents the pre-dose concentration of afatinib in plasma at steady state on day 15.

Note: At day 15, values for afatinib 40 mg no values reported in stage 1 and stage 2.

Time Frame Day 15
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Pharmacokinetic Set (PK): The PK analysis was based on all patients who were treated with afatinib and who had evaluable plasma concentration data, which consisted of data for 60 patients in Stage 1 and 35 patients in Stage 2.
Arm/Group Title Afatinib 50 mg - Stage 1 Afatinib 50 mg - Stage 2
Hide Arm/Group Description:
Patients were randomised to receive Afatinib 50 mg in stage 1
Patients were randomized to Cetuximab 250 mg/m2 received 400mg/m2 once in the first week followed by 250 mg/m2 weekly thereafter in Stage 1 and if the patients had disease progression or intolerable AEs were crossed over to Afatinib 50 mg once daily (q.d.) for Stage 2
Overall Number of Participants Analyzed 45 26
Geometric Mean (Geometric Coefficient of Variation)
Unit of Measure: ng/mL
39.3
(70.1%)
46.6
(81.4%)
21.Secondary Outcome
Title Pre-dose Concentration of Afatinib in Plasma for Dose 40mg and 50mg at Steady State on Day 29 (Cpre,ss,29)
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Cpre,ss,29 represents the pre-dose concentration of afatinib in plasma at steady state on day 29.

Note: At day 29, values for afatinib 40 mg no values reported in stage 2.

Time Frame Day 29
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Pharmacokinetic Set (PK)
Arm/Group Title Afatinib 40 mg - Stage 1 Afatinib 50 mg - Stage 1 Afatinib 50 mg - Stage 2
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Patients were randomised to receive Afatinib 50 mg once daily (q.d.) in Stage 1, and had sequential dose reduction to 40 mg in stage 1.
Patients were randomised to receive Afatinib 50 mg in stage 1
Patients were randomized to Cetuximab 250 mg/m2 received 400mg/m2 once in the first week followed by 250 mg/m2 weekly thereafter in Stage 1 and if the patients had disease progression or intolerable AEs were crossed over to Afatinib 50 mg once daily (q.d.) for Stage 2
Overall Number of Participants Analyzed 9 33 22
Geometric Mean (Geometric Coefficient of Variation)
Unit of Measure: ng/mL
8.84
(206%)
31.7
(97.7%)
45.9
(48.9%)
22.Secondary Outcome
Title Pre-dose Concentration of Afatinib in Plasma for Dose 40mg and 50mg at Steady State on Day 57 (Cpre,ss, 57)
Hide Description Cpre,ss,57 represents the pre-dose concentration of afatinib in plasma at steady state on day 57.
Time Frame Day 57
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Pharmacokinetic Set (PK)
Arm/Group Title Afatinib 40 mg - Stage 1 Afatinib 50 mg - Stage 1 Afatinib 50 mg - Stage 2
Hide Arm/Group Description:
Patients were randomised to receive Afatinib 50 mg once daily (q.d.) in Stage 1, and had sequential dose reduction to 40 mg in stage 1.
Patients were randomised to receive Afatinib 50 mg in stage 1
Patients were randomized to Cetuximab 250 mg/m2 received 400mg/m2 once in the first week followed by 250 mg/m2 weekly thereafter in Stage 1 and if the patients had disease progression or intolerable AEs were crossed over to Afatinib 50 mg once daily (q.d.) for Stage 2
Overall Number of Participants Analyzed 7 16 10
Geometric Mean (Geometric Coefficient of Variation)
Unit of Measure: ng/mL
32.7
(25.3%)
19.9
(94.4%)
46.5
(67.2%)
Time Frame 1493 days
Adverse Event Reporting Description [Not Specified]
 
Arm/Group Title Cetuximab 250 mg/m2 / Afatinib 50 mg - Stage 1 Afatinib 50 mg / Cetuximab 250mg/m2 - Stage 2 Cetuximab 250 mg/m2 / Afatinib 50 mg - Stage 2 Afatinib 50 mg / Cetuximab 250mg/m2 - Stage 1
Hide Arm/Group Description Patients were randomized to Cetuximab 250 mg/m2 received 400mg/m2 once in the first week followed by 250 mg/m2 weekly thereafter in Stage 1 and if the patients had disease progression or intolerable AEs were crossed over to Afatinib 50 mg once daily (q.d.) for Stage 2. Patients were randomized to Afatinib monotherapy 50mg once daily (q.d.) in Stage 1 and if the patients had disease progression or intolerable AEs were crossed over to Cetuximab 250 mg/m2 given as 400mg/m2 once in the first week (load) followed by 250mg/m2 weekly thereafter in Stage 2. Patients were randomized to Cetuximab 250 mg/m2 received 400mg/m2 once in the first week followed by 250 mg/m2 weekly thereafter in Stage 1 and if the patients had disease progression or intolerable AEs were crossed over to Afatinib 50 mg once daily (q.d.) for Stage 2. Patients were randomized to Afatinib monotherapy 50mg once daily (q.d.) in Stage 1 and if the patients had disease progression or intolerable AEs were crossed over to Cetuximab 250 mg/m2 given as 400mg/m2 once in the first week (load) followed by 250mg/m2 weekly thereafter in Stage 2.
All-Cause Mortality
Cetuximab 250 mg/m2 / Afatinib 50 mg - Stage 1 Afatinib 50 mg / Cetuximab 250mg/m2 - Stage 2 Cetuximab 250 mg/m2 / Afatinib 50 mg - Stage 2 Afatinib 50 mg / Cetuximab 250mg/m2 - Stage 1
Affected / at Risk (%) Affected / at Risk (%) Affected / at Risk (%) Affected / at Risk (%)
Total   --/--   --/--   --/--   --/-- 
Show Serious Adverse Events Hide Serious Adverse Events
Cetuximab 250 mg/m2 / Afatinib 50 mg - Stage 1 Afatinib 50 mg / Cetuximab 250mg/m2 - Stage 2 Cetuximab 250 mg/m2 / Afatinib 50 mg - Stage 2 Afatinib 50 mg / Cetuximab 250mg/m2 - Stage 1
Affected / at Risk (%) Affected / at Risk (%) Affected / at Risk (%) Affected / at Risk (%)
Total   26/60 (43.33%)   18/36 (50.00%)   13/32 (40.63%)   36/61 (59.02%) 
Blood and lymphatic system disorders         
Anaemia  1  1/60 (1.67%)  0/36 (0.00%)  0/32 (0.00%)  2/61 (3.28%) 
Cardiac disorders         
Angina pectoris  1  0/60 (0.00%)  0/36 (0.00%)  0/32 (0.00%)  1/61 (1.64%) 
Cardiac arrest  1  1/60 (1.67%)  0/36 (0.00%)  0/32 (0.00%)  1/61 (1.64%) 
Cardio-respiratory arrest  1  0/60 (0.00%)  1/36 (2.78%)  0/32 (0.00%)  0/61 (0.00%) 
Cardiopulmonary failure  1  1/60 (1.67%)  0/36 (0.00%)  0/32 (0.00%)  2/61 (3.28%) 
Endocarditis noninfective  1  1/60 (1.67%)  0/36 (0.00%)  0/32 (0.00%)  0/61 (0.00%) 
Myocardial infarction  1  1/60 (1.67%)  0/36 (0.00%)  0/32 (0.00%)  1/61 (1.64%) 
Pericardial effusion  1  1/60 (1.67%)  0/36 (0.00%)  0/32 (0.00%)  0/61 (0.00%) 
Pericarditis  1  1/60 (1.67%)  0/36 (0.00%)  0/32 (0.00%)  0/61 (0.00%) 
Sinus bradycardia  1  0/60 (0.00%)  0/36 (0.00%)  0/32 (0.00%)  1/61 (1.64%) 
Endocrine disorders         
Hypercalcaemia of malignancy  1  0/60 (0.00%)  0/36 (0.00%)  1/32 (3.13%)  0/61 (0.00%) 
Eye disorders         
Periorbital oedema  1  0/60 (0.00%)  0/36 (0.00%)  0/32 (0.00%)  1/61 (1.64%) 
Gastrointestinal disorders         
Abdominal pain upper  1  0/60 (0.00%)  0/36 (0.00%)  0/32 (0.00%)  1/61 (1.64%) 
Diarrhoea  1  0/60 (0.00%)  3/36 (8.33%)  0/32 (0.00%)  8/61 (13.11%) 
Dysphagia  1  1/60 (1.67%)  2/36 (5.56%)  1/32 (3.13%)  3/61 (4.92%) 
Gastrointestinal haemorrhage  1  0/60 (0.00%)  0/36 (0.00%)  0/32 (0.00%)  1/61 (1.64%) 
Mouth haemorrhage  1  0/60 (0.00%)  0/36 (0.00%)  0/32 (0.00%)  2/61 (3.28%) 
Nausea  1  2/60 (3.33%)  0/36 (0.00%)  0/32 (0.00%)  0/61 (0.00%) 
Vomiting  1  2/60 (3.33%)  2/36 (5.56%)  1/32 (3.13%)  0/61 (0.00%) 
General disorders         
Asthenia  1  0/60 (0.00%)  1/36 (2.78%)  0/32 (0.00%)  2/61 (3.28%) 
Chest pain  1  1/60 (1.67%)  0/36 (0.00%)  0/32 (0.00%)  0/61 (0.00%) 
Chills  1  1/60 (1.67%)  0/36 (0.00%)  0/32 (0.00%)  0/61 (0.00%) 
Face oedema  1  1/60 (1.67%)  0/36 (0.00%)  0/32 (0.00%)  0/61 (0.00%) 
General physical health deterioration  1  3/60 (5.00%)  6/36 (16.67%)  3/32 (9.38%)  6/61 (9.84%) 
Mucosal inflammation  1  0/60 (0.00%)  0/36 (0.00%)  0/32 (0.00%)  2/61 (3.28%) 
Oedema peripheral  1  0/60 (0.00%)  0/36 (0.00%)  1/32 (3.13%)  0/61 (0.00%) 
Pain  1  0/60 (0.00%)  2/36 (5.56%)  0/32 (0.00%)  0/61 (0.00%) 
Pyrexia  1  1/60 (1.67%)  0/36 (0.00%)  0/32 (0.00%)  2/61 (3.28%) 
Immune system disorders         
Hypersensitivity  1  1/60 (1.67%)  0/36 (0.00%)  0/32 (0.00%)  0/61 (0.00%) 
Infections and infestations         
Abscess limb  1  1/60 (1.67%)  0/36 (0.00%)  0/32 (0.00%)  0/61 (0.00%) 
Bacteraemia  1  1/60 (1.67%)  0/36 (0.00%)  0/32 (0.00%)  0/61 (0.00%) 
Bronchitis  1  0/60 (0.00%)  0/36 (0.00%)  0/32 (0.00%)  1/61 (1.64%) 
Bronchopneumonia  1  0/60 (0.00%)  0/36 (0.00%)  0/32 (0.00%)  1/61 (1.64%) 
Cellulitis  1  1/60 (1.67%)  0/36 (0.00%)  0/32 (0.00%)  1/61 (1.64%) 
Device related infection  1  0/60 (0.00%)  0/36 (0.00%)  0/32 (0.00%)  1/61 (1.64%) 
Device related sepsis  1  2/60 (3.33%)  0/36 (0.00%)  0/32 (0.00%)  0/61 (0.00%) 
Endocarditis  1  1/60 (1.67%)  0/36 (0.00%)  0/32 (0.00%)  0/61 (0.00%) 
Infectious pleural effusion  1  1/60 (1.67%)  0/36 (0.00%)  0/32 (0.00%)  0/61 (0.00%) 
Lobar pneumonia  1  0/60 (0.00%)  1/36 (2.78%)  0/32 (0.00%)  0/61 (0.00%) 
Lower respiratory tract infection  1  0/60 (0.00%)  0/36 (0.00%)  0/32 (0.00%)  1/61 (1.64%) 
Lung infection  1  1/60 (1.67%)  0/36 (0.00%)  2/32 (6.25%)  0/61 (0.00%) 
Meningitis staphylococcal  1  1/60 (1.67%)  0/36 (0.00%)  0/32 (0.00%)  0/61 (0.00%) 
Pneumonia  1  1/60 (1.67%)  0/36 (0.00%)  1/32 (3.13%)  5/61 (8.20%) 
Respiratory tract infection  1  1/60 (1.67%)  0/36 (0.00%)  1/32 (3.13%)  1/61 (1.64%) 
Sepsis  1  0/60 (0.00%)  0/36 (0.00%)  0/32 (0.00%)  1/61 (1.64%) 
Septic shock  1  0/60 (0.00%)  0/36 (0.00%)  0/32 (0.00%)  1/61 (1.64%) 
Staphylococcal bacteraemia  1  0/60 (0.00%)  0/36 (0.00%)  0/32 (0.00%)  1/61 (1.64%) 
Toxic shock syndrome  1  0/60 (0.00%)  0/36 (0.00%)  1/32 (3.13%)  0/61 (0.00%) 
Urinary tract infection  1  0/60 (0.00%)  0/36 (0.00%)  0/32 (0.00%)  1/61 (1.64%) 
Injury, poisoning and procedural complications         
Infusion related reaction  1  1/60 (1.67%)  0/36 (0.00%)  0/32 (0.00%)  0/61 (0.00%) 
Overdose  1  1/60 (1.67%)  0/36 (0.00%)  0/32 (0.00%)  0/61 (0.00%) 
Post procedural haemorrhage  1  0/60 (0.00%)  1/36 (2.78%)  0/32 (0.00%)  1/61 (1.64%) 
Wound haemorrhage  1  0/60 (0.00%)  1/36 (2.78%)  0/32 (0.00%)  0/61 (0.00%) 
Investigations         
Weight decreased  1  0/60 (0.00%)  0/36 (0.00%)  0/32 (0.00%)  1/61 (1.64%) 
Metabolism and nutrition disorders         
Decreased appetite  1  1/60 (1.67%)  1/36 (2.78%)  0/32 (0.00%)  1/61 (1.64%) 
Dehydration  1  1/60 (1.67%)  0/36 (0.00%)  1/32 (3.13%)  8/61 (13.11%) 
Electrolyte imbalance  1  1/60 (1.67%)  0/36 (0.00%)  0/32 (0.00%)  0/61 (0.00%) 
Hypercalcaemia  1  2/60 (3.33%)  1/36 (2.78%)  1/32 (3.13%)  1/61 (1.64%) 
Hypernatraemia  1  0/60 (0.00%)  1/36 (2.78%)  0/32 (0.00%)  1/61 (1.64%) 
Hypocalcaemia  1  0/60 (0.00%)  0/36 (0.00%)  0/32 (0.00%)  1/61 (1.64%) 
Hypoglycaemia  1  1/60 (1.67%)  0/36 (0.00%)  0/32 (0.00%)  0/61 (0.00%) 
Hypokalaemia  1  0/60 (0.00%)  0/36 (0.00%)  0/32 (0.00%)  1/61 (1.64%) 
Hypomagnesaemia  1  1/60 (1.67%)  0/36 (0.00%)  0/32 (0.00%)  0/61 (0.00%) 
Hypophagia  1  0/60 (0.00%)  0/36 (0.00%)  2/32 (6.25%)  0/61 (0.00%) 
Malnutrition  1  0/60 (0.00%)  2/36 (5.56%)  0/32 (0.00%)  2/61 (3.28%) 
Musculoskeletal and connective tissue disorders         
Arthralgia  1  0/60 (0.00%)  0/36 (0.00%)  0/32 (0.00%)  1/61 (1.64%) 
Fistula  1  0/60 (0.00%)  1/36 (2.78%)  0/32 (0.00%)  0/61 (0.00%) 
Muscular weakness  1  0/60 (0.00%)  1/36 (2.78%)  0/32 (0.00%)  0/61 (0.00%) 
Soft tissue necrosis  1  0/60 (0.00%)  0/36 (0.00%)  0/32 (0.00%)  1/61 (1.64%) 
Neoplasms benign, malignant and unspecified (incl cysts and polyps)         
Infected neoplasm  1  1/60 (1.67%)  0/36 (0.00%)  0/32 (0.00%)  0/61 (0.00%) 
Linitis plastica  1  0/60 (0.00%)  0/36 (0.00%)  0/32 (0.00%)  1/61 (1.64%) 
Malignant neoplasm progression  1  0/60 (0.00%)  1/36 (2.78%)  1/32 (3.13%)  0/61 (0.00%) 
Metastases to central nervous system  1  1/60 (1.67%)  0/36 (0.00%)  0/32 (0.00%)  0/61 (0.00%) 
Metastatic pain  1  0/60 (0.00%)  1/36 (2.78%)  0/32 (0.00%)  0/61 (0.00%) 
Tongue neoplasm malignant stage unspecified  1  1/60 (1.67%)  0/36 (0.00%)  0/32 (0.00%)  0/61 (0.00%) 
Tumour compression  1  0/60 (0.00%)  0/36 (0.00%)  0/32 (0.00%)  1/61 (1.64%) 
Tumour haemorrhage  1  1/60 (1.67%)  1/36 (2.78%)  1/32 (3.13%)  1/61 (1.64%) 
Tumour pain  1  1/60 (1.67%)  0/36 (0.00%)  0/32 (0.00%)  0/61 (0.00%) 
Nervous system disorders         
Brain oedema  1  0/60 (0.00%)  0/36 (0.00%)  1/32 (3.13%)  0/61 (0.00%) 
Cerebrovascular accident  1  2/60 (3.33%)  0/36 (0.00%)  0/32 (0.00%)  0/61 (0.00%) 
Convulsion  1  1/60 (1.67%)  0/36 (0.00%)  0/32 (0.00%)  0/61 (0.00%) 
Ischaemic stroke  1  0/60 (0.00%)  0/36 (0.00%)  0/32 (0.00%)  1/61 (1.64%) 
Neuralgia  1  1/60 (1.67%)  0/36 (0.00%)  0/32 (0.00%)  0/61 (0.00%) 
Somnolence  1  0/60 (0.00%)  0/36 (0.00%)  0/32 (0.00%)  1/61 (1.64%) 
Vocal cord paralysis  1  0/60 (0.00%)  0/36 (0.00%)  0/32 (0.00%)  1/61 (1.64%) 
Psychiatric disorders         
Alcohol abuse  1  1/60 (1.67%)  0/36 (0.00%)  0/32 (0.00%)  0/61 (0.00%) 
Anxiety  1  1/60 (1.67%)  0/36 (0.00%)  0/32 (0.00%)  0/61 (0.00%) 
Confusional state  1  0/60 (0.00%)  0/36 (0.00%)  0/32 (0.00%)  1/61 (1.64%) 
Disorientation  1  1/60 (1.67%)  0/36 (0.00%)  0/32 (0.00%)  0/61 (0.00%) 
Hallucination, auditory  1  0/60 (0.00%)  0/36 (0.00%)  0/32 (0.00%)  1/61 (1.64%) 
Renal and urinary disorders         
Renal failure  1  0/60 (0.00%)  0/36 (0.00%)  0/32 (0.00%)  3/61 (4.92%) 
Renal failure acute  1  0/60 (0.00%)  1/36 (2.78%)  1/32 (3.13%)  3/61 (4.92%) 
Renal tubular necrosis  1  1/60 (1.67%)  0/36 (0.00%)  0/32 (0.00%)  0/61 (0.00%) 
Respiratory, thoracic and mediastinal disorders         
Acute respiratory distress syndrome  1  1/60 (1.67%)  0/36 (0.00%)  0/32 (0.00%)  0/61 (0.00%) 
Asphyxia  1  1/60 (1.67%)  0/36 (0.00%)  0/32 (0.00%)  0/61 (0.00%) 
Aspiration  1  0/60 (0.00%)  1/36 (2.78%)  0/32 (0.00%)  0/61 (0.00%) 
Cough  1  0/60 (0.00%)  0/36 (0.00%)  1/32 (3.13%)  0/61 (0.00%) 
Dyspnoea  1  3/60 (5.00%)  1/36 (2.78%)  2/32 (6.25%)  4/61 (6.56%) 
Haemoptysis  1  1/60 (1.67%)  0/36 (0.00%)  0/32 (0.00%)  0/61 (0.00%) 
Hypoxia  1  0/60 (0.00%)  0/36 (0.00%)  1/32 (3.13%)  0/61 (0.00%) 
Interstitial lung disease  1  0/60 (0.00%)  0/36 (0.00%)  0/32 (0.00%)  1/61 (1.64%) 
Obstructive airways disorder  1  0/60 (0.00%)  0/36 (0.00%)  1/32 (3.13%)  0/61 (0.00%) 
Pleural effusion  1  0/60 (0.00%)  1/36 (2.78%)  1/32 (3.13%)  1/61 (1.64%) 
Pneumonia aspiration  1  1/60 (1.67%)  2/36 (5.56%)  0/32 (0.00%)  2/61 (3.28%) 
Productive cough  1  1/60 (1.67%)  0/36 (0.00%)  0/32 (0.00%)  0/61 (0.00%) 
Pulmonary embolism  1  0/60 (0.00%)  0/36 (0.00%)  0/32 (0.00%)  1/61 (1.64%) 
Respiratory distress  1  0/60 (0.00%)  1/36 (2.78%)  0/32 (0.00%)  0/61 (0.00%) 
Respiratory failure  1  0/60 (0.00%)  1/36 (2.78%)  0/32 (0.00%)  2/61 (3.28%) 
Skin and subcutaneous tissue disorders         
Palmar-plantar erythrodysaesthesia syndrome  1  0/60 (0.00%)  0/36 (0.00%)  0/32 (0.00%)  1/61 (1.64%) 
Rash  1  0/60 (0.00%)  1/36 (2.78%)  0/32 (0.00%)  1/61 (1.64%) 
Surgical and medical procedures         
Gastrointestinal tube insertion  1  0/60 (0.00%)  0/36 (0.00%)  1/32 (3.13%)  0/61 (0.00%) 
Vascular disorders         
Haemorrhage  1  0/60 (0.00%)  2/36 (5.56%)  0/32 (0.00%)  0/61 (0.00%) 
Hypotension  1  0/60 (0.00%)  0/36 (0.00%)  0/32 (0.00%)  2/61 (3.28%) 
Indicates events were collected by systematic assessment
1
Term from vocabulary, 16.1
Show Other (Not Including Serious) Adverse Events Hide Other (Not Including Serious) Adverse Events
Frequency Threshold for Reporting Other Adverse Events 5%
Cetuximab 250 mg/m2 / Afatinib 50 mg - Stage 1 Afatinib 50 mg / Cetuximab 250mg/m2 - Stage 2 Cetuximab 250 mg/m2 / Afatinib 50 mg - Stage 2 Afatinib 50 mg / Cetuximab 250mg/m2 - Stage 1
Affected / at Risk (%) Affected / at Risk (%) Affected / at Risk (%) Affected / at Risk (%)
Total   59/60 (98.33%)   34/36 (94.44%)   29/32 (90.63%)   61/61 (100.00%) 
Blood and lymphatic system disorders         
Anaemia  1  10/60 (16.67%)  3/36 (8.33%)  3/32 (9.38%)  9/61 (14.75%) 
Neutropenia  1  0/60 (0.00%)  2/36 (5.56%)  0/32 (0.00%)  0/61 (0.00%) 
Eye disorders         
Conjunctivitis  1  7/60 (11.67%)  4/36 (11.11%)  1/32 (3.13%)  4/61 (6.56%) 
Gastrointestinal disorders         
Abdominal pain  1  1/60 (1.67%)  0/36 (0.00%)  0/32 (0.00%)  4/61 (6.56%) 
Cheilitis  1  2/60 (3.33%)  1/36 (2.78%)  0/32 (0.00%)  4/61 (6.56%) 
Constipation  1  17/60 (28.33%)  2/36 (5.56%)  6/32 (18.75%)  6/61 (9.84%) 
Diarrhoea  1  15/60 (25.00%)  21/36 (58.33%)  2/32 (6.25%)  45/61 (73.77%) 
Dry mouth  1  5/60 (8.33%)  0/36 (0.00%)  1/32 (3.13%)  2/61 (3.28%) 
Dyspepsia  1  5/60 (8.33%)  2/36 (5.56%)  0/32 (0.00%)  1/61 (1.64%) 
Dysphagia  1  8/60 (13.33%)  2/36 (5.56%)  1/32 (3.13%)  6/61 (9.84%) 
Nausea  1  17/60 (28.33%)  8/36 (22.22%)  2/32 (6.25%)  22/61 (36.07%) 
Oral pain  1  2/60 (3.33%)  0/36 (0.00%)  0/32 (0.00%)  4/61 (6.56%) 
Stomatitis  1  4/60 (6.67%)  4/36 (11.11%)  0/32 (0.00%)  5/61 (8.20%) 
Vomiting  1  12/60 (20.00%)  7/36 (19.44%)  1/32 (3.13%)  15/61 (24.59%) 
General disorders         
Asthenia  1  9/60 (15.00%)  3/36 (8.33%)  4/32 (12.50%)  10/61 (16.39%) 
Fatigue  1  19/60 (31.67%)  5/36 (13.89%)  6/32 (18.75%)  18/61 (29.51%) 
Mucosal inflammation  1  11/60 (18.33%)  7/36 (19.44%)  1/32 (3.13%)  14/61 (22.95%) 
Pyrexia  1  11/60 (18.33%)  3/36 (8.33%)  3/32 (9.38%)  4/61 (6.56%) 
Infections and infestations         
Nasopharyngitis  1  2/60 (3.33%)  0/36 (0.00%)  2/32 (6.25%)  4/61 (6.56%) 
Paronychia  1  4/60 (6.67%)  3/36 (8.33%)  2/32 (6.25%)  3/61 (4.92%) 
Upper respiratory tract infectio  1  1/60 (1.67%)  2/36 (5.56%)  1/32 (3.13%)  1/61 (1.64%) 
Investigations         
Weight decreased  1  8/60 (13.33%)  5/36 (13.89%)  1/32 (3.13%)  9/61 (14.75%) 
Metabolism and nutrition disorders         
Decreased appetite  1  11/60 (18.33%)  7/36 (19.44%)  6/32 (18.75%)  12/61 (19.67%) 
Hypokalaemia  1  6/60 (10.00%)  1/36 (2.78%)  0/32 (0.00%)  6/61 (9.84%) 
Hypomagnesaemia  1  2/60 (3.33%)  3/36 (8.33%)  3/32 (9.38%)  2/61 (3.28%) 
Musculoskeletal and connective tissue disorders         
Back pain  1  5/60 (8.33%)  1/36 (2.78%)  2/32 (6.25%)  2/61 (3.28%) 
Muscle spasms  1  0/60 (0.00%)  2/36 (5.56%)  0/32 (0.00%)  1/61 (1.64%) 
Neck pain  1  5/60 (8.33%)  3/36 (8.33%)  1/32 (3.13%)  3/61 (4.92%) 
Pain in extremity  1  4/60 (6.67%)  0/36 (0.00%)  1/32 (3.13%)  1/61 (1.64%) 
Neoplasms benign, malignant and unspecified (incl cysts and polyps)         
Tumour pain  1  1/60 (1.67%)  2/36 (5.56%)  2/32 (6.25%)  2/61 (3.28%) 
Nervous system disorders         
Dysgeusia  1  1/60 (1.67%)  2/36 (5.56%)  0/32 (0.00%)  3/61 (4.92%) 
Dizziness  1  7/60 (11.67%)  1/36 (2.78%)  1/32 (3.13%)  5/61 (8.20%) 
Headache  1  5/60 (8.33%)  3/36 (8.33%)  5/32 (15.63%)  4/61 (6.56%) 
Paraesthesia  1  1/60 (1.67%)  3/36 (8.33%)  1/32 (3.13%)  0/61 (0.00%) 
Psychiatric disorders         
Anxiety  1  1/60 (1.67%)  2/36 (5.56%)  2/32 (6.25%)  2/61 (3.28%) 
Confusional state  1  3/60 (5.00%)  0/36 (0.00%)  0/32 (0.00%)  4/61 (6.56%) 
Insomnia  1  5/60 (8.33%)  1/36 (2.78%)  1/32 (3.13%)  4/61 (6.56%) 
Respiratory, thoracic and mediastinal disorders         
Cough  1  12/60 (20.00%)  3/36 (8.33%)  3/32 (9.38%)  6/61 (9.84%) 
Dysphonia  1  2/60 (3.33%)  1/36 (2.78%)  1/32 (3.13%)  6/61 (9.84%) 
Dyspnoea  1  9/60 (15.00%)  0/36 (0.00%)  2/32 (6.25%)  5/61 (8.20%) 
Epistaxis  1  5/60 (8.33%)  2/36 (5.56%)  0/32 (0.00%)  9/61 (14.75%) 
Haemoptysis  1  2/60 (3.33%)  1/36 (2.78%)  1/32 (3.13%)  6/61 (9.84%) 
Rhinorrhoea  1  1/60 (1.67%)  0/36 (0.00%)  1/32 (3.13%)  4/61 (6.56%) 
Skin and subcutaneous tissue disorders         
Acne  1  8/60 (13.33%)  3/36 (8.33%)  4/32 (12.50%)  8/61 (13.11%) 
Decubitus ulcer  1  0/60 (0.00%)  2/36 (5.56%)  0/32 (0.00%)  0/61 (0.00%) 
Dermatitis  1  3/60 (5.00%)  2/36 (5.56%)  0/32 (0.00%)  0/61 (0.00%) 
Dermatitis acneiform  1  8/60 (13.33%)  3/36 (8.33%)  3/32 (9.38%)  12/61 (19.67%) 
Dry skin  1  16/60 (26.67%)  4/36 (11.11%)  3/32 (9.38%)  9/61 (14.75%) 
Erythema  1  2/60 (3.33%)  2/36 (5.56%)  0/32 (0.00%)  2/61 (3.28%) 
Palmar-plantar erythrodysaesthesia syndrome  1  2/60 (3.33%)  5/36 (13.89%)  2/32 (6.25%)  2/61 (3.28%) 
Pruritus  1  5/60 (8.33%)  1/36 (2.78%)  0/32 (0.00%)  8/61 (13.11%) 
Rash  1  25/60 (41.67%)  10/36 (27.78%)  6/32 (18.75%)  26/61 (42.62%) 
Skin fissures  1  11/60 (18.33%)  1/36 (2.78%)  1/32 (3.13%)  3/61 (4.92%) 
Skin toxicity  1  3/60 (5.00%)  4/36 (11.11%)  1/32 (3.13%)  2/61 (3.28%) 
Xeroderma  1  3/60 (5.00%)  0/36 (0.00%)  2/32 (6.25%)  4/61 (6.56%) 
Vascular disorders         
Hypertension  1  1/60 (1.67%)  0/36 (0.00%)  2/32 (6.25%)  1/61 (1.64%) 
Hypotension  1  2/60 (3.33%)  0/36 (0.00%)  1/32 (3.13%)  5/61 (8.20%) 
Indicates events were collected by systematic assessment
1
Term from vocabulary, 16.1
Certain Agreements
Principal Investigators are NOT employed by the organization sponsoring the study.
There IS an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.
Any publication of the result of this trial must be consistent with the Boehringer Ingelheim publication policy. The rights of the investigator and of the sponsor with regard to publication
Results Point of Contact
Name/Title: Boehringer Ingelheim Call Center
Organization: Boehringer Ingelheim
Phone: 1-800-243-0127
Responsible Party: Boehringer Ingelheim
ClinicalTrials.gov Identifier: NCT00514943     History of Changes
Other Study ID Numbers: 1200.28
2008-007097-38 ( EudraCT Number: EudraCT )
First Submitted: August 9, 2007
First Posted: August 10, 2007
Results First Submitted: August 8, 2013
Results First Posted: December 25, 2013
Last Update Posted: July 26, 2016