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Clinical Trial Results:
A Randomized, Open-Label, Controlled, Phase II Trial of Combination Chemotherapy with or without Panitumumab as First-line Treatment of Subjects with Metastatic or Recurrent Head and Neck Cancer, and Cross-over Second-line Panitumumab Monotherapy of Subjects who Fail the Combination Chemotherapy Only Arm

Summary
EudraCT number	2007-005722-79
Trial protocol	CZ FR SK ES AT LT BE
Global end of trial date	06 Mar 2014

Results information
Results version number	v1(current)
This version publication date	20 Jun 2016
First version publication date	31 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

20050236

ISRCTN number

US NCT number

NCT00454779

WHO universal trial number (UTN)

Sponsor organisation name

Amgen, Inc.

Sponsor organisation address

One Amgen Center Drive, Thousand Oaks, CA, United States, 91320

Public contact

IHQ Medical Info-Clinical Trials, Amgen (EUROPE) GmbH, MedInfoInternational@amgen.com

Scientific contact

IHQ Medical Info-Clinical Trials, Amgen (EUROPE) GmbH, MedInfoInternational@amgen.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

11 Jun 2012

Is this the analysis of the primary completion data?

Global end of trial reached?

Yes

Global end of trial date

06 Mar 2014

Was the trial ended prematurely?

Main objective of the trial

To estimate the effect of panitumumab on progression-free survival based on investigators’ tumor response assessments when added to combination chemotherapy in the first-line treatment of metastatic or recurrent squamous cell carcinoma of the head and neck (SCCHN).

Protection of trial subjects

This study was conducted in accordance with applicable FDA and International Conference on Harmonisation (ICH) Good Clinical Practice (GCP) regulations/guidelines. All subjects provided written informed consent before undergoing any study-related procedures, including screening procedures. The study protocol, amendments, and the informed consent form (ICF) were reviewed by the Institutional Review Boards (IRBs) and Independent Ethics Committees (IECs). No subjects were recruited into the study and no investigational product (IP) was shipped until the IRB/IEC gave written approval of the protocol and ICF and Amgen received copies of these approvals.

Background therapy

Evidence for comparator

Actual start date of recruitment

29 Jan 2007

Long term follow-up planned

Yes

Long term follow-up rationale

Efficacy

Long term follow-up duration

24 Months

Independent data monitoring committee (IDMC) involvement?

Yes

Number of subjects enrolled per country

Country: Number of subjects enrolled

Austria: 10

Country: Number of subjects enrolled

Belgium: 16

Country: Number of subjects enrolled

Czech Republic: 2

Country: Number of subjects enrolled

France: 5

Country: Number of subjects enrolled

Lithuania: 1

Country: Number of subjects enrolled

Slovakia: 2

Country: Number of subjects enrolled

Spain: 9

Country: Number of subjects enrolled

United States: 68

Worldwide total number of subjects

113

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)

From 65 to 84 years

85 years and over

Subject disposition

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Recruitment details

Subjects were enrolled from 29 January 2007 to 1 September 2010.

Screening details

A total of 148 subjects were screened; 113 subjects were randomized to first-line treatment (56 in the panitumumab plus chemotherapy arm and 57 in the chemotherapy alone arm) and 35 were considered screen failures.

Period 1 title

First-line Treatment Phase

Is this the baseline period?

Yes

Allocation method

Randomised - controlled

Blinding used

Not blinded

Are arms mutually exclusive

Yes

Panitumumab + Chemotherapy

Arm description

During the first-line treatment phase, subjects received panitumumab 9 mg/kg as an intravenous infusion before docetaxel 75 mg/m² and cisplatin 75 mg/m² combination chemotherapy in cycles repeated every 21 days for a maximum of 6 cycles. Subjects who had complete response, partial response, or stable disease and completed 6 cycles of first-line treatment and those subjects who discontinued chemotherapy for intolerability prior to progression remained on first-line panitumumab monotherapy until disease progression, unacceptable toxicities, withdrawal of consent, or death, whichever occurred first.

Arm type

Experimental

Investigational medicinal product name

Panitumumab

Investigational medicinal product code

AMG 954

Other name

Vectibix®

Pharmaceutical forms

Solution for infusion

Routes of administration

Intravenous use

Dosage and administration details

Panitumumab 9 mg/kg was administered intravenously over 1 hour every 21 ± 3 days.

Investigational medicinal product name

Docetaxel

Investigational medicinal product code

Other name

Pharmaceutical forms

Solution for infusion

Routes of administration

Intravenous use

Dosage and administration details

Docetaxel 75 mg/m² was administered by continuous intravenous infusion over 1 hour on day 1 of each cycle.

Investigational medicinal product name

Cisplatin

Investigational medicinal product code

Other name

Pharmaceutical forms

Solution for infusion

Routes of administration

Intravenous use

Dosage and administration details

Cisplatin 75 mg/m² was infused after docetaxel infusion over 1 hour ± 15 minutes on day 1 of each cycle.

Chemotherapy Alone

Arm description

During the first-line treatment phase, subjects received docetaxel 75 mg/m² and cisplatin 75 mg/m² combination chemotherapy in cycles repeated every 21 days for a maximum of 6 cycles.

Arm type

Active comparator

Investigational medicinal product name

Docetaxel

Investigational medicinal product code

Other name

Pharmaceutical forms

Solution for infusion

Routes of administration

Intravenous use

Dosage and administration details

Docetaxel 75 mg/m² was administered by continuous intravenous infusion over 1 hour on day 1 of each cycle.

Investigational medicinal product name

Cisplatin

Investigational medicinal product code

Other name

Pharmaceutical forms

Solution for infusion

Routes of administration

Intravenous use

Dosage and administration details

Cisplatin 75 mg/m² was infused after docetaxel infusion over 1 hour ± 15 minutes on day 1 of each cycle.

Number of subjects in period 1	Panitumumab + Chemotherapy	Chemotherapy Alone
Started	56	57
Received Study Medication	56	55
Completed	51	49
Not completed	5	8
Consent withdrawn by subject	2	4
Ongoing	1	-
Ended follow-up prior to analysis	1	1
Lost to follow-up	1	-
Lack of efficacy	-	2
Protocol deviation	-	1

Period 2 title

Second-line Treatment Phase

Is this the baseline period?

Allocation method

Not applicable

Blinding used

Not blinded

Panitumumab Monotherapy

Arm description

Eligible subjects in the chemotherapy alone arm who were determined to have disease progression before or after completing 6 cycles of chemotherapy in first-line treatment received second-line panitumumab monotherapy in cycles repeated every 21 days until disease progression, unacceptable toxicities, withdrawal of consent, or death, whichever occurred first.

Arm type

Crossover

Investigational medicinal product name

Panitumumab

Investigational medicinal product code

AMG 954

Other name

Vectibix®

Pharmaceutical forms

Solution for infusion

Routes of administration

Intravenous use

Dosage and administration details

Panitumumab 9 mg/kg was administered intravenously over 1 hour every 21 ± 3 days.

Number of subjects in period 2 ^[1]	Panitumumab Monotherapy
Started	30
Completed	27
Not completed	3
Consent withdrawn by subject	1
Ongoing	1
Ended follow-up prior to analysis	1

Notes
[1] - The number of subjects starting the period is not consistent with the number completing the preceding period. It is expected the number of subjects starting the subsequent period will be the same as the number completing the preceding period.
Justification: Only eligible subjects in the chemotherapy alone arm who were determined to have disease progression before or after completing 6 cycles of chemotherapy in first-line treatment received second-line panitumumab monotherapy.

Baseline characteristics

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Reporting group title

Panitumumab + Chemotherapy

Reporting group description

Reporting group title

Chemotherapy Alone

Reporting group description

During the first-line treatment phase, subjects received docetaxel 75 mg/m² and cisplatin 75 mg/m² combination chemotherapy in cycles repeated every 21 days for a maximum of 6 cycles.

Reporting group values	Panitumumab + Chemotherapy	Chemotherapy Alone	Total
Number of subjects	56	57	113
Age categorical
Units: Subjects
Age Continuous
Units: Years
arithmetic mean (standard deviation)	58.2 ( 8.6 )	58.9 ( 7.4 )	-
Gender, Male/Female
Units: Participants
Female	9	5	14
Male	47	52	99
Eastern Cooperative Oncology Group (ECOG) Performance Status
Grade 0: Fully active, able to carry on all pre-disease performance without restriction; Grade 1: Restricted in physically strenuous activity but ambulatory and able to carry out work of a light or sedentary nature, e.g., light house or office work; Grade 2: Ambulatory and capable of all selfcare but unable to carry out any work activities. Up and about more than 50% of waking hours; Grade 3: Capable of only limited selfcare, confined to bed or chair more than 50% of waking hours; Grade 4: Completely disabled. Cannot carry on any selfcare. Totally confined to bed or chair; Grade 5: Dead.
Units: Subjects
ECOG Performance Status: 0	21	20	41
ECOG Performance Status: 1	35	37	72
Disease Status
Units: Subjects
newly diagnosed/previously untreated	8	7	15
Recurrent	48	50	98

End points

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Reporting group title

Panitumumab + Chemotherapy

Reporting group description

Reporting group title

Chemotherapy Alone

Reporting group description

During the first-line treatment phase, subjects received docetaxel 75 mg/m² and cisplatin 75 mg/m² combination chemotherapy in cycles repeated every 21 days for a maximum of 6 cycles.

Reporting group title

Panitumumab Monotherapy

Reporting group description

Primary: Progression Free Survival (PFS) During the First-line Treatment Phase

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End point title

Progression Free Survival (PFS) During the First-line Treatment Phase

End point description

The time from the date of randomization to the date of first disease progression determined by the investigators per a modified version of the Response Evaluation Criteria in Solid Tumors (RECIST v1.0) guidelines, or death within 60 days after the last evaluable tumor assessment or randomization date (whichever is later) during the first-line treatment phase. Subjects not meeting the criteria by the cutoff date were censored at the last evaluable tumor assessment during the first-line treatment phase. This analysis was performed in the Primary Analysis Set: all randomized subjects < 70 years of age who provided informed consent and received at least 1 dose of first-line treatment.

End point type

Primary

End point timeframe

Every 6 weeks until disease progression or death, up to 67 months

End point values	Panitumumab + Chemotherapy	Chemotherapy Alone
Number of subjects analysed	52	51
Units: Months
median (confidence interval 95%)	6.9 (4.7 to 8.3)	5.5 (4.1 to 6.8)

Primary Analysis

Statistical analysis description

The primary analysis reflects the Cox proportional hazards model stratified by the interactive voice response system (IVRS) randomization factors: ECOG performance score (0 vs. 1) and disease status (newly diagnosed/previously untreated vs. recurrent). The hazard ratio is presented as panitumumab plus chemotherapy:chemotherapy alone. A value < 1.0 indicates a lower average event rate and longer time to event for panitumumab plus chemotherapy relative to chemotherapy alone.

Comparison groups

Panitumumab + Chemotherapy v Chemotherapy Alone

Number of subjects included in analysis

103

Analysis specification

Pre-specified

Analysis type

other ^[1]

P-value

= 0.051

Method

Regression, Cox

Parameter type

Hazard ratio (HR)

Point estimate

0.629

Confidence interval

level

95%

sides

2-sided

lower limit

0.395

upper limit

1.002

Notes
[1] - A formal hypothesis was not tested in this trial. This study provided an estimate and corresponding 2-sided 95% confidence interval (CI) of the relative efficacy of panitumumab plus combination chemotherapy vs combination chemotherapy only as measured by the PFS hazard ratio for combination chemotherapy with panitumumab relative to combination chemotherapy only in the first-line treatment of metastatic or recurrent SCCHN.

Secondary Analysis

Statistical analysis description

The secondary analysis reflects a log-rank test stratified by IVRS randomization factors: ECOG performance score (0 vs. 1) and disease status (newly diagnosed/previously untreated vs. recurrent).

Comparison groups

Panitumumab + Chemotherapy v Chemotherapy Alone

Number of subjects included in analysis

103

Analysis specification

Pre-specified

Analysis type

other

P-value

= 0.048

Method

Logrank

Confidence interval

Secondary: Overall Objective Response Rate (ORR) During the First-line Treatment Phase

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End point title

Overall Objective Response Rate (ORR) During the First-line Treatment Phase

End point description

Per Response Evaluation Criteria In Solid Tumors Criteria (RECIST v1.0) for target lesions and assessed by the investigator using magnetic resonance imaging (MRI): Complete Response (CR), the disappearance of all target lesions; Partial Response (PR), >=30% decrease in the sum of the longest diameter (SLD) of target lesions from Baseline; An objective response is defined as a best tumor response of CR or PR. An overall objective response of CR or PR must be confirmed at least 4 weeks after the criteria for response are first met. ORR is the percentage of subjects with an overall objective response among the analysis population. This analysis was performed in the Evaluable for Local Tumor Response Analysis Set: subset of subjects in the Primary Analysis Set with at least one unidimensionally measurable lesion at Baseline using a modified RECIST v1.0 per investigators’ review.

End point type

Secondary

End point timeframe

Every 6 weeks until disease progression or death, up to 67 months

End point values	Panitumumab + Chemotherapy	Chemotherapy Alone
Number of subjects analysed	52	51
Units: Percentage of Participants
arithmetic mean (confidence interval 95%)	44.23 (30.73 to 57.73)	37.25 (23.99 to 50.52)

Weighted Difference in Rates

Statistical analysis description

The difference in rates and confidence intervals are calculated using the Mantel-Haenszel weights within strata defined by IVRS randomization factors: ECOG performance score (0 vs. 1) and disease status (newly diagnosed/previously untreated vs recurrent).

Comparison groups

Panitumumab + Chemotherapy v Chemotherapy Alone

Number of subjects included in analysis

103

Analysis specification

Pre-specified

Analysis type

other

Method

Parameter type

Mean difference (final values)

Point estimate

6.23

Confidence interval

level

95%

sides

2-sided

lower limit

-11.67

upper limit

24.12

Treatment Odds Ratio

Statistical analysis description

The odds ratio is defined as the odds of having an objective response in the panitumumab plus chemotherapy arm relative to the odds in the chemotherapy alone arm. It is calculated from a logistic regression model with treatment indicator and randomization factors (recorded on the case report form [CRF]) as covariates: ECOG performance status (0 vs. 1/2) and disease status (newly diagnosed/previously untreated vs previously treated).

Comparison groups

Panitumumab + Chemotherapy v Chemotherapy Alone

Number of subjects included in analysis

103

Analysis specification

Pre-specified

Analysis type

other

Method

Parameter type

Odds ratio (OR)

Point estimate

1.37

Confidence interval

level

95%

sides

2-sided

lower limit

0.57

upper limit

3.33

Secondary: Rate of Disease Control (RDC) During the First-line Treatment Phase

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End point title

Rate of Disease Control (RDC) During the First-line Treatment Phase

End point description

Per Response Evaluation Criteria In Solid Tumors Criteria (RECIST v1.0) for target lesions and assessed by MRI: Complete Response (CR), the disappearance of all target lesions; Partial Response (PR), >=30% decrease in the sum of the longest diameter (SLD) of target lesions from baseline; Disease Progression (PD), >=20% increase in the SLD of target lesions from nadir; Stable Disease (SD), neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for PD. An overall response of CR or PR must be confirmed at least 4 weeks after the criteria for response are first met. A best overall response of SD requires a visit response of SD or better no earlier than 35 days after randomization. RDC is the percentage of subjects with a best overall response of CR, PR or SD among the analysis population (Evaluable for Local Tumor Response Analysis Set).

End point type

Secondary

End point timeframe

Every 6 weeks until disease progression or death, up to 67 months

End point values	Panitumumab + Chemotherapy	Chemotherapy Alone
Number of subjects analysed	52	51
Units: Percentage of Participants
arithmetic mean (confidence interval 95%)	80.77 (70.06 to 91.48)	72.55 (60.3 to 84.8)

Treatment Odds Ratio

Statistical analysis description

The odds ratio is defined as the odds of having an objective response in the panitumumab plus chemotherapy arm relative to the odds in the chemotherapy alone arm. It is calculated from a logistic regression model with treatment indicator and randomization factors (recorded on the case report form) as covariates: ECOG performance status (0 vs. 1/2) and disease status (newly diagnosed/previously untreated vs. previously treated).

Comparison groups

Panitumumab + Chemotherapy v Chemotherapy Alone

Number of subjects included in analysis

103

Analysis specification

Pre-specified

Analysis type

other

Method

Parameter type

Odds ratio (OR)

Point estimate

1.76

Confidence interval

level

95%

sides

2-sided

lower limit

0.62

upper limit

5.26

Weighted Difference in Rates

Statistical analysis description

The difference in rates and confidence intervals are calculated using the Mantel-Haenszel weights within strata defined by randomization factors recorded in the IVRS: ECOG performance score (0 vs. 1) and disease status (newly diagnosed/previously untreated vs. recurrent).

Comparison groups

Panitumumab + Chemotherapy v Chemotherapy Alone

Number of subjects included in analysis

103

Analysis specification

Pre-specified

Analysis type

other

Method

Parameter type

Mean difference (final values)

Point estimate

7.78

Confidence interval

level

95%

sides

2-sided

lower limit

-8.29

upper limit

23.85

Secondary: Duration of Response (DOR) During the First-line Treatment Phase

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End point title

Duration of Response (DOR) During the First-line Treatment Phase

End point description

Calculated only for the subset of subjects with an overall response of CR or PR while on first-line treatment (subsequently confirmed at least 4 weeks thereafter) assessed by the investigator, and defined as the time from the first CR or PR to the first observed disease progression according to a modified RECIST v1.0. Subjects not meeting the criteria for progression by the analysis data cutoff date were censored at their last evaluable disease assessment date. Analyzed in the Evaluable for Local Tumor Response Analysis Set; Subjects With Objective Responses.

End point type

Secondary

End point timeframe

Every 6 weeks until disease progression or death, up to 67 months

End point values	Panitumumab + Chemotherapy	Chemotherapy Alone
Number of subjects analysed	23	19
Units: Months
median (confidence interval 95%)	8 (5.7 to 11.1)	5.1 (4.4 to 7.2)

No statistical analyses for this end point

Secondary: Time to Response (TTR) During the First-line Treatment Phase

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End point title

Time to Response (TTR) During the First-line Treatment Phase

End point description

Time from the date of randomization to the first CR or PR during first line treatment phase (subsequently confirmed at least 4 weeks thereafter), analyzed in the Evaluable for Local Tumor Response Analysis Set; Subjects With Objective Responses.

End point type

Secondary

End point timeframe

Every 6 weeks until disease progression or death, up to 67 months

End point values	Panitumumab + Chemotherapy	Chemotherapy Alone
Number of subjects analysed	23	19
Units: Weeks
arithmetic mean (standard deviation)	8.8 ( 3.9 )	10.6 ( 6.1 )

No statistical analyses for this end point

Secondary: Overall Survival (OS) For the First-line Treatment

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End point title

Overall Survival (OS) For the First-line Treatment

End point description

Time from the date of randomization to the date of death during the entire study, analyzed in the Primary Analysis Set.

End point type

Secondary

End point timeframe

Until death, up to 67 months

End point values	Panitumumab + Chemotherapy	Chemotherapy Alone
Number of subjects analysed	52	51
Units: Months
median (confidence interval 95%)	12.9 (9.4 to 18.5)	13.8 (11.8 to 22.9)

Primary Analysis

Statistical analysis description

The primary analysis reflects the Cox proportional hazards model stratified by IVRS randomization factors: ECOG performance score (0 vs. 1) and disease status (newly diagnosed/previously untreated vs. recurrent). Hazard ratio is presented as panitumumab plus chemotherapy:chemotherapy alone. A value < 1.0 indicates a lower average event rate and longer time to event for panitumumab plus chemotherapy relative to chemotherapy alone.

Comparison groups

Panitumumab + Chemotherapy v Chemotherapy Alone

Number of subjects included in analysis

103

Analysis specification

Pre-specified

Analysis type

other

P-value

= 0.663

Method

Regression, Cox

Parameter type

Hazard ratio (HR)

Point estimate

1.103

Confidence interval

level

95%

sides

2-sided

lower limit

0.709

upper limit

1.717

Secondary Analysis

Statistical analysis description

The secondary analysis reflects a log-rank test stratified by IVRS randomization factors: ECOG performance score (0 vs. 1) and disease status (newly diagnosed/previously untreated vs. recurrent).

Comparison groups

Panitumumab + Chemotherapy v Chemotherapy Alone

Number of subjects included in analysis

103

Analysis specification

Pre-specified

Analysis type

other

P-value

= 0.666

Method

Logrank

Confidence interval

Secondary: Progression Free Survival (PFS) During the Second-line Treatment Phase

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End point title

Progression Free Survival (PFS) During the Second-line Treatment Phase

End point description

The time from the first dose of panitumumab monotherapy to the date of first disease progression determined by the investigator per modified RECIST v1.0, or death within 60 days after the last evaluable tumor assessment or the second-line first dose date (whichever is later) during the second-line treatment phase. Subjects not meeting the criteria by the cutoff date were censored at the last evaluable tumor assessment during the second-line treatment phase. This endpoint was analyzed in the Evaluable Subset for Second-line Panitumumab Monotherapy: subjects who were randomized to docetaxel and cisplatin chemotherapy alone treatment for their first-line treatments and treated subsequently with at least 1 dose of panitumumab monotherapy.

End point type

Secondary

End point timeframe

From the first dose of panitumumab monotherapy, every 6 weeks until disease progression or death, up to 57 months

End point values	Panitumumab Monotherapy
Number of subjects analysed	30
Units: Months
median (confidence interval 95%)	4.2 (1.5 to 7.6)

No statistical analyses for this end point

Secondary: Overall Objective Response Rate (ORR) During the Second-line Treatment Phase

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End point title

Overall Objective Response Rate (ORR) During the Second-line Treatment Phase

End point description

Per Response Evaluation Criteria In Solid Tumors Criteria (RECIST v1.0) for target lesions and assessed by the investigator using MRI: Complete Response (CR), the disappearance of all target lesions; Partial Response (PR), >=30% decrease in the sum of the longest diameter (SLD) of target lesions from baseline; Overall Response (OR) = CR + PR. An overall response of CR or PR must be confirmed at least 4 weeks after the criteria for response are first met. ORR is the percentage of subjects with an overall objective response among the Evaluable for Local Tumor Response Analysis Set for Second-line Panitumumab Monotherapy population.

End point type

Secondary

End point timeframe

Every 6 weeks until disease progression or death, up to 57 months

End point values	Panitumumab Monotherapy
Number of subjects analysed	30
Units: Percentage of Participants
arithmetic mean (confidence interval 95%)	13.33 (1.17 to 25.5)

No statistical analyses for this end point

Secondary: Duration of Response (DOR) During the Second-line Treatment Phase

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End point title

Duration of Response (DOR) During the Second-line Treatment Phase

End point description

Time from the first CR or PR in the second-line treatment phase to the first observed disease progression by a modified RECIST v1.0 per Investigator assessment. Subjects not meeting the criteria for progression by the analysis data cutoff date were censored at their last evaluable disease assessment date. Analyzed in the Evaluable for Local Tumor Response Analysis Set for Second-line Panitumumab Monotherapy: Subjects With Objective Responses. "99999" indicates values not estimable due to the low number of events.

End point type

Secondary

End point timeframe

Every 6 weeks until disease progression or death, up to 57 months

End point values	Panitumumab Monotherapy
Number of subjects analysed	4
Units: Months
median (confidence interval 95%)	99999 (5.1 to 99999)

No statistical analyses for this end point

Secondary: Rate of Disease Control (RDC) During the Second-line Treatment Phase

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End point title

Rate of Disease Control (RDC) During the Second-line Treatment Phase

End point description

Per Response Evaluation Criteria In Solid Tumors Criteria (RECIST v1.0) for target lesions and assessed by MRI: Complete Response (CR), the disappearance of all target lesions; Partial Response (PR), >=30% decrease in the sum of the longest diameter (SLD) of target lesions from Baseline; Disease Progression (PD), >=20% increase in the SLD of target lesions from nadir; Stable Disease (SD), neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for PD. An overall response of CR or PR must be confirmed at least 4 weeks after the criteria for response are first met. A best overall response of SD requires a visit response of SD or better no earlier than 35 days after the first dose date in second-line treatment. RDC is the percentage of subjects with a best overall response of CR, PR or SD among the Evaluable for Local Tumor Response Analysis Set for Second-line Panitumumab Monotherapy population.

End point type

Secondary

End point timeframe

Every 6 weeks until disease progression or death, up to 57 months

End point values	Panitumumab Monotherapy
Number of subjects analysed	30
Units: Percentage of Participants
arithmetic mean (confidence interval 95%)	53.33 (35.48 to 71.19)

No statistical analyses for this end point

Secondary: Time to Response (TTR) During the Second-line Treatment Phase

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End point title

Time to Response (TTR) During the Second-line Treatment Phase

End point description

Time from the first dose of panitumumab monotherapy to the first CR or PR during second-line treatment phase (subsequently confirmed at least 4 weeks thereafter) analyzed in the Evaluable for Local Tumor Response Analysis Set for Second-line Panitumumab Monotherapy: Subjects With Objective Responses.

End point type

Secondary

End point timeframe

Every 6 weeks until disease progression or death, up to 57 months

End point values	Panitumumab Monotherapy
Number of subjects analysed	4
Units: Weeks
arithmetic mean (standard deviation)	10.6 ( 5.6 )

No statistical analyses for this end point

Secondary: Overall Survival (OS) for Second-line Treatment

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End point title

Overall Survival (OS) for Second-line Treatment

End point description

Time from the first dose of panitumumab monotherapy to the date of death during the second-line treatment phase, analyzed in the Evaluable Subset for Second-line Panitumumab Monotherapy population.

End point type

Secondary

End point timeframe

Until death, up to 57 months

End point values	Panitumumab Monotherapy
Number of subjects analysed	30
Units: Months
median (confidence interval 95%)	8.5 (6.5 to 13.2)

No statistical analyses for this end point

Adverse events

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Timeframe for reporting adverse events

The time frame for adverse event reporting is from the first dose date to 30 days since the last dose date in each part of the study. The median time frame is 4.5, 4.4 and 3.7 months by treatment group respectively.

Assessment type

Systematic

Dictionary name

MedDRA

Dictionary version

15.0

Reporting group title

First-line: Panitumumab Plus Chemotherapy

Reporting group description

Reporting group title

First-line: Chemotherapy Alone

Reporting group description

During the first-line treatment phase, subjects received docetaxel 75 mg/m² and cisplatin 75 mg/m² combination chemotherapy in cycles repeated every 21 days for a maximum of 6 cycles.

Reporting group title

Second-line: Panitumumab Monotherapy

Reporting group description

Serious adverse events	First-line: Panitumumab Plus Chemotherapy	First-line: Chemotherapy Alone	Second-line: Panitumumab Monotherapy
Total subjects affected by serious adverse events
subjects affected / exposed	34 / 56 (60.71%)	27 / 55 (49.09%)	10 / 30 (33.33%)
number of deaths (all causes)	9	3	1
number of deaths resulting from adverse events
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
HEAD AND NECK CANCER
subjects affected / exposed	2 / 56 (3.57%)	0 / 55 (0.00%)	1 / 30 (3.33%)
occurrences causally related to treatment / all	0 / 2	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
MALIGNANT ASCITES
subjects affected / exposed	1 / 56 (1.79%)	0 / 55 (0.00%)	0 / 30 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
NEOPLASM MALIGNANT
subjects affected / exposed	0 / 56 (0.00%)	1 / 55 (1.82%)	0 / 30 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 1	0 / 0
NEOPLASM PROGRESSION
subjects affected / exposed	1 / 56 (1.79%)	1 / 55 (1.82%)	0 / 30 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 1	0 / 1	0 / 0
TUMOUR HAEMORRHAGE
subjects affected / exposed	2 / 56 (3.57%)	0 / 55 (0.00%)	0 / 30 (0.00%)
occurrences causally related to treatment / all	0 / 2	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
TUMOUR ULCERATION
subjects affected / exposed	0 / 56 (0.00%)	1 / 55 (1.82%)	0 / 30 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Vascular disorders
ARTERIAL HAEMORRHAGE
subjects affected / exposed	1 / 56 (1.79%)	0 / 55 (0.00%)	0 / 30 (0.00%)
occurrences causally related to treatment / all	0 / 2	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 1	0 / 0	0 / 0
DEEP VEIN THROMBOSIS
subjects affected / exposed	1 / 56 (1.79%)	0 / 55 (0.00%)	0 / 30 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
HYPOTENSION
subjects affected / exposed	5 / 56 (8.93%)	0 / 55 (0.00%)	0 / 30 (0.00%)
occurrences causally related to treatment / all	2 / 5	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
General disorders and administration site conditions
ASTHENIA
subjects affected / exposed	1 / 56 (1.79%)	0 / 55 (0.00%)	0 / 30 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
CHILLS
subjects affected / exposed	0 / 56 (0.00%)	1 / 55 (1.82%)	0 / 30 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
DEVICE DISLOCATION
subjects affected / exposed	0 / 56 (0.00%)	1 / 55 (1.82%)	0 / 30 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
GENERAL PHYSICAL HEALTH DETERIORATION
subjects affected / exposed	3 / 56 (5.36%)	0 / 55 (0.00%)	0 / 30 (0.00%)
occurrences causally related to treatment / all	2 / 5	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 2	0 / 0	0 / 0
LOCALISED OEDEMA
subjects affected / exposed	1 / 56 (1.79%)	0 / 55 (0.00%)	0 / 30 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
MALAISE
subjects affected / exposed	0 / 56 (0.00%)	1 / 55 (1.82%)	0 / 30 (0.00%)
occurrences causally related to treatment / all	0 / 0	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
MUCOSAL INFLAMMATION
subjects affected / exposed	0 / 56 (0.00%)	1 / 55 (1.82%)	0 / 30 (0.00%)
occurrences causally related to treatment / all	0 / 0	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
OEDEMA PERIPHERAL
subjects affected / exposed	1 / 56 (1.79%)	0 / 55 (0.00%)	0 / 30 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
PYREXIA
subjects affected / exposed	2 / 56 (3.57%)	4 / 55 (7.27%)	0 / 30 (0.00%)
occurrences causally related to treatment / all	0 / 2	2 / 4	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Respiratory, thoracic and mediastinal disorders
ASPIRATION
subjects affected / exposed	1 / 56 (1.79%)	0 / 55 (0.00%)	0 / 30 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
DYSPNOEA
subjects affected / exposed	0 / 56 (0.00%)	1 / 55 (1.82%)	0 / 30 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
HAEMOPTYSIS
subjects affected / exposed	1 / 56 (1.79%)	0 / 55 (0.00%)	0 / 30 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
HYPOXIA
subjects affected / exposed	2 / 56 (3.57%)	0 / 55 (0.00%)	0 / 30 (0.00%)
occurrences causally related to treatment / all	0 / 2	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
INTERSTITIAL LUNG DISEASE
subjects affected / exposed	0 / 56 (0.00%)	1 / 55 (1.82%)	0 / 30 (0.00%)
occurrences causally related to treatment / all	0 / 0	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
PNEUMONIA ASPIRATION
subjects affected / exposed	1 / 56 (1.79%)	0 / 55 (0.00%)	0 / 30 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
PULMONARY EMBOLISM
subjects affected / exposed	1 / 56 (1.79%)	0 / 55 (0.00%)	0 / 30 (0.00%)
occurrences causally related to treatment / all	0 / 2	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 1	0 / 0	0 / 0
RESPIRATORY FAILURE
subjects affected / exposed	1 / 56 (1.79%)	1 / 55 (1.82%)	0 / 30 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 2	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 1	0 / 0
Psychiatric disorders
CONFUSIONAL STATE
subjects affected / exposed	0 / 56 (0.00%)	0 / 55 (0.00%)	1 / 30 (3.33%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
MENTAL STATUS CHANGES
subjects affected / exposed	0 / 56 (0.00%)	1 / 55 (1.82%)	0 / 30 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Investigations
BLOOD CREATINE INCREASED
subjects affected / exposed	1 / 56 (1.79%)	0 / 55 (0.00%)	0 / 30 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
HEPATIC ENZYME INCREASED
subjects affected / exposed	0 / 56 (0.00%)	1 / 55 (1.82%)	0 / 30 (0.00%)
occurrences causally related to treatment / all	0 / 0	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
INTERNATIONAL NORMALISED RATIO INCREASED
subjects affected / exposed	1 / 56 (1.79%)	0 / 55 (0.00%)	0 / 30 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
TRANSAMINASES INCREASED
subjects affected / exposed	1 / 56 (1.79%)	0 / 55 (0.00%)	0 / 30 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Injury, poisoning and procedural complications
ARTERIAL INJURY
subjects affected / exposed	0 / 56 (0.00%)	1 / 55 (1.82%)	0 / 30 (0.00%)
occurrences causally related to treatment / all	0 / 0	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
FEEDING TUBE COMPLICATION
subjects affected / exposed	1 / 56 (1.79%)	1 / 55 (1.82%)	1 / 30 (3.33%)
occurrences causally related to treatment / all	0 / 1	0 / 1	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
HUMERUS FRACTURE
subjects affected / exposed	0 / 56 (0.00%)	1 / 55 (1.82%)	0 / 30 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
POST PROCEDURAL DISCHARGE
subjects affected / exposed	1 / 56 (1.79%)	0 / 55 (0.00%)	0 / 30 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
POST PROCEDURAL HAEMORRHAGE
subjects affected / exposed	1 / 56 (1.79%)	0 / 55 (0.00%)	0 / 30 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
STERNAL FRACTURE
subjects affected / exposed	1 / 56 (1.79%)	0 / 55 (0.00%)	0 / 30 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Cardiac disorders
ACUTE MYOCARDIAL INFARCTION
subjects affected / exposed	1 / 56 (1.79%)	1 / 55 (1.82%)	0 / 30 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
ARTERIOSCLEROSIS CORONARY ARTERY
subjects affected / exposed	0 / 56 (0.00%)	1 / 55 (1.82%)	0 / 30 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
ATRIAL FIBRILLATION
subjects affected / exposed	2 / 56 (3.57%)	0 / 55 (0.00%)	0 / 30 (0.00%)
occurrences causally related to treatment / all	0 / 2	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
CARDIAC FAILURE CONGESTIVE
subjects affected / exposed	0 / 56 (0.00%)	1 / 55 (1.82%)	0 / 30 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Nervous system disorders
ATAXIA
subjects affected / exposed	0 / 56 (0.00%)	0 / 55 (0.00%)	1 / 30 (3.33%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
CEREBROVASCULAR ACCIDENT
subjects affected / exposed	0 / 56 (0.00%)	0 / 55 (0.00%)	1 / 30 (3.33%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 1
CONVULSION
subjects affected / exposed	0 / 56 (0.00%)	0 / 55 (0.00%)	1 / 30 (3.33%)
occurrences causally related to treatment / all	0 / 0	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
DIZZINESS
subjects affected / exposed	0 / 56 (0.00%)	0 / 55 (0.00%)	1 / 30 (3.33%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
PRESYNCOPE
subjects affected / exposed	1 / 56 (1.79%)	0 / 55 (0.00%)	0 / 30 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
SYNCOPE
subjects affected / exposed	1 / 56 (1.79%)	0 / 55 (0.00%)	0 / 30 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Blood and lymphatic system disorders
ANAEMIA
subjects affected / exposed	1 / 56 (1.79%)	3 / 55 (5.45%)	0 / 30 (0.00%)
occurrences causally related to treatment / all	0 / 1	3 / 3	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
FEBRILE NEUTROPENIA
subjects affected / exposed	3 / 56 (5.36%)	4 / 55 (7.27%)	0 / 30 (0.00%)
occurrences causally related to treatment / all	3 / 4	4 / 4	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
NEUTROPENIA
subjects affected / exposed	3 / 56 (5.36%)	3 / 55 (5.45%)	0 / 30 (0.00%)
occurrences causally related to treatment / all	4 / 4	3 / 3	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
PANCYTOPENIA
subjects affected / exposed	2 / 56 (3.57%)	1 / 55 (1.82%)	0 / 30 (0.00%)
occurrences causally related to treatment / all	2 / 2	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
THROMBOCYTOPENIA
subjects affected / exposed	2 / 56 (3.57%)	0 / 55 (0.00%)	0 / 30 (0.00%)
occurrences causally related to treatment / all	2 / 2	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Gastrointestinal disorders
ABDOMINAL PAIN
subjects affected / exposed	2 / 56 (3.57%)	0 / 55 (0.00%)	0 / 30 (0.00%)
occurrences causally related to treatment / all	1 / 2	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
ABDOMINAL WALL DISORDER
subjects affected / exposed	0 / 56 (0.00%)	0 / 55 (0.00%)	1 / 30 (3.33%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
APHAGIA
subjects affected / exposed	1 / 56 (1.79%)	0 / 55 (0.00%)	0 / 30 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
APHTHOUS STOMATITIS
subjects affected / exposed	1 / 56 (1.79%)	0 / 55 (0.00%)	0 / 30 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
CONSTIPATION
subjects affected / exposed	0 / 56 (0.00%)	1 / 55 (1.82%)	0 / 30 (0.00%)
occurrences causally related to treatment / all	0 / 0	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
DIARRHOEA
subjects affected / exposed	6 / 56 (10.71%)	2 / 55 (3.64%)	0 / 30 (0.00%)
occurrences causally related to treatment / all	8 / 9	3 / 3	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
DUODENAL ULCER PERFORATION
subjects affected / exposed	0 / 56 (0.00%)	1 / 55 (1.82%)	0 / 30 (0.00%)
occurrences causally related to treatment / all	0 / 0	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
DYSPHAGIA
subjects affected / exposed	0 / 56 (0.00%)	3 / 55 (5.45%)	0 / 30 (0.00%)
occurrences causally related to treatment / all	0 / 0	1 / 3	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
GASTROINTESTINAL HAEMORRHAGE
subjects affected / exposed	2 / 56 (3.57%)	0 / 55 (0.00%)	0 / 30 (0.00%)
occurrences causally related to treatment / all	1 / 2	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
HAEMATEMESIS
subjects affected / exposed	1 / 56 (1.79%)	0 / 55 (0.00%)	0 / 30 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
ILEUS
subjects affected / exposed	0 / 56 (0.00%)	1 / 55 (1.82%)	0 / 30 (0.00%)
occurrences causally related to treatment / all	0 / 0	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
INTESTINAL OBSTRUCTION
subjects affected / exposed	0 / 56 (0.00%)	1 / 55 (1.82%)	0 / 30 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
NAUSEA
subjects affected / exposed	2 / 56 (3.57%)	4 / 55 (7.27%)	0 / 30 (0.00%)
occurrences causally related to treatment / all	2 / 2	4 / 4	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
OESOPHAGEAL STENOSIS
subjects affected / exposed	0 / 56 (0.00%)	0 / 55 (0.00%)	1 / 30 (3.33%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
ORAL CAVITY FISTULA
subjects affected / exposed	0 / 56 (0.00%)	1 / 55 (1.82%)	0 / 30 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
TONGUE HAEMORRHAGE
subjects affected / exposed	0 / 56 (0.00%)	0 / 55 (0.00%)	1 / 30 (3.33%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
VOMITING
subjects affected / exposed	2 / 56 (3.57%)	4 / 55 (7.27%)	1 / 30 (3.33%)
occurrences causally related to treatment / all	2 / 2	4 / 4	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Hepatobiliary disorders
CHOLECYSTITIS
subjects affected / exposed	1 / 56 (1.79%)	0 / 55 (0.00%)	0 / 30 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
HEPATIC FAILURE
subjects affected / exposed	0 / 56 (0.00%)	1 / 55 (1.82%)	0 / 30 (0.00%)
occurrences causally related to treatment / all	0 / 0	2 / 2	0 / 0
deaths causally related to treatment / all	0 / 0	1 / 1	0 / 0
Skin and subcutaneous tissue disorders
ACNE
subjects affected / exposed	1 / 56 (1.79%)	0 / 55 (0.00%)	0 / 30 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Renal and urinary disorders
ACUTE PRERENAL FAILURE
subjects affected / exposed	1 / 56 (1.79%)	0 / 55 (0.00%)	0 / 30 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
RENAL FAILURE
subjects affected / exposed	0 / 56 (0.00%)	3 / 55 (5.45%)	0 / 30 (0.00%)
occurrences causally related to treatment / all	0 / 0	3 / 3	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
RENAL FAILURE ACUTE
subjects affected / exposed	2 / 56 (3.57%)	0 / 55 (0.00%)	0 / 30 (0.00%)
occurrences causally related to treatment / all	2 / 3	0 / 0	0 / 0
deaths causally related to treatment / all	1 / 1	0 / 0	0 / 0
Musculoskeletal and connective tissue disorders
MUSCULAR WEAKNESS
subjects affected / exposed	0 / 56 (0.00%)	0 / 55 (0.00%)	1 / 30 (3.33%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
MUSCULOSKELETAL CHEST PAIN
subjects affected / exposed	1 / 56 (1.79%)	0 / 55 (0.00%)	0 / 30 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
RHABDOMYOLYSIS
subjects affected / exposed	0 / 56 (0.00%)	1 / 55 (1.82%)	0 / 30 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Infections and infestations
ABDOMINAL ABSCESS
subjects affected / exposed	1 / 56 (1.79%)	0 / 55 (0.00%)	0 / 30 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
BETA HAEMOLYTIC STREPTOCOCCAL INFECTION
subjects affected / exposed	1 / 56 (1.79%)	0 / 55 (0.00%)	0 / 30 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
BRONCHITIS
subjects affected / exposed	0 / 56 (0.00%)	0 / 55 (0.00%)	1 / 30 (3.33%)
occurrences causally related to treatment / all	0 / 0	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
CELLULITIS
subjects affected / exposed	1 / 56 (1.79%)	0 / 55 (0.00%)	0 / 30 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
CLOSTRIDIUM DIFFICILE COLITIS
subjects affected / exposed	1 / 56 (1.79%)	0 / 55 (0.00%)	0 / 30 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
FUNGAEMIA
subjects affected / exposed	0 / 56 (0.00%)	1 / 55 (1.82%)	0 / 30 (0.00%)
occurrences causally related to treatment / all	0 / 0	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
NEUTROPENIC SEPSIS
subjects affected / exposed	1 / 56 (1.79%)	0 / 55 (0.00%)	0 / 30 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
ORAL INFECTION
subjects affected / exposed	0 / 56 (0.00%)	1 / 55 (1.82%)	0 / 30 (0.00%)
occurrences causally related to treatment / all	0 / 0	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
OSTEOMYELITIS
subjects affected / exposed	0 / 56 (0.00%)	1 / 55 (1.82%)	0 / 30 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
PNEUMONIA
subjects affected / exposed	4 / 56 (7.14%)	6 / 55 (10.91%)	3 / 30 (10.00%)
occurrences causally related to treatment / all	3 / 5	4 / 6	0 / 4
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
PNEUMONIA STAPHYLOCOCCAL
subjects affected / exposed	2 / 56 (3.57%)	0 / 55 (0.00%)	0 / 30 (0.00%)
occurrences causally related to treatment / all	1 / 3	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 1	0 / 0	0 / 0
PSEUDOMONAL SEPSIS
subjects affected / exposed	1 / 56 (1.79%)	0 / 55 (0.00%)	0 / 30 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
PSEUDOMONAS INFECTION
subjects affected / exposed	0 / 56 (0.00%)	1 / 55 (1.82%)	0 / 30 (0.00%)
occurrences causally related to treatment / all	0 / 0	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
SEPSIS
subjects affected / exposed	3 / 56 (5.36%)	0 / 55 (0.00%)	0 / 30 (0.00%)
occurrences causally related to treatment / all	3 / 5	0 / 0	0 / 0
deaths causally related to treatment / all	1 / 2	0 / 0	0 / 0
SEPTIC SHOCK
subjects affected / exposed	0 / 56 (0.00%)	1 / 55 (1.82%)	1 / 30 (3.33%)
occurrences causally related to treatment / all	0 / 0	1 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
STAPHYLOCOCCAL INFECTION
subjects affected / exposed	1 / 56 (1.79%)	2 / 55 (3.64%)	0 / 30 (0.00%)
occurrences causally related to treatment / all	0 / 1	2 / 2	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
STAPHYLOCOCCAL SEPSIS
subjects affected / exposed	1 / 56 (1.79%)	0 / 55 (0.00%)	0 / 30 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
STENOTROPHOMONAS INFECTION
subjects affected / exposed	0 / 56 (0.00%)	1 / 55 (1.82%)	0 / 30 (0.00%)
occurrences causally related to treatment / all	0 / 0	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
URINARY TRACT INFECTION
subjects affected / exposed	1 / 56 (1.79%)	0 / 55 (0.00%)	0 / 30 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
UROSEPSIS
subjects affected / exposed	1 / 56 (1.79%)	0 / 55 (0.00%)	0 / 30 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
WOUND INFECTION
subjects affected / exposed	1 / 56 (1.79%)	0 / 55 (0.00%)	0 / 30 (0.00%)
occurrences causally related to treatment / all	0 / 2	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Metabolism and nutrition disorders
DECREASED APPETITE
subjects affected / exposed	0 / 56 (0.00%)	1 / 55 (1.82%)	0 / 30 (0.00%)
occurrences causally related to treatment / all	0 / 0	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
DEHYDRATION
subjects affected / exposed	8 / 56 (14.29%)	2 / 55 (3.64%)	1 / 30 (3.33%)
occurrences causally related to treatment / all	6 / 10	2 / 2	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
ELECTROLYTE IMBALANCE
subjects affected / exposed	2 / 56 (3.57%)	0 / 55 (0.00%)	0 / 30 (0.00%)
occurrences causally related to treatment / all	2 / 2	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
FAILURE TO THRIVE
subjects affected / exposed	0 / 56 (0.00%)	0 / 55 (0.00%)	1 / 30 (3.33%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
HYPERNATRAEMIA
subjects affected / exposed	1 / 56 (1.79%)	0 / 55 (0.00%)	0 / 30 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
HYPOCALCAEMIA
subjects affected / exposed	0 / 56 (0.00%)	1 / 55 (1.82%)	0 / 30 (0.00%)
occurrences causally related to treatment / all	0 / 0	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
HYPOKALAEMIA
subjects affected / exposed	1 / 56 (1.79%)	1 / 55 (1.82%)	0 / 30 (0.00%)
occurrences causally related to treatment / all	0 / 1	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
HYPOMAGNESAEMIA
subjects affected / exposed	1 / 56 (1.79%)	2 / 55 (3.64%)	1 / 30 (3.33%)
occurrences causally related to treatment / all	1 / 1	2 / 2	3 / 3
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
HYPONATRAEMIA
subjects affected / exposed	1 / 56 (1.79%)	1 / 55 (1.82%)	1 / 30 (3.33%)
occurrences causally related to treatment / all	1 / 1	0 / 1	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
MALNUTRITION
subjects affected / exposed	0 / 56 (0.00%)	0 / 55 (0.00%)	1 / 30 (3.33%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0

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

Non-serious adverse events	First-line: Panitumumab Plus Chemotherapy	First-line: Chemotherapy Alone	Second-line: Panitumumab Monotherapy
Total subjects affected by non serious adverse events
subjects affected / exposed	54 / 56 (96.43%)	53 / 55 (96.36%)	26 / 30 (86.67%)
Vascular disorders
HYPERTENSION
subjects affected / exposed	3 / 56 (5.36%)	2 / 55 (3.64%)	0 / 30 (0.00%)
occurrences all number	5	2	0
HYPOTENSION
subjects affected / exposed	6 / 56 (10.71%)	2 / 55 (3.64%)	2 / 30 (6.67%)
occurrences all number	6	3	2
General disorders and administration site conditions
ASTHENIA
subjects affected / exposed	13 / 56 (23.21%)	5 / 55 (9.09%)	3 / 30 (10.00%)
occurrences all number	25	6	4
CHILLS
subjects affected / exposed	5 / 56 (8.93%)	3 / 55 (5.45%)	2 / 30 (6.67%)
occurrences all number	6	3	2
FACE OEDEMA
subjects affected / exposed	4 / 56 (7.14%)	1 / 55 (1.82%)	1 / 30 (3.33%)
occurrences all number	5	1	1
LOCALISED OEDEMA
subjects affected / exposed	1 / 56 (1.79%)	1 / 55 (1.82%)	2 / 30 (6.67%)
occurrences all number	1	1	2
FATIGUE
subjects affected / exposed	28 / 56 (50.00%)	28 / 55 (50.91%)	5 / 30 (16.67%)
occurrences all number	50	43	5
MUCOSAL INFLAMMATION
subjects affected / exposed	15 / 56 (26.79%)	7 / 55 (12.73%)	1 / 30 (3.33%)
occurrences all number	24	7	2
OEDEMA
subjects affected / exposed	4 / 56 (7.14%)	1 / 55 (1.82%)	0 / 30 (0.00%)
occurrences all number	4	1	0
OEDEMA PERIPHERAL
subjects affected / exposed	4 / 56 (7.14%)	10 / 55 (18.18%)	2 / 30 (6.67%)
occurrences all number	4	12	2
PAIN
subjects affected / exposed	4 / 56 (7.14%)	1 / 55 (1.82%)	1 / 30 (3.33%)
occurrences all number	4	1	1
PYREXIA
subjects affected / exposed	8 / 56 (14.29%)	8 / 55 (14.55%)	3 / 30 (10.00%)
occurrences all number	12	8	3
Respiratory, thoracic and mediastinal disorders
COUGH
subjects affected / exposed	8 / 56 (14.29%)	5 / 55 (9.09%)	3 / 30 (10.00%)
occurrences all number	10	8	3
DYSPNOEA
subjects affected / exposed	11 / 56 (19.64%)	9 / 55 (16.36%)	2 / 30 (6.67%)
occurrences all number	14	10	2
EPISTAXIS
subjects affected / exposed	6 / 56 (10.71%)	2 / 55 (3.64%)	1 / 30 (3.33%)
occurrences all number	7	2	1
HAEMOPTYSIS
subjects affected / exposed	3 / 56 (5.36%)	1 / 55 (1.82%)	0 / 30 (0.00%)
occurrences all number	3	2	0
HICCUPS
subjects affected / exposed	2 / 56 (3.57%)	6 / 55 (10.91%)	0 / 30 (0.00%)
occurrences all number	2	6	0
OROPHARYNGEAL PAIN
subjects affected / exposed	3 / 56 (5.36%)	4 / 55 (7.27%)	2 / 30 (6.67%)
occurrences all number	7	4	4
PLEURAL EFFUSION
subjects affected / exposed	2 / 56 (3.57%)	3 / 55 (5.45%)	0 / 30 (0.00%)
occurrences all number	2	3	0
PRODUCTIVE COUGH
subjects affected / exposed	1 / 56 (1.79%)	2 / 55 (3.64%)	2 / 30 (6.67%)
occurrences all number	1	2	2
RHINORRHOEA
subjects affected / exposed	4 / 56 (7.14%)	1 / 55 (1.82%)	0 / 30 (0.00%)
occurrences all number	4	1	0
Psychiatric disorders
ANXIETY
subjects affected / exposed	8 / 56 (14.29%)	6 / 55 (10.91%)	3 / 30 (10.00%)
occurrences all number	10	7	4
DEPRESSION
subjects affected / exposed	7 / 56 (12.50%)	4 / 55 (7.27%)	0 / 30 (0.00%)
occurrences all number	7	4	0
INSOMNIA
subjects affected / exposed	5 / 56 (8.93%)	4 / 55 (7.27%)	1 / 30 (3.33%)
occurrences all number	7	4	1
Investigations
HAEMOGLOBIN DECREASED
subjects affected / exposed	3 / 56 (5.36%)	1 / 55 (1.82%)	0 / 30 (0.00%)
occurrences all number	4	1	0
WEIGHT DECREASED
subjects affected / exposed	13 / 56 (23.21%)	11 / 55 (20.00%)	6 / 30 (20.00%)
occurrences all number	21	12	7
Injury, poisoning and procedural complications
LACERATION
subjects affected / exposed	3 / 56 (5.36%)	0 / 55 (0.00%)	0 / 30 (0.00%)
occurrences all number	4	0	0
Nervous system disorders
DIZZINESS
subjects affected / exposed	13 / 56 (23.21%)	7 / 55 (12.73%)	4 / 30 (13.33%)
occurrences all number	17	8	5
DYSGEUSIA
subjects affected / exposed	5 / 56 (8.93%)	6 / 55 (10.91%)	1 / 30 (3.33%)
occurrences all number	11	6	1
HEADACHE
subjects affected / exposed	5 / 56 (8.93%)	8 / 55 (14.55%)	2 / 30 (6.67%)
occurrences all number	5	9	2
NEUROPATHY PERIPHERAL
subjects affected / exposed	9 / 56 (16.07%)	11 / 55 (20.00%)	1 / 30 (3.33%)
occurrences all number	15	15	1
PARAESTHESIA
subjects affected / exposed	2 / 56 (3.57%)	3 / 55 (5.45%)	0 / 30 (0.00%)
occurrences all number	2	4	0
PERIPHERAL SENSORY NEUROPATHY
subjects affected / exposed	2 / 56 (3.57%)	5 / 55 (9.09%)	2 / 30 (6.67%)
occurrences all number	2	6	3
POLYNEUROPATHY
subjects affected / exposed	0 / 56 (0.00%)	1 / 55 (1.82%)	2 / 30 (6.67%)
occurrences all number	0	1	2
SOMNOLENCE
subjects affected / exposed	3 / 56 (5.36%)	0 / 55 (0.00%)	0 / 30 (0.00%)
occurrences all number	4	0	0
SYNCOPE
subjects affected / exposed	3 / 56 (5.36%)	0 / 55 (0.00%)	0 / 30 (0.00%)
occurrences all number	3	0	0
TREMOR
subjects affected / exposed	3 / 56 (5.36%)	0 / 55 (0.00%)	0 / 30 (0.00%)
occurrences all number	3	0	0
Blood and lymphatic system disorders
ANAEMIA
subjects affected / exposed	22 / 56 (39.29%)	27 / 55 (49.09%)	7 / 30 (23.33%)
occurrences all number	58	87	7
FEBRILE NEUTROPENIA
subjects affected / exposed	0 / 56 (0.00%)	3 / 55 (5.45%)	0 / 30 (0.00%)
occurrences all number	0	3	0
LEUKOPENIA
subjects affected / exposed	7 / 56 (12.50%)	5 / 55 (9.09%)	0 / 30 (0.00%)
occurrences all number	8	9	0
NEUTROPENIA
subjects affected / exposed	9 / 56 (16.07%)	9 / 55 (16.36%)	1 / 30 (3.33%)
occurrences all number	13	16	1
THROMBOCYTOPENIA
subjects affected / exposed	5 / 56 (8.93%)	5 / 55 (9.09%)	1 / 30 (3.33%)
occurrences all number	8	14	1
Ear and labyrinth disorders
TINNITUS
subjects affected / exposed	0 / 56 (0.00%)	4 / 55 (7.27%)	2 / 30 (6.67%)
occurrences all number	0	5	2
VERTIGO
subjects affected / exposed	0 / 56 (0.00%)	4 / 55 (7.27%)	1 / 30 (3.33%)
occurrences all number	0	4	1
Eye disorders
CONJUNCTIVITIS
subjects affected / exposed	8 / 56 (14.29%)	0 / 55 (0.00%)	2 / 30 (6.67%)
occurrences all number	13	0	2
DRY EYE
subjects affected / exposed	1 / 56 (1.79%)	0 / 55 (0.00%)	2 / 30 (6.67%)
occurrences all number	1	0	2
LACRIMATION INCREASED
subjects affected / exposed	2 / 56 (3.57%)	4 / 55 (7.27%)	0 / 30 (0.00%)
occurrences all number	2	4	0
Gastrointestinal disorders
ABDOMINAL PAIN
subjects affected / exposed	7 / 56 (12.50%)	3 / 55 (5.45%)	0 / 30 (0.00%)
occurrences all number	7	6	0
ABDOMINAL PAIN UPPER
subjects affected / exposed	2 / 56 (3.57%)	3 / 55 (5.45%)	1 / 30 (3.33%)
occurrences all number	2	3	1
CONSTIPATION
subjects affected / exposed	15 / 56 (26.79%)	9 / 55 (16.36%)	3 / 30 (10.00%)
occurrences all number	19	11	3
DIARRHOEA
subjects affected / exposed	25 / 56 (44.64%)	16 / 55 (29.09%)	5 / 30 (16.67%)
occurrences all number	51	20	5
DRY MOUTH
subjects affected / exposed	2 / 56 (3.57%)	3 / 55 (5.45%)	2 / 30 (6.67%)
occurrences all number	2	3	2
DYSPEPSIA
subjects affected / exposed	4 / 56 (7.14%)	6 / 55 (10.91%)	1 / 30 (3.33%)
occurrences all number	4	6	1
DYSPHAGIA
subjects affected / exposed	9 / 56 (16.07%)	4 / 55 (7.27%)	5 / 30 (16.67%)
occurrences all number	11	4	6
MOUTH ULCERATION
subjects affected / exposed	4 / 56 (7.14%)	0 / 55 (0.00%)	0 / 30 (0.00%)
occurrences all number	4	0	0
NAUSEA
subjects affected / exposed	34 / 56 (60.71%)	33 / 55 (60.00%)	4 / 30 (13.33%)
occurrences all number	60	45	4
RECTAL HAEMORRHAGE
subjects affected / exposed	3 / 56 (5.36%)	0 / 55 (0.00%)	0 / 30 (0.00%)
occurrences all number	3	0	0
STOMATITIS
subjects affected / exposed	9 / 56 (16.07%)	3 / 55 (5.45%)	1 / 30 (3.33%)
occurrences all number	12	4	1
VOMITING
subjects affected / exposed	15 / 56 (26.79%)	18 / 55 (32.73%)	2 / 30 (6.67%)
occurrences all number	28	26	2
Skin and subcutaneous tissue disorders
ACNE
subjects affected / exposed	7 / 56 (12.50%)	0 / 55 (0.00%)	3 / 30 (10.00%)
occurrences all number	23	0	4
ALOPECIA
subjects affected / exposed	18 / 56 (32.14%)	14 / 55 (25.45%)	0 / 30 (0.00%)
occurrences all number	22	18	0
DECUBITUS ULCER
subjects affected / exposed	3 / 56 (5.36%)	0 / 55 (0.00%)	1 / 30 (3.33%)
occurrences all number	3	0	1
DERMATITIS
subjects affected / exposed	4 / 56 (7.14%)	0 / 55 (0.00%)	1 / 30 (3.33%)
occurrences all number	4	0	1
DERMATITIS ACNEIFORM
subjects affected / exposed	13 / 56 (23.21%)	0 / 55 (0.00%)	3 / 30 (10.00%)
occurrences all number	33	0	4
DRY SKIN
subjects affected / exposed	13 / 56 (23.21%)	3 / 55 (5.45%)	10 / 30 (33.33%)
occurrences all number	16	3	10
ERYTHEMA
subjects affected / exposed	7 / 56 (12.50%)	0 / 55 (0.00%)	0 / 30 (0.00%)
occurrences all number	11	0	0
NAIL DISORDER
subjects affected / exposed	6 / 56 (10.71%)	2 / 55 (3.64%)	1 / 30 (3.33%)
occurrences all number	21	3	1
PRURITUS
subjects affected / exposed	5 / 56 (8.93%)	3 / 55 (5.45%)	4 / 30 (13.33%)
occurrences all number	6	3	4
RASH
subjects affected / exposed	21 / 56 (37.50%)	2 / 55 (3.64%)	13 / 30 (43.33%)
occurrences all number	42	2	24
SKIN EXFOLIATION
subjects affected / exposed	4 / 56 (7.14%)	0 / 55 (0.00%)	0 / 30 (0.00%)
occurrences all number	4	0	0
SKIN FISSURES
subjects affected / exposed	1 / 56 (1.79%)	0 / 55 (0.00%)	2 / 30 (6.67%)
occurrences all number	1	0	2
Renal and urinary disorders
NOCTURIA
subjects affected / exposed	0 / 56 (0.00%)	3 / 55 (5.45%)	0 / 30 (0.00%)
occurrences all number	0	3	0
Musculoskeletal and connective tissue disorders
ARTHRALGIA
subjects affected / exposed	3 / 56 (5.36%)	0 / 55 (0.00%)	2 / 30 (6.67%)
occurrences all number	5	0	2
BACK PAIN
subjects affected / exposed	5 / 56 (8.93%)	2 / 55 (3.64%)	1 / 30 (3.33%)
occurrences all number	5	2	1
BONE PAIN
subjects affected / exposed	1 / 56 (1.79%)	3 / 55 (5.45%)	0 / 30 (0.00%)
occurrences all number	2	4	0
MUSCLE SPASMS
subjects affected / exposed	2 / 56 (3.57%)	0 / 55 (0.00%)	2 / 30 (6.67%)
occurrences all number	2	0	2
MUSCULAR WEAKNESS
subjects affected / exposed	1 / 56 (1.79%)	3 / 55 (5.45%)	0 / 30 (0.00%)
occurrences all number	1	3	0
NECK PAIN
subjects affected / exposed	4 / 56 (7.14%)	0 / 55 (0.00%)	2 / 30 (6.67%)
occurrences all number	4	0	3
PAIN IN EXTREMITY
subjects affected / exposed	4 / 56 (7.14%)	1 / 55 (1.82%)	1 / 30 (3.33%)
occurrences all number	6	1	1
PAIN IN JAW
subjects affected / exposed	3 / 56 (5.36%)	4 / 55 (7.27%)	0 / 30 (0.00%)
occurrences all number	3	5	0
Infections and infestations
BRONCHITIS
subjects affected / exposed	3 / 56 (5.36%)	1 / 55 (1.82%)	1 / 30 (3.33%)
occurrences all number	3	1	1
CANDIDIASIS
subjects affected / exposed	3 / 56 (5.36%)	2 / 55 (3.64%)	1 / 30 (3.33%)
occurrences all number	3	3	1
CELLULITIS
subjects affected / exposed	1 / 56 (1.79%)	1 / 55 (1.82%)	2 / 30 (6.67%)
occurrences all number	2	1	2
PARONYCHIA
subjects affected / exposed	2 / 56 (3.57%)	0 / 55 (0.00%)	2 / 30 (6.67%)
occurrences all number	3	0	2
PNEUMONIA
subjects affected / exposed	4 / 56 (7.14%)	1 / 55 (1.82%)	0 / 30 (0.00%)
occurrences all number	4	1	0
URINARY TRACT INFECTION
subjects affected / exposed	3 / 56 (5.36%)	1 / 55 (1.82%)	0 / 30 (0.00%)
occurrences all number	4	1	0
Metabolism and nutrition disorders
CACHEXIA
subjects affected / exposed	3 / 56 (5.36%)	0 / 55 (0.00%)	0 / 30 (0.00%)
occurrences all number	3	0	0
DECREASED APPETITE
subjects affected / exposed	20 / 56 (35.71%)	10 / 55 (18.18%)	4 / 30 (13.33%)
occurrences all number	26	12	4
DEHYDRATION
subjects affected / exposed	11 / 56 (19.64%)	3 / 55 (5.45%)	3 / 30 (10.00%)
occurrences all number	12	3	3
HYPOALBUMINAEMIA
subjects affected / exposed	4 / 56 (7.14%)	1 / 55 (1.82%)	0 / 30 (0.00%)
occurrences all number	5	1	0
HYPOCALCAEMIA
subjects affected / exposed	7 / 56 (12.50%)	4 / 55 (7.27%)	1 / 30 (3.33%)
occurrences all number	13	17	1
HYPOKALAEMIA
subjects affected / exposed	17 / 56 (30.36%)	6 / 55 (10.91%)	0 / 30 (0.00%)
occurrences all number	29	12	0
HYPOMAGNESAEMIA
subjects affected / exposed	23 / 56 (41.07%)	13 / 55 (23.64%)	5 / 30 (16.67%)
occurrences all number	84	21	17
HYPONATRAEMIA
subjects affected / exposed	5 / 56 (8.93%)	3 / 55 (5.45%)	0 / 30 (0.00%)
occurrences all number	8	5	0
HYPOPHOSPHATAEMIA
subjects affected / exposed	4 / 56 (7.14%)	3 / 55 (5.45%)	2 / 30 (6.67%)
occurrences all number	4	3	2

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Were there any global substantial amendments to the protocol? Yes

12 Dec 2007

- Added global language from protocol template and increased enrollment period to allow for EU expansion  - Incorporated information from the EXTREME trial into the background and sample size calculation section. This change resulted in a reduction of the sample size from 150 to 110. - Added a requirement for first-cycle G-CSF prophylaxis. - Inclusion and exclusion criteria were modified to minimize identified burdens to enrollment and to be consistent with other internal/external head and neck trials.

10 Aug 2009

- Subjects ≥ 70 years of age were excluded. This is based on an observation that prior to Amendment 2, more deaths that occurred within 60 days of last protocol treatment arm occurred among older subjects (50% of deaths within 60 days of the last protocol-defined treatment among 13% of randomized subjects across arms). - A mid cycle (day 11 visit) was added to check subjects’ vital signs, key laboratory values, and to document adverse events - The entry criterion for creatinine clearance was increased to ≥ 60 mL/min - Added an additional safety data review once each additional group of 10 randomized subjects all had the opportunity to complete 2 cycles of treatment.

11 Jan 2012

- Revised the definition of PFS to “the time from the date of randomization to the date of first disease progression determined by the investigators per modified RECIST v1.0, or death within 60 days after the last evaluable tumor assessment or randomization date (whichever was later) during the first-line treatment phase.” Subjects not meeting the criteria by the cutoff date are censored at the last evaluable tumor assessment date during the first-line treatment. - Used the investigators’ assessment of response to determine the primary endpoint of PFS because the target 80 PFS events based on response assessment by the independent central review group may not be attained at the time of data cut-off of the PFS analysis. - Consolidated the timing the primary and final analyses into a single analysis approximately 24 months after the last subject was randomized.

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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Baseline characteristics

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Primary: Progression Free Survival (PFS) During the First-line Treatment Phase

Primary: Progression Free Survival (PFS) During the First-line Treatment Phase

Secondary: Overall Objective Response Rate (ORR) During the First-line Treatment Phase

Secondary: Overall Objective Response Rate (ORR) During the First-line Treatment Phase

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Secondary: Rate of Disease Control (RDC) During the First-line Treatment Phase

Secondary: Duration of Response (DOR) During the First-line Treatment Phase

Secondary: Duration of Response (DOR) During the First-line Treatment Phase

Secondary: Time to Response (TTR) During the First-line Treatment Phase

Secondary: Time to Response (TTR) During the First-line Treatment Phase

Secondary: Overall Survival (OS) For the First-line Treatment

Secondary: Overall Survival (OS) For the First-line Treatment

Secondary: Progression Free Survival (PFS) During the Second-line Treatment Phase

Secondary: Progression Free Survival (PFS) During the Second-line Treatment Phase

Secondary: Overall Objective Response Rate (ORR) During the Second-line Treatment Phase

Secondary: Overall Objective Response Rate (ORR) During the Second-line Treatment Phase

Secondary: Duration of Response (DOR) During the Second-line Treatment Phase

Secondary: Duration of Response (DOR) During the Second-line Treatment Phase

Secondary: Rate of Disease Control (RDC) During the Second-line Treatment Phase

Secondary: Rate of Disease Control (RDC) During the Second-line Treatment Phase

Secondary: Time to Response (TTR) During the Second-line Treatment Phase

Secondary: Time to Response (TTR) During the Second-line Treatment Phase

Secondary: Overall Survival (OS) for Second-line Treatment

Secondary: Overall Survival (OS) for Second-line Treatment

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Substantial protocol amendments (globally)

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