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Clinical Trial Results:
A randomized, open-label Phase II study of BIBW 2992 versus cetuximab (Erbitux®) in patients with metastatic or recurrent Head and Neck Squamous Cell Carcinoma (HNSCC) after failure of platinum-containing therapy with a cross-over period for progressing patients.

Summary
EudraCT number	2008-007097-38
Trial protocol	BE ES FR
Global end of trial date	26 Jul 2013

Results information
Results version number	v1(current)
This version publication date	20 Jun 2016
First version publication date	16 Jul 2015
Other versions

Trial Information
Subject Disposition
Baseline Characteristics
End Points
Adverse Events
More Information

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Trial information

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Sponsor protocol code

1200.28

ISRCTN number

US NCT number

NCT00514943

WHO universal trial number (UTN)

Sponsor organisation name

Boehringer Ingelheim

Sponsor organisation address

Binger Strasse 173 , Ingelheim am Rhein , Germany, 55216

Public contact

QRPE Processes and Systems Coordination Clinical Trial Information Disclosure , Boehringer Ingelheim Pharma GmbH & Co. KG , + 1 800 243 0127 , clintriage.rdg@boehringer-ingelheim.com

Scientific contact

QRPE Processes and Systems Coordination Clinical Trial Information Disclosure , Boehringer Ingelheim Pharma GmbH & Co. KG , + 1 800 243 0127 , clintriage.rdg@boehringer-ingelheim.com

Is trial part of an agreed paediatric investigation plan (PIP)

Does article 45 of REGULATION (EC) No 1901/2006 apply to this trial?

Does article 46 of REGULATION (EC) No 1901/2006 apply to this trial?

Analysis stage

Final

Date of interim/final analysis

07 Mar 2014

Is this the analysis of the primary completion data?

Global end of trial reached?

Yes

Global end of trial date

26 Jul 2013

Was the trial ended prematurely?

Main objective of the trial

The primary objective of this study is to evaluate the efficacy and safety of afatinib compared with cetuximab (Erbitux®) in patients with metastatic or recurrent head and neck cancer after failure of platinum-containing therapy. The primary endpoint is Tumor Shrinkage before cross-over (Stage 1) of the trial: maximum decrease in the sum of the longest diameters of the target lesions (according to RECIST) compared to baseline, with baseline defined as the sum of tumor measurement of the target lesion longest diameters measured before the patient start the first administration of the randomized treatment.

Protection of trial subjects

Only subjects who were considered eligible by investigators based on the protocol-specific inclusion and exclusion criteria were to be entered in the study. All subjects were free to withdraw from the clinical trial at any time for any reason given. Close monitoring of all subjects was adhered to throughout the trial conduct. For patients who experienced CTCAE (version 3.0) grade ≥3 drug-related adverse events (AEs) despite appropriate supportive care, or grade ≥2 AEs, a dose reduction scheme was followed after a treatment pause to allow the AE to decrease to CTCAE grade ≤1 (within a maximum of 14 days). Further dose reduction instructions related to diarrhea, nausea and vomiting, and rash, respectively were provided.

Background therapy

Evidence for comparator

Actual start date of recruitment

02 Oct 2007

Long term follow-up planned

Yes

Long term follow-up rationale

Efficacy

Long term follow-up duration

2 Years

Independent data monitoring committee (IDMC) involvement?

Number of subjects enrolled per country

Country: Number of subjects enrolled

Spain: 27

Country: Number of subjects enrolled

Belgium: 12

Country: Number of subjects enrolled

France: 43

Country: Number of subjects enrolled

United States: 64

Worldwide total number of subjects

146

EEA total number of subjects

Number of subjects enrolled per age group

In utero

Preterm newborn - gestational age < 37 wk

Newborns (0-27 days)

Infants and toddlers (28 days-23 months)

Children (2-11 years)

Adolescents (12-17 years)

Adults (18-64 years)

104

From 65 to 84 years

85 years and over

Subject disposition

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Recruitment details

Screening details

All subjects were screened for eligibility to the trial. Subjects attended specialist sites which would then ensure that they (the subjects) met all strict inclusion/exclusion criteria. Thus, out of 146 screened patients, 22 patients failed screening.

Period 1 title

Stage 1

Is this the baseline period?

Yes

Allocation method

Randomised - controlled

Blinding used

Not blinded

Are arms mutually exclusive

Yes

Afatinib 50 mg / Cetuximab 250mg/m2 - Stage 1

Arm 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 given the option to cross 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.

Arm type

Treatment sequence

Investigational medicinal product name

Afatinib

Investigational medicinal product code

Other name

Pharmaceutical forms

Film-coated tablet

Routes of administration

Oral use

Dosage and administration details

50 mg Once daily Oral as tablet or dispersion via gastric feeding tube

Cetuximab 250 mg/m2 / Afatinib 50 mg - Stage 1

Arm 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 given the option to cross over to Afatinib 50 mg once daily (q.d.) for Stage 2

Arm type

Treatment sequence

Investigational medicinal product name

Cetuximab (Erbitux®)

Investigational medicinal product code

Other name

Pharmaceutical forms

Solution for infusion

Routes of administration

Intravenous use

Dosage and administration details

400 mg/m2 in the first week given over 120 minutes; 250 mg/m2 weekly thereafter given over 60 minutes. Intravenous.

Number of subjects in period 1 ^[1]	Afatinib 50 mg / Cetuximab 250mg/m2 - Stage 1	Cetuximab 250 mg/m2 / Afatinib 50 mg - Stage 1
Started	62	62
Completed	32	36
Not completed	30	26
Adverse event, serious fatal	6	3
Adverse event, non-fatal	10	3
Other	1	7
Patient refused to continue study meds	8	3
Progressive disease	4	8
Not treated	1	2

Notes
[1] - The number of subjects reported to be in the baseline period are not the same as the worldwide number enrolled in the trial. It is expected that these numbers will be the same.
Justification: Baseline characteristics are based on patients who were randomised after successfully completing the screening period and received at least one of the trial medication. Twenty-two patients were not entered and three were not treated.

Period 2 title

Stage 2

Is this the baseline period?

Allocation method

Randomised - controlled

Blinding used

Not blinded

Are arms mutually exclusive

Yes

Afatinib 50 mg / Cetuximab 250mg/m2 - Stage 2

Arm 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.

Arm type

Treatment sequence

Investigational medicinal product name

Cetuximab (Erbitux®)

Investigational medicinal product code

Other name

Pharmaceutical forms

Film-coated tablet

Routes of administration

Oral use

Dosage and administration details

50 mg Once daily Oral as tablet or dispersion via gastric feeding tube

Cetuximab 250 mg/m2 / Afatinib 50 mg - Stage 2

Arm 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

Arm type

Treatment sequence

Investigational medicinal product name

Afatinib

Investigational medicinal product code

Other name

Pharmaceutical forms

Solution for infusion

Routes of administration

Intravenous use

Dosage and administration details

400 mg/m2 in the first week given over 120 minutes; 250 mg/m2 weekly thereafter given over 60 minutes. Intravenous.

Number of subjects in period 2	Afatinib 50 mg / Cetuximab 250mg/m2 - Stage 2	Cetuximab 250 mg/m2 / Afatinib 50 mg - Stage 2
Started	32	36
Completed	0	0
Not completed	32	36
Adverse event, serious fatal	1	5
Adverse event, non-fatal	2	5
'Refused to continue medication '	2	-
Progressive disease	27	24
'Reasons other than already stated '	-	2

Baseline characteristics

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Reporting group title

Afatinib 50 mg / Cetuximab 250mg/m2 - Stage 1

Reporting group description

Reporting group title

Cetuximab 250 mg/m2 / Afatinib 50 mg - Stage 1

Reporting group description

Reporting group values	Afatinib 50 mg / Cetuximab 250mg/m2 - Stage 1	Cetuximab 250 mg/m2 / Afatinib 50 mg - Stage 1	Total
Number of subjects	62	62	124
Age categorical
Units: Subjects
Adults (18-64 years)	45	46	91
From 65-84 years	17	16	33
85 years and over	0	0	0
Age continuous
Units: years
arithmetic mean (standard deviation)	57.9 ± 9.4	58.8 ± 8.7	-
Gender categorical
Units: Subjects
Female	7	10	17
Male	55	52	107
Prior chemotherapies (CT)for recurrent/metastatic disease (R/M)
Units: Subjects
Yes	42	41	83
No	20	21	41
Baseline sum of longest diameters (SLD) of target lesions by investigator assessments
Baseline measures were available for only 61 patients in the Afatinib/Cetuximab group and only 60 patients in the Cetuximab/Afatinib group
Units: millimeter(s)
arithmetic mean (standard deviation)	71.4 ± 44.6	65.4 ± 44.2	-

End points

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Reporting group title

Afatinib 50 mg / Cetuximab 250mg/m2 - Stage 1

Reporting group description

Reporting group title

Cetuximab 250 mg/m2 / Afatinib 50 mg - Stage 1

Reporting group description

Reporting group title

Afatinib 50 mg / Cetuximab 250mg/m2 - Stage 2

Reporting group description

Reporting group title

Cetuximab 250 mg/m2 / Afatinib 50 mg - Stage 2

Reporting 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

Subject analysis set title

Afatinib 40 mg - Stage 1

Subject analysis set type

Sub-group analysis

Subject analysis set 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. This is not a defined treatment group, this is for patients who required dose reduction in Afatinib. This group is only applicable for the pharmaco-kinetic endpoints.

Primary: Tumor Shrinkage Before Crossover (Stage 1) of the Trial as Per Investigator Assessment

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End point title

Tumor Shrinkage Before Crossover (Stage 1) of the Trial as Per Investigator Assessment

End point 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 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. 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.

End point type

Primary

End point timeframe

From randomization until start of Stage 2 treatment, or within 28 days after the termination of Stage 1. Evaluations were done for stage 1 after 2 cycles (8 weeks) then every 8 weeks thereafter.

End point values	Afatinib 50 mg / Cetuximab 250mg/m2 - Stage 1	Cetuximab 250 mg/m2 / Afatinib 50 mg - Stage 1
Number of subjects analysed	50 ^[1]	55 ^[2]
Units: millimeter(s)
least squares mean (standard error)	-3.86 ± 3.62	-2.37 ± 3.47

Notes
[1] - RS
[2] - RS

Tumor Shrinkage Before Crossover (Stage 1)

Statistical analysis description

Statistical Analysis for Tumor Shrinkage Before Crossover (Stage 1) of the Trial as Per Investigator Assessment. Receipt of prior chemotherapy for recurrent/metastatic disease and the baseline sum of longest distance for target lesions are covariates. Mean difference calculated is the adjusted mean difference (Afatinib - Cetuximab).

Comparison groups

Cetuximab 250 mg/m2 / Afatinib 50 mg - Stage 1 v Afatinib 50 mg / Cetuximab 250mg/m2 - Stage 1

Number of subjects included in analysis

105

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.7606 ^[3]

Method

ANCOVA

Parameter type

Mean difference (net)

Point estimate

-1.49

Confidence interval

level

95%

sides

2-sided

lower limit

-11.188

upper limit

8.202

Notes
[3] - 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.

Secondary: Tumor Shrinkage After Crossover (Stage 2) as Per Investigator Assessments

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End point title

Tumor Shrinkage After Crossover (Stage 2) as Per Investigator Assessments

End point 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. Patients treated in stage 2: This analysis set included all patients who received treatment: 32 pateints in the cetuximab arm and 36 patients in the afatinib.

End point type

Secondary

End point timeframe

From baseline assessed prior to first dose of Stage 2 study medication to 28 days after termination of Stage 2 treatment. For stage 2 first assessment was done 28 days (4 weeks) after treatment then every 8 weeks thereafter.

End point values	Afatinib 50 mg / Cetuximab 250mg/m2 - Stage 2	Cetuximab 250 mg/m2 / Afatinib 50 mg - Stage 2
Number of subjects analysed	27 ^[4]	29 ^[5]
Units: millimeter(s)
arithmetic mean (standard deviation)	16 ± 30	2 ± 15

Notes
[4] - Patients treated in stage 2
[5] - Patients treated in stage 2

No statistical analyses for this end point

Secondary: 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).

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End point 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).

End point 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.

End point type

Secondary

End point timeframe

Response determined from randomization until patient started Stage 2 or within 28 days after termination of Stage 1 treatment. Evaluations were done for stage 1 after 2 cycles (8 weeks) then every 8 weeks thereafter.

End point values	Afatinib 50 mg / Cetuximab 250mg/m2 - Stage 1	Cetuximab 250 mg/m2 / Afatinib 50 mg - Stage 1
Number of subjects analysed	62 ^[6]	62 ^[7]
Units: 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

Notes
[6] - RS
[7] - RS

No statistical analyses for this end point

Secondary: Best RECIST Assessment as Per ICR for Stage 1 (as Confirmed Disease Control (Clinical Benefit) and Objective Response Are Simply Categories of RECIST Assessment)

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End point 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)

End point 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.

End point type

Secondary

End point timeframe

End point values	Afatinib 50 mg / Cetuximab 250mg/m2 - Stage 1	Cetuximab 250 mg/m2 / Afatinib 50 mg - Stage 1
Number of subjects analysed	62 ^[8]	62 ^[9]
Units: 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

Notes
[8] - RS
[9] - RS

No statistical analyses for this end point

Secondary: Best RECIST Assessment as Per Investigator Assessment for Stage 2 (as Confirmed Disease Control (Clinical Benefit) and Objective Response Are Simply Categories of RECIST Assessment)

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End point title

Best RECIST Assessment as Per Investigator Assessment for Stage 2 (as Confirmed Disease Control (Clinical Benefit) and Objective Response Are Simply Categories of RECIST Assessment)

End point description

End point type

Secondary

End point timeframe

Response determined during Stage 2 or within 28 days after termination of Stage 2 treatment. For stage 2 first assessment was done 28 days (4 weeks) after treatment then every 8 weeks thereafter.

End point values	Afatinib 50 mg / Cetuximab 250mg/m2 - Stage 2	Cetuximab 250 mg/m2 / Afatinib 50 mg - Stage 2
Number of subjects analysed	32 ^[10]	36 ^[11]
Units: Number of participants
Disease control (CR, PR, SD)	6	14
Objective response (CR,PR)	2	1
Complete response (CR)	0	1
Partial response (PR)	2	0
Stable disease (SD)	4	13
Progressive disease (PD)	20	16
Not evaluable	4	1
Missing	2	5

Notes
[10] - Patients treated in stage 2
[11] - Patients treated in stage 2

No statistical analyses for this end point

Secondary: Best RECIST Assessment as Per ICR for Stage2 (as Confirmed Disease Control (Clinical Benefit) and Objective Response Are Simply Categories of RECIST Assessment)

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End point title

Best RECIST Assessment as Per ICR for Stage2 (as Confirmed Disease Control (Clinical Benefit) and Objective Response Are Simply Categories of RECIST Assessment)

End point description

End point type

Secondary

End point timeframe

Response determined during Stage 2 or within 28 days after termination of Stage 2 treatment. For stage 2 first assessment was done 28 days (4 weeks) after treatment then every 8 weeks thereafter.

End point values	Afatinib 50 mg / Cetuximab 250mg/m2 - Stage 2	Cetuximab 250 mg/m2 / Afatinib 50 mg - Stage 2
Number of subjects analysed	32 ^[12]	36 ^[13]
Units: Number of participants
Disease control (CR, PR, SD)	6	12
Objective response	0	0
Complete response (CR)	0	0
Partial response (PR)	0	0
Stable disease (SD)	6	12
Progressive disease (PD)	21	18
Not evaluable	4	1
Missing	1	5

Notes
[12] - Patients treated in stage 2
[13] - Patients treated in stage 2

No statistical analyses for this end point

Secondary: Best RECIST Assessment as Onset of Confirmed Objective Response as Per Investigator Assessment for Stage 1

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End point title

Best RECIST Assessment as Onset of Confirmed Objective Response as Per Investigator Assessment for Stage 1

End point description

Best RECIST Assessment as onset of confirmed objective response as per Investigator assessment for Stage 1.

End point type

Secondary

End point timeframe

End point values	Afatinib 50 mg / Cetuximab 250mg/m2 - Stage 1	Cetuximab 250 mg/m2 / Afatinib 50 mg - Stage 1
Number of subjects analysed	10 ^[14]	4 ^[15]
Units: 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

Notes
[14] - RS
[15] - RS

No statistical analyses for this end point

Secondary: Best RECIST Assessment as Onset of Confirmed Objective Response as Per ICR for Stage 1

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End point title

Best RECIST Assessment as Onset of Confirmed Objective Response as Per ICR for Stage 1

End point description

Best RECIST Assessment as onset of confirmed objective response as per the independent central review (ICR) according to the RECIST 1.0 criteria.

End point type

Secondary

End point timeframe

End point values	Afatinib 50 mg / Cetuximab 250mg/m2 - Stage 1	Cetuximab 250 mg/m2 / Afatinib 50 mg - Stage 1
Number of subjects analysed	5 ^[16]	6 ^[17]
Units: 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

Notes
[16] - RS
[17] - RS

No statistical analyses for this end point

Secondary: Best RECIST Assessment as Onset of Confirmed Objective Response as Per Investigator Assessment for Stage 2

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End point title

Best RECIST Assessment as Onset of Confirmed Objective Response as Per Investigator Assessment for Stage 2

End point description

Best RECIST Assessment as onset of confirmed objective response as per Investigator assessment according to the RECIST 1.0 criteria.

End point type

Secondary

End point timeframe

Response determined during Stage 2 or within 28 days after termination of Stage 2 treatment (Week 2, 4 and 12). For stage 2 first assessment was done 28 days (4 weeks) after treatment then every 8 weeks thereafter.

End point values	Afatinib 50 mg / Cetuximab 250mg/m2 - Stage 2	Cetuximab 250 mg/m2 / Afatinib 50 mg - Stage 2
Number of subjects analysed	2 ^[18]	1 ^[19]
Units: Number of participants
Week 2 (Day 1 − 14)	0	0
Week 4 (Day 15 − 56)	1	1
Week 12 (Day 57 − 112)	1	0

Notes
[18] - Patients treated in stage 2
[19] - Patients treated in stage 2

No statistical analyses for this end point

Secondary: Best RECIST Assessment as Confirmed Duration of Objective Response and Disease Control as Per Investigator Assessment for Stage 1

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End point title

Best RECIST Assessment as Confirmed Duration of Objective Response and Disease Control as Per Investigator Assessment for Stage 1

End point description

Best RECIST Assessment as duration of confirmed objective response and disease control as per Investigator assessment according to the RECIST 1.0 criteria.

End point type

Secondary

End point timeframe

End point values	Afatinib 50 mg / Cetuximab 250mg/m2 - Stage 1	Cetuximab 250 mg/m2 / Afatinib 50 mg - Stage 1
Number of subjects analysed	62 ^[20]	62 ^[21]
Units: Weeks
arithmetic mean (standard deviation)
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

Notes
[20] - RS
[21] - RS

No statistical analyses for this end point

Secondary: Best RECIST Assessment as Confirmed Duration of Confirmed Objective Response and Disease Control as Per ICR for Stage 1

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End point title

Best RECIST Assessment as Confirmed Duration of Confirmed Objective Response and Disease Control as Per ICR for Stage 1

End point 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.

End point type

Secondary

End point timeframe

End point values	Afatinib 50 mg / Cetuximab 250mg/m2 - Stage 1	Cetuximab 250 mg/m2 / Afatinib 50 mg - Stage 1
Number of subjects analysed	62	62
Units: Weeks
arithmetic mean (standard deviation)
Duration of objective response (N=5; N=6)	28 ± 12.6	55.1 ± 76.6
Duration of disease control(N=29; N=30)	22.8 ± 11	28.8 ± 38.1

No statistical analyses for this end point

Secondary: Best RECIST Assessment as Confirmed Duration of Objective Response and Disease Control as Per Investigator Assessment for Stage 2

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End point title

Best RECIST Assessment as Confirmed Duration of Objective Response and Disease Control as Per Investigator Assessment for Stage 2

End point description

Best RECIST Assessment as confirmed duration of objective response and disease control as per Investigator assessment according to the RECIST 1.0 criteria.

End point type

Secondary

End point timeframe

Response determined during Stage 2 or within 28 days after termination of Stage 2 treatment. For stage 2 first assessment was done 28 days (4 weeks) after treatment then every 8 weeks thereafter.

End point values	Afatinib 50 mg / Cetuximab 250mg/m2 - Stage 2	Cetuximab 250 mg/m2 / Afatinib 50 mg - Stage 2
Number of subjects analysed	32 ^[22]	36 ^[23]
Units: Weeks
arithmetic mean (standard deviation)
Duration of objective response (N=1; N=2)	19.4 ± 21.1	24.7 ± 0
Duration of disease control(N=14; N=6)	21.5 ± 12.3	21.8 ± 6.1

Notes
[22] - Patients treated in stage 2
[23] - Patients treated in stage 2

No statistical analyses for this end point

Secondary: Best RECIST Assessment as Confirmed Duration of Disease Control as Per ICR for Stage 2

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End point title

Best RECIST Assessment as Confirmed Duration of Disease Control as Per ICR for Stage 2

End point 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.

End point type

Secondary

End point timeframe

Response determined during Stage 2 or within 28 days after termination of Stage 2 treatment. For stage 2 first assessment was done 28 days (4 weeks) after treatment then every 8 weeks thereafter.

End point values	Afatinib 50 mg / Cetuximab 250mg/m2 - Stage 2	Cetuximab 250 mg/m2 / Afatinib 50 mg - Stage 2
Number of subjects analysed	32 ^[24]	36 ^[25]
Units: Weeks
arithmetic mean (standard deviation)	18.4 ± 10	17.4 ± 5

Notes
[24] - Patients treated in stage 2
[25] - Patients treated in stage 2

No statistical analyses for this end point

Secondary: Progression Free Survival (PFS) Before Crossover Based on Investigator Assessment

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End point title

Progression Free Survival (PFS) Before Crossover Based on Investigator Assessment

End point 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.

End point type

Secondary

End point timeframe

From randomisation to disease progression in Stage 1 or death whichever occurred first before crossover . Evaluations were done for stage 1 after 2 cycles (8 weeks) then every 8 weeks thereafter.

End point values	Afatinib 50 mg / Cetuximab 250mg/m2 - Stage 1	Cetuximab 250 mg/m2 / Afatinib 50 mg - Stage 1
Number of subjects analysed	62 ^[26]	62 ^[27]
Units: Weeks
median (confidence interval 95%)	15.86 (10.29 to 17.14)	15.14 (8.29 to 19.29)

Notes
[26] - RS
[27] - RS

PFS Before Crossover Based on IA

Statistical analysis description

Progression Free Survival (PFS) Before Crossover Based on Investigator Assessment (IA). 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)

Comparison groups

Afatinib 50 mg / Cetuximab 250mg/m2 - Stage 1 v Cetuximab 250 mg/m2 / Afatinib 50 mg - Stage 1

Number of subjects included in analysis

124

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.764

Method

Regression, Cox

Parameter type

Hazard ratio (HR)

Point estimate

0.942

Confidence interval

level

95%

sides

2-sided

lower limit

0.64

upper limit

1.387

Secondary: Progression Free Survival (PFS) After Crossover Based on Investigator Assessment

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End point title

Progression Free Survival (PFS) After Crossover Based on Investigator Assessment

End point 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.

End point type

Secondary

End point timeframe

From first administration of study medication after cross over to disease progression in Stage 2 or death whichever came first after crossover. For stage 2 first assessment was done 28 days (4 weeks) after treatment then every 8 weeks thereafter.

End point values	Afatinib 50 mg / Cetuximab 250mg/m2 - Stage 2	Cetuximab 250 mg/m2 / Afatinib 50 mg - Stage 2
Number of subjects analysed	32 ^[28]	36 ^[29]
Units: Weeks
median (confidence interval 95%)	6.43 (4.14 to 8.29)	7.93 (4.29 to 14.43)

Notes
[28] - Patients treated in stage 2
[29] - Patients treated in stage 2

PFS After Crossover Based on IA

Statistical analysis description

Progression Free Survival (PFS) After Crossover Based on Investigator Assessment (IA). 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)

Comparison groups

Afatinib 50 mg / Cetuximab 250mg/m2 - Stage 2 v Cetuximab 250 mg/m2 / Afatinib 50 mg - Stage 2

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.219

Method

Regression, Cox

Parameter type

Hazard ratio (HR)

Point estimate

0.725

Confidence interval

level

95%

sides

2-sided

lower limit

0.434

upper limit

1.212

Secondary: Overall Survival (OS)

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End point title

Overall Survival (OS)

End point description

OS is defined as time from randomisation to death. Median is calculated from the Kaplan−Meier curve for each treatment group.

End point type

Secondary

End point timeframe

From randomisation to data cut-off date (07-MAR-2014).

End point values	Afatinib 50 mg / Cetuximab 250mg/m2 - Stage 1	Cetuximab 250 mg/m2 / Afatinib 50 mg - Stage 1
Number of subjects analysed	62	62
Units: Weeks
median (confidence interval 95%)	35.86 (25.71 to 45)	47.14 (24.14 to 64.17)

Overall Survival (OS)

Statistical analysis description

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)

Comparison groups

Cetuximab 250 mg/m2 / Afatinib 50 mg - Stage 1 v Afatinib 50 mg / Cetuximab 250mg/m2 - Stage 1

Number of subjects included in analysis

124

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.758

Method

Regression, Cox

Parameter type

Hazard ratio (HR)

Point estimate

1.067

Confidence interval

level

95%

sides

2-sided

lower limit

0.708

upper limit

1.608

Secondary: Time to Deterioration in HRQoL - Stage 1

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End point title

Time to Deterioration in HRQoL - Stage 1

End point 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 QLQC30) 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)

End point type

Secondary

End point timeframe

From randomisation to deterioration in HRQoL scores before crossover. Evaluations were done for stage 1 after 2 cycles (8 weeks) then every 8 weeks thereafter.

End point values	Afatinib 50 mg / Cetuximab 250mg/m2 - Stage 1	Cetuximab 250 mg/m2 / Afatinib 50 mg - Stage 1
Number of subjects analysed	62 ^[30]	62 ^[31]
Units: Months
median (confidence interval 95%)
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)	6.6 (2.92 to 8.48)

Notes
[30] - RS
[31] - RS

No statistical analyses for this end point

Secondary: Patients With AEs Resulting in Diarrhea, Skin Rash, Dose Reduction, Treatement Discontinuation and Decreased Cardiac Left Ventricular Function

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End point title

Patients With AEs Resulting in Diarrhea, Skin Rash, Dose Reduction, Treatement Discontinuation and Decreased Cardiac Left Ventricular Function

End point description

Patients with adverse events (AEs) resulting in Diarrhea, Skin Rash, dose reduction, treatment discontinuation and decreased cardiac left ventricular function. Treated set in stage 1 (TS stage 1): This analysis set included the randomized patients who took at least 1 dose of the ramdomized treatment (61 afatinib and 60 cetuximab patients). Treated set in stage 2 (TS stage 2): This analysis set included all patients who received treatment in stage 2 (36 patients in the afatinib and 32 patients in the cetuximab arm). 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.

End point type

Secondary

End point timeframe

First administration of trial medication until 28 days after last drug administration.

End point values	Afatinib 50 mg / Cetuximab 250mg/m2 - Stage 1	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
Number of subjects analysed	61 ^[32]	60 ^[33]	32 ^[34]	36 ^[35]
Units: Number of participants
With AE leading to Diarrhea	49	15	2	22
With AE leading to skin rash	48	46	14	23
With AE leading to dose reduction	18	2	0	11
With AE leading to treatement discontinuation	23	11	6	8

Notes
[32] - TS stage 1
[33] - TS stage 1
[34] - TS stage 2
[35] - TS stage 2

No statistical analyses for this end point

Secondary: Incidence and Intensity of Adverse Events With Grading According CTCAE

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End point title

Incidence and Intensity of Adverse Events With Grading According CTCAE

End point description

Incidence and intensity of Adverse Events with grading according to the Common Terminology Criteria for Adverse Events (CTCAE version 3.0).

End point type

Secondary

End point timeframe

First administration of trial medication until 28 days after last drug administration

End point values	Afatinib 50 mg / Cetuximab 250mg/m2 - Stage 1	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
Number of subjects analysed	61 ^[36]	60 ^[37]	32 ^[38]	36 ^[39]
Units: Percentage of participants
number (not applicable)
CTCAE grade 1	3.3	5	9.4	5.6
CTCAE grade 2	24.6	41.7	37.5	25
CTCAE grade 3	39.3	28.3	25	25
CTCAE grade 4	8.2	6.7	9.4	13.9
CTCAE grade 5	24.6	16.7	15.6	30.6

Notes
[36] - TS stage 1
[37] - TS stage 1
[38] - TS stage 2
[39] - TS stage 2

No statistical analyses for this end point

Secondary: 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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End point title

Pre-dose Concentration of Afatinib in Plasma for Dose 40mg and 50mg at Steady State on Day 15 (Cpre,ss,15) ^[40]

End point description

Cpre,ss,15 represents the pre-dose concentration of afatinib in plasma at steady state on day 15. 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. Note: At day 15, values for Afitanib 40 mg no values reported in stage 1 and stage 2.

End point type

Secondary

End point timeframe

Day 15

Notes
[40] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: Only those arms for which the comparisons are presented in the clinical trial report thus, those that would yield meaningful results were reported.

End point values	Afatinib 50 mg / Cetuximab 250mg/m2 - Stage 1	Cetuximab 250 mg/m2 / Afatinib 50 mg - Stage 2
Number of subjects analysed	45 ^[41]	26 ^[42]
Units: ng/mL
geometric mean (geometric coefficient of variation)	39.3 ± 70.1	46.6 ± 81.4

Notes
[41] - PKS from stage 1
[42] - PKS from stage 2

No statistical analyses for this end point

Secondary: 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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End point title

Pre-dose Concentration of Afatinib in Plasma for Dose 40mg and 50mg at Steady State on Day 29 (Cpre,ss,29) ^[43]

End point description

Cpre,ss,29 represents the pre-dose concentration of afatinib in plasma at steady state on day 29. Note: At day 29, values for Afitanib 40 mg no values reported in stage 2.

End point type

Secondary

End point timeframe

Day 29

Notes
[43] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: Only those arms for which the comparisons are presented in the clinical trial report thus, those that would yield meaningful results were reported.

End point values	Afatinib 50 mg / Cetuximab 250mg/m2 - Stage 1	Cetuximab 250 mg/m2 / Afatinib 50 mg - Stage 2	Afatinib 40 mg - Stage 1
Number of subjects analysed	33 ^[44]	22 ^[45]	9 ^[46]
Units: ng/mL
geometric mean (geometric coefficient of variation)	31.7 ± 97.7	45.9 ± 48.9	8.84 ± 206

Notes
[44] - PK set
[45] - PK set
[46] - PK set

No statistical analyses for this end point

Secondary: Pre-dose Concentration of Afatinib in Plasma for Dose 40mg and 50mg at Steady State on Day 57 (Cpre,ss, 57)

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End point title

Pre-dose Concentration of Afatinib in Plasma for Dose 40mg and 50mg at Steady State on Day 57 (Cpre,ss, 57) ^[47]

End point description

Cpre,ss,57 represents the pre-dose concentration of afatinib in plasma at steady state on day 57.

End point type

Secondary

End point timeframe

Day 57

Notes
[47] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: Only those arms for which the comparisons are presented in the clinical trial report thus, those that would yield meaningful results were reported.

End point values	Afatinib 50 mg / Cetuximab 250mg/m2 - Stage 1	Cetuximab 250 mg/m2 / Afatinib 50 mg - Stage 2	Afatinib 40 mg - Stage 1
Number of subjects analysed	16 ^[48]	10 ^[49]	7 ^[50]
Units: ng/mL
geometric mean (geometric coefficient of variation)	19.9 ± 94.4	46.5 ± 67.2	32.7 ± 25.3

Notes
[48] - PK set
[49] - PK set
[50] - PK set

No statistical analyses for this end point

Adverse events

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Timeframe for reporting adverse events

First administration of trial medication until 28 days after last administration of trial medication, up to 1493 days

Adverse event reporting additional description

AE additional description

Assessment type

Systematic

Dictionary name

MedDRA

Dictionary version

16.1

Reporting group title

Afatinib 50 mg / Cetuximab 250mg/m2 - Stage 1

Reporting group description

Reporting group title

Cetuximab 250 mg/m2 / Afatinib 50 mg - Stage 1

Reporting 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

Reporting group title

Cetuximab 250 mg/m2 / Afatinib 50 mg - Stage 2

Reporting 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

Reporting group title

Afatinib 50 mg / Cetuximab 250mg/m2 - Stage 2

Reporting group description

Serious adverse events	Afatinib 50 mg / Cetuximab 250mg/m2 - Stage 1	Cetuximab 250 mg/m2 / Afatinib 50 mg - Stage 1	Cetuximab 250 mg/m2 / Afatinib 50 mg - Stage 2	Afatinib 50 mg / Cetuximab 250mg/m2 - Stage 2
Total subjects affected by serious adverse events
subjects affected / exposed	36 / 61 (59.02%)	26 / 60 (43.33%)	18 / 36 (50.00%)	13 / 32 (40.63%)
number of deaths (all causes)	21	19	31	29
number of deaths resulting from adverse events	1	0	0	0
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Infected neoplasm
subjects affected / exposed	0 / 61 (0.00%)	1 / 60 (1.67%)	0 / 36 (0.00%)	0 / 32 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Linitis plastica
subjects affected / exposed	1 / 61 (1.64%)	0 / 60 (0.00%)	0 / 36 (0.00%)	0 / 32 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Malignant neoplasm progression
subjects affected / exposed	0 / 61 (0.00%)	0 / 60 (0.00%)	1 / 36 (2.78%)	1 / 32 (3.13%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 1
Metastases to central nervous system
subjects affected / exposed	0 / 61 (0.00%)	1 / 60 (1.67%)	0 / 36 (0.00%)	0 / 32 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Metastatic pain
subjects affected / exposed	0 / 61 (0.00%)	0 / 60 (0.00%)	1 / 36 (2.78%)	0 / 32 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Tongue neoplasm malignant stage unspecified
subjects affected / exposed	0 / 61 (0.00%)	1 / 60 (1.67%)	0 / 36 (0.00%)	0 / 32 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0
Tumour compression
subjects affected / exposed	1 / 61 (1.64%)	0 / 60 (0.00%)	0 / 36 (0.00%)	0 / 32 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Tumour haemorrhage
subjects affected / exposed	1 / 61 (1.64%)	1 / 60 (1.67%)	1 / 36 (2.78%)	1 / 32 (3.13%)
occurrences causally related to treatment / all	0 / 1	0 / 1	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0
Tumour pain
subjects affected / exposed	0 / 61 (0.00%)	1 / 60 (1.67%)	0 / 36 (0.00%)	0 / 32 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Vascular disorders
Haemorrhage
subjects affected / exposed	0 / 61 (0.00%)	0 / 60 (0.00%)	2 / 36 (5.56%)	0 / 32 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 2	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0
Hypotension
subjects affected / exposed	2 / 61 (3.28%)	0 / 60 (0.00%)	0 / 36 (0.00%)	0 / 32 (0.00%)
occurrences causally related to treatment / all	1 / 2	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Surgical and medical procedures
Gastrointestinal tube insertion
subjects affected / exposed	0 / 61 (0.00%)	0 / 60 (0.00%)	0 / 36 (0.00%)	1 / 32 (3.13%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
General disorders and administration site conditions
Asthenia
subjects affected / exposed	2 / 61 (3.28%)	0 / 60 (0.00%)	1 / 36 (2.78%)	0 / 32 (0.00%)
occurrences causally related to treatment / all	2 / 2	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Chest pain
subjects affected / exposed	0 / 61 (0.00%)	1 / 60 (1.67%)	0 / 36 (0.00%)	0 / 32 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Chills
subjects affected / exposed	0 / 61 (0.00%)	1 / 60 (1.67%)	0 / 36 (0.00%)	0 / 32 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Face oedema
subjects affected / exposed	0 / 61 (0.00%)	1 / 60 (1.67%)	0 / 36 (0.00%)	0 / 32 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
General physical health deterioration
subjects affected / exposed	6 / 61 (9.84%)	3 / 60 (5.00%)	6 / 36 (16.67%)	3 / 32 (9.38%)
occurrences causally related to treatment / all	3 / 7	0 / 3	0 / 6	0 / 3
deaths causally related to treatment / all	0 / 4	0 / 3	0 / 5	0 / 3
Mucosal inflammation
subjects affected / exposed	2 / 61 (3.28%)	0 / 60 (0.00%)	0 / 36 (0.00%)	0 / 32 (0.00%)
occurrences causally related to treatment / all	2 / 2	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Oedema peripheral
subjects affected / exposed	0 / 61 (0.00%)	0 / 60 (0.00%)	0 / 36 (0.00%)	1 / 32 (3.13%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Pain
subjects affected / exposed	0 / 61 (0.00%)	0 / 60 (0.00%)	2 / 36 (5.56%)	0 / 32 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 2	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Pyrexia
subjects affected / exposed	2 / 61 (3.28%)	1 / 60 (1.67%)	0 / 36 (0.00%)	0 / 32 (0.00%)
occurrences causally related to treatment / all	1 / 2	1 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	1 / 1	0 / 0	0 / 0	0 / 0
Immune system disorders
Hypersensitivity
subjects affected / exposed	0 / 61 (0.00%)	1 / 60 (1.67%)	0 / 36 (0.00%)	0 / 32 (0.00%)
occurrences causally related to treatment / all	0 / 0	1 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Respiratory, thoracic and mediastinal disorders
Acute respiratory distress syndrome
subjects affected / exposed	0 / 61 (0.00%)	1 / 60 (1.67%)	0 / 36 (0.00%)	0 / 32 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Asphyxia
subjects affected / exposed	0 / 61 (0.00%)	1 / 60 (1.67%)	0 / 36 (0.00%)	0 / 32 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Aspiration
subjects affected / exposed	0 / 61 (0.00%)	0 / 60 (0.00%)	1 / 36 (2.78%)	0 / 32 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Cough
subjects affected / exposed	0 / 61 (0.00%)	0 / 60 (0.00%)	0 / 36 (0.00%)	1 / 32 (3.13%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Dyspnoea
subjects affected / exposed	4 / 61 (6.56%)	3 / 60 (5.00%)	1 / 36 (2.78%)	2 / 32 (6.25%)
occurrences causally related to treatment / all	0 / 4	0 / 3	0 / 1	0 / 2
deaths causally related to treatment / all	0 / 1	0 / 1	0 / 0	0 / 0
Haemoptysis
subjects affected / exposed	0 / 61 (0.00%)	1 / 60 (1.67%)	0 / 36 (0.00%)	0 / 32 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Hypoxia
subjects affected / exposed	0 / 61 (0.00%)	0 / 60 (0.00%)	0 / 36 (0.00%)	1 / 32 (3.13%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Interstitial lung disease
subjects affected / exposed	1 / 61 (1.64%)	0 / 60 (0.00%)	0 / 36 (0.00%)	0 / 32 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Obstructive airways disorder
subjects affected / exposed	0 / 61 (0.00%)	0 / 60 (0.00%)	0 / 36 (0.00%)	1 / 32 (3.13%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Pleural effusion
subjects affected / exposed	1 / 61 (1.64%)	0 / 60 (0.00%)	1 / 36 (2.78%)	1 / 32 (3.13%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Pneumonia aspiration
subjects affected / exposed	2 / 61 (3.28%)	1 / 60 (1.67%)	2 / 36 (5.56%)	0 / 32 (0.00%)
occurrences causally related to treatment / all	0 / 2	0 / 1	0 / 2	0 / 0
deaths causally related to treatment / all	0 / 1	0 / 0	0 / 1	0 / 0
Productive cough
subjects affected / exposed	0 / 61 (0.00%)	1 / 60 (1.67%)	0 / 36 (0.00%)	0 / 32 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Pulmonary embolism
subjects affected / exposed	1 / 61 (1.64%)	0 / 60 (0.00%)	0 / 36 (0.00%)	0 / 32 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Respiratory distress
subjects affected / exposed	0 / 61 (0.00%)	0 / 60 (0.00%)	1 / 36 (2.78%)	0 / 32 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0
Respiratory failure
subjects affected / exposed	2 / 61 (3.28%)	0 / 60 (0.00%)	1 / 36 (2.78%)	0 / 32 (0.00%)
occurrences causally related to treatment / all	0 / 2	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 2	0 / 0	0 / 0	0 / 0
Psychiatric disorders
Alcohol abuse
subjects affected / exposed	0 / 61 (0.00%)	1 / 60 (1.67%)	0 / 36 (0.00%)	0 / 32 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Anxiety
subjects affected / exposed	0 / 61 (0.00%)	1 / 60 (1.67%)	0 / 36 (0.00%)	0 / 32 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Confusional state
subjects affected / exposed	1 / 61 (1.64%)	0 / 60 (0.00%)	0 / 36 (0.00%)	0 / 32 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Disorientation
subjects affected / exposed	0 / 61 (0.00%)	1 / 60 (1.67%)	0 / 36 (0.00%)	0 / 32 (0.00%)
occurrences causally related to treatment / all	0 / 0	1 / 2	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Hallucination, auditory
subjects affected / exposed	1 / 61 (1.64%)	0 / 60 (0.00%)	0 / 36 (0.00%)	0 / 32 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Investigations
Weight decreased
subjects affected / exposed	1 / 61 (1.64%)	0 / 60 (0.00%)	0 / 36 (0.00%)	0 / 32 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Injury, poisoning and procedural complications
Infusion related reaction
subjects affected / exposed	0 / 61 (0.00%)	1 / 60 (1.67%)	0 / 36 (0.00%)	0 / 32 (0.00%)
occurrences causally related to treatment / all	0 / 0	1 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Overdose
subjects affected / exposed	0 / 61 (0.00%)	1 / 60 (1.67%)	0 / 36 (0.00%)	0 / 32 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Post procedural haemorrhage
subjects affected / exposed	1 / 61 (1.64%)	0 / 60 (0.00%)	1 / 36 (2.78%)	0 / 32 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Wound haemorrhage
subjects affected / exposed	0 / 61 (0.00%)	0 / 60 (0.00%)	1 / 36 (2.78%)	0 / 32 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Cardiac disorders
Angina pectoris
subjects affected / exposed	1 / 61 (1.64%)	0 / 60 (0.00%)	0 / 36 (0.00%)	0 / 32 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Cardiac arrest
subjects affected / exposed	1 / 61 (1.64%)	1 / 60 (1.67%)	0 / 36 (0.00%)	0 / 32 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 1	0 / 1	0 / 0	0 / 0
Cardio-respiratory arrest
subjects affected / exposed	0 / 61 (0.00%)	0 / 60 (0.00%)	1 / 36 (2.78%)	0 / 32 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0
Cardiopulmonary failure
subjects affected / exposed	2 / 61 (3.28%)	1 / 60 (1.67%)	0 / 36 (0.00%)	0 / 32 (0.00%)
occurrences causally related to treatment / all	1 / 2	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 1	0 / 1	0 / 0	0 / 0
Endocarditis noninfective
subjects affected / exposed	0 / 61 (0.00%)	1 / 60 (1.67%)	0 / 36 (0.00%)	0 / 32 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Myocardial infarction
subjects affected / exposed	1 / 61 (1.64%)	1 / 60 (1.67%)	0 / 36 (0.00%)	0 / 32 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0
Pericardial effusion
subjects affected / exposed	0 / 61 (0.00%)	1 / 60 (1.67%)	0 / 36 (0.00%)	0 / 32 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Pericarditis
subjects affected / exposed	0 / 61 (0.00%)	1 / 60 (1.67%)	0 / 36 (0.00%)	0 / 32 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Sinus bradycardia
subjects affected / exposed	1 / 61 (1.64%)	0 / 60 (0.00%)	0 / 36 (0.00%)	0 / 32 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Nervous system disorders
Brain oedema
subjects affected / exposed	0 / 61 (0.00%)	0 / 60 (0.00%)	0 / 36 (0.00%)	1 / 32 (3.13%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Cerebrovascular accident
subjects affected / exposed	0 / 61 (0.00%)	2 / 60 (3.33%)	0 / 36 (0.00%)	0 / 32 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 2	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Convulsion
subjects affected / exposed	0 / 61 (0.00%)	1 / 60 (1.67%)	0 / 36 (0.00%)	0 / 32 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Ischaemic stroke
subjects affected / exposed	1 / 61 (1.64%)	0 / 60 (0.00%)	0 / 36 (0.00%)	0 / 32 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0
Neuralgia
subjects affected / exposed	0 / 61 (0.00%)	1 / 60 (1.67%)	0 / 36 (0.00%)	0 / 32 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Somnolence
subjects affected / exposed	1 / 61 (1.64%)	0 / 60 (0.00%)	0 / 36 (0.00%)	0 / 32 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Vocal cord paralysis
subjects affected / exposed	1 / 61 (1.64%)	0 / 60 (0.00%)	0 / 36 (0.00%)	0 / 32 (0.00%)
occurrences causally related to treatment / all	0 / 2	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Blood and lymphatic system disorders
Anaemia
subjects affected / exposed	2 / 61 (3.28%)	1 / 60 (1.67%)	0 / 36 (0.00%)	0 / 32 (0.00%)
occurrences causally related to treatment / all	0 / 2	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Eye disorders
Periorbital oedema
subjects affected / exposed	1 / 61 (1.64%)	0 / 60 (0.00%)	0 / 36 (0.00%)	0 / 32 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Gastrointestinal disorders
Abdominal pain upper
subjects affected / exposed	1 / 61 (1.64%)	0 / 60 (0.00%)	0 / 36 (0.00%)	0 / 32 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Diarrhoea
subjects affected / exposed	8 / 61 (13.11%)	0 / 60 (0.00%)	3 / 36 (8.33%)	0 / 32 (0.00%)
occurrences causally related to treatment / all	8 / 8	0 / 0	2 / 3	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Dysphagia
subjects affected / exposed	3 / 61 (4.92%)	1 / 60 (1.67%)	2 / 36 (5.56%)	1 / 32 (3.13%)
occurrences causally related to treatment / all	2 / 3	0 / 1	0 / 2	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Gastrointestinal haemorrhage
subjects affected / exposed	1 / 61 (1.64%)	0 / 60 (0.00%)	0 / 36 (0.00%)	0 / 32 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Mouth haemorrhage
subjects affected / exposed	2 / 61 (3.28%)	0 / 60 (0.00%)	0 / 36 (0.00%)	0 / 32 (0.00%)
occurrences causally related to treatment / all	0 / 2	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0
Nausea
subjects affected / exposed	0 / 61 (0.00%)	2 / 60 (3.33%)	0 / 36 (0.00%)	0 / 32 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 2	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Vomiting
subjects affected / exposed	0 / 61 (0.00%)	2 / 60 (3.33%)	2 / 36 (5.56%)	1 / 32 (3.13%)
occurrences causally related to treatment / all	0 / 0	0 / 2	0 / 2	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Skin and subcutaneous tissue disorders
Palmar-plantar erythrodysaesthesia syndrome
subjects affected / exposed	1 / 61 (1.64%)	0 / 60 (0.00%)	0 / 36 (0.00%)	0 / 32 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Rash
subjects affected / exposed	1 / 61 (1.64%)	0 / 60 (0.00%)	1 / 36 (2.78%)	0 / 32 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Renal and urinary disorders
Renal failure
subjects affected / exposed	3 / 61 (4.92%)	0 / 60 (0.00%)	0 / 36 (0.00%)	0 / 32 (0.00%)
occurrences causally related to treatment / all	3 / 3	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Renal failure acute
subjects affected / exposed	3 / 61 (4.92%)	0 / 60 (0.00%)	1 / 36 (2.78%)	1 / 32 (3.13%)
occurrences causally related to treatment / all	2 / 3	0 / 0	1 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Renal tubular necrosis
subjects affected / exposed	0 / 61 (0.00%)	1 / 60 (1.67%)	0 / 36 (0.00%)	0 / 32 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Endocrine disorders
Hypercalcaemia of malignancy
subjects affected / exposed	0 / 61 (0.00%)	0 / 60 (0.00%)	0 / 36 (0.00%)	1 / 32 (3.13%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1
Musculoskeletal and connective tissue disorders
Arthralgia
subjects affected / exposed	1 / 61 (1.64%)	0 / 60 (0.00%)	0 / 36 (0.00%)	0 / 32 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Fistula
subjects affected / exposed	0 / 61 (0.00%)	0 / 60 (0.00%)	1 / 36 (2.78%)	0 / 32 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Muscular weakness
subjects affected / exposed	0 / 61 (0.00%)	0 / 60 (0.00%)	1 / 36 (2.78%)	0 / 32 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Soft tissue necrosis
subjects affected / exposed	1 / 61 (1.64%)	0 / 60 (0.00%)	0 / 36 (0.00%)	0 / 32 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Infections and infestations
Abscess limb
subjects affected / exposed	0 / 61 (0.00%)	1 / 60 (1.67%)	0 / 36 (0.00%)	0 / 32 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Bacteraemia
subjects affected / exposed	0 / 61 (0.00%)	1 / 60 (1.67%)	0 / 36 (0.00%)	0 / 32 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Bronchitis
subjects affected / exposed	1 / 61 (1.64%)	0 / 60 (0.00%)	0 / 36 (0.00%)	0 / 32 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Bronchopneumonia
subjects affected / exposed	1 / 61 (1.64%)	0 / 60 (0.00%)	0 / 36 (0.00%)	0 / 32 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Cellulitis
subjects affected / exposed	1 / 61 (1.64%)	1 / 60 (1.67%)	0 / 36 (0.00%)	0 / 32 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Device related infection
subjects affected / exposed	1 / 61 (1.64%)	0 / 60 (0.00%)	0 / 36 (0.00%)	0 / 32 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Device related sepsis
subjects affected / exposed	0 / 61 (0.00%)	2 / 60 (3.33%)	0 / 36 (0.00%)	0 / 32 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 2	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0
Endocarditis
subjects affected / exposed	0 / 61 (0.00%)	1 / 60 (1.67%)	0 / 36 (0.00%)	0 / 32 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Infectious pleural effusion
subjects affected / exposed	0 / 61 (0.00%)	1 / 60 (1.67%)	0 / 36 (0.00%)	0 / 32 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0
Lobar pneumonia
subjects affected / exposed	0 / 61 (0.00%)	0 / 60 (0.00%)	1 / 36 (2.78%)	0 / 32 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Lower respiratory tract infection
subjects affected / exposed	1 / 61 (1.64%)	0 / 60 (0.00%)	0 / 36 (0.00%)	0 / 32 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Lung infection
subjects affected / exposed	0 / 61 (0.00%)	1 / 60 (1.67%)	0 / 36 (0.00%)	2 / 32 (6.25%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1
Meningitis staphylococcal
subjects affected / exposed	0 / 61 (0.00%)	1 / 60 (1.67%)	0 / 36 (0.00%)	0 / 32 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0
Pneumonia
subjects affected / exposed	5 / 61 (8.20%)	1 / 60 (1.67%)	0 / 36 (0.00%)	1 / 32 (3.13%)
occurrences causally related to treatment / all	0 / 6	0 / 1	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 3	0 / 0	0 / 0	0 / 0
Respiratory tract infection
subjects affected / exposed	1 / 61 (1.64%)	1 / 60 (1.67%)	0 / 36 (0.00%)	1 / 32 (3.13%)
occurrences causally related to treatment / all	0 / 1	0 / 1	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0
Sepsis
subjects affected / exposed	1 / 61 (1.64%)	0 / 60 (0.00%)	0 / 36 (0.00%)	0 / 32 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Septic shock
subjects affected / exposed	1 / 61 (1.64%)	0 / 60 (0.00%)	0 / 36 (0.00%)	0 / 32 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Staphylococcal bacteraemia
subjects affected / exposed	1 / 61 (1.64%)	0 / 60 (0.00%)	0 / 36 (0.00%)	0 / 32 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Toxic shock syndrome
subjects affected / exposed	0 / 61 (0.00%)	0 / 60 (0.00%)	0 / 36 (0.00%)	1 / 32 (3.13%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1
Urinary tract infection
subjects affected / exposed	1 / 61 (1.64%)	0 / 60 (0.00%)	0 / 36 (0.00%)	0 / 32 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Metabolism and nutrition disorders
Decreased appetite
subjects affected / exposed	1 / 61 (1.64%)	1 / 60 (1.67%)	1 / 36 (2.78%)	0 / 32 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 1	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Dehydration
subjects affected / exposed	8 / 61 (13.11%)	1 / 60 (1.67%)	0 / 36 (0.00%)	1 / 32 (3.13%)
occurrences causally related to treatment / all	7 / 8	0 / 1	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Electrolyte imbalance
subjects affected / exposed	0 / 61 (0.00%)	1 / 60 (1.67%)	0 / 36 (0.00%)	0 / 32 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Hypercalcaemia
subjects affected / exposed	1 / 61 (1.64%)	2 / 60 (3.33%)	1 / 36 (2.78%)	1 / 32 (3.13%)
occurrences causally related to treatment / all	0 / 1	0 / 2	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0
Hypernatraemia
subjects affected / exposed	1 / 61 (1.64%)	0 / 60 (0.00%)	1 / 36 (2.78%)	0 / 32 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Hypocalcaemia
subjects affected / exposed	1 / 61 (1.64%)	0 / 60 (0.00%)	0 / 36 (0.00%)	0 / 32 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Hypoglycaemia
subjects affected / exposed	0 / 61 (0.00%)	1 / 60 (1.67%)	0 / 36 (0.00%)	0 / 32 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 2	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Hypokalaemia
subjects affected / exposed	1 / 61 (1.64%)	0 / 60 (0.00%)	0 / 36 (0.00%)	0 / 32 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Hypomagnesaemia
subjects affected / exposed	0 / 61 (0.00%)	1 / 60 (1.67%)	0 / 36 (0.00%)	0 / 32 (0.00%)
occurrences causally related to treatment / all	0 / 0	1 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Hypophagia
subjects affected / exposed	0 / 61 (0.00%)	0 / 60 (0.00%)	0 / 36 (0.00%)	2 / 32 (6.25%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Malnutrition
subjects affected / exposed	2 / 61 (3.28%)	0 / 60 (0.00%)	2 / 36 (5.56%)	0 / 32 (0.00%)
occurrences causally related to treatment / all	1 / 2	0 / 0	0 / 2	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0

Frequency threshold for reporting non-serious adverse events: 5%

Non-serious adverse events	Afatinib 50 mg / Cetuximab 250mg/m2 - Stage 1	Cetuximab 250 mg/m2 / Afatinib 50 mg - Stage 1	Cetuximab 250 mg/m2 / Afatinib 50 mg - Stage 2	Afatinib 50 mg / Cetuximab 250mg/m2 - Stage 2
Total subjects affected by non serious adverse events
subjects affected / exposed	61 / 61 (100.00%)	59 / 60 (98.33%)	34 / 36 (94.44%)	29 / 32 (90.63%)
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Tumour pain
subjects affected / exposed	2 / 61 (3.28%)	1 / 60 (1.67%)	2 / 36 (5.56%)	2 / 32 (6.25%)
occurrences all number	2	1	2	2
Vascular disorders
Hypertension
subjects affected / exposed	1 / 61 (1.64%)	1 / 60 (1.67%)	0 / 36 (0.00%)	2 / 32 (6.25%)
occurrences all number	1	1	0	2
Hypotension
subjects affected / exposed	5 / 61 (8.20%)	2 / 60 (3.33%)	0 / 36 (0.00%)	1 / 32 (3.13%)
occurrences all number	5	2	0	1
General disorders and administration site conditions
Asthenia
subjects affected / exposed	10 / 61 (16.39%)	9 / 60 (15.00%)	3 / 36 (8.33%)	4 / 32 (12.50%)
occurrences all number	10	11	3	4
Fatigue
subjects affected / exposed	18 / 61 (29.51%)	19 / 60 (31.67%)	5 / 36 (13.89%)	6 / 32 (18.75%)
occurrences all number	19	20	5	7
Mucosal inflammation
subjects affected / exposed	14 / 61 (22.95%)	11 / 60 (18.33%)	7 / 36 (19.44%)	1 / 32 (3.13%)
occurrences all number	17	14	8	1
Pyrexia
subjects affected / exposed	4 / 61 (6.56%)	11 / 60 (18.33%)	3 / 36 (8.33%)	3 / 32 (9.38%)
occurrences all number	8	13	3	3
Respiratory, thoracic and mediastinal disorders
Cough
subjects affected / exposed	6 / 61 (9.84%)	12 / 60 (20.00%)	3 / 36 (8.33%)	3 / 32 (9.38%)
occurrences all number	6	13	3	3
Dysphonia
subjects affected / exposed	6 / 61 (9.84%)	2 / 60 (3.33%)	1 / 36 (2.78%)	1 / 32 (3.13%)
occurrences all number	6	2	1	1
Dyspnoea
subjects affected / exposed	5 / 61 (8.20%)	9 / 60 (15.00%)	0 / 36 (0.00%)	2 / 32 (6.25%)
occurrences all number	6	12	0	2
Epistaxis
subjects affected / exposed	9 / 61 (14.75%)	5 / 60 (8.33%)	2 / 36 (5.56%)	0 / 32 (0.00%)
occurrences all number	9	5	2	0
Haemoptysis
subjects affected / exposed	6 / 61 (9.84%)	2 / 60 (3.33%)	1 / 36 (2.78%)	1 / 32 (3.13%)
occurrences all number	6	2	1	1
Rhinorrhoea
subjects affected / exposed	4 / 61 (6.56%)	1 / 60 (1.67%)	0 / 36 (0.00%)	1 / 32 (3.13%)
occurrences all number	5	1	0	1
Psychiatric disorders
Anxiety
subjects affected / exposed	2 / 61 (3.28%)	1 / 60 (1.67%)	2 / 36 (5.56%)	2 / 32 (6.25%)
occurrences all number	2	1	2	2
Confusional state
subjects affected / exposed	4 / 61 (6.56%)	3 / 60 (5.00%)	0 / 36 (0.00%)	0 / 32 (0.00%)
occurrences all number	5	3	0	0
Insomnia
subjects affected / exposed	4 / 61 (6.56%)	5 / 60 (8.33%)	1 / 36 (2.78%)	1 / 32 (3.13%)
occurrences all number	4	5	1	1
Investigations
Weight decreased
subjects affected / exposed	9 / 61 (14.75%)	8 / 60 (13.33%)	5 / 36 (13.89%)	1 / 32 (3.13%)
occurrences all number	11	9	5	1
Nervous system disorders
Dizziness
subjects affected / exposed	5 / 61 (8.20%)	7 / 60 (11.67%)	1 / 36 (2.78%)	1 / 32 (3.13%)
occurrences all number	5	9	1	1
Dysgeusia
subjects affected / exposed	3 / 61 (4.92%)	1 / 60 (1.67%)	2 / 36 (5.56%)	0 / 32 (0.00%)
occurrences all number	3	1	2	0
Headache
subjects affected / exposed	4 / 61 (6.56%)	5 / 60 (8.33%)	3 / 36 (8.33%)	5 / 32 (15.63%)
occurrences all number	6	5	3	6
Paraesthesia
subjects affected / exposed	0 / 61 (0.00%)	1 / 60 (1.67%)	3 / 36 (8.33%)	1 / 32 (3.13%)
occurrences all number	0	1	3	1
Blood and lymphatic system disorders
Anaemia
subjects affected / exposed	9 / 61 (14.75%)	10 / 60 (16.67%)	3 / 36 (8.33%)	3 / 32 (9.38%)
occurrences all number	17	11	3	3
Neutropenia
subjects affected / exposed	0 / 61 (0.00%)	0 / 60 (0.00%)	2 / 36 (5.56%)	0 / 32 (0.00%)
occurrences all number	0	0	2	0
Eye disorders
Conjunctivitis
subjects affected / exposed	4 / 61 (6.56%)	7 / 60 (11.67%)	4 / 36 (11.11%)	1 / 32 (3.13%)
occurrences all number	6	7	5	1
Gastrointestinal disorders
Abdominal pain
subjects affected / exposed	4 / 61 (6.56%)	1 / 60 (1.67%)	0 / 36 (0.00%)	0 / 32 (0.00%)
occurrences all number	4	1	0	0
Cheilitis
subjects affected / exposed	4 / 61 (6.56%)	2 / 60 (3.33%)	1 / 36 (2.78%)	0 / 32 (0.00%)
occurrences all number	4	2	1	0
Constipation
subjects affected / exposed	6 / 61 (9.84%)	17 / 60 (28.33%)	2 / 36 (5.56%)	6 / 32 (18.75%)
occurrences all number	6	27	3	6
Diarrhoea
subjects affected / exposed	45 / 61 (73.77%)	15 / 60 (25.00%)	21 / 36 (58.33%)	2 / 32 (6.25%)
occurrences all number	58	18	26	3
Dry mouth
subjects affected / exposed	2 / 61 (3.28%)	5 / 60 (8.33%)	0 / 36 (0.00%)	1 / 32 (3.13%)
occurrences all number	2	5	0	2
Dyspepsia
subjects affected / exposed	1 / 61 (1.64%)	5 / 60 (8.33%)	2 / 36 (5.56%)	0 / 32 (0.00%)
occurrences all number	1	7	2	0
Dysphagia
subjects affected / exposed	6 / 61 (9.84%)	8 / 60 (13.33%)	2 / 36 (5.56%)	1 / 32 (3.13%)
occurrences all number	6	9	2	1
Nausea
subjects affected / exposed	22 / 61 (36.07%)	17 / 60 (28.33%)	8 / 36 (22.22%)	2 / 32 (6.25%)
occurrences all number	23	24	8	2
Oral pain
subjects affected / exposed	4 / 61 (6.56%)	2 / 60 (3.33%)	0 / 36 (0.00%)	0 / 32 (0.00%)
occurrences all number	4	2	0	0
Stomatitis
subjects affected / exposed	5 / 61 (8.20%)	4 / 60 (6.67%)	4 / 36 (11.11%)	0 / 32 (0.00%)
occurrences all number	5	4	5	0
Vomiting
subjects affected / exposed	15 / 61 (24.59%)	12 / 60 (20.00%)	7 / 36 (19.44%)	1 / 32 (3.13%)
occurrences all number	15	17	10	1
Skin and subcutaneous tissue disorders
Acne
subjects affected / exposed	8 / 61 (13.11%)	8 / 60 (13.33%)	3 / 36 (8.33%)	4 / 32 (12.50%)
occurrences all number	11	10	3	4
Decubitus ulcer
subjects affected / exposed	0 / 61 (0.00%)	0 / 60 (0.00%)	2 / 36 (5.56%)	0 / 32 (0.00%)
occurrences all number	0	0	2	0
Dermatitis
subjects affected / exposed	0 / 61 (0.00%)	3 / 60 (5.00%)	2 / 36 (5.56%)	0 / 32 (0.00%)
occurrences all number	0	4	2	0
Dermatitis acneiform
subjects affected / exposed	12 / 61 (19.67%)	8 / 60 (13.33%)	3 / 36 (8.33%)	3 / 32 (9.38%)
occurrences all number	13	8	3	3
Dry skin
subjects affected / exposed	9 / 61 (14.75%)	16 / 60 (26.67%)	4 / 36 (11.11%)	3 / 32 (9.38%)
occurrences all number	10	16	4	4
Erythema
subjects affected / exposed	2 / 61 (3.28%)	2 / 60 (3.33%)	2 / 36 (5.56%)	0 / 32 (0.00%)
occurrences all number	2	2	2	0
Palmar-plantar erythrodysaesthesia syndrome
subjects affected / exposed	2 / 61 (3.28%)	2 / 60 (3.33%)	5 / 36 (13.89%)	2 / 32 (6.25%)
occurrences all number	2	2	6	2
Pruritus
subjects affected / exposed	8 / 61 (13.11%)	5 / 60 (8.33%)	1 / 36 (2.78%)	0 / 32 (0.00%)
occurrences all number	8	7	1	0
Rash
subjects affected / exposed	26 / 61 (42.62%)	25 / 60 (41.67%)	10 / 36 (27.78%)	6 / 32 (18.75%)
occurrences all number	36	30	11	7
Skin fissures
subjects affected / exposed	3 / 61 (4.92%)	11 / 60 (18.33%)	1 / 36 (2.78%)	1 / 32 (3.13%)
occurrences all number	5	18	1	1
Skin toxicity
subjects affected / exposed	2 / 61 (3.28%)	3 / 60 (5.00%)	4 / 36 (11.11%)	1 / 32 (3.13%)
occurrences all number	2	4	5	1
Xeroderma
subjects affected / exposed	4 / 61 (6.56%)	3 / 60 (5.00%)	0 / 36 (0.00%)	2 / 32 (6.25%)
occurrences all number	4	3	0	2
Musculoskeletal and connective tissue disorders
Back pain
subjects affected / exposed	2 / 61 (3.28%)	5 / 60 (8.33%)	1 / 36 (2.78%)	2 / 32 (6.25%)
occurrences all number	2	6	1	3
Muscle spasms
subjects affected / exposed	1 / 61 (1.64%)	0 / 60 (0.00%)	2 / 36 (5.56%)	0 / 32 (0.00%)
occurrences all number	1	0	2	0
Neck pain
subjects affected / exposed	3 / 61 (4.92%)	5 / 60 (8.33%)	3 / 36 (8.33%)	1 / 32 (3.13%)
occurrences all number	3	5	3	1
Pain in extremity
subjects affected / exposed	1 / 61 (1.64%)	4 / 60 (6.67%)	0 / 36 (0.00%)	1 / 32 (3.13%)
occurrences all number	1	5	0	1
Infections and infestations
Nasopharyngitis
subjects affected / exposed	4 / 61 (6.56%)	2 / 60 (3.33%)	0 / 36 (0.00%)	2 / 32 (6.25%)
occurrences all number	5	3	0	3
Paronychia
subjects affected / exposed	3 / 61 (4.92%)	4 / 60 (6.67%)	3 / 36 (8.33%)	2 / 32 (6.25%)
occurrences all number	3	5	3	2
Upper respiratory tract infection
subjects affected / exposed	1 / 61 (1.64%)	1 / 60 (1.67%)	2 / 36 (5.56%)	1 / 32 (3.13%)
occurrences all number	1	1	2	1
Metabolism and nutrition disorders
Decreased appetite
subjects affected / exposed	12 / 61 (19.67%)	11 / 60 (18.33%)	7 / 36 (19.44%)	6 / 32 (18.75%)
occurrences all number	13	13	7	6
Hypokalaemia
subjects affected / exposed	6 / 61 (9.84%)	6 / 60 (10.00%)	1 / 36 (2.78%)	0 / 32 (0.00%)
occurrences all number	7	9	1	0
Hypomagnesaemia
subjects affected / exposed	2 / 61 (3.28%)	2 / 60 (3.33%)	3 / 36 (8.33%)	3 / 32 (9.38%)
occurrences all number	2	3	3	3

More information

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Were there any global substantial amendments to the protocol? Yes

15 Oct 2008

The duration of the study period (planned dates of trial) was lengthened, the number of study centers was increased, and the potential for inclusion of study centers in Europe was added. Modified exclusion criterion 1 to change the length of time between prior therapy for localized/locoregionally advanced disease and PD from 6 months to 3 months as a significant portion of patients' progress within 6 months after completion of curative intent treatment. Modified inclusion criterion 2 to allow enrollment of patients with well-differentiated (keratinizing) nasopharyngeal cancer, well-differentiated squamous cell carcinomas of the head and neck, and patients with squamous cell carcinomas metastatic to the neck from an unknown head and neck primary site. Modified exclusion criterion 3 to clarify that therapies refer to regimens, ie, more than 2 chemotherapeutic regimens for R/M disease. Removed exclusion criterion 5 that disallowed administration of afatinib via a gastric-tube as an estimated 20% to 30% of the target population only swallow by gastric-tubes and could potentially benefit from anti-EGFR therapy. Applicable information on route and instructions added on how to disperse afatinib in saline and administer it via a gastric-tube. Added guidance for the management of skin rash to dose reduction scheme. Appropriate information was added on drug supply (cetuximab), and applicable packaging according to EU law. Added analysis of pharmacokinetics and biomarkers to secondary endpoints. Updated the primary and secondary endpoints to improve distinction between observations required for endpoints and to correct placement in endpoint sections. Updated guidance for management of diarrhea, nausea and vomiting, and rash to agree with recommendations incorporated across all afatinib protocols. Clarified RECIST categories and defined additional response categories. Split flow chart into 2 flow charts and updated as appropriate to include changes to procedures.

06 Feb 2009

Added information on cetuximab solution (ie, 5 mg/mL concentration) available in Europe. Specified that all patients must have a baseline MUGA or echocardiography prior to randomization, not only those randomized to afatinib. Updated total sample size to require randomization to continue until 80 patients (40 per group) underwent at least 1 post-randomization tumor assessment, or until a maximum of 100 patients were randomized.

03 Apr 2009

Added exclusion criterion 21 to exclude patients with known preexisting ILD because ILD is a rare and serious AE reported with other EGFR tyrosine kinase inhibitors. Added background and safety information on ILD throughout the protocol, as applicable.

26 May 2010

Added information and restrictions for concomitant use of medications with afatinib that were potent P-gp inhibitors and inducers. Removed the 100 patient restriction on number of patients to be randomized; randomization was to continue until 80 patients underwent at least 1 post-randomization tumor assessment. Provided additional guidance for patients presenting with acute pulmonary symptoms which are similar to symptoms related to ILD. Provided guidance on compliance related to cetuximab therapy. Updated information on drug formulation provided, available dosage strengths, and labeling of afatinib used in the trial. Clarified that the analyses of trial data performed on an ongoing basis would be used for planning of future trials.

31 Jan 2011

Added information on role of HPV in HNSCC. Updated General Aim - Objectives to clarify the role of biomarkers that may predict tumor response, rather than limit it to the influence of EGFR genotype on tumor response. Updated the biomarker section based on changes to plan for analysis of samples. Updated information on formulation and labeling of afatinib used in the trial.

Were there any global interruptions to the trial? No

Limitations of the trial such as small numbers of subjects analysed or technical problems leading to unreliable data.

None reported

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Clinical trials

Clinical Trial Results: A randomized, open-label Phase II study of BIBW 2992 versus cetuximab (Erbitux®) in patients with metastatic or recurrent Head and Neck Squamous Cell Carcinoma (HNSCC) after failure of platinum-containing therapy with a cross-over period for progressing patients.

Trial information

Trial information

Subject disposition

Subject disposition

Baseline characteristics

Baseline characteristics

End points

End points

Primary: Tumor Shrinkage Before Crossover (Stage 1) of the Trial as Per Investigator Assessment

Primary: Tumor Shrinkage Before Crossover (Stage 1) of the Trial as Per Investigator Assessment

Secondary: Tumor Shrinkage After Crossover (Stage 2) as Per Investigator Assessments

Secondary: Tumor Shrinkage After Crossover (Stage 2) as Per Investigator Assessments

Secondary: 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).

Secondary: 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).

Secondary: Best RECIST Assessment as Per ICR for Stage 1 (as Confirmed Disease Control (Clinical Benefit) and Objective Response Are Simply Categories of RECIST Assessment)

Secondary: Best RECIST Assessment as Per ICR for Stage 1 (as Confirmed Disease Control (Clinical Benefit) and Objective Response Are Simply Categories of RECIST Assessment)

Secondary: Best RECIST Assessment as Per Investigator Assessment for Stage 2 (as Confirmed Disease Control (Clinical Benefit) and Objective Response Are Simply Categories of RECIST Assessment)

Secondary: Best RECIST Assessment as Per Investigator Assessment for Stage 2 (as Confirmed Disease Control (Clinical Benefit) and Objective Response Are Simply Categories of RECIST Assessment)

Secondary: Best RECIST Assessment as Per ICR for Stage2 (as Confirmed Disease Control (Clinical Benefit) and Objective Response Are Simply Categories of RECIST Assessment)

Secondary: Best RECIST Assessment as Per ICR for Stage2 (as Confirmed Disease Control (Clinical Benefit) and Objective Response Are Simply Categories of RECIST Assessment)

Secondary: Best RECIST Assessment as Onset of Confirmed Objective Response as Per Investigator Assessment for Stage 1

Secondary: Best RECIST Assessment as Onset of Confirmed Objective Response as Per Investigator Assessment for Stage 1

Secondary: Best RECIST Assessment as Onset of Confirmed Objective Response as Per ICR for Stage 1

Secondary: Best RECIST Assessment as Onset of Confirmed Objective Response as Per ICR for Stage 1

Secondary: Best RECIST Assessment as Onset of Confirmed Objective Response as Per Investigator Assessment for Stage 2

Secondary: Best RECIST Assessment as Onset of Confirmed Objective Response as Per Investigator Assessment for Stage 2

Secondary: Best RECIST Assessment as Confirmed Duration of Objective Response and Disease Control as Per Investigator Assessment for Stage 1

Secondary: Best RECIST Assessment as Confirmed Duration of Objective Response and Disease Control as Per Investigator Assessment for Stage 1

Secondary: Best RECIST Assessment as Confirmed Duration of Confirmed Objective Response and Disease Control as Per ICR for Stage 1

Secondary: Best RECIST Assessment as Confirmed Duration of Confirmed Objective Response and Disease Control as Per ICR for Stage 1

Secondary: Best RECIST Assessment as Confirmed Duration of Objective Response and Disease Control as Per Investigator Assessment for Stage 2

Secondary: Best RECIST Assessment as Confirmed Duration of Objective Response and Disease Control as Per Investigator Assessment for Stage 2

Secondary: Best RECIST Assessment as Confirmed Duration of Disease Control as Per ICR for Stage 2

Secondary: Best RECIST Assessment as Confirmed Duration of Disease Control as Per ICR for Stage 2

Secondary: Progression Free Survival (PFS) Before Crossover Based on Investigator Assessment

Secondary: Progression Free Survival (PFS) Before Crossover Based on Investigator Assessment

Secondary: Progression Free Survival (PFS) After Crossover Based on Investigator Assessment

Secondary: Progression Free Survival (PFS) After Crossover Based on Investigator Assessment

Secondary: Overall Survival (OS)

Secondary: Overall Survival (OS)

Secondary: Time to Deterioration in HRQoL - Stage 1

Secondary: Time to Deterioration in HRQoL - Stage 1

Secondary: Patients With AEs Resulting in Diarrhea, Skin Rash, Dose Reduction, Treatement Discontinuation and Decreased Cardiac Left Ventricular Function

Secondary: Patients With AEs Resulting in Diarrhea, Skin Rash, Dose Reduction, Treatement Discontinuation and Decreased Cardiac Left Ventricular Function

Secondary: Incidence and Intensity of Adverse Events With Grading According CTCAE

Secondary: Incidence and Intensity of Adverse Events With Grading According CTCAE

Secondary: Pre-dose Concentration of Afatinib in Plasma for Dose 40mg and 50mg at Steady State on Day 15 (Cpre,ss,15)

Secondary: Pre-dose Concentration of Afatinib in Plasma for Dose 40mg and 50mg at Steady State on Day 15 (Cpre,ss,15)

Secondary: Pre-dose Concentration of Afatinib in Plasma for Dose 40mg and 50mg at Steady State on Day 29 (Cpre,ss,29)

Secondary: Pre-dose Concentration of Afatinib in Plasma for Dose 40mg and 50mg at Steady State on Day 29 (Cpre,ss,29)

Secondary: Pre-dose Concentration of Afatinib in Plasma for Dose 40mg and 50mg at Steady State on Day 57 (Cpre,ss, 57)

Secondary: Pre-dose Concentration of Afatinib in Plasma for Dose 40mg and 50mg at Steady State on Day 57 (Cpre,ss, 57)

Adverse events

Adverse events

More information

Substantial protocol amendments (globally)

Interruptions (globally)

Limitations and caveats

More information

Clinical Trial Results:
A randomized, open-label Phase II study of BIBW 2992 versus cetuximab (Erbitux®) in patients with metastatic or recurrent Head and Neck Squamous Cell Carcinoma (HNSCC) after failure of platinum-containing therapy with a cross-over period for progressing patients.