A Multicenter, Randomized, Open-label, Phase III Trial to Assess Efficacy and Safety of Cetuximab When Given in Combination With Cisplatin Plus 5 Fluorouracil Versus Cisplatin Plus 5-fluorouracil Alone for the First-line Treatment of Chinese Subjects With Recurrent and/or Metastatic Squamous Cell Carcinoma of the Head and Neck
Phase: PHASE3
Conditions: Carcinoma, Squamous Cell of Head and Neck
Sponsor: Merck KGaA, Darmstadt, Germany

Cetuximab
China First-line Head and Neck Trial (CHANGE2)
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Clinical Trial Protocol
Clinical Trial Protocol Number
EMR062202-060
Title
A multicenter, randomized, open-label, Phase III trial
to assess efficacy and safety of cetuximab when given 
in combination with cisplatin plus 5-fluorouracil
versus cisplatin plus 5-fluorouracil alone for the 
first-line treatment of Chinese subjects with recurrent 
and/or metastatic squamous cell carcinoma of the 
head and neck
Phase
III
IND Number
Not applicable
EudraCT Number 
Not applicable
Coordinating Investigators
Sponsor
Merck KGaA
Frankfurter Strasse 250
64293 Darmstadt, Germany
Clinical Trial Protocol Version
26 February 2018 / Final 3.0
Replaces Version
20 April 2016 / Final 2.0 
-
-
This document is the property of Merck KGaA, Darmstadt, Germany, or one of its subsidiaries. It 
is intended for restricted use only and may not – in full or part – be passed on, reproduced, 
published or used without express permission of Merck KGaA, Darmstadt, Germany, or its 
subsidiaries. Copyright © 2018 by Merck KGaA, Darmstadt, Germany, or its affiliate. All rights 
reserved.
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Protocol Table of Contents
Protocol Table of Contents ..................................................................................................2
Table of In-Text Tables .......................................................................................................7
Table of In-Text Figures......................................................................................................7
List of Abbreviations ...........................................................................................................8
1
Synopsis..............................................................................................11
2
Sponsor, Investigators and Trial Administrative Structure ................20
3
Background Information.....................................................................21
3.1
Cetuximab...........................................................................................21
3.2
Epidermal Growth Factor Receptor in Cancer ...................................21
3.3
Epidermal Growth Factor Receptor Inhibition and the Cell Cycle ....22
3.4
Nonclinical Studies of Cetuximab......................................................22
3.4.1
Nonclinical Absorption, Distribution, Metabolism, and Excretion....22
3.4.2
Nonclinical Toxicology ......................................................................23
3.4.3
Nonclinical Efficacy Pharmacology and Safety Pharmacology.........23
3.5
Dose Selection Criteria and Clinical Pharmacokinetics of 
Cetuximab...........................................................................................24
3.6
Immunogenicity..................................................................................24
3.7
Clinical Development of Cetuximab ..................................................24
3.7.1
Clinical Pharmacology........................................................................24
3.7.2
Cetuximab plus Chemotherapy in the Treatment of Recurrent 
and/or Metastatic SCCHN..................................................................25
3.7.3
Reasonably Anticipated Serious Adverse Events...............................26
3.7.4
Related Adverse Events......................................................................26
3.8
Trial Rationale ....................................................................................28
3.9
Risk-Benefit Assessment....................................................................28
4
Trial Objectives ..................................................................................29
4.1
Primary objective................................................................................29
4.2
Secondary objectives ..........................................................................29
5
Investigational Plan ............................................................................29
5.1
Overall Trial Design and Plan ............................................................29
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5.2
Discussion of Trial Design .................................................................32
5.3
Selection of Trial Population..............................................................33
5.3.1
Inclusion Criteria ................................................................................33
5.3.2
Exclusion Criteria...............................................................................34
5.4
Criteria for Subject Withdrawal..........................................................35
5.4.1
Withdrawal from Trial Therapy..........................................................35
5.4.2
Withdrawal from the Trial..................................................................37
5.5
Premature Termination of the Trial ....................................................37
5.6
Definition of End of Trial...................................................................37
6
Investigational Medicinal Product and Other Drugs Used in the 
Trial.....................................................................................................38
6.1
Description of Investigational Medicinal Product..............................38
6.2
Dosage and Administration ................................................................38
6.2.1
Selection and Timing of Cetuximab...................................................38
6.2.2
Dose Reductions and Treatment Alterations for Cetuximab..............40
6.3
Assignment to Treatment Arms..........................................................44
6.4
Noninvestigational Medicinal Products to be Used............................44
6.4.1
Chemotherapy.....................................................................................44
6.4.2
Other Drugs ........................................................................................51
6.5
Concomitant Medications and Therapies ...........................................52
6.5.1
Permitted Medicines...........................................................................52
6.5.2
Prohibited Medicines..........................................................................53
6.5.3
Other Trial Considerations .................................................................53
6.5.4
Special Precautions.............................................................................54
6.6
Packaging and Labeling of the Investigational Medicinal Product....54
6.7
Preparation, Handling and Storage of the Investigational 
Medicinal Product...............................................................................54
6.8
Investigational Medicinal Product Accountability.............................55
6.9
Assessment of Investigational Medicinal Product Compliance .........56
6.10
Blinding ..............................................................................................56
6.11
Emergency Unblinding.......................................................................56
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6.12
Treatment of Overdose .......................................................................56
6.13
Medical Care of Subjects after End of Trial.......................................57
7
Trial Procedures and Assessments......................................................57
7.1
Schedule of Assessments....................................................................57
7.1.1
Screening Visit....................................................................................57
7.1.2
Weekly Cetuximab Administration Visit ...........................................58
7.1.3
Start of Each Cycle Visit (Day 1 of Each 21-Day Cycle) ..................59
7.1.4
6-Weekly Evaluation Visit .................................................................59
7.1.5
End of Efficacy Assessment Visit ......................................................60
7.1.6
Safety Follow-Up Visit.......................................................................60
7.1.7
Survival Follow-Up ............................................................................60
7.2
Demographic and Other Baseline Characteristics ..............................61
7.2.1
Demographic Data..............................................................................61
7.2.2
Diagnosis of Tumor............................................................................61
7.2.3
Medical History ..................................................................................61
7.2.4
Viral Serology.....................................................................................61
7.2.5
Pregnancy Testing and Contraception................................................61
7.2.6
Echocardiogram..................................................................................62
7.2.7
Creatinine Clearance...........................................................................62
7.2.8
Other Baseline Assessments...............................................................62
7.3
Efficacy Assessment...........................................................................62
7.3.1
Documentation of Tumor Assessments..............................................62
7.3.2
Criteria for Tumor Response Evaluation............................................63
7.4
Assessment of Safety..........................................................................63
7.4.1
Adverse Events...................................................................................64
7.4.2
Pregnancy and In Utero Drug Exposure.............................................69
7.4.3
Clinical Laboratory Assessments .......................................................69
7.4.4
Vital Signs, Physical Examinations, and Other Assessments.............70
7.5
Pharmacokinetics................................................................................71
7.6
Biomarkers/Pharmacogenetics ...........................................................71
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7.7
Other Assessments..............................................................................71
8
Statistics..............................................................................................72
8.1
Sample Size ........................................................................................72
8.2
Randomization....................................................................................72
8.3
Endpoints............................................................................................73
8.3.1
Primary Endpoint................................................................................73
8.3.2
Secondary Endpoints ..........................................................................73
8.3.3
Safety Endpoints.................................................................................73
8.4
Analysis Sets.......................................................................................74
8.5
Description of Statistical Analyses.....................................................75
8.5.1
General Considerations.......................................................................75
8.5.2
Analysis of Primary Endpoint ............................................................76
8.5.3
Analysis of Secondary Endpoints.......................................................77
8.5.4
Analysis of Safety...............................................................................78
8.6
Interim and Additional Planned Analyses ..........................................79
9
Ethical and Regulatory Aspects..........................................................79
9.1
Responsibilities of the Investigator ....................................................79
9.2
Subject Information and Informed Consent .......................................79
9.3
Subject Identification and Privacy......................................................80
9.4
Emergency Medical Support and Subject Card..................................80
9.5
Clinical Trial Insurance and Compensation to Subjects.....................81
9.6
Independent Ethics Committee or Institutional Review Board..........81
9.7
Health Authorities...............................................................................81
10
Trial Management...............................................................................82
10.1
Case Report Form Handling...............................................................82
10.2
Source Data and Subject Files............................................................82
10.3
Investigator Site File and Archiving...................................................83
10.4
Monitoring, Quality Assurance and Inspection by Health 
Authorities ..........................................................................................83
10.5
Changes to the Clinical Trial Protocol................................................84
10.6
Clinical Trial Report and Publication Policy......................................84
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10.6.1
Clinical Trial Report...........................................................................84
10.6.2
Publication..........................................................................................84
11
References Cited in the Text...............................................................85
12
Appendices .........................................................................................89
Appendix I
Response Evaluation Criteria in Solid Tumors Version 1.1...............89
Appendix II
Signature Pages and Responsible Persons for the Trial......................99
Signature Page – Protocol Lead.........................................................................................99
Signature Page – Coordinating Investigator ....................................................................100
Signature Page – Principal Investigator...........................................................................102
Appendix III
Protocol Amendment 1.0 and List of Changes.................................104
Appendix IV
Protocol Amendment 1.0_Changes on Schedule of Assessment 
Table 1.1 ...........................................................................................111
Appendix V
Protocol Amendment 1.0_Changes on Figure 5.1............................114
Appendix VI
Protocol Amendment 2.0 and List of Changes.................................115
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Table of In-Text Tables
Table 1.1
Schedule of Assessments....................................................................17
Table 3.1
Adverse Events that Have Been Found to Have an Association 
with Cetuximab...................................................................................26
Table 6.1
Dose and Administration Procedure for Cetuximab...........................39
Table 6.2
Recommended Prophylaxis for Skin Toxicities .................................40
Table 6.3
Treatment Adjustment for Symptoms of Cetuximab Infusion-
related Reactions.................................................................................43
Table 6.4
Chemotherapy Regimen Every 21 Days in Arm A and B..................45
Table 6.5
Dose Reductions for Chemotherapy...................................................48
Table 6.6
Chemotherapy Dose Reduction and Treatment for Febrile 
Neutropenia.........................................................................................50
Table 6.7
Criteria for Dose Reductions Based on Hematologic Results on 
the Schedule Day of Treatment ..........................................................50
Table 6.8
Criteria for Dose Reductions Based on Nonhematologic Toxicities 
on the Scheduled Day of Treatment ...................................................51
Table 7.1
Standard Safety Laboratory Parameters .............................................69
Table 8.1
Expected Outcome of the Trial Given Different True Hazard 
Ratios..................................................................................................72
Table of In-Text Figures
Figure 5.1
Schematic of the Trial Design ............................................................30
Figure 6.1
Treatment Adjustment in the Event of Grade 3 Skin Reactions 
Considered to be Related to Cetuximab .............................................41
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List of Abbreviations
AE
Adverse event
ALT
Alanine aminotransferase
ANC
Absolute neutrophil count
AST
Aspartate aminotransferase
AUC
Area under the concentration-time curve
BOR
Best overall response
BSA
Body surface area
CI
Confidence interval
Cmax
Peak concentration
CR
Complete response
CT
Computed tomography
CTCAE
Common Terminology Criteria for Adverse Events
DCR
Disease control rate
ECG
Electrocardiogram
ECOG
Eastern Cooperative Oncology Group
eCRF
Electronic case report form
EGF
Epidermal growth factor
EGFR
Epidermal growth factor receptor
EOEA
End of efficacy assessment
5-FU
5-fluorouracil
FDG-PET
Fludeoxyglucose Positron Emission Tomography
GCP
Good Clinical Practice
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GMP
Good Manufacturing Practice
HBV
Hepatitis B virus
HCV
Hepatitis C virus
HIV
Human immunodeficiency virus
HPV
Human papilloma virus
ICF
Informed consent form
ICH
International Council for Harmonisation
IDMC
Independent Data Monitoring Committee
IEC
Independent Ethics Committee
IMP
Investigational Medicinal Product
IRB
Institutional Review Board
IRC
Independent Review Committee
ITT
Intent to Treat
IWRS
Interactive Web Response System
MedDRA
Medical Dictionary for Regulatory Affairs
MRI
Magnetic resonance imaging
OS
Overall survival
PD
Progressive disease
PET
Positron emission tomography
PFS
Progression-free survival
PK
Pharmacokinetics
PP
Per protocol
PR
Partial response
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RECIST
Response Evaluation Criteria in Solid Tumors
SAE
Serious adverse event
SCCHN
Squamous cell carcinoma of the head and neck
SD
Stable disease
TEAE
Treatment-emergent adverse event
ULN
Upper limit of normality
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1
Synopsis
Clinical Trial Protocol Number
EMR062202-060
Trial title
A multicenter, randomized, open-label, Phase III trial to 
assess efficacy and safety of cetuximab when given in 
combination with cisplatin plus 5-fluorouracil versus 
cisplatin plus 5-fluorouracil alone for the first-line 
treatment of Chinese subjects with recurrent and/or 
metastatic squamous cell carcinoma of the head and neck
Trial Phase
III
IND Number
Not applicable 
FDA covered trial
No 
EudraCT number
Not applicable 
Coordinating Investigators
Sponsor
Merck KGaA, Darmstadt, Germany
Trial centers/country
Approximately 30 trial centers in mainland China 
Planned trial period
(first subject in-last subject out)
The third quarter of 2015-The fourth quarter of 2018
Trial Registry
This trial was registered on clinicaltrials.gov as well as 
chinadrugtrials.org.cn
Objectives: 
Primary objective: The primary objective of this trial is to evaluate whether progression-free 
survival (PFS) time, as assessed by an Independent Review Committee (IRC), in subjects 
receiving cetuximab in combination with cisplatin plus 5-fluorouracil (5-FU) is longer than 
that in subjects receiving cisplatin plus 5-FU alone in the first-line treatment of recurrent and/or 
metastatic squamous cell carcinoma of the head and neck (SCCHN). 
Secondary objectives: The secondary objectives are to compare the 2 treatment arms in the 
following: 
!
PFS time, as assessed by the Investigator
!
Overall survival (OS) time
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!
Best overall response (BOR) rate
!
Disease control rate (DCR)
!
Duration of response
!
Safety
Methodology: 
This is an open-label, randomized, parallel-group trial. At the end of a 28-day screening period, 
all eligible subjects will be randomly assigned into treatment Arm A or B in a 2:1 ratio. Subjects 
in Arm A will receive a maximum of 6 cycles of chemotherapy (cisplatin plus 5-FU) and 
cetuximab weekly in the absence of progressive disease (PD), as assessed by the Investigator, 
and unacceptable toxicity. After 6 cycles of treatment, subjects who derive clinical benefit will 
continue treatment with cetuximab as monotherapy until either PD or unacceptable toxicity. 
Subjects in Arm B will receive the same chemotherapy regimen as Arm A alone for a maximum 
of 6 cycles in the absence of PD and unacceptable toxicity. 
Tumor assessment will be performed according to Response Evaluation Criteria in Solid 
Tumors (RECIST) version 1.1. The baseline tumor assessment is to be performed during the 
screening period within 28 days before the start of trial treatment. Computed tomography (CT) 
or magnetic resonance imaging (MRI) with contrast enhancement is recommended for tumor 
assessment. Subsequent tumor response evaluations will be assessed every 6 weeks (± 3 days) 
starting from the first dose of trial treatment until occurrence of PD regardless of any cycle 
delay. If treatment is discontinued for reasons other than PD, subjects will continue to have 
tumor assessments until either PD, the start of a new antitumor treatment, death, the termination 
of the trial, or loss of follow up, whichever comes first. If symptoms are suggestive of PD, 
subjects will be evaluated by imaging studies thereafter for documentation and confirmation of 
the tumor responses. 
All subjects in Arm A and B will be followed up continuously for safety evaluations according 
to schedule of assessments in Table 1.1 starting from date of first signature of informed consent.
A Safety Follow-up visit will be performed 30 days (± 3 days) after the last dose of trial 
treatment or immediately before starting any new antitumor treatment. During the treatment 
period, additional safety evaluations will be on a weekly basis (Arm A only) for physical 
examination, vital signs, documentation of adverse events and concomitant medications, and 
also at the start of each cycle (for both arms) Eastern Cooperative Oncology Group (ECOG) 
performance status, electrocardiogram (ECG), hematology, biochemistry and urinalysis. 
Survival data will be collected every 3 months after the end of efficacy assessment (EOEA)
visit until either death, loss of follow up, or the termination of the trial, whichever comes first. 
The trial will be terminated when the last subject has discontinued the trial treatment or OS 
cut-off, whichever is later. After OS cut-off and before the trial termination, only SAEs during 
treatment and at the EOEA visit will be reported, following the usual reporting procedure.
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Information collected in the EOEA forms will be limited to data on date of trial treatment 
completion, date of last treatment, subject status at end of trial, reason for discontinuation, 
disease progression (yes/no). From alive, but trial-treatment-discontinued subjects, no tumor 
response data, anti-cancer treatment and survival information will be collected.
Planned number of subjects: 240 subjects.
Primary endpoint: The primary endpoint is PFS time, as assessed by an IRC. 
Secondary endpoints: The secondary endpoints include PFS time, as assessed by the 
Investigator, OS time, BOR rate, DCR, duration of response, and safety. 
Pharmacokinetics: Not applicable. 
Other assessments: Not applicable. 
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Diagnosis and key inclusion and exclusion criteria: 
Trial population: Subjects who have recurrent and/or metastatic SCCHN excluding 
nasopharyngeal carcinoma and who have not received chemotherapy for recurrent and/or 
metastatic SCCHN. 
Key inclusion criteria: 
!
18 years of age. 
!
Histologically and/or cytologically confirmed diagnosis of SCCHN. 
!
Recurrent and/or metastatic SCCHN, not suitable for local-regional treatment. Subjects
with recurrent disease only (no metastases) must have received prior radiotherapy (as 
adjuvant treatment after surgery or as treatment for locally advanced SCCHN) as part of 
“loco-region   al treatment”, and the radiotherapy must have been completed more than 
6 months before screening imaging.
!
Presence of at least 1 measurable lesion according to RECIST version 1.1. 
!
Signed written informed consent before any trial-related activities are carried out. 
!
ECOG performance status of 0 or 1. 
Key exclusion criteria: 
!
Prior systemic chemotherapy, except if given as part of multimodal treatment, for locally 
advanced SCCHN that was completed more than 6 months before randomization. 
!
Major surgery or irradiation within 4 weeks before randomization. 
!
Previous treatment with monoclonal antibody or signal transduction inhibitors targeting 
epidermal growth factor receptor. 
!
Nasopharyngeal carcinoma. 
!
Known central nervous system metastasis and/or leptomeningeal disease. 
!
Medical or psychological condition that would not permit the subject to complete the trial 
or sign informed consent. 
!
Legal incapacity or limited legal capacity. 
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Investigational Medicinal Product: dose/mode of administration/ dosing schedule:
Cetuximab, supplied in ready-to-use 20 mL vials containing 5 mg/mL solution, will be 
administered on a weekly basis to subjects in Arm A. The initial dose will be 400 mg/m2 as an 
intravenous infusion up to a maximum speed of 5 mg/minute. The subsequent weekly dose will 
be 250 mg/m2 as an intravenous infusion up to a maximum speed of 10 mg/minute. 
Reference therapy: dose/mode of administration/dosing schedule:
Subjects in both arms will receive a maximum of 6 cycles of chemotherapy of 75 mg/m2
cisplatin as intravenous infusion (refer to China package insert) on Day 1 of each 21-day 
treatment cycle, and then 750 mg/m2/day of 5-FU as a continuous intravenous infusion over 
24 hours ± 6 hours a day from Day 1 to Day 5 of each 21-day treatment cycle. 
In the case of cisplatin-related nonhematologic toxicity, cisplatin may be replaced by 
carboplatin at a dose of target area under the serum concentration time curve of 5 in subsequent 
cycles. The decision needs to be made in discussion with the Medical Monitor on a 
case-by-case basis. Carboplatin will be administered using an intravenous infusion of 
15 minutes or longer, and in accordance with the China package insert on Day 1 of each 21-day 
treatment cycle. 
Planned treatment duration per subject:
The treatment duration per subject may vary. Subjects will be treated with a maximum of 
6 cycles of chemotherapy and/or cetuximab weekly in the absence of PD, as assessed by the 
Investigator, and unacceptable toxicity. Subjects (in Arm A) who demonstrate at least a tumor 
response of stable disease (RECIST version 1.1) after 6 cycles of trial treatment will continue 
monotherapy with cetuximab until either PD or occurrence of unacceptable toxicity. Subjects 
who stop treatment before reaching PD will continue to have tumor assessments (CT or MRI) 
every 6 weeks until either PD, the start of a new antitumor treatment, death, or termination of 
the trial, or loss of follow up, whichever comes first. Upon occurrence of PD, all trial treatments 
should be discontinued.
Statistical methods: 
Sample Size Calculation:
 
 
 
 
 
 
 
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Randomization: Randomization will be performed centrally using an interactive web response 
system (IWRS). A central stratified permuted block randomization procedure will be used to 
balance between treatment arms. The stratification factors are ECOG performance status (0 
versus 1) and the primary tumor site (oral cavity versus hypopharynx versus others).
Statistical Analyses:
The hazard ratio between the treatment arms in PFS time (based on imaging as assessed by 
IRC) will be estimated by Cox's proportional hazards model stratified by randomization strata
to assess the stratified hazard ratio. The 95% confidence interval (CI) will also be provided to 
characterize the variability of the point estimate. In discussion with Chinese Health Authority, 
this bridging trial would be regarded as positive from regulatory point of view if the point 
estimation for stratified hazard ratio less than or equal to 0.77. All secondary analyses of the 
primary variable will be performed to support the results of the primary confirmatory analysis 
and regarded as purely exploratory. 
The time-to-event endpoints will follow standard methodology by employing Kaplan-Meier
estimates, Cox’s proportional hazard model to estimate stratified hazard ratios and 
corresponding 95% CI.
The counts and percentages will be summarized for dichotomous data. 
The main statistical analysis of data is event driven and is expected to be approximately 
22 months after trial initiation (i.e., after the 144 PFS events with respect to the primary 
endpoint have occurred). The final analysis of OS (OS cut-off date should be at least 180 deaths 
[e.g., 75% of randomized subjects] have been reported, or up to 12 months after the last subject 
is randomized, whichever is earlier), will be presented in a clinical trial report addendum.
Safety data collected after the OS cut-off will be reported through patient profile. No additional 
statistical analyses will be conducted.
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Table 1.1
Schedule of Assessments
Trial Period
Screening
Cycle 1
Cycles 2-6
> 6 cycles1
6-weekly
evaluation2
EOEA3
Safety Follow-Up4
Survival 
Follow-Up5
Day
-28 to -1
1
8
15
1
8
15
1
8
15
6-weekly
30 days after treatment 
discontinuation
3-monthly
± 3 days
Informed consent
X
Randomization6
X
Primary tumor diagnosis
X
Demographics, height
X
Medical history
X
Physical examination/weight
X
X
X
X
X
X
X
X
X
X
X
X
X
Vital signs7
X
X
X
X
X
X
X
X
X
X
X
X
X
ECOG
X
X
X
X
X
X
ECG8, 11
X
X19
X
X
X
X
Hematology9, 11
X
X19
X
X
X
X
Biochemistry9, 11
X
X19
X
X
X
X
Urinalysis10, 11
X
X19
X
X
X
X
Calculated creatinine clearance12
X
24 hours creatinine clearance12
X
Serum pregnancy test (if applicable13)
X
HBV, HCV, HIV tests14
X
Known HPV status15, tobacco, and 
alcohol consumptions status
collection
X
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Trial Period
Screening
Cycle 1
Cycles 2-6
> 6 cycles1
6-weekly
evaluation2
EOEA3
Safety Follow-Up4
Survival 
Follow-Up5
Day
-28 to -1
1
8
15
1
8
15
1
8
15
6-weekly
30 days after treatment 
discontinuation
3-monthly
± 3 days
Echocardiogram
X
Inclusion/Exclusion criteria
X
Tumor assessment16
X
Will be done every 6 weeks (± 3 days)
X
Cetuximab administration17
X
X
X
X
X
X
X
X
X
Cisplatin18 and 5-FU
X
X
Survival and antitumor therapies
X
Adverse events assessment
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Concomitant medication
X
X
X
X
X
X
X
X
X
X
X
X
X
5-FU: 5-fluorouracil, ALT: alanine aminotransferase, AST: aspartate aminotransferase, CT: computed tomography, ECG: electrocardiogram, ECOG: Eastern 
Cooperative Oncology Group, EOEA: end of efficacy assessment, GGT: gamma-glutamyl transferase, HBV: hepatitis B virus, HCV: hepatitis C virus, HIV: human 
immunodeficiency virus, HPV: human papilloma virus, MRI: magnetic resonance imaging, PD: progressive disease, RECIST: Response Evaluation Criteria in Solid 
Tumors. 
1.
Arm A only: until PD or unacceptable toxicity. 
2.
All subjects in Arm A and B will be followed up continuously for safety evaluations according to schedule of assessments in this table starting from date of 
first signature of informed consent. The evaluations which are completed within 7 days at 6-weekly evaluation visit for physical examination/weight; vital 
sign; ECG; hematology; biochemistry, and urinalysis can be accepted, and these evaluations at 6-weely evaluation visit will be optional.
3.
EOEA visit will be performed on the day of the last efficacy assessment, whether or not at the end of a cycle. The day of the last efficacy assessment is 
defined as the day on which it is determined that the subject will no longer be followed up for efficacy. 
4.
Safety Follow-up visit will be performed 30 days (± 3 days) after the last dose of trial treatment or immediately before starting any new antitumor treatment. 
5.
Survival follow-up (telephone contact) will be performed every 3 months after the EOEA visit until death or the termination of the trial, whichever comes first. 
6.
If the Investigator is willing to administer prophylactic tetracycline to reduce the incidence of Grade 3 skin reactions related to cetuximab, randomization 
and the initiation of prophylactic tetracycline should be performed on Day -1 (1 day before the initiation of cetuximab treatment). 
7.
Heart rate and blood pressure will be measured in a supine position after 5 minutes at rest. For those in Arm A, vital signs must be continuously monitored 
before, during, and up to 1 hour after each cetuximab infusion. 
8.
All 12-lead ECGs will be performed after the subject has rested for 5 minutes.
9.
The results of all safety laboratory parameters must be available within 3 days before start of next chemotherapy cycle. Required hematologic parameters 
include hemoglobin, red blood cell count, white blood cell count and differential count, and platelet count. Required biochemistry parameters include 
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creatinine, AST, ALT, GGT, total bilirubin (including direct bilirubin if total bilirubin abnormal), total protein, albumin, alkaline phosphatase, sodium, 
potassium, calcium, magnesium, glucose, blood urea, and uric acid. Blood samples will be collected after fasting for at least 8 hours. 
10.
Urinalysis dipstick will be followed by microscopic examination if results are abnormal. 
11.
If 6 weekly evaluation visits and EOEA visit take place after safety follow up visit, the ECG, hematology, biochemistry, urinalysis tests can be optional.
12.
If calculated creatinine clearance is <60 mL/min, 24 hour creatinine clearance might be requested by the Investigator for confirmation.
13.
Only for female subjects of childbearing potential, including those who have had a tubal ligation. Performed within 7 days before the first dose of the trial 
treatment. Regular urine pregnancy tests are also recommended during the trial for female subjects of childbearing potential. 
14.
Viral serology will be performed only if clinically indicated. 
15.
This information to be collected is only for those who have known HPV status of their tumor at screening.
16.
Tumor assessment will be performed according to RECIST version 1.1. The baseline tumor assessment is to be performed during the screening period 
within 28 days before the start of trial treatment. The CT or MRI with contrast enhancement is recommended for tumor assessment. Subsequent tumor 
response evaluations will be assessed every 6 weeks starting from the first dose of trial treatment until occurrence of PD regardless of any cycle delay. If 
treatment is discontinued for reasons other than PD, subjects will continue to have tumor assessments until either PD, the start of a new antitumor treatment,
death, the termination of the trial, or loss of follow up, whichever comes first. If symptoms are suggestive of PD, subjects will be evaluated by imaging 
studies thereafter for documentation and confirmation of the tumor responses. Imaging must include CT or MRI of the neck (base skull to clavicles), chest, 
and abdomen. A CT or MRI of the brain and a bone scan or positron emission tomography should be considered for subjects who have possible central 
nervous system metastasis and possible bone metastasis, respectively. Tumor assessment should include a complete assessment of all target and 
nontarget lesions. 
17.
Arm A only: until PD or unacceptable toxicity. 
18.
Arm A and B for a maximum of 6 cycles in the absence of PD or unacceptable toxicity. If cisplatin results in a nonhematologic toxicity, cisplatin may be 
replaced by carboplatin in subsequent cycles. 
19.
Only if screening/last assessments were performed more than 7 days before Cycle 1, Day 1. 
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2
Sponsor, Investigators and Trial Administrative Structure
This clinical trial with cetuximab will be sponsored by Merck KGaA, Darmstadt, Germany. 
This trial will be conducted at approximately 30 centers with inpatient setting in mainland China. 
The Coordinating Investigators
 
, represent all 
Investigators for decisions and discussions regarding this trial, consistent with the International 
Council for Harmonisation (ICH) Topic E6 Good Clinical Practice (GCP; hereafter referred to as 
ICH GCP). The Coordinating Investigators will provide expert medical input and advice relating 
to trial design and execution and is responsible for the review and signoff of the clinical trial report. 
Signature pages for the Protocol Lead and the Coordinating Investigators as well as a list of 
Sponsor responsible persons are in Appendix II. 
The trial appears in the following clinical trial registry: clinicaltrials.gov and chinadrugtrials.org.cn 
(preregister number: CDEL20140112). 
An Independent Review Committee (IRC) will conduct a blinded review of the images and 
predefined clinical data of all subjects according to Response Evaluation Criteria in Solid Tumors 
(RECIST) version 1.1, based on a separate charter outlining details of the review process. 
An Independent Data Monitoring Committee (IDMC) will perform periodic reviews to evaluate 
the safety of the subjects in this trial. The details and periodicity of the safety monitoring process 
will be specified in a dedicated charter. 
The Sponsor will supply the cetuximab medication. Cetuximab will be produced under Good 
Manufacturing Practice (GMP) conditions by the Sponsor, and will be finally released by the 
Department of Clinical Trial Supplies of the Sponsor. 
Trial monitoring, data management and statistical analysis of this trial will be performed by the 
Sponsor or a designated contract research organization. 
The Department of Drug Safety of the Sponsor or their designated representatives will supervise 
drug safety and the timely reporting of adverse events (AEs) and serious AEs (SAEs) to all 
concerned parties in accordance with applicable guideline, laws, and regulations. 
Quality assurance will be supervised by the Quality Assurance Department of the Sponsor. 
Details of structures and associated procedures will be defined in a separate Manual of Operation, 
which will be prepared under the supervision of the Clinical Trial Leader. 
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3
Background Information
3.1
Cetuximab
As an antibody to epidermal growth factor receptor (EGFR), as of 2015, Erbitux® (cetuximab) was 
granted marketing authorizations in 100 countries for colorectal cancer and 98 countries for 
squamous cell carcinoma of head and neck (SCCHN). The indications included metastatic 
colorectal cancer in combination with irinotecan and/or as monotherapy, and SCCHN in 
combination with radiotherapy (locally advanced SCCHN), in combination with platinum-based 
chemotherapy, and/or as monotherapy (in subjects with recurrent or metastatic disease). 
Cetuximab is a chimerized antibody of the immunoglobulin G1 subclass, which was originally 
derived from a mouse myeloma cell-line (1). It was constructed by cloning the heavy and light
chains of a murine monoclonal antibody directed against the EGFR (M225) and adapting them for
expression together with the constant regions of the human kappa light chain and human gamma 
1 heavy chain. The chimerization process resulted in an antibody with binding affinity to EGFR 
approximately one log higher than endogenous ligands, such as epidermal growth factor (EGF) 
and transforming growth factor alpha (2, 3).
Cetuximab blocks the binding of EGF and other ligands to the EGFR and prevents EGFR
dimerization (4), thereby inhibiting ligand induced activation of this receptor tyrosine kinase. This 
results in the inhibition of cell growth, induction of apoptosis, and decreased production of matrix 
metalloproteinase and vascular endothelial growth factor (2).
Cetuximab also stimulates EGFR internalization (5) and eventual degradation (6), by removing 
the receptor from the cell surface and thereby preventing interaction with its ligand. In addition, 
cetuximab can mediate antibody-dependent cell-mediated cytotoxicity (7), a process dependent on 
both the affinity of cetuximab for the extracellular domain of EGFR and the level of cellular EGFR 
expression (8).
3.2
Epidermal Growth Factor Receptor in Cancer
The EGFR is a commonly expressed transmembrane glycoprotein of the tyrosine kinase growth 
factor receptor family. The EGFR gene, which is expressed in many normal human tissues, has 
been found to be a proto-oncogene; its activation results in the high expression of EGFR in many 
human tumor types. As a transmembrane glycoprotein, the extracellular domain of the EGFR is a 
ligand-binding site for transforming growth factor alpha and EGF. Upon ligand binding, the
intracellular domain of EGFR is activated, thereby triggering cellular mechanisms that regulate 
cell growth (9). The EGFR signal transduction network plays an important role in multiple 
tumorigenic processes, including cell cycle progression, angiogenesis, and metastasis, as well as 
protection from apoptosis (10).
The EGFR is constitutively expressed in many normal epithelial tissues, including the skin and 
hair follicles. In addition, high EGFR expression and/or gene copy number is common in a range 
of human tumors, including head and neck (11), colorectal (12), pancreatic, renal and non-small 
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cell lung cancers (13), and is often associated with poor prognosis (11, 14). The EGFR is richly 
expressed by a wide variety of solid tumors, including SCCHN, in which nearly all lesions 
demonstrate EGFR expression on immunohistochemistry analysis (15). High levels of expression 
appear to be directly correlated with aggressive tumor growth and reduced survival (16, 17, 18). 
The EGFR is also known to mediate the resistance of cancer cells to radiation in a manner 
proportional to the degree of receptor expression (19). The prognostic significance of high levels 
of expression has emphasized the importance of EGFR as an anticancer drug target (20, 21, 22, 
23).
3.3
Epidermal Growth Factor Receptor Inhibition and the Cell 
Cycle
The effects of EGFR blockade on cell cycle progression have been investigated in several human 
cell types, including DiFi colon adenocarcinoma cells, non-transformed breast epithelial MCF10A 
cells, A431 squamous epithelial cancer cells, and DU145 prostatic cancer cells (24). These studies 
suggest that blocking EGFR with monoclonal antibodies such as cetuximab leads to cell cycle 
arrest in G1, which is accompanied by a decrease in cyclin-dependent kinase 2 activity, and an 
increase in the expression of cyclin-dependent kinase inhibitor p27KIP1 (25). In addition to 
inducing G1-phase arrest, EGFR blockade has also been shown to lead to cell death via apoptosis 
in DiFi colon adenocarcinoma cells (24, 26).
3.4
Nonclinical Studies of Cetuximab
3.4.1
Nonclinical Absorption, Distribution, Metabolism, and 
Excretion
The pharmacokinetics (PK) and toxicokinetics of cetuximab were studied in single-dose and 
repeat-dose toxicity studies in rats and cynomolgus monkeys. In single-dose and 4-week 
toxicology studies in rats, serum concentration of cetuximab was increased along with an increase 
of dose. No significant accumulation was observed over 8 doses administered twice weekly during 
the 4-week trial. In cynomolgus monkeys, mean peak serum levels across treatment groups were 
dose dependent without significant gender differences. In the 39-week toxicology trial, 
steady-state levels of cetuximab were reached in Trial Week 4. The dose and the apparent half-life 
(between 50 and 94 hours) showed a linear PK relationship within the dose range from 7.5 mg/kg 
to 38 mg/kg weekly (low dose and mid-dose levels). At the high dose (120 mg/kg initially followed 
by 75 mg/kg weekly), elimination was becoming saturated by showing a greater area under the 
concentration-time curve (AUC), a longer half-life, and a slower clearance. No significant gender 
differences and no accumulation of cetuximab were observed in this trial. In the development 
toxicity trial in pregnant female cynomolgus monkeys, toxicokinetic parameters were similar to 
those found in the 39-week trial with the same doses (12/7.5, 38/24, and 120/75 mg/kg). 
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3.4.2
Nonclinical Toxicology
Rodent data are not relevant for assessment of mechanism-based toxicity because cetuximab does 
not react with rodent (mice and rats) EGFR.
In a 39-week toxicology trial in cynomolgus monkeys, infusions of 0, 7.5, 24, and 75 mg/kg were 
administered weekly via intravenous infusion over 1 hour following a 1-time 2-hour infusion of 0, 
12, 38, and 120 mg/kg, respectively on Day 1. The peak concentration (Cmax) and AUC from the 
time of dosing to the last measurable concentration achieved with the high dose under steady-state 
conditions were approximately 21- and 17-fold, respectively, as the values found in humans at the 
recommended dose. In the high-dose group, treatment was terminated after 36 weeks in 2 males 
and 3 females reported as secondary bacterial infection and intercurrent deaths. The animals in the 
high-dose group displayed reduced food consumption, weight loss or reduced weight gain, apathy, 
prostration, and general morbidity. Epithelial effects on the skin and the oral, oesophageal, and 
nasal mucosa were the major toxicologically relevant lesions.
Skin reactions were dose-related. Epidermal lesions of the skin, including hyperparakeratosis, 
acanthosis, and acantholysis with clefts, pustules, and vesicle formation were observed by 
histopathological tests. The low- and intermediate-dose levels were considered to be tolerated. 
Cetuximab showed good local tolerability after single IV, paravenous, intramuscular, and 
subcutaneous administrations in rabbits (Merck KGaA Studies T15386 [2002], T15509 [2003], 
and T15510 [2003]). Single intra-arterial administration of cetuximab led to a reddening of the ear, 
which was regarded as a transient sign of intolerance. Cetuximab showed no indications of 
genotoxic potential under in vitro and in vivo conditions (Merck KGaA Studies T15386 [2002] 
and T15361 [2002]). 
3.4.3
Nonclinical Efficacy Pharmacology and Safety Pharmacology
In vitro assays and in vivo animal studies have shown that cetuximab inhibits the growth and 
survival of tumor cells that express EGFR. No antitumor effects of cetuximab were observed in 
human tumour xenografts lacking EGFR expression. In animal studies, the addition of cetuximab 
to cisplatin and oxaliplatin resulted in an increase in antitumor effects compared to chemotherapy 
alone.
Cardiovascular and respiratory endpoints relevant for a safety pharmacological assessment were 
evaluated within the 39-week repeat-dose primate toxicity trial (070-087) without resulting in any 
treatment-related changes in electrocardiogram (ECG) data, heart rate, arterial blood pressure, or 
respiratory rate. Clinical observations within this trial revealed no findings indicative of central 
nervous system effects related to cetuximab. An additional trial (0070/100) assessed safety 
pharmacologically relevant hemodynamic and respiratory parameters in anesthetized male 
cynomolgus monkeys without yielding noticeable changes of the cardiovascular and respiratory 
system attributable to cetuximab treatment. 
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3.5
Dose Selection Criteria and Clinical Pharmacokinetics of 
Cetuximab
An initial dose of 400 mg/m2 followed by repetitive weekly doses of 250 mg/m2 is the dosing 
regimen included in the approved label. Detailed information on the PK of cetuximab in humans 
can be found in the Investigator’s brochure.
3.6
Immunogenicity
As with all therapeutic proteins, there is potential for immunogenicity. Immunogenic responses to 
cetuximab were assessed using either a double-antigen radiometric assay or an enzyme-linked 
immunosorbant assay. Due to high drug levels in the circulation, antibody determination may be 
impaired by enabling measurement of anti-drug antibodies in the presence of excess drug. 
Anti-cetuximab antibodies have been detected in 4.9% (49 of 1001) of evaluable subjects. In 
subjects with positive anti-cetuximab antibody, the median time to onset was 44 days (range: 8 to 
281 days). Although the number of sero-positive subjects is limited, there does not appear to be 
any relationship between the appearance of antibodies to cetuximab and the safety or antitumor 
activity of the molecule.
The incidence of antibody formation is highly dependent on the sensitivity and specificity of the 
assay. Additionally, the observed incidence of antibody (including neutralizing antibody) 
positivity in an assay may be influenced by several factors including assay methodology, sample 
handling, timing of sample collection, concomitant medications, and underlying disease. For these 
reasons, comparison of the incidence of antibodies to cetuximab with the incidence of antibodies 
to other products may be misleading.
3.7
Clinical Development of Cetuximab
A large clinical development program has investigated cetuximab in various cancer indications 
including SCCHN, colorectal cancer, non-small cell lung cancer, breast cancer, pancreatic cancer, 
renal carcinomas, and gastric cancer. In these studies, cetuximab was given at a fixed dose regimen, 
either in combination with radiotherapy or chemotherapy or as a single agent. The completed and 
ongoing Phase I, II and III clinical studies that have been performed with cetuximab are discussed 
in more detail in the Investigator’s brochure. 
3.7.1
Clinical Pharmacology
Cetuximab administered as monotherapy or in combination with concomitant chemotherapy or 
radiotherapy exhibits nonlinear PK. The AUC increased in a greater than dose-proportional 
manner as the dose increased from 20 to 400 mg/m2. Cetuximab clearance decreased from 0.08 to 
0.02 L/h/m2 as the dose increased from 20 to 200 mg/m2, and at doses > 200 mg/m2, it appeared to 
plateau. The volume of the distribution for cetuximab appeared to be independent of dose and 
approximated the vascular space of 2 to 3 L/m2. Following a 2-hour infusion of 400 mg/m2 of 
cetuximab, Cmax was 199 Vg/mL (range: 70 to 380 Vg/mL) and the mean elimination half-life was 
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97 hours (range: 41 to 213 hours). A 1-hour infusion of 250 mg/m2 produced a mean Cmax of 
168 Vg/mL (range: 69 to 404 Vg/mL).
Following the recommended dose regimen (400 mg/m2 initial dose 250 mg/m2 weekly dose), 
cetuximab concentrations reached steady-state levels by the third weekly infusion with mean peak 
and trough concentrations across studies ranging from 168 to 235 and 41 to 85 Vg/mL, 
respectively. The mean half-life was 112 hours (range: 63 to 230 hours).
3.7.2
Cetuximab plus Chemotherapy in the Treatment of Recurrent 
and/or Metastatic SCCHN
A large development program, including phase I-II studies, has also investigated the efficacy and 
safety of cetuximab alone or in combination with platinum-based chemotherapy in human subjects 
with recurrent and/or metastatic SCCHN who failed platinum-based regimens given for recurrent 
or metastatic disease (27, 28, 29). In studies investigating the combination of cetuximab with 
platinum-based chemotherapy, the overall response rate was 11 to 13% and the disease control 
rate (DCR) was 51% in these chemorefractory subjects. In a trial where cetuximab alone was 
investigated in the same refractory setting (EMR 62 202-016 trial) (29), the overall response rate 
was 12% and the DCR was 45.5%.
The use of cetuximab plus platinum-based chemotherapy as first-line treatment of subjects with 
recurrent and/or metastatic SCCHN has been investigated in a number of studies. The largest trial, 
the EXTREME trial (EMR 62 202-002) confirmed the benefit of adding cetuximab to platinum-
based chemotherapy in the first-line treatment of recurrent and/or metastatic SCCHN subjects. A 
total of 442 subjects were randomized to a regimen of cisplatin or carboplatin and 5-fluorouracil
(5-FU) with or without cetuximab. The addition of cetuximab to platinum-based chemotherapy 
significantly improved overall survival (OS) time versus chemotherapy alone (median 10.1 versus 
7.4 months; hazard ratio: 0.80; p= 0.04). Progression-free survival (PFS) time was significantly 
improved in the combination arm (5.6 months) compared with chemotherapy alone (3.3 months; 
46% risk reduction, p < 0.001). Furthermore, there was an absolute difference of 16% in response 
rate in the combination arm compared with chemotherapy alone (objective response rate 36%
versus 20%, p < 0.001). The addition of cetuximab only slightly modified the characteristic AE 
profile of platinum-based chemotherapy and did not have a negative impact on quality of life (30).
A further phase III trial performed by the Eastern Cooperative Oncology Group (ECOG) compared 
cisplatin plus cetuximab versus cisplatin plus placebo in 117 subjects (E5397) (31). All efficacy 
time parameters favored the cetuximab-containing arm, although the treatment differences did not 
reach statistical significance (OS time: 9.2 versus 8.0 months, PFS time: 4.2 versus 2.7 months), 
and the overall response rate was superior (26% versus 10%, p= 0.03). Notably, the safety profile 
of cisplatin was not affected by concomitant administration of cetuximab.
A phase I/II trial (EMR 62-202-008) (32) also showed that cetuximab does not alter the known 
safety profile of the chemotherapeutic combination and vice versa. Efficacy data were promising 
in the cisplatin group with an overall response rate of 33.3%, a DCR of 67%, and a median OS
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time of 10.6 months, and in the carboplatin group, with an overall response rate of 38.5%, a DCR 
of 80.8%, and a median OS time of 8.5 months. An overall 36% response rate was observed with 
a regimen of cetuximab plus cisplatin or carboplatin and 5-FU.
3.7.3
Reasonably Anticipated Serious Adverse Events
In the solid tumor population, the occurrence of acute cardiovascular events, acute cerebrovascular 
events, deep vein thrombosis, and symptoms or signs of (progression of) underlying malignancy 
are reasonably anticipated due to age, comorbid conditions or the disease state, and concomitant 
medications. However, if adverse signs and symptoms occur in association with disease (tumor) 
progression, such as dyspnea, tumor pain, bleeding etc., then these should be recorded as AEs or 
reported as SAEs (see Section 7.4.1.1). 
3.7.4
Related Adverse Events
Safety data are summarized in the Investigator’s Brochure in tabular format for all Phase I trials, 
by indication for Phase II trials, and by indication for Phase III trials. 
Cetuximab was investigated in 4 randomized controlled trials in more than 3000 subjects with 
metastatic colorectal cancer: cetuximab in combination with irinotecan plus 5-FU in trial EMR 
62202-013, cetuximab in combination with irinotecan in trial CA225006, cetuximab in 
combination with oxaliplatin plus infusional 5-FU/folinic acid in trial EMR 62202-047, and 
cetuximab as a single agent and best supportive care in trial CA225025. In addition, cetuximab 
was investigated in combination with radiotherapy in subjects with locally advanced SCCHN in 
trial EMR 62202-006 and in combination with platinum-based chemotherapy in recurrent and/or 
metastatic SCCHN in trial EMR 62202-002. 
Safety data of these 6 trials with more than 2,100 cetuximab-treated subjects are available. The 
known side effects of cetuximab are listed in Table 3.1.
Table 3.1
Adverse Events that Have Been Found to Have an Association with 
Cetuximab
Nervous system disorders
Headache (common) 
Aseptic meningitis (frequency not known)
Eye disorders
Conjunctivitis (common)
Blepharitis, keratitis (uncommon)
Respiratory, thoracic, and 
mediastinal disorders
Pulmonary embolism (uncommon)
Interstitial lung disease (rare)
Gastrointestinal disorders 
Diarrhea, nausea, vomiting (common)
Skin and subcutaneous tissue 
disorders
Skin reactions (very common)
Stevens-Johnson syndrome/toxic epidermal necrolysis (very rare)
Superinfections of skin lesions (frequency not known)
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Metabolism and nutrition 
disorders
Hypomagnesaemia (very common)
Dehydration, hypocalcaemia, anorexia which may lead to weight decrease 
(common)
Vascular disorders
Deep vein thrombosis (uncommon)
General disorders and 
administration site conditions
Mild or moderate infusion-related reactions comprising symptoms such as 
fever, chills, dizziness, or dyspnoea (very common)
Mucositis, in some cases severe. Mucositis may lead to epistaxis (very 
common)
Severe infusion-related reactions, in rare cases with fatal outcome (common)
Fatigue (common)
Hepatobiliary disorders
Increase in liver enzyme levels (aspartate amino transferase, alanine 
aminotransferase, and alkaline phosphatase) (very common)
Note: The expected frequencies in brackets are defined as: very common (E 1/10), common (E 1/100, < 1/10), 
uncommon (E 1/1,000, < 1/100), rare (E 1/10,000, < 1/1,000), very rare (< 1/10,000), frequency not known (cannot be 
estimated from the available data). 
Skin reactions: Skin reactions may develop in more than 80% of subjects and mainly present as 
acne-like rash and/or, less frequently, as pruritus, dry skin, desquamation, hypertrichosis, or nail 
disorders (e.g., paronychia). Approximately 15% of the skin reactions are severe, including single 
cases of skin necrosis. The majority of skin reactions develop within the first 3 weeks of treatment. 
They generally resolve without sequelae over time following cessation of treatment, if the 
recommended adjustments in dose regimen are followed. According to the National Cancer 
Institute – Common Terminology Criteria for Adverse Events (CTCAE) version 4.03, Grade 2 
skin reactions are characterized by rash affecting up to 50% of body surface area (BSA), while 
Grade 3 reactions affect equal or more than 50% of BSA. Skin lesions induced by cetuximab may 
predispose subjects to superinfections (e.g., with Staphylococcus aureus), which may lead to 
subsequent complications, e.g., cellulitis, erysipelas or potentially fatal outcomes such as 
staphylococcal scalded skin syndrome or sepsis. 
Infusion-related reactions: Mild or moderate infusion-related reactions are very common and 
comprise symptoms such as fever, chills, dizziness, or dyspnea that occur in a close temporal 
relationship, mainly to the first cetuximab infusion. Severe infusion-related reactions may occur 
commonly, but the outcome is rarely fatal. They usually develop during or within 1 hour of the 
initial cetuximab infusion, but may occur after several hours or with subsequent infusions. 
Although the underlying mechanism has not been identified, some of these reactions may be 
anaphylactoid/anaphylactic in nature and may include symptoms such as bronchospasm, urticaria, 
decrease or increase in blood pressure, loss of consciousness or shock. In rare cases, angina 
pectoris, myocardial infarction or cardiac arrest have been observed.
Combination with 5-FU: When cetuximab was used in combination with intermittent infusional 
5-FU, the frequencies of cardiac ischemia including myocardial infarction and congestive heart 
failure as well as the frequency of hand-foot syndrome (palmar-plantar erythrodysesthesia) were 
increased compared to infusional 5-FU alone. 
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Combination with platinum-based chemotherapy: If cetuximab is used in combination with 
platinum-based chemotherapy, the frequency of severe leukopenia or severe neutropenia may be 
increased, and thus may lead to a higher rate of infectious complications such as febrile neutropenia, 
pneumonia, and sepsis compared to platinum-based chemotherapy alone.
3.8
Trial Rationale
The use of cetuximab plus platinum-based chemotherapy as first-line treatment of subjects with 
recurrent and/or metastatic SCCHN has been investigated in a number of studies. The largest trial, 
the EXTREME trial (EMR 62202-002) confirmed the benefit of adding cetuximab to 
platinum-based chemotherapy in the target population. A total of 442 subjects were randomized 
to a regimen of cisplatin or carboplatin and 5-FU with or without cetuximab. The addition of 
cetuximab to platinum-based chemotherapy significantly improved OS time versus chemotherapy 
alone (median 10.1 versus 7.4 months; hazard ratio: 0.80; p= 0.04). Progression-free survival time 
was significantly improved in the combination arm (5.6 months) compared with chemotherapy 
alone (3.3 months; 46% risk reduction, p< 0.001). Furthermore, there was a significant increase in 
response rate in the combination arm compared with chemotherapy alone (objective response rate
36% versus 20%, odds ratio [95% confidence interval (CI)], 2.326 [1.504, 3.600], p< 0.001). The 
addition of cetuximab only slightly modified the characteristic AE profile of platinum-based 
chemotherapy and did not have a negative impact on quality of life (30).
 
 
 
 
 
 
 
 
This trial aims to assess efficacy and safety of cetuximab when given in combination with 
chemotherapy compared with chemotherapy alone in Chinese subjects with recurrent and/or 
metastatic SCCHN as the first-line treatment, in response to the Chinese Health Authority 
requirements regarding trial design and sample size for local registration proposes.
3.9
Risk-Benefit Assessment
The efficacy and safety of cisplatin plus 5-FU has already been widely demonstrated.
The preclinical, clinical-pharmacological, and current clinical data on cetuximab suggest a 
favorable benefit/risk of cetuximab in combination with platinum-based chemotherapy and that 
the treatment is effective in subjects with recurrent and/or metastatic SCCHN.
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In Asia, the treatment guidelines follow the National Comprehensive Cancer Network guidelines. 
The proposed trial will use a dosage regimen of 75 mg/m2 cisplatin on Day 1 and 750 mg/m2/day 
5-FU from Day 1 to Day 5 of each 3-week treatment cycle to allow for the different chemotherapy 
tolerability profiles that are seen in Asian subjects. Cetuximab will be given according to the 
dosage regimen approved for use in the European Union and the United States.
The benefit/ risk has been carefully considered in the preparation of this trial protocol. Based on 
the preclinical and clinical data available to date, the conduct of the trial is considered justifiable 
using the dose(s) and dosage regimen(s) of the Investigational Medicinal Product (IMP) as 
specified in this protocol. During the trial conduct the benefit/risk of the IMP will be assessed on 
an ongoing basis by an IDMC. 
The trial will be conducted in compliance with the clinical trial protocol, GCP and the applicable 
regulatory requirement(s). 
4
Trial Objectives
4.1
Primary objective 
The primary objective of this trial is to evaluate whether PFS time, as assessed by an IRC, in 
subjects receiving cetuximab in combination with cisplatin plus 5-FU is longer than that in subjects 
receiving cisplatin plus 5-FU alone in the first-line treatment of recurrent and/or metastatic 
SCCHN. 
4.2
Secondary objectives 
The secondary objectives are to compare the 2 treatment arms regarding the following:
!
PFS time, as assessed by the Investigator.
!
OS time.
!
Best overall response (BOR) rate.
!
DCR.
!
Duration of response.
!
Safety.
5
Investigational Plan
5.1
Overall Trial Design and Plan
This multicenter, open-label, randomized, parallel-group, phase III trial will randomize 
approximately 240 subjects with recurrent and/or metastatic SCCHN and involve approximately 
30 trial centers in China. The overall trial design is illustrated in Figure 5.1. 
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Figure 5.1
Schematic of the Trial Design
5-FU: 5-fluorouracil, PD: progressive disease.
All eligible subjects will be randomized to 1 of 2 treatment arms in a 2:1 ratio:
!
Arm A (cetuximab plus chemotherapy): Combination of cetuximab and cisplatin plus 5-FU. 
Subjects who are without progressive disease (PD) after 6 cycles of treatment will continue 
monotherapy with cetuximab until occurrence of PD or unacceptable toxicity. 
!
Arm B (chemotherapy alone): Cisplatin plus 5-FU only. 
Randomization will be performed centrally using an interactive web response system (IWRS). 
Randomization will be stratified according to ECOG performance status (0 versus 1) and the 
primary tumor site (oral cavity versus hypopharynx versus others) (see Section 6.3).
Definition of treatment cycle: The ideal cycle in each arm is 21 days long and is determined by 
the chemotherapy as follows:
!
Arm A: 1 treatment cycle consists of dosing with chemotherapy plus cetuximab on Day 1, 
and doses of cetuximab on Days 8 and 15, with follow-up through to Day 21 of the cycle. 
!
Arm B: 1 treatment cycle consists of dosing with chemotherapy staring from Day 1 of each 
cycle. 
The regimen of cetuximab for subjects in Arm A is shown in Table 6.1. Subjects in Arm A and B 
will receive the same chemotherapy regimen every 21 days, which is based on cisplatin plus 5-FU 
and is shown in Table 6.4. 
Duration of treatment for subjects in Arm A: Subjects with absence of PD, as assessed by the 
Investigator, and unacceptable toxicity will receive a maximum of 6 cycles of chemotherapy
(cisplatin plus 5-FU) and cetuximab weekly. Subjects who have not experienced PD after end of 
chemotherapy will continue treatment with cetuximab until either PD, as assessed by the 
Screening 
Period
Treatment Period*
Safety Follow-up Period
Survival Follow-
up
Within 28 
days before 
trial 
treatment 
starts
Efficacy assessments
every 6 weeks until PD
Cisplatin/Carboplatin+5-
FU every 21 days / Max 
of 6 cycles
+ Cetuximab weekly
End of efficacy 
assessment *
Safety assessment will be 
performed 30 days (± 3 
days) after the last dose of 
trial treatment or 
immediately before starting 
any new antitumor treatment
Safety Follow-up
visit
Survival status and 
subsequent 
anticancer therapy
Cetuximab 
monotherapy
Eligibility 
confirmation 
R
Cisplatin/Carboplatin+5-
FU every 21 days / Max 
of 6 cycles
2
1
*: This can be done after safety follow-up 
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Investigator, or occurrence of an unacceptable toxicity. Subjects with an unacceptable toxicity due 
to one of the trial drugs will receive other trial drug(s) without unacceptable toxicity until either 
PD or completion of 6 cycles of chemotherapy. If treatment with cetuximab is delayed because of
a related toxicity, the 21-day rhythm of chemotherapy is retained. A maximum of 2 consecutive 
cetuximab infusions can be withheld (no more than 21+3 days without cetuximab infusions) due 
to unacceptable toxicity, otherwise the subject must stop cetuximab. If treatment is delayed 
because of toxic effects of the chemotherapy, the 7-day rhythm of cetuximab infusions is retained. 
Chemotherapy can be delayed for a maximum of 21+3 days; after this, the subject must stop the 
chemotherapy treatment. The subject may continue on cetuximab monotherapy (if still benefiting). 
Duration of treatment for subjects in Arm B: Subjects with absence of PD, as assessed by the 
Investigator, and unacceptable toxicity will receive a maximum of 6 cycles of chemotherapy. 
Subjects with an unacceptable toxicity due to one of the trial drugs will receive other trial drug(s) 
without unacceptable toxicity until either PD, as assessed by the Investigator, or completion of 
6 cycles of chemotherapy. Chemotherapy can be delayed for a maximum of 21+3 days; after this, 
the subject must stop the chemotherapy treatment.
Tumor assessment: Tumor assessment will be performed according to RECIST version 1.1. The 
baseline tumor assessment is to be performed during the screening period within 28 days before 
the start of trial treatment. Computed tomography (CT) or magnetic resonance imaging (MRI) with 
contrast enhancement is recommended for tumor assessment. Subsequent tumor response 
evaluations will be assessed every 6 weeks (± 3 days) starting from the randomization day until 
occurrence of PD regardless of any cycle delay. If treatment is discontinued for reasons other than 
PD, subjects will continue to have tumor assessments until either PD, the start of a new antitumor 
treatment, death, the termination of the trial, or loss of follow up, whichever comes first. If 
symptoms are suggestive of PD, subjects will be evaluated by imaging studies thereafter for 
documentation and confirmation of the tumor responses. The details of documentation of tumor 
assessment is described in Section 7.3.1.
Safety follow-up period: All subjects in Arm A and B will be followed up continuously for safety 
evaluations according to schedule of assessments in Table 1.1 starting from date of first signature 
of informed consent. A Safety Follow-up visit will be performed 30 days (± 3 days) after the last 
dose of trial treatment or immediately before starting any new antitumor treatment. During the 
treatment period, additional safety evaluations will be on a weekly basis (Arm A only) for physical 
examination, vital signs, documentation of AEs and concomitant medications, and also at the start 
of each cycle (for both arms) for ECOG performance status, ECG, hematology, biochemistry and 
urinalysis. Survival data and any information on new antitumor treatments will be collected every 
3 months after the EOEA visit until either death, loss of follow up, or the termination of the trial, 
whichever comes first. 
Primary and secondary endpoints: The primary endpoint of this trial is PFS time, as assessed 
by an IRC. Secondary endpoints include PFS time, as assessed by the Investigator, OS time, BOR
rate, DCR, duration of response, and safety (see Section 8). 
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Duration of the whole trial: The anticipated duration of the recruitment period is from the fourth 
quarter of 2015 to the fourth quarter of 2017. The trial will be terminated when the last subject
discontinued to the trial or OS cut-off, whichever is later. The OS cut-off date should be at least 
180 deaths (e.g., 75% of randomized subjects) have been reported, or up to 12 months after the 
last subject is randomized, whichever is earlier. The last subject’s last visit is anticipated in 
November 2018. The actual duration of recruitment period will be based on the trial set-up process. 
The medical care of subjects after the termination of this trial is described in Section 6.13. 
5.2
Discussion of Trial Design
This clinical trial is being proposed in response to the Chinese Health Authority which requested 
that a randomized controlled trial be performed for local registration proposes. 
The use of cetuximab plus platinum-based chemotherapy as first-line treatment of subjects with 
recurrent and/or metastatic SCCHN has been investigated in a number of trials. The treatment 
duration, control group, and treatment allocation designed for this trial are similar to those in the 
largest trial, the EXTREME trial (EMR 62 202-002), which confirmed the benefit of adding 
cetuximab to platinum-based chemotherapy in the first-line treatment of subjects with recurrent 
and/or metastatic SCCHN. The dose of cisplatin and 5-FU applied in this trial has been modified 
according to local clinical practice (cisplatin dose intensity decreased by 25% and 5-FU dose 
intensity decreased by 6.25% compared with that in the EXTREME trial) (33).
 
 
 
If cisplatin results in a 
nonhematologic toxicity (see Section 6.4.1.2.2), cisplatin may be replaced by carboplatin in 
subsequent cycles. The dose of carboplatin in this trial is the same as that in the EXTREME trial, 
which is accepted by Chinese Investigators (33). 
The primary endpoint in this trial is PFS time, as assessed by an IRC. While OS time is still 
considered the ‘gold standard’ of clinical efficacy, PFS time has been recommended in SCCHN 
trials as a primary endpoint. A recently published trial analyzed aggregate data from all published 
phase III clinical trials (ECOG, EXTREME, and SPECTRUM) using EGFR monoclonal 
antibodies as first-line treatment in recurrent and/or metastatic SCCHN, to investigate PFS time as 
a surrogate endpoint to OS time. The limited data indicated a linear relationship between PFS time
and OS time with a constant difference between them of 5 months. This data suggested that PFS
time to be a useful surrogate endpoint for OS time in this indication (33). 
In addition, especially in China, OS time data may be confounded by a cross-over and/or second-
and third-line treatments, while the treatment effect on PFS time is not confounded by these
factors. 
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The PFS as primary endpoint has been well recognized and accepted as a surrogate endpoint by 
the Chinese Health Authority. Therefore, PFS is considered as an acceptable primary endpoint for 
this trial. 
The endpoint of PFS time will be assessed by an IRC to mitigate any Investigator bias in 
determining PFS time in this open-label trial. Progression-free survival, as assessed by the 
Investigator, will be one of the secondary endpoints. 
5.3
Selection of Trial Population
Subjects who have recurrent and/or metastatic SCCHN excluding nasopharyngeal carcinoma and 
who have not received chemotherapy for recurrent and/or metastatic SCCHN.
Only persons meeting all inclusion criteria and no exclusion criteria may be enrolled into the trial 
as subjects. Before performing any trial assessments not part of the subject’s routine medical care, 
the Investigator will ensure that the subject or the subject’s legal representative has provided 
written informed consent following the procedure described in Section 9.2.
5.3.1
Inclusion Criteria
For inclusion in the trial, subjects should fulfill all of the following inclusion criteria:
1.
18 years of age. 
2.
Histologically and/or cytologically confirmed diagnosis of SCCHN. 
3.
Recurrent and/or metastatic SCCHN, not suitable for local-regional treatment. Subjects with 
recurrent disease only (no metastases) must have received prior radiotherapy (as adjuvant 
treatment after surgery or as treatment for locally advanced SCCHN) as part of 
“loco-regional treatment”, and the radiotherapy and the radiotherapy must have been
completed more than 6 months before screening imaging.
4.
Presence of at least 1 measurable lesion according to RECIST version 1.1. 
5.
Signed written informed consent before any trial-related activities are carried out.
6.
ECOG performance status of 0 or 1. 
7.
Neutrophils 1.5 # 109/L, platelet count 100#109/L, and hemoglobin 90 g/L. 
8.
Total bilirubin 2 # upper limit of normality (ULN); aspartate aminotransferase (AST) and 
alanine aminotransferase (ALT) 3 # ULN (if liver metastasis exists, ALT and AST 5 #
ULN). 
9.
Serum corrected calcium, potassium and magnesium corrected within normal range 
(electrolyte correction is permitted during screening). 
10.
Creatinine clearance 60 mL/minute (24 hours creatinine clearance might be requested by 
the Investigator for confirmation, if calculated creatinine clearance is <60 mL/min). 
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11.
Effective contraception if procreative potential exists (applicable for both male and female 
subjects) until at least 3 months after the last dose of trial treatment. 
5.3.2
Exclusion Criteria
Subjects are not eligible for this trial if they fulfill any of the following criteria:
1.
Prior systemic chemotherapy, except if given as part of multimodal treatment for locally 
advanced SCCHN that was completed more than 6 months before randomization. 
2.
Major surgery or irradiation within 4 weeks before randomization. 
3.
Previous treatment with monoclonal antibody or signal transduction inhibitors targeting 
EGFR. 
4.
Nasopharyngeal carcinoma. 
5.
Known allergic reaction against any of the components of the trial treatment. 
6.
Active
infection 
including 
active 
tuberculosis, 
known 
and 
declared
human 
immunodeficiency virus (HIV) infection, or active hepatitis B/C virus (HBV/HCV) infection 
resulting in an impaired liver function or cirrhosis (see Section 7.2.4).  
7.
History of organ allograft, autologous/allogeneic stem cell transplantation, and renal 
replacement therapy. 
8.
Asymptomatic severe hypertension or hypertensive crisis defined as systolic blood pressure 
180 mmHg and/or diastolic blood pressure 110 mmHg under resting conditions. 
9.
Impaired cardiac function, evidenced by any of the following conditions: 
o
Left ventricular ejection fraction < 45% 
o
Serious arrhythmia
o
Unstable angina pectoris
o
Congestive heart failure New York Heart Association class III or IV
o
Myocardial infarction within the 12 months before randomization
o
Pericardial effusion. 
10.
Known central nervous system metastasis and/or leptomeningeal disease. Subjects with 
neurological symptoms should undergo a CT/MRI of the brain to exclude brain metastasis. 
11.
Known uncontrolled diabetes mellitus, pulmonary fibrosis, interstitial lung diseases, acute
pulmonary diseases, or liver failure. 
12.
Peripheral neuropathy or hearing loss Grade 2. 
13.
Subjects not recovered from any acute effects of prior surgery, chemotherapy, or radiation 
therapy, that is, to \ Grade 1 (CTCAE, version 4.03). Chronic late toxicities resulting from 
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prior radiation and/or surgery (pharyngeal/laryngeal toxicity, i.e., xerostomia, speech, 
swallowing abnormalities etc.) are permitted if nutritional status is stable. 
14.
Known alcohol and/or drug abuse. 
15.
Medical or psychological condition that would not permit the subject to complete the trial or 
sign informed consent. 
16.
Past or current history of neoplasm other than SCCHN, except for curatively treated 
nonmelanoma skin cancer, in situ carcinoma of the cervix, or other cancer curatively treated 
and with no evidence of disease for at least 5 years. 
17.
Any investigational medication within 30 days before randomization. 
18.
Female subjects who are pregnant (absence to be confirmed by serum ]-human chorionic 
gonadotropin [HCG] test) or breast feeding, or males and females of reproductive potential 
not willing or not able to employ a highly effective method of birth control/contraception to 
prevent pregnancy from 2 weeks before receiving trial treatment until 3 months after 
receiving the last dose of trial treatment. A highly effective method of contraception is 
defined as having a low failure rate (< 1% per year) when used consistently and correctly.
19.
Concurrent treatment with a prohibited medication (see Section 6.5.2). 
20.
Subjects with any concurrent medical condition or disease that will potentially compromise 
the conduct of the trial at the discretion of the Investigator. 
21.
Legal incapacity or limited legal capacity. 
Subjects must fulfill all eligibility criteria to be enrolled in this trial. No exemption from any 
inclusion and exclusion criteria will be allowed. If any deviation from eligibility is retrospectively 
detected for an already enrolled subject, the Investigator and Sponsor must decide immediately 
whether it is safe to treat this subject further within the trial (see Section 5.4.2). 
5.4
Criteria for Subject Withdrawal
5.4.1
Withdrawal from Trial Therapy
A subject must be withdrawn from all trial treatment (cetuximab and chemotherapy) in the event 
of any of the following but should stay in the trial: 
!
Occurrence of an exclusion criterion that is clinically relevant and affects the subject’s safety 
and discontinuation is considered necessary by the Investigator and/or Sponsor. 
!
Occurrence of AEs and discontinuation of trial treatment is desired or considered necessary 
by the Investigator and/or the subject. 
!
Occurrence of pregnancy during trial treatment. 
!
Occurrence of PD according to RECIST version 1.1. 
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!
Intake of prohibited medications, as defined in Section 6.5.2, if deemed necessary by the 
Investigator and/or Sponsor. 
!
Non-compliance. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
In case of premature withdrawal from the trial treatment for reasons other than PD, the subjects 
will be asked to attend scheduled visits until an assessment of PD as planned. 
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5.4.2
Withdrawal from the Trial
Upon death or loss of follow-up, subjects may be considered as having completed the trial. 
Subjects may withdraw from the trial at any time without giving a reason. Withdrawal of consent 
will be considered withdrawal from the trial.
A subject must be withdrawn if any of the following occur during the trial: 
!
Withdrawal of consent.
!
Participation in another clinical trial (In this case, collection of survival data should 
continue).
If a subject has failed to attend scheduled trial assessments, the Investigator must determine the 
reasons and the circumstances as completely and accurately as possible, and record the reasons in 
appropriate sections of the electronic case report form (eCRF). 
5.5
Premature Termination of the Trial
The whole trial may be discontinued prematurely in the event of any of the following:
!
New information leading to unfavorable risk-benefit judgment of the IMP, such as:
o
Evidence of inefficacy of the IMP, 
o
Occurrence of significant previously unknown adverse reactions or unexpectedly 
high intensity or incidence of known adverse reactions, or 
o
Other unfavorable safety findings. 
!
Sponsor’s decision that continuation of the trial is unjustifiable for medical or ethical reasons. 
!
Poor enrollment of subjects making completion of the trial within an acceptable time frame 
unlikely. 
!
Discontinuation of development of the Sponsor’s IMP. 
!
Withdrawal of IMP from the market for safety. 
Health Authorities and Independent Ethics Committees (IECs)/Institutional Review Boards (IRBs) 
will be informed about the discontinuation of the trial in accordance with applicable regulations.
The clinical trial may also be terminated or suspended upon request of Health Authorities. 
5.6
Definition of End of Trial
The trial will be terminated when the last subject has discontinued the trial treatment or OS cut-off, 
whichever is later. 
The OS cut-off will occur when the following conditions are met: 
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!
Follow-up after the randomization of the last subject is at least 12 months, OR
!
At least 180 deaths have been reported in this trial. 
6
Investigational Medicinal Product and Other Drugs Used in 
the Trial
In this trial, trial treatment consists of cetuximab and cisplatin plus 5-FU. Cetuximab is considered 
as the IMP and cisplatin plus 5-FU as the background first-line standard chemotherapy for 
recurrent and/or metastatic SCCHN. If cisplatin results in a nonhematologic toxicity (see 
Section 6.4.1.2.2), cisplatin may be replaced by carboplatin in subsequent cycles. 
Cisplatin, carboplatin, and 5-FU are commercially available cytotoxic agents for the treatment of 
various cancers, including SCCHN. The chemotherapeutic drugs for this trial will be supplied by 
the local pharmacy/the third party vendor at each trial center. The Sponsor will provide financial 
compensation for the cost of chemotherapeutic drugs depending on the procedures of each 
participating center. 
6.1
Description of Investigational Medicinal Product
Cetuximab will be made available in ready-to-use 20 mL vials containing 5 mg/mL solution.
Cetuximab (Erbitux%) 5 mg/mL is manufactured by the Sponsor, packed, labeled and distributed 
for clinical trial supply by a suitable service provider, and finally released by the Sponsor under 
GMP conditions. 
Cetuximab 5 mg/mL gained approval from the European Medicines Agency in March 2007 and a 
licence for first-line SCCHN in the European Union in November 2008. This formulation of 
cetuximab does not require filtration before administration. Cetuximab is formulated as 5 mg 
protein/mL in glycine/sodium chloride/tween/citrate buffer solution at pH 5.5 ± 0.2, and is 
aseptically filled in sterile glass vials. 
Batch numbers will be provided in the certificates of release. From the documentation of 
cetuximab, it will be possible to retrace the composition and pharmaceutical quality according to 
current GMP guidelines. The Sponsor will provide cetuximab free of charge for all eligible 
subjects. 
6.2
Dosage and Administration 
6.2.1
Selection and Timing of Cetuximab 
Subjects in Arm A only, will receive cetuximab in combination with cisplatin or carboplatin plus 
5-FU chemotherapy. Cetuximab will be given every 7 days as outlined in Table 6.1. 
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Table 6.1
Dose and Administration Procedure for Cetuximab
Dosage
Infusion rate
Flush of line with saline 
solution (0.9%) at the 
end of infusion
Prophylactic pretreatment with 
an appropriate antihistamine and 
corticosteroid
First infusion
400 mg/m2
maximum 
5 mg/minute
Yes
Mandatory
Subsequent 
infusions
250 mg/m2
maximum 
10 mg/minute
Yes
Recommend
The cetuximab dose will be based on the subject’s BSA and has to be recalculated and the dose 
adjusted accordingly before each cetuximab infusion. The BSA should be calculated according to 
the Mosteller formula: BSA (m2) = sqrt ([height (cm) × weight (kg)] / 3600). The calculation will 
be based on the weight measured at each relevant visit and the height as measured and recorded at 
the screening visit. 
The maximum infusion rate must NOT exceed 5 mg/minute for first infusion and must NOT 
exceed 10 mg/minute at subsequent infusions. 
Cetuximab will always be administered before cisplatin or carboplatin on Day 1 of a cycle. 
Cetuximab infusions should be performed, if possible, on the same day of each week with no more 
than 3 days deviation.
Pretreatment with an appropriate antihistamine and a corticosteroid are mandatory at least 1 hour 
before the first cetuximab administration and these premedications are recommended before all 
subsequent infusions of cetuximab (see Section 6.4.2). 
Before, during, and up to 1 hour after each cetuximab infusion, subjects must have their vital signs 
continuously monitored to detect any AEs (specifically, allergic/hypersensitivity reactions). A 
physician should be available during each cetuximab administration, i.e., until the complete 
infusion has been given and for 1 hour after the end of the infusion. Exact documentation of actual 
dose, date, start time, and end time of each cetuximab infusion is mandatory. 
Cetuximab must not be mixed with any other substance and therefore requires a separate infusion 
line. If another intravenous infusion is required at the same time as the cetuximab infusion (e.g.,
for hydration), a second line must be used.
All subjects randomized to Arm A will receive cetuximab until radiographically documented PD,
as assessed by the Investigator, or unacceptable toxicity occurs, or consent is withdrawn. If 
chemotherapy is delayed, administration of cetuximab every 7 days is continued. If chemotherapy 
is discontinued for any reason, treatment with cetuximab monotherapy every 7 days is continued.
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6.2.2
Dose Reductions and Treatment Alterations for Cetuximab
6.2.2.1
Skin Reactions
Prophylactic use of oral tetracyclines is highly recommended for subjects in Arm A for reducing 
the incidence of Grade 3 skin reactions (34). Unless there are contraindications based on subject 
and/or health care provider factors, prophylactic systemic treatment with minocycline 100 mg 
daily or doxycycline 100 mg twice daily is recommended for 6-8 weeks for subjects randomized 
to Arm A, starting 1 day before the administration of the first dose of cetuximab (34, 35). The 
recommended prophylaxis for skin toxicities are described in Table 6.2. 
Table 6.2
Recommended Prophylaxis for Skin Toxicities
Treatment
Dose
Start
Stop
Alternatives
Systemic therapy1
Minocycline
1 × 100 mg/day
Day -1
6-8 weeks2
In case of intolerance:
Or
!
First generation 
cephalosporins
!
Amoxicillin
!
Erythromycin
!
Limecycline
Doxycycline
2 × 100 mg/day
Topical therapy
Low potency steroid creams 
such as:
2 × daily on 
face and chest
Day -1
6-8 weeks
!
Alclometasone 0.05%
!
Desonide 0.05%
!
Fluocinolone 0.01%
Emollient (creams or ointments)
3 × daily to the 
hands, 
and after hand 
washing
Day -1
Continue
2 × daily on
the rest of the body
1
If infection is suspected (yellow crusts, purulent discharge, painful skin / nares), obtain culture and change to 
oral antibiotic based on sensitivities. 
2
May be continued beyond 6-8 weeks at the Investigator’s discretion in the event of CTCAE Grade 2 rash. 
For a Grade 1 or 2 acne-like rash (as defined in the CTCAE version 4.03), treatment with topical 
antibiotics (e.g., benzoylperoxide, erythromycin) or systemic antibiotics (e.g., oral tetracyclines)
should be considered. Subjects with at least Grade 3 reactions should be referred to a dermatologist 
for advice and management if needed. If pruritus occurs, an oral antihistamine is advised. In the 
case of dry skin, the use of emollient creams is beneficial. Fissures may occur in dry skin and 
topical dressings are helpful. 
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If a subject experiences a Grade 3 skin reaction (as defined in the CTCAE version 4.03), cetuximab
treatment may be delayed for up to 14 days (omission of 1 or 2 scheduled administrations) without 
changing the dose level (see Figure 6.1). If skin reactions resolve to Grade 2 or less by the 
following treatment period, treatment may be resumed. 
If Grade 3 skin reactions occur for a second and third time, cetuximab treatment may again be 
delayed for up to 14 days with dose reductions to 200 mg/m² and then 150 mg/m². Cetuximab 
dose reductions are permanent. Subjects must discontinue cetuximab if more than 2 consecutive 
infusions are withheld or Grade 3 skin reactions occur for a fourth time despite the appropriate 
dose reduction (see Figure 6.1). Any Grade 4 toxicity (including skin reactions) considered related 
to cetuximab is to result in discontinuation of cetuximab treatment permanently. 
If, in the opinion of the Investigator, the discontinuation of cetuximab is considered necessary, the 
subject should be withdrawn from cetuximab treatment immediately, but should be further treated 
with chemotherapy and remain in the trial for scheduled visits. 
Figure 6.1
Treatment Adjustment in the Event of Grade 3 Skin Reactions 
Considered to be Related to Cetuximab
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6.2.2.2
Infusion-related Reactions
Mild or moderate infusion-related reactions are very common. Symptoms include fever, chills, 
dizziness or dyspnea occurring in a close temporal relationship mainly to the first cetuximab 
infusion. 
Severe infusion-related reactions may occur, in some cases with a fatal outcome. Some of these 
reactions may be anaphylactoid/anaphylactic in nature or represent a cytokine release syndrome. 
This syndrome typically occurs within 1 hour after infusion and is less commonly associated with 
bronchospasm and urticaria, but may also occur for up to several hours after infusion or with 
subsequent infusions. Cytokine release syndrome is normally most severe in relation to the first 
infusion. 
Symptoms of severe infusion-related reaction may include bronchospasm, urticaria, hypertension 
or hypotension, loss of consciousness, or shock. In rare cases angina pectoris, myocardial 
infarction, or cardiac arrest have been observed.
Anaphylactic reactions may occur as early as within a few minutes of the first infusion, e.g., due 
to preformed Immunoglobulin E antibodies cross-reacting with cetuximab. These reactions are 
commonly associated with bronchospasm and urticaria. They can occur despite the use of 
premedication.
These symptoms usually occur during the first infusion and up to 1 hour after the end of infusion, 
but may happen several hours after or with subsequent infusions. It is recommended to warn
subjects of the possibility of such a late onset and to instruct them to contact their physician if 
symptoms of an infusion-related reaction occur. Special attention is recommended for subjects 
with reduced performance status and pre-existing cardiopulmonary disease.
The Investigator must treat all symptoms of infusion-related reactions with the best available 
medical measures. Based on previous experience with cetuximab infusion-related reactions, the 
treatment guidelines given in Table 6.3, graded according to the CTCAE version 4.03 should be 
followed:
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Table 6.3
Treatment Adjustment for Symptoms of Cetuximab Infusion-related 
Reactions
CTCAE Grade1
Treatment adjustment for cetuximab
Grade 1 mild
Transient flushing or rash; drug fever < 38ºC; 
Decrease the cetuximab infusion rate by 50% and monitor 
closely for any worsening.
The total infusion time for cetuximab should not exceed 
240 minutes.
Grade 2 moderate
Rash: flushing; urticaria; dyspnea; drug fever 
`38ºC 
Stop cetuximab infusion and immediately administer treatment 
for symptoms.
Resume infusion at 50% of previous rate once infusion-related 
reaction has resolved or decreased to at least Grade 1 in 
severity, and monitor closely for any worsening.
Grade 3 or Grade 4 severe or life-threatening
Grade 3: Symptomatic bronchospasm, with or 
without urticaria; parenteral medication(s) 
indicated; allergy-related edema/angioedema; 
hypotension
Grade 4 Anaphylaxis;
Stop the cetuximab infusion immediately and disconnect 
infusion tubing from the subject.
Treat symptoms vigorously. Subjects have to be withdrawn 
immediately from treatment and must not receive any further 
cetuximab treatment.
1
Graded according to Common Terminology Criteria for Adverse Events, version 4.03. 
Resumption of cetuximab treatment following infusion-related reactions
Once the cetuximab infusion rate has been decreased after an infusion-related reaction, it must 
remain decreased for all subsequent infusions. If the subject has a second infusion-related reaction 
on the slower infusion rate, the infusion should be stopped and the subject should be withdrawn 
from cetuximab treatment permanently. If a subject experiences a Grade 3 or 4 infusion-related 
reaction (excluding fever) at any time, she/he must discontinue cetuximab immediately, but should 
be further treated with chemotherapy and remain in the trial for scheduled visits.
6.2.2.3
Other Reasons
If a subject develops an intercurrent illness (e.g., infection) that, in the opinion of the Investigator 
and/or Sponsor, mandates interruption of treatment, this intercurrent illness must resolve within a 
time frame such that no more than 2 consecutive cetuximab infusions are withheld. In the event of 
delayed cetuximab treatment, there will be no new 400 mg/m² initial dose at treatment restart, and
all subsequent treatments will be continued at the assigned dose level or the last dose before 
interruption if the dose had been reduced. 
If cetuximab must be withheld for a longer period of time, cetuximab treatment will be 
permanently discontinued; in special cases, the Investigator may request that the subject is allowed 
to continue to receive cetuximab after consulting the Sponsor. 
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Cetuximab treatment will not be delayed for a chemotherapy-related toxicity. Therefore, if there 
is a delay for chemotherapy, the subject will continue to receive weekly infusions of cetuximab. If 
chemotherapy is completely terminated for a related toxicity, cetuximab may be continued as 
monotherapy up to until either PD, as assessed by the Investigator, unacceptable toxicity, or 
withdrawal of consent. No other antitumor treatment should be given to subjects until 
radiographically documented PD. Subjects will continue to receive scheduled evaluation visits 
until PD, as assessed by the Investigator. 
6.3
Assignment to Treatment Arms
All subjects will be assigned a subject number by the Investigator at the screening visit. Subjects 
who enter the trial will retain this number throughout the trial. 
Randomization will occur on Day 1, the same day the trial treatment is initiated, but before the 
first dose of trial treatment. For subjects randomized to Arm A, prophylactic administration of a 
tetracycline is recommended, starting 1 day before the administration of the first dose of 
cetuximab. In this case, trial treatment will be initiated 1 day after randomization which will be 
performed on Day -1. Once an eligible subject has signed the informed consent form (ICF), the 
center will use an IWRS and receive instructions regarding treatment assignment. Allocation to 
the 2 treatment arms will be in a ratio of 2:1.
Randomization will be stratified according to ECOG (0 versus 1) and the primary tumor site (oral 
cavity versus hypopharynx versus others) to balance these factors across the treatment arms and 
thus improve comparability of the results.
The randomization list will be generated by the designated contract research organization under 
the responsibility of the Sponsor’s trial statistician. Specific details will be provided in a separate 
Manual of Operations.
6.4
Noninvestigational Medicinal Products to be Used
6.4.1
Chemotherapy
All subjects will receive chemotherapy for up to 6 cycles. As a rule, each cycle will last 21 days. 
In the absence of PD and unacceptable toxicity, subjects will receive 6 cycles of chemotherapy. 
The start of each cycle of chemotherapy will be defined by the start of cisplatin infusion (or 
carboplatin infusion, if cisplatin have been switched to carboplatin). Chemotherapy should be 
administered, if possible, on the same day of each cycle with no more than 3 days deviation. 
Details of chemotherapy regimens are given in Table 6.4. 
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Table 6.4
Chemotherapy Regimen Every 21 Days in Arm A and B
Order of administration
Drug
Dose
First
Cisplatin
infusion (refer to China 
package insert) on Day 1
75 mg/m²
In the case of cisplatin 
intolerability1
Carboplatin
infusion time of 
15 minutes or longer, and 
in accordance with the 
China package insert on 
Day 1
AUC 5
Then
5-Fluorouracil
Day 1 to Day 5
750 mg/m²/day continuous infusion
Abbreviation: AUC, area under serum concentration time curve.
1
If cisplatin results in a nonhematologic toxicity (see Section 6.4.1.2.2), cisplatin may be replaced by 
carboplatin in subsequent cycles. 
6.4.1.1
Selection and Timing of Chemotherapy
6.4.1.1.1
Cisplatin 
Cisplatin (75 mg/m2) will be administered as intravenous infusion (refer to China package insert)
on Day 1 of each 21-day treatment cycle.
For any BSA value more than 2.0 m2, the cisplatin dosage must be restricted to the dose appropriate 
for a BSA of 2.0 m2. Adequate hydration and maintenance of sufficient urinary output is 
mandatory. Centers should follow their related local practice and the approved local package insert 
or the following hydration scheme:
!
Before cisplatin: 2 liters of any fluid taken orally on the day before chemotherapy AND 
1 liters orally plus a minimum of 500 mL of intravenous fluid given on the morning of 
cisplatin treatment. The 500 mL of intravenous fluid may be part of the antiemesis infusion. 
!
After cisplatin: Immediately after cisplatin, an intravenous infusion of 200 to 250 mL/hour 
of 5% dextrose in half normal saline, 5% dextrose in normal saline, or normal saline and 
30 mEq KCl/L will be given for 4 to 6 hours. 
Total hydration fluid volume, including enteral and parenteral, should be at least 3500 mL on the 
day of cisplatin administration. 
There must be at least 1 hour between the end of the cetuximab infusion and the start of the cisplatin 
infusion. Intravenous prehydration can be performed concomitant to cetuximab administration but 
a separate line must be used. 
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Antiemetic prophylaxis is mandatory to prevent acute and delayed nausea and vomiting due to the 
high emetogenicity of cisplatin. It is highly recommended that the guidelines of the Multinational 
Association of Supportive Care in Cancer and the American Society of Clinical Oncology are 
followed, i.e., inclusion of dexamethasone, a 5-hydroxytryptamine-3 antagonist and a neurokinin-
1 antagonist. 
All infusions and medications given for hydration, urinary output maintenance and antiemesis
must be documented in the eCRF. Investigators should refer to the approved cisplatin package 
insert for additional information such as safety issues, adverse reactions, and storage information.
Exact documentation of the actual doses, dates, and start and end times of infusions is mandatory. 
6.4.1.1.2
Carboplatin 
If cisplatin results in a nonhematologic toxicity (see Section 6.4.1.2.2), carboplatin at a dose of 
target AUC=5 may be used as the replacement of cisplatin in subsequent cycles. The decision 
needs to be made in discussion with the Medical Monitor on a case-by-case basis.
Carboplatin will be administered using an intravenous infusion of 15 minutes or longer (refer to 
China package insert) on Day 1 of each 21-day treatment cycle. The dose of carboplatin will be 
calculated considering the subject’s renal function as described by the glomerular filtration rate 
using the Calvert formula or the Chatelut formula, given that the target AUC is 5. 
For those subjects in Arm A, there must be at least 1 hour between the end of the cetuximab 
infusion and the start of the carboplatin infusion. 
Exact documentation of the actual doses, dates, and start and end times of infusions is mandatory. 
6.4.1.1.3
5-Fluorouracil 
Investigators should treat subjects with commercially available forms of 5-FU, and must refer to 
the approved 5-FU prescribing information on dosage and administration, safety issues (warnings, 
precautions), adverse reactions, dose reductions and omissions. Investigators should also follow 
their related local practice for the administration of 5-FU.
5-Fluorouracil will be administered as a dose of 750 mg/m2/day as a continuous intravenous 
infusion over 24 hours a day from Day 1 to Day 5 (± 6 hours of the overall duration) of each 21-
day treatment cycle. Administration of 5-FU is to start upon completion of cisplatin/carboplatin 
administration and may be performed via the same infusion line. 
For those subjects in Arm A, there must be at least 1 hour between the end of the cetuximab 
infusion and the start of the 5-FU infusion. 
Exact documentation of the actual doses, dates, and start and end times of infusions is mandatory. 
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6.4.1.1.4
Criteria for Starting the Next Cycle of Chemotherapy
Before starting the next cycle of chemotherapy, the following criteria must be fulfilled:
!
Absolute neutrophil count (ANC) is `1.5#109/L.
!
Platelet count is `100#109/L.
!
Nonhematologic chemotherapy-related toxicities have resolved to \ Grade 1 or baseline 
(excluding weight loss, skin reactions, paronychia, fatigue, ototoxicity or neurotoxicity 
which must have resolved to \ Grade 2).
If these criteria are not met, the start of the next cycle must be delayed to allow for recovery. If a 
delay of more than 21 days is necessary as a result of an unresolved toxicity, one or both of the 
chemotherapeutic drugs should be discontinued.
If the start of the next cycle must be delayed due to either a cisplatin/carboplatin-, or 5-FU-related 
toxicity, the start of the other compound should also be postponed. However, if either 
cisplatin/carboplatin or 5-FU dosing must be permanently discontinued, dosing should be 
continued with the remaining compound according to the schedule.
The BSA must be recalculated and the cisplatin and 5-FU doses adapted accordingly before each 
subsequent cycle (for formula see Section 6.4.1.1.1). A delay in the next cycle of up to 3 calendar 
days from the calculated Day 1 of that cycle for administrative reasons such as a weekend is at the 
discretion of the treating Investigator. 
For those in Arm A, in case of cetuximab-related toxicity, chemotherapy will not be delayed and 
the planned schedule for administration should be maintained. If cetuximab treatment is terminated 
for a cetuximab-related toxicity, chemotherapy will be continued. If chemotherapy is completely 
terminated for a related toxicity, cetuximab may be continued as monotherapy until either PD, as 
assessed by the Investigator, an unacceptable toxicity or withdrawal of consent.
6.4.1.2
Dose Reductions of Chemotherapy
Every effort will be made to administer the full doses of cisplatin/carboplatin and 5-FU. 
Dose reductions are always based on the dose of the previous cycle. Only 2 dose reductions for 
cisplatin and 5-FU and 1 dose reduction for carboplatin are permitted. If further toxicity occurs or 
the criteria for resuming treatment are not met, the subject must be withdrawn from chemotherapy 
(see Table 6.5). 
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Table 6.5
Dose Reductions for Chemotherapy
Dose reduction levels
Dosage1
Cisplatin
0
75mg/m2
-1 (decreased by 20%)
60mg/m2
-2 (decreased by 20% from -1 level)
48mg/m2
Carboplatin2
0
AUC 5
-1 (decreased by 20%)
AUC 4
5-Fluorouracil
0
750mg/m2
-1 (decreased by 20%)
600mg/m2
-2 (decreased by 20% from -1 level)
480mg/m2
Abbreviation: AUC, area under serum concentration time curve.
1
The doses which have been reduced for toxicity must not be re-escalated. 
2
Carboplatin can be considered, if the subject experiences a nonhematologic toxicity. The starting dose of 
carboplatin would be the first dose level of AUC 5 at the Investigator’s discretion. 
Dose adjustments are to be made according to the body system showing the greatest degree of 
toxicity experienced during the previous cycle. Toxicities will be graded using the CTCAE 
version 4.03. 
All implemented dose reductions are permanent. The doses must be modified according to the 
lowest hematology values and the highest degree of nonhematologic toxicities observed at the 
scheduled date of chemotherapy. If a subject develops several different toxic effects and there are 
conflicting recommendations, the dose modification will be based on the AE on the scheduled day 
of treatment.
Dose reduction and delays and related management will be documented in the subject’s medical 
record and in the related section in the eCRF. 
If a subject has a Grade 3 or 4 toxicity after 2 dose reductions, or if a treatment delay is longer than 
3 consecutive weeks, then the discontinuation of chemotherapy treatment has to be considered. 
For those in Arm A, chemotherapy will not be delayed for cetuximab-related toxicities. 
Major toxicities observed with cisplatin: nephrotoxicity; ototoxicity; myelodepression with 
leukopenia, thrombocytopenia and anemia; infectious complications; nausea and vomiting; and 
peripheral neuropathies.
Renal function will be assessed on a regular basis as specified in the protocol (see Table 1.1). 
Cisplatin should be used with caution in subjects with pre-existing peripheral neuropathy. Cisplatin 
is contraindicated in subjects with a pre-existing hearing deficit. Audiometric testing and periodic 
neurological examination at baseline and during treatment are recommended to monitor the effects 
of cisplatin on hearing and neurological function.
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Major toxicities observed with carboplatin: myelodepression with thrombopenia, leucopenia,
neutropenia and/or anemia; infectious complications; nausea and vomiting; ototoxicity; and 
peripheral neuropathies.
Major toxicities observed with 5-FU: 
!
Cardiac toxicity: The typical signs of cardiac toxicity related to 5-FU are ischemic pain 
occurring a few hours after a bolus or after the start of a continuous infusion, together with 
characteristic ECG changes. Silent ECG alterations may also occur. Myocardial infarction 
has been reported. Thus, treatment with 5-FU must be stopped in subjects who develop such 
symptoms or have any other cardiac events of unclear origin during or after treatment with 
5-FU.
!
Hand-Foot syndrome: Subjects treated with 5-FU may develop hand-foot syndrome, 
characterized by redness and swelling of the palms and soles of the feet. Mild hand-foot 
syndrome is painless, but in 10 to 15% of cases it can be painful and is usually associated 
with blisters, ulcerations, cracks, and desquamation. Pyridoxine (vitamin B6) at 100-150 mg 
per day may be helpful.
!
Diarrhea and mucositis: Subjects treated with 5-FU may develop mucositis, or more 
commonly diarrhea. In case of diarrhea, symptomatic treatment with loperamide is 
recommended.
6.4.1.2.1
Chemotherapy Hematologic Toxicities
Febrile Neutropenia
Febrile neutropenia is defined as follows: 
!
Grade 2 fever (temperature 38.1°C) concomitant with Grade 4 neutropenia 
(ANC < 500/mm³) requiring intravenous antibiotics and/or hospitalization. 
Fever should be graded using the CTCAE version 4.03 grading system. The reported temperature 
should be the axillary temperature. 
In cases of febrile neutropenia, the following approach is recommended: 
!
Hospital admission except where outpatient care may be suitable. 
!
Pre-antibiotic evaluation (e.g., antibiogram). 
!
White blood cell count with differential and blood culture should be performed. 
!
Dose reductions and commencement of an antibiotic treatment as outlined in Table 6.6. 
In case of febrile neutropenia, blood counts must be done every 2 days until recovery to 
ANC 500/mm³ or temperature < 38.1°C. 
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Table 6.6
Chemotherapy Dose Reduction and Treatment for Febrile Neutropenia
Adverse Event
Treatment
Febrile neutropenia
Documented infection
1) The first episode of febrile neutropenia or documented infection will result in 
antibiotic treatment and reduction by 20% of both the cisplatin and 5-FU doses while 
maintaining the duration of 5-FU infusion of 5 days (or dose
reduction of carboplatin to AUC 4 if applicable)
2) If there is a second episode despite dose reduction, the subject must receive 
prophylactic antibiotics (quinolone) during the subsequent cycles and a second dose
reduction by 20% of both cisplatin and 5-FU during the subsequent cycles
3) If there is a third episode, the subject will be withdrawn
Criteria for Dose Reductions Based on Hematologic Results
If a subject’s blood sample on the scheduled day of treatment shows abnormal hematology results, 
chemotherapy dose may need to be reduced. If any of the hematologic criteria presented in 
Table 6.7 are met, a dose reduction of chemotherapy is required. 
Table 6.7
Criteria for Dose Reductions Based on Hematologic Results on the 
Schedule Day of Treatment
Neutropenia
Grade 3 
(500-999/mm³)
Chemotherapy treatment delay until < Grade 1 (` 1500/mm³)
Grade 4
Chemotherapy treatment delay until no more than Grade 1; dose 
reduction of all further doses of cisplatin or carboplatin and 5-FU by 
20%
Thrombopenia
Grade 1 
Chemotherapy treatment delay until thrombocytes > 100000/mm³
At least Grade 2
Chemotherapy treatment delay until thrombocytes > 100000/mm³; 
dose reduction of all further doses of cisplatin or carboplatin and
5-FU by 20%
6.4.1.2.2
Nonhematologic Toxicities
If a subject has a Grade 3 or 4 toxicity, as defined in Table 6.8, after 2 dose reductions, or if a 
treatment delay is longer than 3 consecutive weeks, then the discontinuation of chemotherapy 
treatment has to be considered. 
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Table 6.8
Criteria for Dose Reductions Based on Nonhematologic Toxicities on the 
Scheduled Day of Treatment
Toxicity
Grade1
Action to be taken
Mucositis 
Grade 1
Delay chemotherapy treatment until Grade 0
> Grade 1
Delay chemotherapy treatment until Grade 0; dose reduction 
of all further doses of 5-FU only by 20%
Diarrhea
Grade 1
Delay chemotherapy treatment until Grade 0
> Grade 1
Delay chemotherapy treatment until Grade 0; dose reduction 
of all further doses of 5-FU only by 20%
Hypercreatinemia
` Grade 1
Delay chemotherapy treatment until Grade 0, change 
cisplatin to carboplatin
Ototoxicity
Grade 2
Dose reduction of all further doses of cisplatin by 20%
> Grade 2
Delay chemotherapy treatment until \ Grade 2, change 
cisplatin to carboplatin 
> Grade 3
Stop carboplatin
Hand-foot syndrome
Grade 2
Delay chemotherapy treatment until \ Grade 1
> Grade 2
Delay chemotherapy treatment until \ Grade 1; dose 
reduction of all further doses of 5-FU by 20%
Other organ toxicity2
Grade 2
Delay chemotherapy treatment until Grade 1
> Grade 2
Delay chemotherapy treatment until Grade 13; dose 
reduction of all further doses of platinum-based treatment 
and 5-FU by 20% (or dose reduction of carboplatin to 
AUC 4 if applicable)
Sensory neuropathy
Grade 2
Dose reduction for all further doses of cisplatin by 20%
> Grade 2
Stop cisplatin, change cisplatin to carboplatin 
> Grade 3
Stop carboplatin
5-FU: 5-fluorouracil. 
1
Graded according to Common Terminology Criteria for Adverse Events, version 4.03. 
2
Except asymptomatic increase in transaminases, cetuximab-induced skin reactions and medically irrelevant 
side effects (e.g., nausea, alopecia, altered taste).
3
Nonhematologic chemotherapy-related toxicities have resolved to \ Grade 1 or baseline (excluding weight 
loss, skin reactions, paronychia, fatigue, ototoxicity or neurotoxicity which must have resolved to \ Grade 2). 
The results of hematology and blood biochemistry analyses must be available before the start of 
each cycle of chemotherapy. 
6.4.2
Other Drugs
Subjects must be given an antihistamine and a corticosteroid at least 1 hour before receiving the 
first infusion of cetuximab (see Section 6.2.1). All pretreatment must be documented in the eCRF. 
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The prophylactic drugs will be prescribed via the hospital pharmacy at each trial center. The 
Investigator should administer the drugs in accordance with the information given in the product 
package insert with respect to dosage and administration, safety issues (warnings, precautions), 
adverse reactions, dose modifications and omissions. The Investigator should also follow any 
related local practices for the administration of such pretreatment. The Sponsor will not assume 
the costs for these pretreatment drugs. 
Subjects must receive hydration treatment, medication to maintain urinary output and antiemetic 
prophylaxis for each cisplatin infusion as outlined in Section 6.4.1.1.1. Centers should follow their 
related local practices and the approved local package insert or the scheme outlined in 
Section 6.4.1.1.1. All of these drugs and infusions must be documented in the eCRF. 
6.5
Concomitant Medications and Therapies
The following must be recorded in the eCRF: 
!
All medication administered during the trial until the safety follow-up visit or EOEA visit, 
whichever is later, including the generic name, total daily dosage, and duration of treatment. 
!
All (neo-) adjuvant chemotherapy administered before inclusion in the trial, with start and 
stop dates, treatment, dose, and regimen. 
!
Any previous surgery on the underlying tumor (date, extent of surgical procedure). 
!
Any previous radiotherapy for the underlying tumor (date, dose). 
!
All diagnostic or therapeutic procedures performed during the trial period (i.e., from signing 
of informed consent onwards), including the date, indication, description of the procedures, 
and any clinical findings. 
!
Any change in the permitted concomitant medications being taken at the beginning of the 
clinical trial, with the type of medication, dose, duration, and indication. 
6.5.1
Permitted Medicines
All subjects, male and female, must practice medically-accepted contraception throughout the trial 
if the risk of conception exists. 
Sedatives, antiemetics, antibiotics, analgesics, antihistamines, steroids, granulocyte-colony 
stimulating factor, as well as red blood cells, erythropoietin, platelets or fresh frozen plasma 
transfusions may be given at the discretion of the Investigator according to local practices to assist 
in the management of pain, infection, and other complications of the malignancy. In the case of 
febrile neutropenia or documented infection, intravenous antibiotics may be administered for 
curative use (see Section 6.4.1.2.1). Prophylactic use of quinolone is also permitted in cases of 
recurrent febrile neutropenia despite dose reduction of chemotherapy.
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For any skin AE of Grade 1–3, topical and/or oral antibiotics are permitted (see Section 6.2.2.1). 
Subjects with Grade 3 or higher reactions should be referred to a dermatologist for advice and 
management if needed. If pruritus occurs, an oral antihistamine is advised. In case of dry skin, the 
use of emollient creams is beneficial. Fissures may occur in dry skin and topical dressings are 
helpful. 
Localized radiation therapy for pain relief is permitted providing it is not directed towards an area 
in which the subject’s only available target lesion is located. Any target or nontarget lesion 
assessed according to RECIST version 1.1 which will be radiated during the trial must not be 
further considered for response assessment. If any localized radiation therapy during trial 
treatment, e.g., due to increasing bone pain, is considered, it should always firstly be checked if 
the subject has PD according to RECIST version 1.1. 
Bisphosphonates might be given for bone metastases. If any dose increase of an already ongoing 
bisphosphonate treatment or the start of bisphosphonate treatment due to increasing bone pain is 
considered, it should always firstly be checked if this subject might have PD according to RECIST 
version 1.1. 
Any medications (other than those excluded by the protocol, see Section 6.5.2) that are considered 
necessary for the subject’s welfare and will not interfere with the trial medication may be given at 
the Investigator’s discretion. 
Rescue medications may be administered to address ineffective treatment, anticipated adverse 
reactions or anticipated emergency situations.
6.5.2
Prohibited Medicines
Additional concurrent chronic systemic immune treatment, chemotherapy, radiotherapy (except
the situation described in Section 6.5.1), hormone treatment for treatment of cancer (other than 
corticosteroids as antiemetic treatment and gestagens for tumor cachexia which are allowed) or 
any other investigational agent may not be administered to subjects in this trial.
Any traditional Chinese medication with approval for use as anticancer treatment (regardless of 
the type of cancer) will not be permitted. Traditional Chinese medication for indications other than 
anticancer treatment, such as supportive care, may be administered at the discretion of the 
Investigator.
If the administration of a nonpermitted concomitant drug becomes necessary during the trial, e.g.,
for AEs or in an urgent medical situation, it is at the Investigator’s discretion. In such a case, this 
subject has to be withdrawn from trial treatment and detailed information needs be recorded. 
6.5.3
Other Trial Considerations
After the end of the trial, all subjects will receive further treatment based on local medical practice. 
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6.5.4
Special Precautions
Subjects enrolled in this clinical trial will be provided with an Emergency Medical Support Card 
during their trial participation. The Emergency Medical Support Card, which will be provided by 
the Sponsor, is based on the need to provide clinical trial subjects with a way of identifying 
themselves as participating in a clinical trial, and subsequently to provide any health care provider 
with access to the necessary information about their participation. This may be needed to determine 
the course of the subject’s medical treatment. This service is designed to provide information to 
health care providers who are not part of the clinical trial. Clinical Trial Investigators, who are 
already aware of the protocol and treatment, have other means of accessing necessary medical 
information for the management of emergencies occurring in their subjects. 
The first point of contact for all emergency situations will be the Clinical Trial Investigator caring 
for the affected subject. The Investigator agrees to provide emergency contact information on the 
Emergency Medical Support Card for this purpose. If the Investigator is available when an event 
occurs, she/he will answer the question. 
6.6
Packaging and Labeling of the Investigational Medicinal 
Product
The packaging, labeling, and documentation of the cetuximab will be in accordance with
applicable local regulatory requirements and applicable GMP Guidelines, so that it shall be 
possible to retrace the composition and pharmaceutical quality. All labels are given in the Trial 
File. 
6.7
Preparation, Handling and Storage of the Investigational 
Medicinal Product
Instructions for the handling and preparation of the cetuximab solution for infusion will be 
provided. 
All cetuximab treatment boxes supplied to each trial center must be stored carefully, safely, and 
separately from other drugs. Cetuximab should be stored in a refrigerator at 2° to 8°C until use, 
with a temperature log maintained daily. 
The IMP must not be used for any purpose other than the trial. The administration of IMP to 
subjects who have not been enrolled into the trial is not covered by the trial insurance for subjects. 
The Investigator (or the pharmacist or another person who is designated by the Investigator) will 
maintain the following records for the IMP: 
!
Receipt of treatment boxes at the trial center. 
!
Inventory at the center. 
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!
Administration to each subject. 
!
Destruction of unused IMPs. 
It must be ensured that the IMPs are not used at each trial center: 
!
After the expiry date, or
!
After the retest date unless the IMP is reanalyzed and its release date extended. 
This is to be closely monitored by the trial monitor and trial manager. 
Upon completion or termination of the trial, the Investigator/pharmacist will destroy all unused 
IMPs after approval by the monitor. The Investigator/pharmacist will provide the local monitor 
with a copy of the inventory record for filing and a record of the used, unused and destroyed 
clinical supplies, to facilitate inventory procedures. This form shall include information on: 
!
All administered units. 
!
All unused units. 
!
All units destroyed at the end of the trial. 
!
Date of destruction. 
!
Name and signature of the Investigator/pharmacist. 
6.8
Investigational Medicinal Product Accountability
The Investigator (or designee) is responsible for ensuring IMP accountability, including 
reconciliation of drugs and maintenance of records.
!
Upon receipt of IMP, the responsible person will check for accurate delivery and 
acknowledge receipt by signing or initialing and dating the appropriate documentation and 
returning it to the location specified. A copy will be archived for the Investigator Site File.
!
IMP dispensing will be carefully recorded on the appropriate drug accountability forms so 
that accurate records will be available for verification at each monitoring visit. 
!
Trial center IMP accountability records will include the following: 
o
Confirmation of IMP receipt, in good condition and in the defined temperature 
range. 
o
The inventory of IMP provided for the clinical trial and prepared at the center. 
o
The use of each dose by each subject. 
o
The disposition (including return, if applicable) of any unused IMP.
o
Dates, quantities, batch numbers, vial numbers, expiry dates, formulation (for IMP 
prepared at the center), and the individual subject trial numbers.
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The Investigator center should maintain records, which adequately document that subjects were 
provided the doses specified in this protocol, and all IMPs provided were fully reconciled.
Unused IMP must not be discarded or used for any purpose other than the present trial. No IMP 
that is dispensed to a subject may be redispensed to a different subject.
A Trial Monitor will periodically collect the IMP accountability forms and will check all returns 
(both unused and used containers) before arranging for their return to the Sponsor or authorizing 
their destruction by the trial center, or following the local hospital medical waste destruction 
practice for used containers. 
6.9
Assessment of Investigational Medicinal Product Compliance
Cetuximab treatment and chemotherapy will be administered either by the Investigator or under 
his or her supervision in an inpatient setting. 
The application dates and exact amounts of cetuximab, cisplatin, carboplatin, and 5-FU given at 
each infusion will be documented in the eCRF. If cetuximab and/or cisplatin and/or carboplatin 
and/or 5-FU treatment is interrupted during the actual infusion, the clinical staff will estimate the 
percentage of the dose received by the subject and document it in the eCRF. 
Any reason for noncompliance should also be documented. Insufficient compliance is defined as 
a subject missing > 2 consecutive infusions of cetuximab or > 21 consecutive days chemotherapy 
infusion delay for nonmedical reasons. In the event of insufficient compliance, discontinuation of 
the trial treatment will be considered in mutual agreement between the Investigator and Sponsor 
on a case-by-case basis. 
The IMP administration must be recorded in the eCRF.
6.10
Blinding
This trial will be an open-label trial as most subjects treated with cetuximab will experience skin 
reactions, facilitating their identification. 
6.11
Emergency Unblinding
Not applicable. 
6.12
Treatment of Overdose
An overdose is defined as any dose greater than the highest daily dose included in a clinical trial 
protocol or planned for an individual subject enrolled in the trial (\5% more than planned dose 
will not be considered as overdose). Even if it does not meet other criteria for an SAE, any overdose 
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must be recorded in the trial medication section of the CRF and reported to Drug Safety in an 
expedited manner using the SAE Report Form, and following the procedure in Section 7.4. To 
date, there is limited experience with single cetuximab doses higher than 400 mg/m2 BSA or 
weekly administrations of cetuximab doses higher than 250 mg/m2 BSA. In clinical studies with 
cetuximab doses up to 700 mg/m2 given every 2 weeks, the safety profile was consistent with that 
described in Section 3.7.4. Any drug overdose (>10% of calculated dose per plan) occurring in the 
present trial must be reported as an SAE (see Section 7.4.1.4). 
In the case of overdose of chemotherapy/cetuximab, the Investigator should provide all possible 
medical care and treatment in accordance with local medical practice.
6.13
Medical Care of Subjects after End of Trial
After a subject has completed the trial or has withdrawn early, usual treatment will be 
administered, if required, in accordance with the trial center’s standard of care and generally 
accepted medical practice and depending on the subject’s individual medical needs. The Sponsor 
will provide trial treatment for free if the Investigator considers the subject is benefiting from it, 
until cetuximab is approved and marketed in China for the indication of SCCHN. 
7
Trial Procedures and Assessments
7.1
Schedule of Assessments
Before performing any trial assessments that are not part of routine medical care for the subject, 
the Investigator will obtain written informed consent as described in Section 9.2. 
This section summarizes the types of assessment to be performed by visit type. A complete 
schedule of assessments is given in Table 1.1. 
The trial will be terminated when the last subject has discontinued the trial treatment or OS cut-off, 
whichever is later. After OS cut-off and before the trial termination, only SAEs during treatment 
and at the EOEA visit will be reported, following the usual reporting procedure. Information 
collected in the EOEA forms will be limited to data on date of trial treatment completion, date of 
last treatment, subject status at end of trial, reason for discontinuation, disease progression 
(yes/no). From alive, but trial-treatment-discontinued subjects, no tumor response data, anti-cancer 
treatment and survival information will be collected. 
7.1.1
Screening Visit
The screening visit (baseline) must take place in the 28 days before the start of trial treatment. 
The following tests and procedures will be performed at this visit: 
!
Written informed consent. 
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!
Primary tumor diagnosis (see Section 7.2.2). 
!
Documentation of AEs starting from the date of first signature of informed consent. 
!
Documentation of demographic data, height, and relevant medical history (see 
Section 7.2.3). 
!
Documentation of prior and concomitant medications (see Section 6.5). 
!
Check of inclusion and exclusion criteria (see Section 5.3). 
!
Physical examination, check of vital signs, and assessment of ECOG performance status (see 
Section 7.4.4).
!
ECG (to be repeated if performed more than 7 days before the first dose of trial treatment)
(see Section 7.4.4.4). 
!
Blood samples collected after fasting for at least 8 hours for safety laboratory assessments 
(hematology and biochemistry [see Section 7.4.3]), and to be repeated if performed more 
than 7 days before the first dose of trial treatment. 
!
Urinalysis (to be repeated if performed more than 7 days before the first dose of trial 
treatment) (see Section 7.4.3). 
!
If calculated creatinine clearance is <60 mL/min, 24 hour creatinine clearance might be 
requested by the Investigator for confirmation (see Sections 7.1 and 7.2.7). 
!
Serum pregnancy test (if applicable) (see Section 7.2.5). 
!
HBV antigen and antibody test, HCV antibody test, and HIV test (see Section 7.2.4). 
!
Collect HPV, tobacco, and alcohol consumptions status (if the subjects has done HPV test 
before the screening, the HPV data should be collected. Tobacco and alcohol consumptions
status should also be documented) (see Section 7.1).
!
Echocardiogram (see Section 7.2.6). 
!
Tumor assessment (see Section 7.3). 
7.1.2
Weekly Cetuximab Administration Visit 
For subjects in Arm A, the following procedures and investigations will be performed at weekly 
intervals (± 3 days) until the last dose of cetuximab: 
!
Physical examination (see Section 7.4.4). 
!
Check of vital signs. 
!
Documentation of AEs and concomitant medications. 
!
Administration of cetuximab (based on BSA). 
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7.1.3
Start of Each Cycle Visit (Day 1 of Each 21-Day Cycle) 
For all subjects in Arm A and B, the following procedures and investigations will be performed 
on Day 1 of each 21-day chemotherapy cycle. A visit window of 3 days is acceptable. 
!
Randomization (for Cycle 1 only, see Section 6.3).
!
Physical examination, check of vital signs, and assessment of ECOG performance status (see 
Section 7.4.4). 
!
ECG (see Section 7.4.4.4). 
!
Blood samples collected after fasting for at least 8 hours for safety laboratory assessments 
(within 3 days before start of next cycle) (see Section 7.4.3). 
!
Urinalysis (within 3 days before start of next cycle) (see Section 7.4.3). 
!
Documentation of AEs and concomitant medications. 
!
Administration of cetuximab (based on BSA) only for subjects in Arm A. 
!
Administration of cisplatin (cisplatin may be replaced by carboplatin in subsequent cycles if 
there are cisplatin-related nonhematologic toxicities) and 5-FU (based on BSA) for subjects 
in Arm A and B. 
Note: ECG and laboratory safety results must be available at start of each cycle visit. 
Note: If the subject is not able to visit the Investigator for this evaluation or misses the scheduled 
visits, the Investigator should attempt to contact the subject or the referring physician by 
appropriate means to determine the subject’s well-being. 
7.1.4
6-Weekly Evaluation Visit
For all subjects in Arm A and B, the following procedures and investigations will be performed at 
6-week intervals starting from the first dose of trial treatment until the EOEA. A visit window of 
3 days is acceptable. 
!
The evaluations which are completed within 7 days at 6-weekly evaluation visit for physical 
examination/weight; vital sign; ECG; hematology; biochemistry, and urinalysis can be 
accepted, and these evaluations at 6-weely evaluation visit will be optional.
!
Assessment of ECOG performance status (see Section 7.4.4).
!
Documentation of AEs and concomitant medications. 
!
Tumor assessment (see Section 7.3).
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7.1.5
End of Efficacy Assessment Visit
Subjects are to attend the EOEA visit on the day of the last efficacy assessment. A visit window 
of 3 days is acceptable. The following procedure and investigations will be performed: 
!
Physical examination, check of vital signs, and assessment of ECOG performance status (see 
Section 7.4.4). 
!
ECG (see Section 7.4.4.4)*. 
!
Blood samples collected after fasting for at least 8 hours for safety laboratory assessments 
(see Section 7.4.3)*. 
!
Urinalysis (see Section 7.4.3)*. 
!
Documentation of AEs and concomitant medications. 
!
Tumor assessment (see Section 7.3). 
*If the EOEA Visit is after the safety follow-up visit, these tests are optional.
7.1.6
Safety Follow-Up Visit
Subjects are to attend the Safety Follow-up visit 30 days (± 3 days) after the last dose of trial 
treatment or immediately before commencing the start of any new anticancer treatment (see 
Section 6.5.3 for details). The planned procedures and investigations, except tumor assessment, 
are the same as the EOEA visit (see Section 7.1.5). 
7.1.7
Survival Follow-Up
The following assessments will be performed every 3 months after the EOEA visit until death or 
termination of the trial, whichever comes first. This follow-up can take the form of a telephone 
contact to the subject or the subject’s family, or their referring doctor. 
!
Survival status.
!
Documentation of subsequent antitumor treatment after the end of trial treatment. 
!
Outcome and resolution date of skin reactions. 
!
Resolution of ongoing SAEs (see Section 7.4.1.6). 
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7.2
Demographic and Other Baseline Characteristics
7.2.1
Demographic Data
At screening, the following demographic data will be collected: date of birth, sex, and ethnic origin 
data.
7.2.2
Diagnosis of Tumor
At the screening visit, the following data will be recorded for the tumor: 
!
Date of initial diagnosis and date of recurrence and/or metastasis. 
!
Histology.
!
Localization.
!
Recurrence or metastasis. 
!
Classification at initial diagnosis, according to TNM staging system, version 7, 2009. 
7.2.3
Medical History
The following medical history data will be documented: 
!
Relevant previous and concomitant disease(s), other than SCCHN.
!
Previous treatment for SCCHN. 
7.2.4
Viral Serology
The antigen and antibody test for HBV, antibody test for HCV, and HIV test will be performed if 
clinically indicated. Subjects with known and declared HIV infection, as well as subjects with an 
active HBV or HCV infection resulting in an impaired liver function or cirrhosis will be excluded 
from the trial. These subjects will be identified during screening by either elevation of serum 
transaminases (i.e., not meeting inclusion criteria 8 for enrollment) (Section 5.3.1) and/or by the 
presence of a combination of markers of liver fibrosis (e.g., clinical, laboratory abnormalities, 
serologic markers, radiologic). Chronic asymptomatic HBV/HCV carriers are permitted into the 
trial. 
7.2.5
Pregnancy Testing and Contraception 
All female subjects of childbearing potential must have a negative blood pregnancy test at 
screening, which should be done within 7 days before the initiation of the trial treatment. 
Pregnancy testing must be repeated regularly throughout the trial if required by local legislation.
All subjects, male or female, must practice medically-accepted contraception throughout the trial 
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if the risk of conception exists. The Investigator will decide together with the subject on adequate 
methods of contraception. 
7.2.6
Echocardiogram
The left ventricular ejection fraction will be measured at screening by echocardiogram. Subjects 
with left ventricular ejection fraction less than 45% will be excluded from the trial. 
7.2.7
Creatinine Clearance
The creatinine clearance will be calculated by trial centers based on serum creatinine according to 
local practices. Subjects with creatinine clearance less than 60 mL/minute will be excluded from 
the trial (24-hour creatinine clearance might be requested by the Investigator for confirmation, if 
calculated creatinine clearance is <60 mL/min). 
7.2.8
Other Baseline Assessments
Other baseline assessments include physical examination, measurement of vital signs, assessment 
of ECOG performance status, ECG, CT or MRI of the brain (only if clinically indicated), neck, 
chest, and abdomen, safety laboratory assessments (hematology, clinical chemistry, electrolytes, 
urinalysis). 
As these assessments are also performed at subsequent visits during the trial, refer to the relevant 
subsections of Sections 7.3 and 7.4 below for details of any method to be used. 
7.3
Efficacy Assessment
7.3.1
Documentation of Tumor Assessments
A CT or MRI with contrast enhancement is recommended for tumor assessment. 
Imaging, including CT or MRI of the brain (only if clinically indicated), neck (base skull to 
clavicles), chest, and abdomen, must be performed at baseline in order to review potential 
metastasis (\28 days before trial treatment is acceptable). A bone scan and/or positron emission 
tomography (PET) scan should be considered for subjects who have possible bone metastasis at 
baseline or if bone metastasis is suspected during the trial; however, CT/MRI must be used for 
tumor assessment at baseline and at subsequent visits. The bone scan or PET cannot be used for 
measurement of target lesions.
At baseline, the organs with metastatic disease and the target and nontarget lesions should be 
documented. Evaluation of lesions should be performed at baseline and then every 6 weeks 
(± 3 days), regardless of any delays in trial treatment, until PD, as assessed by the Investigator. 
Tumor assessments should be conducted at each tumor assessment time point including a complete 
assessment of all target and nontarget lesions (see Table 1.1). 
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In the case of skin lesions, clinical evaluation should be made with a caliper and photos must be 
taken and made available. 
All measurements should be recorded in metric notation. 
Apart from trial center radiological reading to determine tumor responses, all images will also be 
assessed by an IRC. The IRC review will not interfere with the Investigator’s judgment on tumor 
assessments. 
Confirmation of progression needs to be based on radiological measurements. Clinical 
symptoms/signs suggestive of progression need radiological confirmation of PD. Subjects with a 
global deterioration of health status requiring discontinuation of treatment without radiological
evidence of PD should be classified as “symptomatic deterioration”. Any effort should be made to 
document the objective progression even after discontinuation of treatment (i.e., the subject needs 
to return for a final tumor assessment. 
7.3.2
Criteria for Tumor Response Evaluation
Tumor response evaluation will be performed according to RECIST version 1.1 (see Appendix I) 
by using CT or MRI and other modalities at a 6-week interval starting from the first dose of trial 
treatment. In the case of symptoms suggesting progression, subjects should be evaluated by 
imaging thereafter for documentation and confirmation of the tumor responses. 
Evaluation of lesions should be based on images obtained by either CT or MRI. The same method 
of assessment and the same technique should be used to characterize each identified and reported 
lesion at baseline and during the trial. If a chest X-ray indicates metastatic disease while the subject 
is enrolled in this trial, a CT of the chest is required for confirmation. All assessments should be 
provided by the same physician or radiologist if possible during the trial. 
Evaluation criteria for possible combination of tumor responses (e.g., target lesion, nontarget 
lesion, new lesion, and overall response) are provided in Appendix I.
7.4
Assessment of Safety
The safety profile of the IMP will be assessed through the recording, reporting and analysis of 
baseline medical conditions, AEs, physical examination findings including vital signs and 
laboratory tests. 
Comprehensive assessment of any apparent toxicity experienced by each subject will be performed 
from the time of giving informed consent and throughout the trial. The Investigator will report any 
AEs, whether observed by the Investigator or reported by the subject (see Section 7.4.1.2). The 
reporting period of AEs is described in Section 7.4.1.3. 
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7.4.1
Adverse Events
7.4.1.1
Adverse Event Definitions
Adverse Event
An AE is any untoward medical occurrence in a subject or clinical investigation subject 
administered a pharmaceutical product, regardless of causal relationship with this treatment. An 
AE can therefore be any unfavorable and unintended sign (including an abnormal laboratory 
finding), symptom, or disease temporally associated with the use of a medicinal product, whether 
or not considered related to the medicinal product.
For surgical or diagnostic procedures, the condition/illness leading to such a procedure is 
considered as the AE rather than the procedure itself.
The Investigator is required to grade the severity or toxicity of each AE. Investigators will 
reference the National Cancer Institute - CTCAE, version 4.03 (publication date: 14 June 2010), a 
descriptive terminology that can be used for AE reporting.
A general grading (severity/intensity; hereafter referred to as severity) scale is provided at the 
beginning of the above referenced document, and specific event grades are also provided.
If a particular AE’s severity is not specifically graded by the guidance document, the Investigator 
is to use the general CTCAE definitions of Grade 1 through Grade 5 following his or her best 
medical judgment.
The 5 general grades are:
!
Grade 1 or Mild.
!
Grade 2 or Moderate.
!
Grade 3 or Severe.
!
Grade 4 or Life-threatening.
!
Grade 5 or Death. 
According to the Sponsor’s convention, any clinical AE with severity of Grade 4 or 5 must also 
be reported as an SAE; however, a laboratory abnormality of Grade 4, such as anemia or 
neutropenia, is considered serious only if the condition meets one of the serious criteria described 
below.
If death occurs, the primary cause of death or event leading to death should be recorded and 
reported as an SAE. “Fatal” will be recorded as the outcome of this specific event and death will 
not be recorded as separate event. Only, if no cause of death can be reported (for example, sudden 
death, unexplained death), the death per se might then be reported as an SAE.
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Investigators must also systematically assess the causal relationship of AEs to the IMP/trial 
treatment (including any other non-IMPs, radiation therapy, etc.) using the following definitions. 
Decisive factors for the assessment of causal relationship of an AE to the IMP/trial treatments 
include, but may not be limited to, temporal relationship between the AE and the IMP/trial 
treatments, known side effects of IMP/trial treatments, medical history, concomitant medication, 
course of the underlying disease, trial procedures. 
Unrelated:
Not reasonably related to the IMP/trial treatments. The AE could not medically 
(pharmacologically/clinically) be attributed to the IMP/trial treatments under study 
in this clinical trial protocol. A reasonable alternative explanation must be available. 
Related:
Reasonably related to the IMP/trial treatments. The AE could medically 
(pharmacologically/clinically) be attributed to the IMP/trial treatments under study 
in this clinical trial protocol. 
Abnormal Laboratory Findings and Other Abnormal Investigational Findings
Abnormal laboratory findings (Grade 1-3) and other abnormal investigational findings (for 
example, on an ECG trace) should not be reported as AEs unless they are associated with clinical 
signs and symptoms, lead to treatment discontinuation or are considered otherwise medically 
important by the Investigator. If a laboratory abnormality fulfills these criteria, the identified 
medical condition (for example, anemia, increased ALT) must be reported as the AE rather than 
the abnormal value itself. 
For abnormal laboratory findings, which are recorded as AE, follow up measures should be 
performed.
Serious Adverse Event
An SAE is any untoward medical occurrence that at any dose: 
!
Results in death. 
!
Is life-threatening. (Note: The term “life-threatening” refers to an event in which the subject 
is at risk of death at the time of the event, not an event that hypothetically might have caused 
death if it was more severe.) 
!
Requires inpatient hospitalization or prolongs an existing hospitalization. 
!
Results in persistent or significant disability or incapacity. 
!
Is a congenital anomaly or birth defect. 
!
Is otherwise considered to be medically important. (Note: Important medical events that may 
not result in death, be life-threatening, or require hospitalization may be considered as SAEs 
when, based upon appropriate medical judgment, they may jeopardize the subject or may 
require medical or surgical intervention to prevent one of the outcomes listed above. 
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Examples of such events include allergic bronchospasm requiring intensive treatment in an 
emergency room or at home, blood dyscrasias or convulsions that do not result in inpatient 
hospitalization, or the development of drug dependency or drug abuse.) 
For the purposes of reporting, any suspected transmission of an infectious agent via an IMP is also 
considered an SAE and described in Section 7.4.1.4.
Events that Do Not Meet the Definition of an SAE
Elective hospitalizations to administer, or to simplify trial treatment or trial procedures (for 
example, an overnight stay to facilitate chemotherapy and related hydration treatment application)
are not considered SAEs. However, all events leading to unplanned hospitalizations or unplanned 
prolongation of an elective hospitalization (for example, undesirable effects of any administered 
treatment) must be documented and reported as SAEs.
Events Not to Be Considered as AEs/SAEs 
Medical conditions present at the initial trial visit that do not worsen in severity or frequency during 
the trial are defined as Baseline Medical Conditions, and are NOT to be considered AEs.
In this trial, PD is the only medically anticipated clinical event which is considered as a clinical 
efficacy outcome rather than an AE. No other medically anticipated events are defined in this trial 
as efficacy outcomes. 
However, if adverse signs or symptoms occur in association with PD then these should be recorded 
as AEs.
AE/SAEs Observed in Association with Disease Progression
Disease progression recorded in the course of efficacy assessments only, but without any adverse 
signs or symptoms should not be reported as AEs.
However, if adverse signs and symptoms occur in association with disease (tumor) progression, 
such as dyspnea, tumor pain, bleeding etc., then these should be recorded as AEs or reported as 
SAEs, if they meet criteria for seriousness. 
7.4.1.2
Methods of Recording and Assessing Adverse Events
At each trial visit, the subject will be queried on changes in his or her condition. During the 
reporting period, any unfavorable changes in the subject’s condition will be recorded as AEs, 
whether reported by the subject or observed by the Investigator. 
Complete, accurate and consistent data on all AEs experienced for the duration of the reporting 
period (defined below) will be reported on an ongoing basis in the appropriate section of the eCRF. 
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All SAEs must be additionally documented and reported using the appropriate Report Form as 
described in Section 7.4.1.4.
It is important that each AE report include a description of the event, its duration (onset and 
resolution dates [and times when it is important to assess the time of AE onset relative to the 
recorded treatment administration time]), its severity, its causal relationship with the trial 
treatment, any other potential causal factors, any treatment given or other action taken, including 
dose reduction or discontinuation of the IMP, and its outcome. In addition, serious cases should 
be identified and the appropriate seriousness criteria documented.
Specific guidance can be found in the eCRF Completion and Monitoring Conventions provided 
by the Sponsor.
7.4.1.3
Definition of the Adverse Event Reporting Period
The AE reporting period for safety surveillance begins when the subject is initially included in the 
trial (date of first signature of informed consent) and continues until the Safety Follow-up visit. 
Any SAE assessed as related to cetuximab must be reported whenever it occurs, irrespective of the 
time elapsed since the last administration of cetuximab. 
7.4.1.4
Procedure for Reporting Serious Adverse Events
Serious Adverse Events
In the event of any new SAE occurring during the reporting period, the Investigator must 
immediately (within a maximum of 24 hours after becoming aware of the event) inform the 
Sponsor or its designee in writing. All written reports should be transmitted using the SAE Report 
Form, which must be completed by the Investigator following specific completion instructions. 
For each SAE, all relevant medical information should be documented on the SAE report form. 
In exceptional circumstances, an SAE (or follow-up information) may be reported by telephone; 
in these cases, a written report must be sent immediately by fax or e-mail. Names, addresses, and 
telephone and fax numbers for SAE reporting will be included in the trial-specific SAE Report 
Form. 
Relevant pages from the eCRF may be provided in parallel (for example, medical history, 
concomitant medications). Additional documents may be provided by the Investigator, if available 
(for example, laboratory results, hospital report, and autopsy report). In all cases, the information 
provided on the SAE Report Form must be consistent with the data about the event recorded in the 
eCRF. 
The Investigator must respond to any request for follow-up information (for example, additional 
information, outcome, final evaluation, other records where needed) or to any question the 
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Sponsor/designee may have on the AE within the same timelines as those noted above for initial 
reports. This is necessary to ensure prompt assessment of the event by the Sponsor or designee and 
(as applicable) to allow the Sponsor to meet strict regulatory timelines associated with expedited 
safety reporting obligations. 
Requests for follow-up will usually be made via the responsible Monitor, although in exceptional 
circumstances the Global Drug Safety department may contact the Investigator directly to obtain 
further information or to discuss the event. 
7.4.1.5
Safety Reporting to Health Authorities, Independent Ethics 
Committees/ Institutional Review Boards and Investigators
The Sponsor will send appropriate safety notifications to Health Authorities in accordance with 
applicable laws and regulations.
The Investigator must comply with any applicable center-specific requirements related to the 
reporting of SAEs (particular deaths) involving trial subjects to the IEC/IRB that approved the 
trial.
In accordance with ICH GCP, the Sponsor will inform the Investigator of “findings that could 
adversely affect the safety of subjects, impact the conduct of the trial or alter the IEC’s/IRB’s 
approval/favorable opinion to continue the trial”. In particular, and in line with respective 
regulations, the Sponsor will inform the Investigator of AEs that are both serious and unexpected 
and are considered to be related to the administered product (suspected unexpected serious adverse 
reactions [SUSARs]). The Investigator should place copies of Safety reports in the Investigator 
Site File. National regulations with regard to Safety report notifications to Investigators will be 
taken into account.
When specifically required by regulations and guidelines, the Sponsor will provide appropriate 
Safety Reports directly to the concerned lead IEC/IRB and will maintain records of these 
notifications. When direct reporting is not clearly defined by national or center-specific 
regulations, the Investigator will be responsible for promptly notifying the concerned IEC/IRB of 
any Safety Reports provided by the Sponsor and of filing copies of all related correspondence in 
the Investigator Site File. 
7.4.1.6
Monitoring of Subjects with Adverse Events
Any AEs are recorded and assessed continuously throughout the trial (see Section 7.4.1.3) and are 
assessed for final outcome at the Safety Follow-up visit. All SAEs ongoing at the Safety Follow-up 
visit must be monitored and followed up by the Investigator until stabilization or until the outcome 
is known, unless the subject is documented as “lost to follow-up”. Reasonable attempts to obtain 
this information must be made and documented. It is also the responsibility of the Investigator to 
ensure that any necessary additional therapeutic measures and follow-up procedures are 
performed. 
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7.4.2
Pregnancy and In Utero Drug Exposure 
Only pregnancies considered by the Investigator to be related to trial treatment (for example, 
resulting from a drug interaction with a contraceptive medication) are considered to be AEs. 
However, all pregnancies with an estimated conception date during the period defined in 
Section 7.4.1.3 must be recorded by convention in the AE page/section of the eCRF. The same 
rule applies to pregnancies in female subjects and to pregnancies in female partners of male 
subjects. The Investigator must notify the Sponsor/designee in an expedited manner (within a 
maximum of 24 HOURS after becoming aware of the event) of any pregnancy using the Pregnancy 
Report Form, which must be transmitted according to the same process as described for SAE 
reporting in Section 7.4.1.4. 
Investigators must actively follow up, document and report on the outcome of all these 
pregnancies, even if the subjects are withdrawn from the trial.
The Investigator must notify the Sponsor/designee of these outcomes using the Pregnancy Report 
Form. If an abnormal outcome occurs, the SAE Report Form will be used if the subject sustains 
an event and the Parent-Child/Fetus Adverse Event Report Form if the child/fetus sustains an 
event. 
Any abnormal outcome must be reported in an expedited manner as described in Section 7.4.1.4, 
while normal outcomes must be reported within 45 days after delivery. 
In the event of a pregnancy in a subject occurring during the course of the trial, the subject must 
be discontinued from trial medication immediately. The Sponsor/designee must be notified 
without delay and the subject must be followed as mentioned above.
7.4.3
Clinical Laboratory Assessments
Blood and urine samples will be collected for hematology, biochemistry, electrolytes, and 
urinalysis following the timing noted in the Schedule of Assessments (Table 1.1) and will include 
the following mentioned below in Table 7.1. The results of all safety laboratory parameters must 
be available within 3 days before start of next chemotherapy cycle. 
Table 7.1
Standard Safety Laboratory Parameters
Category
Parameters
Hematology 
hemoglobin, red blood cell count, white blood cell count and differential count, platelet count 
Biochemistry
creatinine, aspartate aminotransferase, alanine aminotransferase, gamma-glutamyl transferase, 
total bilirubin (including direct bilirubin if total bilirubin abnormal), total protein, albumin, 
alkaline phosphatase, glucose, blood urea, uric acid 
Electrolytes
sodium, potassium, chloride, calcium, magnesium,
Urinalysis*
pH value, specific gravity, protein, glucose, red blood cell, white blood cell
*
Urinalysis dipstick will be followed by microscopic examination if results are abnormal. 
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All samples should be clearly identified. Blood samples will be collected after fasting for at least 
8 hours. All laboratory assessments will be performed at local laboratories and will comply with 
local requirements. Analysis of additional laboratory parameters is at the discretion of the 
Investigator. Viral serology tests will be performed if clinically indicated (see Section 7.2.4). 
At the screening visit, female subjects of childbearing potential including those who have had tubal 
ligation must additionally have a blood pregnancy test performed within 7 days before the first 
dose of trial treatment. Pregnancy testing must be repeated regularly throughout the trial if required 
by local legislation.
All laboratory test results obtained (including any potential repeat tests) must be documented in 
the eCRF. 
Any laboratory result leading to an interruption or dose reduction of trial treatments will be 
considered as an untoward medical occurrence and therefore has to be documented as an AE (see 
Section 7.4.1.1). 
The Sponsor should receive a list of laboratory normal ranges before shipment of trial drug. Any 
change in laboratory normal ranges during the trial should be forwarded to the Sponsor/designee. 
7.4.4
Vital Signs, Physical Examinations, and Other Assessments
7.4.4.1
Vital Signs
Vital signs will be assessed at the time points outlined in Table 1.1 and must include axillary 
temperature, heart rate and blood pressure (measured in a supine position after 5 minutes at rest), 
and respiratory rate. For those in Arm A, vital signs must be continuously monitored before, 
during, and up to 1 hour after each cetuximab infusion. 
7.4.4.2
Physical Examination
Physical examination will be performed at the time points outlined in Table 1.1 and must include 
the following: height (screening only), weight, general appearance, skin, head, neck, ears, eyes, 
nose, 
mouth, 
throat, 
respiratory/pulmonary, 
cardiovascular, 
gastrointestinal/abdominal, 
genito-urinary, neurological, musculoskeletal/extremities, and lymphatic systems, and any other 
that may be relevant. 
For physical examinations after the screening visit, only new findings compared to the previous 
one have to be documented in the eCRF.
7.4.4.3
Eastern Cooperative Oncology Group Performance Status
The ECOG performance status of each subject will be reviewed at the time points outlined in 
Table 1.1 and will be graded according to the following: 
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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 work, office work. 
Grade 2 
Ambulatory and capable of all self-care, but unable to carry out any work activities 
up and about more than 50% of waking hours. 
Grade 3 
Capable of only limited self-care, confined to bed or chair more than 50% of waking 
hours. 
Grade 4 
Completely disabled, cannot carry on any self-care, totally confined to bed or chair. 
Grade 5
Dead.
7.4.4.4
Electrocardiogram
A computerized 12-lead ECG must be obtained at the time points outlined in Table 1.1 and as 
clinically indicated. An ECG should be performed after the subject has rested for 5 minutes. Each 
lead shall be recorded for at least 3 beats at a speed of 25 mm/second. 
The following parameters will be recorded: rhythm, ventricular rate, PR interval, QRS duration, 
QT interval, and corrected QT interval.
At screening, the Investigator must assess the ECG for signs of cardiac disease that could exclude 
the subject from the trial. An assessment of normal or abnormal will be recorded and if the ECG 
is considered abnormal, the abnormality will be documented in the eCRF. The ECG results must 
be available at start of each cycle visit. 
7.5
Pharmacokinetics
Not applicable. 
7.6
Biomarkers/Pharmacogenetics
Not applicable. 
7.7
Other Assessments
Not applicable. 
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8
Statistics
8.1
Sample Size
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
8.2
Randomization
Subjects will be randomized to one of the 2 treatment arms, cetuximab plus chemotherapy versus 
chemotherapy alone, at a 2:1 ratio stratified by the following:
!
ECOG performance status: 0 versus 1.
!
Primary tumor site: oral cavity versus hypopharynx versus others.
A central stratified permuted block randomization procedure will be employed via IWRS to 
balance prognostic factors between treatment arms (see Section 6.3).
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8.3
Endpoints
8.3.1
Primary Endpoint
The primary endpoint of this trial is PFS time, as assessed by an IRC. The primary endpoint is 
defined as the duration (in months) from the date of randomization until first observation of PD 
(based on imaging as assessed by IRC), or death due to any cause when death occurs within 
60 days after the last tumor assessment or randomization (whichever is later). Any subject with 
neither assessment of tumor progression, nor death date within 60 days after last tumor assessment 
and randomization will be censored on the date of last tumor assessment or randomization. A 
subject who has not received trial treatment and for whom no date of progression or death is known 
will be censored on the date of randomization (Day 1) or date of last tumor assessment, whichever 
comes later.
8.3.2
Secondary Endpoints
The secondary endpoints include PFS time, as assessed by the Investigator, OS time, BOR, DCR, 
and duration of response. 
!
PFS time, as assessed by the Investigator, is defined as the duration (in months) from the 
date of randomization until first observation of radiologically confirmed PD (by the 
Investigator), or death due to any cause when death occurs within 60 days after the last tumor 
assessment or randomization (whichever is later). The same censoring rule as with the PFS
time assessed by IRC is applied. 
!
OS time is defined as the time (in months) from the date of randomization to the date of 
death. If a subject is alive at the time of analysis, survival time will be censored at the last 
date when the subject is known to be alive.
!
The BOR will be based on imaging and classified according to RECIST version 1.1 criteria. 
The BOR rate is defined as the number of subjects, whose BOR was either complete response 
(CR) or PR, relative to the number of subjects belonging to the trial set of interest. 
!
The DCR will be based on imaging and classified according to RECIST version 1.1 criteria. 
The DCR defined as the number of subjects whose BOR is either CR, PR or SD, divided by 
the number of subjects belonging to the trial set of interest. 
!
Duration of response will be determined for subjects whose BOR was either CR or PR. It is 
defined as the time from the first assessment of CR or PR until the event defining PFS time.
8.3.3
Safety Endpoints
The safety and toxicity of the treatment will be evaluated in terms of the following safety variables:
!
Exposure to cetuximab, cisplatin or carboplatin, and 5-FU in terms of duration of therapy, 
cumulative dose, dose intensity and relative dose intensity, number of dose reductions, dose 
delays, and drug discontinuation. 
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!
Incidence and type of AEs in terms of:
o
All treatment-emergent adverse events (TEAEs)
o
Related TEAEs
o
Treatment emergent SAEs
o
Related treatment emergent SAEs
o
CTCAE (version 4.03) Grade 3 and 4 TEAEs
o
Related CTCAE (version 4.03) Grade 3 and 4 TEAEs
o
TEAEs leading to withdrawal, dose modification, or drug discontinuation will be 
summarized by treatment arm.
!
Incidence and reasons for deaths for each treatment arm.
!
Safety laboratory tests graded by CTCAE (version 4.03) where applicable.
!
Vital signs, physical examinations and ECOG performance status.
8.4
Analysis Sets
All screened subjects: The population of all screened subjects will include all subjects who signed
the ICF.
Safety population (all treated subjects): All subjects who received at least 1 dose of any trial
treatment (cetuximab, cisplatin, or 5-FU). Subjects will be allocated as treated.
Intent to Treat (ITT) population (full analysis set - all randomized subjects): All subjects who 
were randomized to trial treatment.  Subjects will be allocated as randomized.
Per protocol (PP) population: All ITT subjects who do not have a clinically important protocol 
deviation. Further details on PP population will be specified in the Statistical Analysis Plan. 
The following subgroups are considered of interest to comparatively explore the treatment effect 
for the definition of subgroups, data as documented in the eCRF will be taken. 
!
Age: <65 years versus ` 65 years.  
!
Sex: Male versus Female.
!
Baseline ECOG performance status: 0 versus 1.
!
Primary tumor site: oral cavity versus oropharynx versus hypopharynx versus larynx versus 
others.
!
Time from initial SCCHN diagnosis: < median versus ` median.
!
Histology: well/moderately versus poorly differentiated.
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!
Extent of disease at trial entry: nonmetastatic recurrent versus nonrecurrent metastatic versus 
metastatic including recurrent.
!
Prior antitumor therapy: 
o
Any: yes versus no 
o
Prior neoadjuvant/induction: yes versus no
o
Prior radiotherapy: yes versus no
o
Prior radiochemotherapy: yes versus no
o
Prior surgery: yes versus no
o
Prior platinum-containing treatment for SCCHN: yes versus no. 
8.5
Description of Statistical Analyses
8.5.1
General Considerations
The ITT population will be primarily used in the analysis of baseline characteristics and efficacy. 
Selected efficacy analyses will be repeated for the PP population and for subgroups. 
The Safety population will be considered for safety analyses. 
This is a bridging trial. The hypothesis test will not be done and P-values will not be provided, 
unless otherwise specified. If CIs are to be calculated, these will be 2-sided with a confidence 
probability of 95%, unless otherwise specified. 
Continuous variables will be summarized using descriptive statistics, i.e., number of subjects (N), 
mean, median, standard deviation, 25th and 75th percentiles (Q1, Q3), minimum and maximum.
Qualitative variables will be summarized by means of counts and percentages. Unless otherwise 
stated the calculation of proportions will be based on the sample size of the population of interest.  
Counts of missing observations will be included in the denominator and presented as a separate
category.
Baseline
In general, the last measurement before or on the day of the first dose of trial treatment will serve 
as the baseline measurement. If such a value is missing, the last measurement before the first dose 
of trial treatment will be used as the baseline measurement.
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Handling of Dropouts and Missing Data
Unless otherwise specified, missing data will not be replaced. Incomplete AE-related dates will be 
handled as follows:
!
In case the onset date is completely missing or the onset is in the same year (if the onset year 
is available only) or the onset is in the same month and year (if the day is missing) as start of 
trial treatment, then the onset date will be replaced by the minimum of start of trial treatment 
and AE resolution date.
!
In all other cases the missing onset day or onset month will be replaced by 1.
!
Incomplete stop dates will be replaced by the last day of the month (if day is missing only), 
if not resulting in a date later than the date of subject's death. In the latter case the date of 
death will be used to impute the incomplete stop date. In all other cases, the incomplete stop 
date will not be imputed. 
Multicenter trial
!
In order to provide overall estimates of the treatment effect data will be pooled across centers.  
The factor center will not be considered in statistical models or for subgroup analyses.
8.5.2
Analysis of Primary Endpoint
The primary endpoint of this trial is PFS time as assessed by IRC. 
The PFS time by IRC is defined as the duration (in months) from the date of randomization until 
first observation of PD (based on imaging as assessed by IRC), or death due to any cause when 
death occurs within 60 days after the last tumor assessment or randomization (whichever is later). 
Any subject with neither assessment of tumor progression, nor death date within 60 days after last 
tumor assessment and randomization will be censored on the date of last tumor assessment or 
randomization. A subject who has not received trial treatment and for whom no date of progression 
or death is known will be censored on the date of randomization (Day 1) or date of last tumor 
assessment, whichever comes later. 
The analysis will be performed on the basis of the ITT principle on the ITT population. 
The treatment effect expressed as hazard ratio of cetuximab plus chemotherapy to chemotherapy 
alone including 95% CI on PFS time will be primarily evaluated using a stratified Cox proportional 
hazard model, including treatment and the randomization strata (as specified in the IWRS), ECOG 
performance status (0 versus 1) and primary tumor site (oral cavity versus hypopharynx versus 
others). 
This is a bridging trial; in discussion with Chinese Health Authority, this trial would be regarded 
as positive if the point estimation of the stratified hazard ratio is less than or equal to 0.77 (retaining 
at least 50% of the estimated treatment effect of EXTREME trial, see Section 8.1). 
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The PFS time of the 2 treatment arms will be described by means of Kaplan-Meier survival curves 
(product-limit estimates) and associated summary statistics (e.g., median PFS time, 95% CI, 
survival estimates at certain time points, and number of subjects under risk).
Secondary Analyses of Primary Variable
All secondary analyses of the primary variable will be performed to support the robustness of the 
primary confirmatory analysis and regarded as exploratory. Such analyses will comprise: 
!
Sensitivity Analyses. 
Sensitivity analysis will be employed to explore the robustness of the primary confirmatory 
analyses to assess the impact of analysis populations, the validity of model assumptions by
o
Executing per-protocol analysis. If PP population includes more than 90% of the 
ITT population, additional efficacy analyses on the PP population will be omitted. 
!
Subgroup analyses to investigate the effect in subgroups (see subgroup as given in 
Section 8.4).
Subgroup analyses will comprise univariable unstratified analysis considering the 
subgroups as defined in Section 8.4. To assess the heterogeneity of treatment effects across 
the subgroups levels Cox proportional hazards model will be performed for PFS time as 
dependent variable and with subgroup type, the treatment arm assignment and with and 
without the treatment by subgroup type interaction as explanatory variables. P-values for 
the interaction test will be provided together with the hazard ratios and 95% CIs.
!
Exploratory analyses to investigate the treatment effect when adjusted for explanatory 
variables of potential prognostic values.
Multivariable Cox regression analysis will be used to assess and adjust the treatment effect 
for potential baseline prognostic factors (see subgroup as given in Section 8.4). A stepwise 
selection procedure will serve to identify explanatory variables of potential prognostic 
values additional to the randomization strata (as documented in the eCRF) which will be 
included in all models during the selection procedure. The potential baseline prognostic 
factors variables used for this analysis will be specified before database lock.
8.5.3
Analysis of Secondary Endpoints
The secondary efficacy analyses considered below are used as supporting evidence to underline 
the clinical benefit of cetuximab plus chemotherapy versus chemotherapy only. The analyses will 
be exploratory, and no adjustment for multiple comparisons will be made. 
For the analysis of time-to-event variables (e.g., OS time, PFS time by Investigator), will follow 
standard methodology by employing Kaplan-Meier estimates (product-limit estimates), Cox’s 
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proportional hazard model to estimate stratified hazard ratios and corresponding CI, subgroup 
analyses will be performed for predefined baseline factors (see subgroup as given in Section 8.4).
Duration of response will be presented descriptively. 
For the analysis of dichotomous variables (e.g., BOR rate, DCR), counts and percentages will be 
summarized.
8.5.4
Analysis of Safety
Safety analyses will be performed according to the as-treated principle. Any TEAEs will be 
summarized, i.e., those events that emerge during treatment having been absent pre-treatment, or 
worsen relative to the pre-treatment state and with onset dates occurring within the first dosing day 
of trial treatment until 30 days after the last dose of trial treatment. No formal statistical 
comparisons are planned.
The extent of exposure for cetuximab, cisplatin or carboplatin, and 5-FU will be characterized by 
duration (weeks), cumulative dose, dose intensity, relative dose intensity (actual dose 
given/planned dose), number of dose reductions, and number of dose delays. 
AEs will be coded according to the current Medical Dictionary for Regulatory Affairs (MedDRA). 
The severity of AEs will be graded using CTCAE toxicity grades. The incidence and type of AEs, 
SAEs, trial treatment-related AEs and SAEs, trial treatment-related AEs by CTCAE toxicity grade, 
CTCAE Grade 3 and 4 AEs, trial treatment-related CTCAE Grade 3 and 4 AEs, AEs leading to 
death, AEs leading to discontinuation of trial treatment, will be summarized in total and for each 
treatment arm according to the MedDRA system organ class and MedDRA preferred terms. 
Missing classifications concerning trial treatment relationship will be considered as related to the 
trial treatment.
All deaths, deaths within 60 days after date of first dose of trial treatment and deaths within 30 days 
after last dose of trial treatment as well as reasons for deaths will be tabulated.
Laboratory results will be classified according to the CTCAE (version 4.03) when applicable. The 
worst on trial grade after date of first dose of trial treatment will be summarized. Shifts in toxicity 
grading from treatment start to highest grade will be displayed. Results for variables that were not 
part of the CTCAE (version 4.03) will be presented as below, within, and above the normal limits 
of the local laboratory. Only subjects with post-baseline laboratory values will be included in these 
analyses. The last measurement before trial treatment will serve as the baseline measurement. 
Vital signs (temperature, heart rate, blood pressure, respiratory rate) will be descriptively 
presented. 
The baseline results of the physical examination will be presented. Clinically significant, abnormal 
findings from the physical examination are to be reported as AEs. Separate summaries of the 
physical examination during and after treatment will therefore not be provided.
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Further details on safety analyses will be specified in the Statistical Analysis Plan.
8.6
Interim and Additional Planned Analyses
No interim analyses on efficacy will be conducted.
An IDMC will be established for this trial. The IDMC will be a group of independent experts 
consisting of clinicians with expertise in the relevant clinical specialties and at least one 
statistician. The IDMC will periodically review safety data and data quality for analysis during the 
trial. Descriptive interim safety and data quality analyses are scheduled but no formal statistical 
comparisons are planned. After each review, the IDMC will provide a recommendation to the 
Sponsor of how to proceed with the trial. Further details regarding the review process will be 
compiled in a trial-specific IDMC charter.
The main analysis will be based on all data recorded until the clinical cut-off date for PFS, e.g.,
defined at the date when the trial collects more than 144 events. The final analysis of OS at the OS 
cut-off date, will be presented in a report addendum. Safety data collected after the OS cut-off will 
be reported through patient profile. No additional statistical analyses will be conducted.
The OS cut-off will occur when the following conditions are met: 
!
Follow-up after the randomization of the last subject is at least 12 months, OR
!
At least 180 deaths have been reported in this trial.
9
Ethical and Regulatory Aspects
9.1
Responsibilities of the Investigator
The Investigator is responsible for the conduct of the trial at the center and will ensure that the trial 
is performed in accordance with this protocol, the ethical principles outlined in the Declaration of 
Helsinki, ICH GCP, and any other applicable regulations. The Investigator must ensure that only 
subjects who have given informed consent are included in the trial.
9.2
Subject Information and Informed Consent
An unconditional prerequisite for each subject prior to participation in the trial is written informed 
consent, which must be given before any trial-related activities are carried out. Adequate 
information must therefore be given to the subject by the Investigator or an appropriate designee 
(if local regulations permit) before informed consent is obtained.
A subject information sheet must be prepared in the local language in accordance with ICH GCP 
and will be provided by the Sponsor for the purpose of obtaining informed consent. In addition to 
providing this written information to a potential subject, the Investigator or a designate will inform 
the subject verbally of all pertinent aspects of the trial, using language chosen so that the 
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information can be fully and readily understood by laypersons. The subject will be given sufficient 
time to read the information and the opportunity to ask questions and to request additional 
information and clarification.
If permitted by national regulations, a person other than the Investigator may inform the subject 
about the trial and sign the ICF, as above.
After the information is provided by the Investigator, the ICF must be signed and dated by the
subject and the Investigator. 
The signed and dated declaration of informed consent will remain at the Investigator’s center, and 
must be safely archived so that the forms can be retrieved at any time for monitoring, auditing and 
inspection purposes. A copy of the signed and dated information and ICF should be provided to 
the subject before participation. 
Whenever important new information becomes available that may be relevant to informed consent, 
the Investigator will revise the subject information sheet and any other written information to be 
provided to the subjects and submit them to the IEC/IRB for review and opinion. Using the 
approved revised subject information sheet and other written information, The Investigator will 
explain the changes to the previous version to each trial subject and obtain new written consent for 
continued participation in the trial. The subject will be given sufficient time to read the information 
and the opportunity to ask questions and to request additional information and clarification about 
the changes. 
9.3
Subject Identification and Privacy
A unique number will be assigned to each subject, immediately after informed consent has been 
obtained. This number will serve as the subject’s identifier in the trial as well as in the clinical trial 
database. All subject data collected in the trial will be stored under the appropriate subject number. 
Only the Investigator will be able to link trial data to an individual subject via an identification list 
kept at the center. For each subject, original medical data will be accessible for the purposes of 
source data verification by the Monitor, audits and regulatory inspections, but subject
confidentiality will be strictly maintained.
Data protection and privacy regulations will be observed in capturing, forwarding, processing, and 
storing subject data. Subjects will be informed accordingly, and will be requested to give their 
consent on data handling procedures in accordance with national regulations.
9.4
Emergency Medical Support and Subject Card
Subjects will be provided with Emergency Medical Support cards supplied by the 
Sponsor/designee for use during trial participation in order to provide clinical trial subjects with a 
way of identifying themselves as participating in a clinical trial and to give health care providers 
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access to any information about this participation that may be needed to determine the course of 
medical treatment for the subject. 
The first point of contact for all emergencies will be the clinical trial Investigator caring for the 
affected subject. The Investigator agrees to provide his or her emergency contact information on 
the card for this purpose. If the Investigator is available when an event occurs, they will answer 
any questions. Any subsequent action will follow the standard process established for 
Investigators.
In cases where the Investigator is not available, the Sponsor/designee provides the appropriate 
means to contact a Sponsor physician/designee. This includes the provision of a 24-hour contact 
number at a call center, whereby the health care providers will be given access to the appropriate 
Sponsor physician/designee to assist with the medical emergency and to provide support for the 
events of the subject concerned.
9.5
Clinical Trial Insurance and Compensation to Subjects
Insurance coverage shall be provided for the country participating to the trial. Insurance conditions 
shall meet good local practices, as applicable. 
9.6
Independent Ethics Committee or Institutional Review Board
Before commencement of the trial at a given trial center, this clinical trial protocol will be 
submitted together with its associated documents to the responsible IEC or IRB for its favorable 
opinion or approval, which will be filed in the Investigator Site File. A copy will be filed in the 
Sponsor Trial Master File at Sponsor or designated organization.
The IEC or IRB will be asked to document the date of the meeting at which the favorable opinion 
or approval was given and the members and voting members present. Written evidence of 
favorable opinion or approval that clearly identifies the trial, the clinical trial protocol version and
the Subject Information and ICF version reviewed should be provided. Where possible, copies of 
the meeting minutes should be obtained.
Amendments to this clinical trial protocol will also be submitted to the concerned IEC or IRB, 
before implementation of substantial changes (see Section 10.5). Relevant safety information will 
be submitted to the IEC or IRB during the course of the trial in accordance with national 
regulations and requirements.
9.7
Health Authorities
The clinical trial protocol and any applicable documentation (for example, IMP Dossier, Subject 
Information and ICF) will be submitted or notified to the Health Authorities in accordance with 
all local and national regulations for each center. 
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10
Trial Management
10.1
Case Report Form Handling
Refer to the Manual of Operations for eCRF handling guidelines.
The main purpose of the eCRF is to obtain data required by the clinical trial protocol in a complete, 
accurate, legible and timely fashion. The data in the eCRF should be consistent with the relevant 
source documents.
The Investigator or designee is responsible for ensuring that the data collected in the course of this 
trial is accurate and documented appropriately on all applicable forms. They will then be 
processed, evaluated, and stored in anonymous form in accordance with applicable data protection 
regulations. The Investigator must ensure that the eCRFs and any other associated documents 
forwarded to Sponsor or its designated organization contain no mention of any subject names.
The data will be entered into a validated database. The Sponsor or its designee will be responsible 
for data processing, in accordance with the Sponsor’s data management procedures. Database lock 
will occur once quality control and quality assurance procedures have been completed. Portable 
Document Format files of the eCRFs will be provided to the Investigators at the completion of the 
trial.
10.2
Source Data and Subject Files
Source data are defined as all data in original records and certified copies of original records of 
clinical findings, observations, or other activities in a clinical trial that are necessary for the 
reconstruction and evaluation of the trial.
The Investigator must keep a file (medical file, original medical records) on paper or electronically 
for every subject in the trial. It must be possible to identify each subject by using this subject file. 
This file will contain the demographic and medical information for the subject listed below and 
should be as complete as possible.
!
Subject’s full name, date of birth, sex, height, weight. 
!
Medical history and concomitant diseases. 
!
Prior and concomitant medications (including changes during the trial). 
!
Trial identification, that is, the Sponsor trial number for this clinical trial, and subject number. 
!
Dates for entry into the trial (informed consent) and visits to the center. 
!
Any medical examinations and clinical findings predefined in this clinical trial protocol. 
!
All AEs. 
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!
Date that the subject left the trial including any reason for early withdrawal from the trial or 
trial treatment (if applicable). 
All documents containing source data must be filed, including, but not limited to CT or MRI scan 
images, ECG recordings, and laboratory results. Such documents must bear the subject number 
and the date of the procedure. If possible, this information should be printed by the instrument 
used to perform the assessment or measurement. As necessary, medical evaluation of such records 
should be performed; all evaluations should be documented, signed, and dated by the Investigator.
Electronic subject files will be printed whenever the Monitor performs source data verification. 
Printouts must be signed and dated by the Investigator, countersigned by the Monitor and kept in 
a safe place at the center. 
10.3
Investigator Site File and Archiving
Upon initiation of the trial, the Investigator will be provided with an Investigator Site File 
containing all necessary trial documents, which will be completed throughout the trial and updated 
as necessary. The file must be available for review by the Monitor, during Sponsor audits and for 
inspection by Health Authorities during and after the trial, and must be safely archived for at least 
15 years (or longer, per local requirements or as otherwise notified by the Sponsor) after the end 
of the trial. The documents to be archived include the Subject Identification List and the signed 
subject ICFs. If archiving of the Investigator Site File is no longer possible at the center, the 
Investigator must notify the Sponsor/designee.
All original subject files (medical records) must be stored at the center (hospital, research institute, 
or practice) for the longest possible time permitted by the applicable regulations, and/or as per ICH 
GCP guidelines, whichever is longer. In any case, the Investigator should ensure that no 
destruction of medical records is performed without the written approval of the Sponsor.
10.4
Monitoring, Quality Assurance and Inspection by Health 
Authorities
This trial will be monitored in accordance with the ICH GCP and any other applicable regulations. 
The center Monitor will perform visits to the trial center at regular intervals.
The clinical trial protocol, each step of the data capture procedure, and the handling of the data, 
including the final clinical trial report, will be subject to independent Quality Assurance activities. 
Audits may be conducted at any time during or after the trial to ensure the validity and integrity of 
the trial data. Representatives of the Quality Assurance unit from the Sponsor or a designated 
organization, as well as Health Authorities, must be permitted to access all trial documents and 
other materials at the center, including the Investigator Site File, the completed eCRFs, all IMP 
and IMP accountability records, and the original medical records or files for each subject.
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10.5
Changes to the Clinical Trial Protocol
Changes to the clinical trial protocol will be documented in writing. Substantive amendments will 
usually require submission to the Health Authorities and to the relevant IEC/IRB for approval or 
favorable opinion. In such cases, the amendment will be implemented only after approval or 
favorable opinion has been obtained. 
Minor (nonsubstantial) protocol amendments, including administrative changes, will be filed by 
the Sponsor and at the center. They will be submitted to the relevant IEC/IRB or to Health 
Authorities only where requested by pertinent regulations. Any amendment that could affect the 
subject’s agreement to participate in the trial requires the subject’s informed consent before 
implementation following the process as described in Section 9.2.
10.6
Clinical Trial Report and Publication Policy
10.6.1
Clinical Trial Report
After completion of the trial, a clinical trial report will be written by the Sponsor/designee in 
consultation with the Coordinating Investigators following the guidance in ICH Topic E3.
10.6.2
Publication
The first publication will include the results of the analysis of the primary endpoints and will 
include data from all trial centers. The Investigator will inform the Sponsor in advance about any 
plans to publish or present data from the center. Any publications and presentations of the results 
(abstracts in journals or newspapers, oral presentations, etc.), either in whole or in part, by 
Investigators or their representatives will require review by the Sponsor before submission. The 
Sponsor will not suppress publication, but maintains the right to delay publication in order to 
protect intellectual property rights.
Posting of data on clinicaltrials.gov is planned and will occur 12 months after the last clinic visit 
of the final trial subject or another appropriate date to meet applicable requirements. 
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11
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pre-emptive skin treatment regimen on skin toxicities and quality of life in patients with 
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12
Appendices
Appendix I
Response Evaluation Criteria in Solid Tumors Version 1.1
The text below was obtained from the following reference: Eisenhauer EA, Therasse P, Bogaerts 
J, Schwartz LH, Sargent D, Ford R, et al. New response evaluation criteria in solid tumors: revised 
RECIST guideline (version 1.1). Eur J Cancer 2009; 45:228-247.
Definitions
Response and progression will be evaluated in this trial using the international criteria proposed 
by the RECIST Committee (version 1.1). Changes in only the largest diameter (uni-dimensional 
measurement) of the tumor lesions are used in the RECIST criteria. Note: Lesions are either 
measurable or non-measurable using the criteria provided below. The term “evaluable” in 
reference to measurability will not be used because it does not provide additional meaning or 
accuracy.
Measurable Disease
Tumor lesions: Must be accurately measured in at least 1 dimension (longest diameter in the plane 
of measurement is to be recorded) with a minimum size of: 
!
10 mm by CT scan (irrespective of scanner type) and MRI (no less than double the slice 
thickness and a minimum of 10 mm) 
!
10 mm caliper measurement by clinical exam (when superficial) 
!
20 mm by chest X-ray (if clearly defined and surrounded by aerated lung) 
Malignant lymph nodes: To be considered pathologically enlarged and measurable, a lymph node 
must be ` 15 mm in short axis when assessed by CT scan (CT scan slice thickness recommended 
to be no greater than 5 mm). At baseline and in follow-up, only the short axis will be measured 
and followed.
Non-measurable Disease
All other lesions (or sites of disease), including small lesions (longest diameter ` 10 to < 15 mm 
with conventional techniques or < 10 mm using spiral CT scan), are considered non-measurable 
disease. Leptomeningeal disease, ascites, pleural or pericardial effusion, inflammatory breast 
disease, lymphangitic involvement of skin or lung, abdominal masses/abdominal organomegaly 
identified by physical examination that is not measurable by reproducible imaging techniques are 
all non-measurable.
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Bone lesions:
!
Bone scan, PET scan, or plain films are not considered adequate imaging techniques to 
measure bone lesions. However, these techniques can be used to confirm the presence or 
disappearance of bone lesions.
!
Lytic bone lesions or mixed lytic-blastic lesions, with identifiable soft tissue components, 
that can be evaluated by cross-sectional imaging techniques such as CT or MRI can be 
considered as measurable lesions if the soft tissue component meets the definition of 
measurability described above.
!
Blastic bone lesions are non-measurable.
Cystic lesions:
!
Lesions that meet the criteria for radiographically defined simple cysts should not be 
considered as malignant lesions (neither measurable nor non-measurable) since they are, by 
definition, simple cysts.
!
Cystic lesions thought to represent cystic metastases can be considered as measurable 
lesions, if they meet the definition of measurability described above. However, if non-cystic 
lesions are present in the same subject, these are preferred for selection as target lesions.
Lesions with prior local treatment:
!
Tumor lesions situated in a previously irradiated area, or in an area subjected to other local 
regional therapy, are usually not considered measurable unless there has been demonstrated 
progression in the lesion. Trial protocols should detail the conditions under which such 
lesions would be considered measurable.
Target Lesions
All measurable lesions up to a maximum of 2 lesions per organ and 5 lesions in total, should be 
identified as target lesions and recorded and measured at baseline. Target lesions should be 
selected on the basis of their size (lesions with the longest diameter), be representative of all 
involved organ, but in addition should be those that lend themselves to reproducible repeated 
measurements.
Lymph nodes merit special mention since they are normal anatomical structures which may be 
visible by imaging even if not involved by tumor. Pathological nodes which are defined as 
measurable and may be identified as target lesions must meet the criterion of a short axis of 
` 15 mm by CT scan. Only the short axis of these nodes will contribute to the baseline sum. The 
short axis of the node is the diameter normally used by radiologists to judge if a node is involved 
by solid tumor. Nodal size is normally reported as 2 dimensions in the plane in which the image is 
obtained (for CT scan this is almost always the axial plane; for MRI the plane of acquisition may 
be axial, saggital, or coronal). The smaller of these measures is the short axis. For example, an 
abdominal node which is reported as being 20 mm × 30 mm has a short axis of 20 mm and qualifies 
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as a malignant, measurable node. In this example, 20 mm should be recorded as the node 
measurement. All other pathological nodes (those with short axis ` 10 mm but < 15 mm) should 
be considered non-target lesions. Nodes that have a short axis < 10 mm are considered non-
pathological and should not be recorded or followed.
A sum of the diameters (longest for non-nodal lesions, short axis for nodal lesions) for all target 
lesions will be calculated and reported as the baseline sum diameters. If lymph nodes are to be 
included in the sum, then as noted above, only the short axis is added into the sum. The baseline 
sum diameters will be used as reference to further characterize any objective tumor regression in 
the measurable dimension of the disease. 
Non-target Lesions
All other lesions (or sites of disease) including pathological lymph nodes should be identified as 
non-target lesions and should also be recorded at baseline. Measurements are not required and 
these lesions should be followed as ‘present’, ‘absent’, or in rare cases ‘unequivocal progression’ 
(more details to follow). In addition, it is possible to record multiple non-target lesions involving 
the same organ as a single item on the case record form (e.g., ‘multiple enlarged pelvic lymph 
nodes’ or ‘multiple liver metastases’). 
GUIDELINES FOR EVALUATION OF MEASURABLE DISEASE
All measurements should be recorded in metric notation, using calipers if clinically assessed. All 
baseline evaluations should be performed as close as possible to the treatment start and never more 
than 4 weeks before the beginning of the treatment.
The same method of assessment and the same technique should be used to characterize each 
identified and reported lesion at baseline and during follow-up. Imaging based evaluation should 
always be done rather than clinical examination unless the lesion(s) being followed cannot be 
imaged but are assessable by clinical exam.
Clinical lesions: Clinical lesions will only be considered measurable when they are superficial 
and P10 mm diameter as assessed using calipers (e.g., skin nodules). For the case of skin lesions, 
documentation by color photography including a ruler to estimate the size of the lesion is 
suggested. As noted above, when lesions can be evaluated by both clinical exam and imaging, 
imaging evaluation should be undertaken since it is more objective and may also be reviewed at 
the end of the trial.
Chest X-ray: Chest CT is preferred over chest X-ray, particularly when progression is an 
important endpoint, since CT is more sensitive than X-ray, particularly in identifying new lesions. 
However, lesions on chest X-ray may be considered measurable if they are clearly defined and 
surrounded by aerated lung. 
CT, MRI: CT is the best currently available and reproducible method to measure lesions selected 
for response assessment. This guideline has defined measurability of lesions on CT scan based on 
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the assumption that CT slice thickness is 5 mm or less. As is described in Appendix II of the 
original source article cited above, when CT scans have slice thickness greater than 5 mm, the 
minimum size for a measurable lesion should be twice the slice thickness. MRI is also acceptable 
in certain situations (e.g., for body scans). 
Ultrasound: Ultrasound is not useful in assessment of lesion size and should not be used as a 
method of measurement. Ultrasound examinations cannot be reproduced in their entirety for 
independent review at a later date and, because they are operator dependent, it cannot be 
guaranteed that the same technique and measurements will be taken from 1 assessment to the next. 
If new lesions are identified by ultrasound in the course of the trial, confirmation by CT or MRI is 
advised. If there is concern about radiation exposure at CT, MRI may be used instead of CT in 
selected instances.
Endoscopy, laparoscopy: The utilization of these techniques for objective tumor evaluation is not 
advised. However, they can be useful to confirm complete pathological response when biopsies 
are obtained or to determine relapse in trials where recurrence following CR or surgical resection 
is an endpoint.
Tumor markers: Tumor markers alone cannot be used to assess objective tumor response. If 
markers are initially above the upper normal limit, however, they must normalize for a subject to 
be considered in CR. Because tumor markers are disease specific, instructions for their 
measurement should be incorporated into protocols on a disease specific basis. Specific guidelines 
for both CA-125 response (in recurrent ovarian cancer) and prostate-specific antigen response (in 
recurrent prostate cancer), have been published. In addition, the Gynecologic Cancer Intergroup 
has developed CA-125 progression criteria which are to be integrated with objective tumor 
assessment for use in first-line trials in ovarian cancer.
Cytology, histology: These techniques can be used to differentiate between partial response (PR)
and CR in rare cases if required by protocol (for example, residual lesions in tumor types such as 
germ cell tumors, where known residual benign tumors can remain). When effusions are known 
to be a potential adverse event (AE) of treatment (e.g., with certain taxane compounds or 
angiogenesis inhibitors), the cytological confirmation of the neoplastic origin of any effusion that 
appears or worsens during treatment can be considered if the measurable tumor has met criteria 
for response or SD in order to differentiate between response (or SD) and progressive disease (PD).
RESPONSE CRITERIA
Evaluation of Target Lesions
CR: Disappearance of all target lesions. Any pathological lymph nodes (whether target or non-
target) must have reduction in short axis to < 10 mm.
PR: At least a 30% decrease in the sum of diameters of target lesions, taking as reference the 
baseline sum diameters. 
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PD: At least a 20% increase in the sum of diameters of target lesions, taking as reference the 
smallest sum on trial (this includes the baseline sum if that is the smallest on trial). In addition to 
the relative increase of 20%, the sum must also demonstrate an absolute increase of at least 5 mm. 
(Note: the appearance of 1 or more new lesions is also considered progression). 
SD: Neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for PD, taking 
as reference the smallest sum diameters while on trial. 
Lymph nodes. Lymph nodes identified as target lesions should always have the actual short axis 
measurement recorded (measured in the same anatomical plane as the baseline examination), even 
if the nodes regress to below 10 mm on trial. This means that when lymph nodes are included as 
target lesions, the ‘sum’ of lesions may not be zero even if CR criteria are met, since a normal 
lymph node is defined as having a short axis of < 10 mm. Electronic case report forms or other 
data collection methods may therefore be designed to have target nodal lesions recorded in a 
separate section where, in order to qualify for CR, each node must achieve a short axis < 10 mm. 
For PR, SD, and PD, the actual short axis measurement of the nodes is to be included in the sum 
of target lesions.
Target lesions that become ‘too small to measure’. While on trial, all lesions (nodal and non-nodal) 
recorded at baseline should have their actual measurements recorded at each subsequent 
evaluation, even when very small (e.g., 2 mm). However, sometimes lesions or lymph nodes which 
are recorded as target lesions at baseline become so faint on CT scan that the radiologist may not 
feel comfortable assigning an exact measure and may report them as being ‘too small to measure’. 
When this occurs it is important that a value be recorded on the CRF. If it is the opinion of the 
radiologist that the lesion has likely disappeared, the measurement should be recorded as 0 mm. If 
the lesion is believed to be present and is faintly seen but too small to measure, a default value of 
5 mm should be assigned. (Note: It is less likely that this rule will be used for lymph nodes since 
they usually have a definable size when normal and are frequently surrounded by fat, such as in 
the retroperitoneum; however, if a lymph node is believed to be present and is faintly seen but too 
small to measure, a default value of 5 mm should be assigned in this circumstance as well). This 
default value is derived from the 5 mm CT slice thickness (but should not be changed with varying 
CT slice thickness). The measurement of these lesions is potentially non-reproducible; therefore, 
providing this default value will prevent false responses or progressions based upon measurement 
error. To reiterate, however, if the radiologist is able to provide an actual measure, that should be 
recorded, even if it is below 5 mm.
Lesions that split or coalesce on treatment. When non-nodal lesions ‘fragment’, the longest 
diameters of the fragmented portions should be added together to calculate the target lesion sum. 
Similarly, as lesions coalesce, a plane between them may be maintained that would aid in obtaining 
maximal diameter measurements of each individual lesion. If the lesions have truly coalesced such 
that they are no longer separable, the vector of the longest diameter in this instance should be the 
maximal longest diameter for the ‘coalesced lesion’.
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Evaluation of Non-target Lesions
While some non-target lesions may actually be measurable, they need not be measured and instead 
should be assessed only qualitatively at the time points specified in the protocol. 
CR: Disappearance of all non-target lesions and normalization of tumor marker level. All lymph 
nodes must be non-pathological in size (< 10 mm short axis). 
Non-CR/Non-PD: Persistence of 1 or more non-target lesion(s) and/or maintenance of tumor 
marker level above the normal limits.
PD: Unequivocal progression (see comments below) of existing non-target lesions. (Note: the 
appearance of 1 or more new lesions is also considered progression). 
When the subject also has measurable disease. In this setting, to achieve ‘unequivocal progression’ 
on the basis of the non-target disease, there must be an overall level of substantial worsening in 
non-target disease such that, even in the presence of SD or PR in target disease, the overall tumor 
burden has increased sufficiently to merit discontinuation of therapy. A modest ‘increase’ in the 
size of 1 or more non-target lesions is usually not sufficient to quality for unequivocal progression 
status. The designation of overall progression solely on the basis of change in non-target disease 
in the face of SD or PR of target disease will therefore be extremely rare.
When the subject has only non-measurable disease. This circumstance arises in some phase III 
trials when it is not a criterion of trial entry to have measurable disease. The same general concept 
apply here as noted above, however, in this instance there is no measurable disease assessment to 
factor into the interpretation of an increase in non-measurable disease burden. Because worsening 
in non-target disease cannot be easily quantified (by definition: if all lesions are truly non-
measurable), a useful test that can be applied when assessing subjects for unequivocal progression 
is to consider if the increase in overall disease burden based on the change in non-measurable 
disease is comparable in magnitude to the increase that would be required to declare PD for 
measurable disease: i.e., an increase in tumor burden representing an additional 73% increase in 
‘volume’ (which is equivalent to a 20% increase diameter in a measurable lesion). Examples 
include an increase in a pleural effusion from ‘trace’ to ‘large’, an increase in lymphangitic disease 
from localized to widespread, or may be described in protocols as ‘sufficient to require a change 
in therapy’. If ‘unequivocal progression’ is seen, the subject should be considered to have had 
overall PD at that point. While it would be ideal to have objective criteria to apply to non-
measurable disease, the very nature of that disease makes it impossible to do so; therefore, the 
increase must be substantial.
New Lesions
The appearance of new malignant lesions denotes disease progression; therefore, some comments 
on detection of new lesions are important. There are no specific criteria for the identification of 
new radiographic lesions; however, the finding of a new lesion should be unequivocal: i.e., not 
attributable to differences in scanning technique, change in imaging modality, or findings thought 
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to represent something other than tumor (for example, some ‘new’ bone lesions may be simply 
healing or flare of pre-existing lesions). This is particularly important when the subject’s baseline 
lesions show PR or CR. For example, necrosis of a liver lesion may be reported on a CT scan 
report as a ‘new’ cystic lesion, which it is not. 
A lesion identified on a follow-up trial in an anatomical location that was not scanned at baseline 
is considered a new lesion and will indicate PD. An example of this is the subject who has visceral 
disease at baseline and while on trial has a brain CT or MRI ordered which reveals metastases. 
The subject’s brain metastases are considered to be evidence of PD even if he/she did not have 
brain imaging at baseline.
If a new lesion is equivocal, for example because of its small size, continued therapy and follow-
up evaluation will clarify if it represents truly new disease. If repeat scans confirm there is 
definitely a new lesion, then progression should be declared using the date of the initial scan.
While fludeoxyglucose positron emission tomography (FDG-PET) response assessments need 
additional trial, it is sometimes reasonable to incorporate the use of FDG-PET scanning to 
complement CT scanning in assessment of progression (particularly possible ‘new’ disease). New 
lesions on the basis of FDG-PET imaging can be identified according to the following algorithm:
a.
Negative FDG-PET at baseline, with a positive FDG-PET at follow-up is a sign of PD based 
on a new lesion.
b. No FDG-PET at baseline and a positive FDG-PET at follow-up: If the positive FDG-PET at 
follow-up corresponds to a new site of disease confirmed by CT, this is PD. If the positive 
FDG-PET at follow-up is not confirmed as a new site of disease on CT, additional follow-up 
CT scans are needed to determine if there is truly progression occurring at that site (if so, the 
date of PD will be the date of the initial abnormal FDG-PET scan). If the positive FDG-PET 
at follow-up corresponds to a pre-existing site of disease on CT that is not progressing on the 
basis of the anatomic images, this is not PD.
Evaluation of Best Overall Response
The best OR is the best response recorded from the start of the trial treatment until the end of 
treatment taking into account any requirement for confirmation. On occasion, a response may not 
be documented until after the end of therapy, so protocols should be clear if post-treatment 
assessments are to be considered in determination of best OR. Protocols must specify how any 
new therapy introduced before progression will affect best response designation. The subject’s 
best OR assignment will depend on the findings of both target and non-target disease and will also 
take into consideration the appearance of new lesions. Furthermore, depending on the nature of 
the trial and the protocol requirements, it may also require confirmatory measurement. 
Specifically, in non-randomized trials where response is the primary endpoint, confirmation of PR 
or CR is needed to deem either one the ‘best OR’. 
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The best OR is determined once all the data for the subject is known. Best response determination 
in trials where confirmation of complete or partial response IS NOT required: Best response in 
these trials is defined as the best response across all time points (for example, a subject who has 
SD at first assessment, PR at second assessment, and PD on last assessment has a best OR of PR). 
When SD is believed to be best response, it must also meet the protocol specified minimum time 
from baseline. If the minimum time is not met when SD is otherwise the best time point response, 
the subject’s best response depends on the subsequent assessments. For example, a subject who 
has SD at first assessment, PD at second and does not meet minimum duration for SD, will have a 
best response of PD. The same subject lost to follow-up after the first SD assessment would be 
considered inevaluable.
Target Lesions
Non-target Lesions
New Lesions
Overall Response
CR
CR
No
CR
CR
CR
Non-CR/non-PD
Not Evaluated
No
No
PR
PR
PR
Non-PD or not all evaluated
No
PR
SD
Not all evaluated
Non-PD or not all evaluated
Non-PD
No
No
SD
Not Evaluable
PD
Any
Yes or No
PD
Any
PD
Yes or No
PD
Any
Any
Yes
PD
CR = complete response; PR = partial response; PD = progressive disease; and SD = stable disease.
See text for more details.
Note:
When nodal disease is included in the sum of target lesions and the nodes decrease to ‘normal’ 
size (< 10 mm), they may still have a measurement reported on scans. This measurement should 
be recorded even though the nodes are normal in order not to overstate progression should it be 
based on increase in size of the nodes. As noted earlier, this means that subjects with CR may not 
have a total sum of ‘zero’ on the CRF. 
In trials where confirmation of response is required, repeated ‘NE’ time point assessments may 
complicate best response determination. The analysis plan for the trial must address how missing 
data/assessments will be addressed in determination of response and progression. For example, in 
most trials, it is reasonable to consider a subject with time point responses of PR-NE-PR as a 
confirmed response.
Subjects with a global deterioration of health status requiring discontinuation of treatment without 
objective evidence of PD at that time should be reported as ‘symptomatic deterioration’. Every 
effort should be made to document objective progression even after discontinuation of treatment. 
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Symptomatic deterioration is not a descriptor of an objective response; it is a reason for stopping 
trial therapy. 
Conditions that define ‘early progression, early death and inevaluability’ are trial specific and 
should be clearly described in each protocol (depending on treatment duration, treatment 
periodicity).
In some circumstances it may be difficult to distinguish residual disease from normal tissue. When 
the evaluation of CR depends upon this determination, it is recommended that the residual lesion 
be investigated (fine needle aspirate/biopsy) before assigning a status of CR. The use of FDG-PET 
may be used to upgrade a response to a CR in a manner similar to a biopsy in cases where a residual 
radiographic abnormality is thought to represent fibrosis or scarring. The use of FDG-PET in this 
circumstance should be prospectively described in the protocol and supported by disease specific 
medical literature for the indication. However, it must be acknowledged that both approaches may 
lead to false positive CR due to limitations of FDG-PET and biopsy resolution/ sensitivity.
For equivocal findings of progression (e.g., very small and uncertain new lesions; cystic changes 
or necrosis in existing lesions), treatment may continue until the next scheduled assessment. If at 
the next scheduled assessment, progression is confirmed, the date of progression should be the 
earlier date when progression was suspected.
CONFIRMATORY MEASUREMENT/DURATION OF RESPONSE
Confirmation
In non-randomized trials where response is the primary endpoint, confirmation of PR and CR is 
required to ensure the responses identified are not the result of measurement error. This will also 
permit appropriate interpretation of results in the context of historical data where response has 
traditionally required confirmation in such trials. However, in all other circumstances, i.e., in 
randomized trials (phase II or III) or studies where SD or progression are the primary endpoints, 
confirmation of response is not required since it will not add value to the interpretation of the trial 
results.  However, elimination of the requirement for response confirmation may increase the 
importance of central review to protect against bias, in particular in studies which are not blinded.
In the case of SD, measurements must have met the SD criteria at least once after trial entry at a 
minimum interval (in general not less than 6 to 8 weeks) that is defined in the trial protocol.
Duration of Overall Response
The duration of OR is measured from the time measurement criteria are first met for CR/PR 
(whichever is first recorded) until the first date that recurrent or progressive disease is objectively 
documented (taking as reference for progressive disease the smallest measurements recorded on 
trial).
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The duration of overall CR is measured from the time measurement criteria are first met for CR 
until the first date that recurrent disease is objectively documented. 
Duration of Stable Disease
Stable disease is measured from the start of the treatment (in randomized trials, from date of 
randomization) until the criteria for progression are met, taking as reference the smallest sum on 
trial (if the baseline sum is the smallest, this is the reference for calculation of PD).
The clinical relevance of the duration of SD varies in different studies and diseases. If the 
proportion of subjects achieving SD for a minimum period of time is an endpoint of importance in 
a particular trial, the protocol should specify the minimal time interval required between 
2 measurements for determination of SD.
Note: The duration of response and SD as well as the progression-free survival are influenced by 
the frequency of follow-up after baseline evaluation. It is not in the scope of this guideline to define 
a standard follow-up frequency. The frequency should take into account many parameters 
including disease types and stages, treatment periodicity, and standard practice. However, these 
limitations of the precision of the measured endpoint should be taken into account if comparisons 
between trials are to be made.
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Appendix II
Signature Pages and Responsible Persons for the Trial
Signature Page – Protocol Lead
Trial Title: A multicenter, randomized, open-label, Phase III trial to assess efficacy and safety of 
cetuximab when given in combination with cisplatin plus 5-fluorouracil versus cisplatin plus 
5-fluorouracil for the first-line treatment of Chinese subjects with recurrent and/or metastatic 
squamous cell carcinoma of the head and neck
Clinical Trial Protocol Date/Version: 26 February 2018 / Final 3.0
Protocol Lead responsible for designing the clinical trial:
I approve the design of the clinical trial.
_____________________________________
____________________________
Signature
Date of Signature
Name, academic degree:
Function / Title:
Institution:
Address:
 
Telephone number:
Fax number:
E-mail address:
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Signature Page – Coordinating Investigator
Trial Title: A multicenter, randomized, open-label, Phase III trial to assess efficacy and safety of 
cetuximab when given in combination with cisplatin plus 5-fluorouracil versus cisplatin plus 
5-fluorouracil for the first-line treatment of Chinese subjects with recurrent and/or metastatic 
squamous cell carcinoma of the head and neck
Clinical Trial Protocol Date/Version: 26 February 2018 / Final 3.0
I approve the design of the clinical trial and I understand and will conduct the trial according to 
the clinical trial protocol, any approved protocol amendments, International Council for 
Harmonisation Good Clinical Practice (Topic E6) and all applicable Health Authority 
requirements and national laws.
_____________________________________
____________________________
Signature
Date of Signature
Name, academic degree
Function / Title
Institution
Address
Telephone number
E-mail address
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Signature Page – Coordinating Investigator
Trial Title: A multicenter, randomized, open-label, Phase III trial to assess efficacy and safety of 
cetuximab when given in combination with cisplatin plus 5-fluorouracil versus cisplatin plus 
5-fluorouracil for the first-line treatment of Chinese subjects with recurrent and/or metastatic 
squamous cell carcinoma of the head and neck
Clinical Trial Protocol Date/Version: 26 February 2018 / Final 3.0
I approve the design of the clinical trial and I understand and will conduct the trial according to 
the clinical trial protocol, any approved protocol amendments, International Council for 
Harmonisation Good Clinical Practice (Topic E6) and all applicable Health Authority 
requirements and national laws.
_____________________________________
____________________________
Signature
Date of Signature
Name, academic degree
Function / Title
Institution
Address
Telephone number
Fax number
E-mail address
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Signature Page – Principal Investigator
Trial Title: A multicenter, randomized, open-label, Phase III trial to assess efficacy and safety of 
cetuximab when given in combination with cisplatin plus 5-fluorouracil versus cisplatin plus 
5-fluorouracil for the first-line treatment of Chinese subjects with recurrent and/or metastatic 
squamous cell carcinoma of the head and neck
Clinical Trial Protocol Date/Version: 26 February 2018 / Final 3.0
Center Number: 
Principal Investigator
I, the undersigned, am responsible for the conduct of the trial at this site and affirm that I 
understand and will conduct the trial according to the clinical trial protocol, any approved protocol 
amendments, International Council for Harmonisation Good Clinical Practice (Topic E6) and all 
applicable Health Authority requirements and national laws.
_____________________________________
____________________________
Signature
Date of Signature
Name, academic degree
Function / Title
Institution
Address
Telephone number
Fax number
E-mail address
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Sponsor Responsible Person not Named on the Cover Page
Name, academic degree
Function / Title
Institution
Address
 
Telephone number
Fax number
E-mail address
Name, academic degree
Function / Title
 
 
 
 
 
 
Institution
Address
 
Telephone number
Fax number
E-mail address
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Appendix III
Protocol Amendment 1.0 and List of Changes
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
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!
 
 
 
 
 
 
 
 
 
 
 
 
 
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