Open Label Randomized, Multi-centre Phase III Trial of TPF Plus Concomitant Treatment With Cisplatin and Radiotherapy Versus Concomitant Cetuximab and Radiotherapy in Locally Advanced, Unresectable Head and Neck Cancer.
Phase: PHASE3
Conditions: Head and Neck Cancer
Sponsor: Grupo Español de Tratamiento de Tumores de Cabeza y Cuello

 
 
 
 
Open Label Randomized, Multi-centre Phase III Trial of TPF Plus 
Concomitant Treatment with Cisplatin and Radiotherapy versus 
Concomitant Cetuximab and Radiotherapy in Locally Advanced, 
Unresectable Head and Neck Cancer. 
 
Study number:  
TTCC-2007-01 
 
EudraCT No.: 
 
 
2007-005540-24 
 
Coordinating investigators:  
 Dr Ricardo Hitt 
Grupo TTCC 
Sede SEOM 
C/ Velazquez, 7, 3ª planta 
28001 Madrid 
rhitt@telefonica.net  
 
Prof Juan Jesús Cruz 
Servicio de Oncología Médica 
Hospital Universitario de Salamanca 
Paseo de San Vicente, 58-182 
37007-Salamanca (Salamanca) 
jjcruz@usal.es 
 
 
Sponsor: 
Spanish Head and Neck Tumour Treatment Group 
[Grupo Español de Tratamiento de Tumores de Cabeza 
y Cuello (TTCC)] 
Sede SEOM 
C/ Velazquez, 7, 3ª planta 
28001 Madrid 
 
Date and version: 
30 April 2012 / Version 8.0  
 
 
Includes: Protocol of 14 September 2007, Amendment 1 of 18 January 2008, Amendment 2 of 
03 March 2008, Amendment 3 of 02 May 2008, Amendment 4 of 19 June 2008, Amendment 5 
of 01 September 2008, Amendment 6 of 30 October 2008, Amendment 7 of 27 April 2009, 
Amendment 8 of 21 September 2009, Amendment 9 of 26 November 2009, Amendment 10 of 
30 August 2010, Amendment 11 of 30 September 2010 and Amendment 12 of 30 April 2012. 
    
CONFIDENCIAL All information and data included in this protocol contains trade secrets and privileged or confidential information. These 
limitations will also apply to all information considered privileged or confidential that will be provided in the future. This material may be 
disclosed 
and 
used 
by 
your 
team 
and 
collaborators, 
as 
necessary 
for 
the 
conduct 
of 
the 
clinical 
study.

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I agree to carry out the study in accordance with the protocol described in this document 
and in accordance with Good Clinical Practice, as well as the applicable legal 
requirements. 
 
Coordinating investigators of the study: 
 
 
Dr Ricardo Hitt 
Grupo TTCC 
Sede SEOM 
C/ Velazquez, 7, 3ª planta 
28001 Madrid 
E-mail: rhitt@telefonica.net  
 
 
 
Date:...........................................           Signature: .......................................................... 
 
 
Prof. Juan Jesús Cruz 
Servicio de Oncología Médica 
Hospital Universitario de Salamanca 
Paseo de San Vicente, 58-182 
37007-Salamanca (Salamanca) 
E-mail: jjcruz@usal.es 
 
 
 
Date:...........................................           Signature: .......................................................... 
 
 
 
Sponsor of the study: 
 
Grupo Español de Tratamiento de Tumores de Cabeza y Cuello (TTCC) 
Sede SEOM 
C/ Velazquez, 7, 3ª planta 
28001 Madrid 
 
 
 
Date:...........................................           Signature: ............................................................. 
Clinical Research Manager: 

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Susana Carner 
Trial Form Support S.L. 
Consell de Cent, 334-336 
08009 Barcelona 
Teléfono: 93 185 02 00 / Fax: 93 185 02 57 
E-mail: susana.carner @tfscro.com  
 
 
 
Date:...........................................             Signature: ........................................................ 
 
 
Biostatistics:  
 
Rosa Alonso 
Trial Form Support S.L. 
Consell de Cent, 334-336 
08009 Barcelona 
E-mail: rosa.alonso@tfscro.com 
 
 
Date:.......................................... 
 
Signature:..................................................... 

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List of abbreviations and definition of terms 
 
5-FU 
5-Fluorouracil 
AE 
Adverse event 
AEMPS 
Spanish Agency of Medicines and Medical Devices 
AJCC 
American Joint Commission for Cancer 
ARF 
ASCO 
BSA 
Serious adverse event alert report form 
American Society of Clinical Oncology 
Body surface area 
BMI 
BMS 
Body mass index 
Bristol-Myers Squibb 
CDK 
CR 
CREC 
CRC 
CRF 
CRO 
CTC 
C225 
DP 
ECG 
ECOG 
EGF 
EGFR 
EMA 
EMR 
EORTC 
FDA 
GCP 
Cyclin-dependent protein kinase 
Complete response 
Clinical Research Ethics Committee 
Colorectal cancer 
Case report form 
Contract Research Organisation 
Common toxicity criteria 
Chimeric monoclonal antibody C225, Cetuximab, ErbituxTM 
Disease progression 
Electrocardiogram 
Eastern Cooperative Oncology Group 
Epidermal growth factor 
Epidermal growth factor receptor 
European Medicines Agency 
E. Merck Research 
European Organization for Research and Treatment of Cancer 
Food and Drug Administration 
Good clinical practice 
CI  
Confidence interval 
Cmax 
Mean of the maximum serum concentration 
CT  
Computed tomography 
CTV 
Clinical target volume 
EU 
European Union 
FND 
Functional neck dissection 
GOT 
Glutamic oxaloacetic transaminase 
GPT 
Alanine aminotransferase 
HIV 
Human Immunodeficiency Virus 
HNSCC 
Head and Neck Squamous Cell Carcinoma 
HR 
Hazard ratio 
ICH 
International Conference on Harmonisation 
ICRU 
International Commission on Radiation Units 
IEC 
Independent Ethics Committee 
NMR 
PET-TC 
Nuclear magnetic resonance 
Positron emission tomography – Computed tomography 
ORR 
Overall response rate 
OS 
Overall survival 
PF 
Cisplatin + 5-FU 
PFS 
Progression-free survival 
PR 
Partial response 

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PTV 
Planning target volume 
QoL 
Quality of life 
RECIST 
Response Evaluation Criteria in Solid Tumours 
RT 
Radiotherapy 
RTOG 
Radiation Therapy Oncology Group 
SAE 
SGOT 
SGPT 
TFS 
TGFα 
TNM 
TPF 
UNL 
USA 
Serious adverse event 
Serum glutamic oxaloacetic transaminase (=ALT = alanine transaminase) 
Serum glutamic pyruvic transaminase (=AST = aspartate transaminase) 
Trial Form Support 
Transforming growth factor alpha 
Tumour-lymph node-metastasis classification 
Docetaxel, cisplatin, 5-fluorouracil 
Upper normal limit 
United States of America 
SD 
Stable disease 
TTP 
Time to progression 
USAN 
United states adopted names 
VAP 
Visit after progression 
Vss 
Steady-state volume of distribution 
WHO 
World Health Organization 
WHO-DRL 
World Health Organization’s Reference list of drugs  
β-HCG 
Human chorionic gonadotropin beta 
 

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1. 
Summary 
 
Title: 
 
Open Label Randomized, Multi-centre Phase III Trial of TPF Plus 
Concomitant Treatment with Cisplatin and Radiotherapy versus 
Concomitant Cetuximab and Radiotherapy in Locally Advanced, 
Unresectable Head and Neck Cancer. 
Study Code:  
TTCC-2007-01 
Sponsor: 
Grupo Español de Tratamiento de Tumores de Cabeza y Cuello 
(TTCC) [Spanish Group for Head and Neck Tumour Treatment] 
Coordinating 
Investigators: 
Dr Ricardo Hitt 
Prof Juan Jesús Cruz 
Sites: 
43 Spanish sites approximately 
Ethics 
Committees: 
Ethical Committees of the Participating Centres 
Planned 
duration of the 
study: 
• November 2007 – October 2015 
• Total: 96 months. 
• Recruitment period: 53 months. 
• Estimated date of the closing of the clinical phase: 36 months 
since the inclusion of the last patient. 
Study phase: 
Study phase III, open, randomized and multi-centre  
Objectives: 
This is a phase III study designed to assess the non-inferiority of the 
experimental arm compared with the standard arm in terms of overall 
survival (OS) in patients with locally advanced and unresectable 
squamous cell carcinoma in the head and neck that responded to 
induction chemotherapy with the docetaxel, cisplatin, 5-fluorouracil 
(TPF) regimen. 
Primary objective: 
• To show that the induction chemotherapy followed by 
radiotherapy (RT) + Cetuximab is at least non-inferior to 
chemotherapy with TPF followed by RT + cisplatin compared 
with OS in patients with unresectable HNSCC. 
Secondary objectives: 
• To evaluate the activity and safety of TPF treatment. 

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• To evaluate the reasons for study non-continuation (possibility 
of complying with randomisation criteria) after induction 
treatment with TPF. 
• To evaluate and compare efficacy in the 2 treatment groups 
(experimental arm versus standard arm): 
- Disease-free survival 
- Specific survival 
- Time to locoregional control of disease 
• To evaluate and compare the safety activity and safety profiles 
of the 2 treatment groups (experimental versus standard): 
- Response rate 
- Acute and chronic toxicity rates 
• To evaluate and compare the patient perceptions using quality-
of-life questionnaires. 
• To evaluate the treatment compliance rate with RT plus 
Cetuximab and RT plus cisplatin, after combination with 
induction and TPF. 
Design and 
population of 
the study 
 
 
 
 
 
 
 
 
 
 
 
 
Phase III, open-label, randomised and multicentre study in patients 
with unresectable locally advanced HNSCC. Before the start of 
protocol-specific procedures, written informed consent must be 
obtained. 
All patients will start treatment with 3 cycles of induction 
chemotherapy with the TPF regimen:  
1. Patients who progress with the treatment with TPF will be 
excluded from the study and will be treated according to each 
site’s protocol. 
2. Patients with TPF toxicity that may not follow a treatment that 
includes cisplatin, will be excluded from the study and treated 
according to each site’s protocol and in accordance with 
international guidelines. 
3. Patients who are unable to receive at least two cycles of 
induction will be excluded from the study and will be treated 
according to each site’s protocol and in accordance with 
international guidelines. 
4. Patients who respond to or are stabilised with TPF and who 
may follow treatment with cisplatin, will be randomised to 
receive normofractionated RT plus cisplatin (Group A) versus 
the combination of cetuximab and normofractionated RT 

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(Experimental Group B). Patients will be stratified according 
to location (oral cavity, versus oropharynx, versus larynx 
versus hypopharynx), to ensure a homogeneous distribution.  
As a result, there are 2 separate parts of the study: 
o Part 1 of the study: the period from the signing of informed 
consent form until the response and toxicity assessment of 
induction chemotherapy with TPF. 
o Part 2 of the study: the period from randomisation following 
induction chemotherapy with TPF until the end of study. 
The assignment of patients to any of the populations mentioned below 
will be made before closing the database. 
Part 1 of the study (period between the signing of informed consent to 
the evaluation of response and toxicity to induction chemotherapy 
with TPF): 
A. Safety population 1: all patients who have signed the informed 
consent form and who have received at least one dose of 
chemotherapy with TPF. 
B. Intention-to-treat population 1: all patients enrolled who have 
received at least one dose of TPF chemotherapy. 
Part 2 of the study (period from randomisation after TPF 
chemotherapy and until the end of study): 
C. Safety population 2: all randomised patients who have 
initiated the assigned radical treatment. 
D. Intention-to-treat population 2: all randomised patients who 
have at least began their assigned radical treatment. 
The following table outlines the foreseen moments of tumour 
evaluation from the beginning of the study: 
 
SCHEME 
CLINICAL 
EVALUATION 
OF TUMOR* 
TUMOR IMAGE 
TECHNIQUES**
THORAX 
RADIOGRAPHY
Pre-treatment 
X 
X 
X 
At the end of the 
3rd TPF cycle 
X 
X 
 
4 weeks post-RT X 
 
 
6-8 weeks post- X 
X 
 

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RT 
During years 1 
and 2  
/ 3 months 
/ 6 months*** 
/ 12 months*** 
During years 3 
and 4 
/ 6 months 
/ 6 months*** 
/ 12 months*** 
During year 5 
/ 12 months 
/ 12 months*** 
(optional) 
/ 12 months*** 
* It will include direct and/or indirect optical examinations of the tumour that they 
consider necessary. The exception would be the assessment at 4 weeks after the end 
of RT 
** CT, PET-CT or MRI of the head and neck (always the same technique) 
*** or at the time of suspected progression and/or recurrence 
Abdominal ECHO, PET-CT and bone scan only if there is a suspicion of metastasis 
in these locations.
Methodology 
The main analysis of the study will be carried out with the intention –
to-treat (ITT) population that has been randomized to the standard 
branch or to the experimental branch. It will be proved, by means of 
the following hypotheses, if the experimental treatment group is, at 
least, not inferior to the standard group: 
- 
H0: Experimental Arm / Standard Arm ≥1.3 
- 
H1: Experimental Arm / Standard Arm <1.3 
It will be concluded that the experimental group is at least not inferior 
to the standard group if the unilateral confidence interval (CI) of 95% 
of the hazard ratio (HR) calculated by the Cox method does not 
contain the 1.3. 
In the analysis of OS, which is the primary endpoint proposed in this 
study, the Cox proportional hazards regression model will be used. 
Calculation of sample size is based on an assumed exponential 
distribution, using the following parameters: 
o Unilateral testing with an alpha of 0.05 and 80% power. 
o A recruitment phase of 53 months. 
o A follow-up phase of 36 months. 
o A HR of 0.0231 for the standard arm (median progression-free 
survival of 30 months) 
o HR Experimental arms / Standard arms = 0.938 (this assumes a median of 
32 months for the experimental arm) 
o Competing risk of 0.01. 

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The total number of randomised and evaluable patients is 398. We 
also have to add the 15% of patients who will progress with TPF or 
will be lost to this total number. Total number of patients: 469. 
 
Evaluation 
criteria: 
Evaluation of efficacy, safety and compliance: 
OVERALL SURVIVAL (OS): the time from the start of induction 
chemotherapy with TPF to death due to any cause or to the last check-
up in the case of living patients. 
OVERALL RESPONSE RATE (ORR): this is defined as the 
response rate (complete + partial) measured according to the solid 
tumour response endpoints (RECIST) 1.0 modified. 
ADVERSE 
EVENT 
(AE) 
RATE 
AND 
LABORATORY 
PARAMETERS: defined as the AE rate, including abnormal 
laboratory parameters, which occurred during the study period, 
according to the following criteria: 
1. Common Toxicity Criteria (CTC) from the National Cancer 
Institute (NCI), version 3.0 during the induction treatment  
2. CTC from the NCI, version 3.0 and CTC from the RTOG 
during chemotherapy/RT or Cetuximab/RT treatment and up 
to 90 days after completion of RT. If in doubt, the criteria that 
assess the AE at the highest level will be used. 
3. Late CTC from the RTOG/EORTC from 90 days after 
completion of RT, which will be basically used to gather 
chronic toxicity associated with radio-chemotherapy  
All abstracts and lists of AE and laboratory data will be based on the 
safety population. 
EARLY STUDY WITHDRAWALS: this is defined as exclusion 
from the study, for any reason, before the end of treatment and before 
the first expected response assessment, at 6-8 weeks after completion 
of RT. 
Lists and summary tables will be provided, giving the reason for the 
end of the study and when it occurred. These summaries and lists will 
be based on the safety population. Part 2 of the study will be 
separated by assigned treatment arm. 
INCIDENCE AND TIME WHEN DOSE REDUCTION OR 
DISCONTINUATION OCCURRED: this is defined as any 
significant variation in the planned treatment dose (modifications 
greater than 10% of the planned dose), modification of the expected 
treatment day (changes of more than 2 working days) or 

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discontinuations of planned treatment. 
Details and summary tables will be provided, providing the incidence 
of reductions or treatment discontinuations and giving the reason. 
These summaries and lists will be based on the safety population. Part 
2 of the study will be separated by assigned treatment arm. 
PROGESSION-FREE SURVIVAL (PFS): time since the start date of 
treatment with TPF induction chemotherapy until the time when 
disease progression occur or death occur due to any cause. Patients 
who show no progression or death will be censored on the date of the 
last check-up. Patients for whom no tumour assessments are available 
after the baseline evaluation will be censored on day 1. Patients who 
show no progression and begin a cancer treatment other than that of 
the study will be censored on the start date of the other treatment. 
DISEASE-SPECIFIC SURVIVAL: time elapsed from the start date 
of treatment with TPF induction chemotherapy to date of death due to 
disease or related to the treatment of the disease. Deaths caused by 
other reasons will be considered "censored" data on the date of death. 
Patients who does not die will be censored on the date of the last 
check-up. 
TIME 
TO 
LOCOREGIONAL 
CONTROL 
OF 
DISEASE: 
locoregional control: defined as permanent and complete resolution of 
the disease in terms of its initial site and lymph nodes (T and N 
categories). If the disease last (regardless of size) or the tumour recur 
or a second tumour appear in the field RT, it will be recorded as a 
therapeutic failure. This allows for surgical rescue on the lymph 
nodes if, after the evaluation at the end of RT, the cervical adenopathy 
remain but the primary tumour will be under control (indicated as part 
of the first treatment). Locoregional failure will be considered in 
cases of patients who have rescue surgery on the primary tumour (T 
surgery) because of its persistence. Lymph node recurrence after a 
complete cervical lymph node remission will also be considered a 
therapeutic failure. In some cases, residual tumours may have 
persisted, consisting of areas of fibrosis or scarring, which may have 
remained stable or resolved gradually over time and which are not 
accompanied by evidence of locoregional disease progression or 
clinical deterioration. 
We define locoregional control time of the disease as time from the 
start of TPF induction chemotherapy to tumour recurrence or the 
appearance of a second tumour within the RT field. Patients who do 
not achieve complete remission at any of the points of the analysis 
will be considered therapeutic failures from day 1 (start of TPF 
chemotherapy). 
SATISFACTION WITH TREATMENT. QUALITY OF LIFE 
ANALYSIS: EORTC quality-of-life questionnaires is chosen for this 
study. QLQ-C30 version 3.0 is a basic questionnaire with 30 items 

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and the QLQ-H&N35 module, made up of 35 items. 
These questionnaires are self-completed by the patients when they are 
at the site. They have to complete them before starting TPF induction 
chemotherapy, after 3 cycles of TPF, just before the patient knows the 
radical treatment arm to which they’ve been assigned, and then 6-8 
weeks after completion of RT (evaluation visit following radical 
treatment) and every 6 months during the follow-up visits for the first 
and second year. If the time for completing the questionnaire 
coincides with an assessment of the tumour, the patient will fil it in 
before knowing the results of the tumour study. 
Overall scores and those per field in the total population and per 
treatment group will be described. A comparative analysis will be 
performed on the different scales according to the treatment assigned 
by the randomisation. 
OTHER VARIABLES: continuous variables will summarised using 
descriptive statistics, i.e. the mean, median, standard deviation, 
minimum, and maximum and two-sided CI of 95%, when 
appropriate. The qualitative variables will be summarised using 
counts, percentages, and 95% two-sided CI, when appropriate. The 
differences between means or percentages will be accompanied by 
95% two-sided CI or will be compared using the corresponding 
statistical test.  
Statistical 
Methods: 
Efficacy and safety analyses will be performed using descriptive 
and/or comparative statistical techniques that are suited to each 
situation.  

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Patients 
selection: 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Inclusion criteria: 
1. Before beginning the specific procedures of the protocol, 
informed written consent has to be obtained and 
documented. 
2. Locally advanced cancer of the head and neck (oral cavity, 
oropharynx, larynx and hypopharynx), stage III-IV, with no 
evidence of metastasis. 
3. The tumour has to be classified as inoperable according to 
Northern California Oncology Group [5] criteria after 
assessment by a multidisciplinary team, which include, at 
least, a specialist in oncological surgery from the Ears, Nose 
and Throat Department or a specialist in maxillofacial 
surgery (as applicable), a specialist in Medical Oncology 
and a specialist in Radiotherapy oncology. The reason for 
inoperability will be noted on the CRF. NCOG inoperability 
criteria: 
- 
Technically 
nonresectable 
(Includes: 
Evidence 
of 
mediastinal dissemination; tumour fixed to the clavicle, base 
of the cranium or cervical vertebrae; involvement of the 
nasopharynx). 
- Medical criteria based on a low surgical curability. 
- Medical contraindication for surgery. 
4. Anatomically 
and 
pathologically 
proven 
epidermoid 
carcinoma. 
5. Disease measurable according to the modified RECIST 1.0 
criteria. 
6. Men or women aged 18 to 70 inclusive. 
7. ECOG performance status: 0 or 1  
8. Patients in a medical condition to be able to receive 
induction 
treatment 
with 
TPF 
followed 
by 
normofractionated RT with cetuximab or cisplatin. 
9. Patients with adequate haematological function: neutrophils 
≥ 2x109 platelets ≥ 100x109, haemoglobin ≥ 9 g/dL and no 
symptoms related to anaemia. 

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10.  Adequate liver function: Bilirubin ≤ 1.5×Upper Normal 
Limit (UNL), and some of the following parameters: GOT ≤ 2.5 
UNL or GPT ≤ 2.5 UNL or alkaline phosphatase < 2 UNL; 
however, if all of these are present, their value should not exceed 
the UNL. 
 
11.  Adequate kidney function: serum creatinine < 1.4 mg/dL 
(120 µmol/L); if the values were > 1.4 mg/dL, creatinine 
clearance has to be > 60 mL/min (real or calculated by the 
Cockcroft–Gault method). 
 
12.  Adequate nutritional status: Body mass index > 18.5% or 
albumin ≥ 30 g/L. 
13. Patients have to be accessible for treatment and follow-up. 
 

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Exclusion criteria: 
1. Metastatic disease. 
2. Previous treatment by surgery, with radiotherapy and/or 
chemotherapy for the disease being studied. 
3. Other tumour locations in the head and neck area, other than 
the oral cavity, oropharynx, larynx and hypopharynx. 
4. Stages other than stage III or IVM0. 
5. A previous and/or synchronous squamous cell carcinoma. 
6. Diagnosis of another neoplasia in the past 5 years except 
properly treated cervical carcinoma in situ and/or basal cell 
carcinoma. 
7. Active infection (infection that requires intravenous 
antibiotics), including diagnosed active tuberculosis and 
HIV. 
8. Uncontrolled hypertension defined as systolic blood pressure 
≥ 180 mm Hg and/or diastolic blood pressure ≥ 130 mm Hg 
at rest. 
9. Pregnancy (its absence should be confirmed by a serum β-
HCG test) or lactation. 
10. Systemic, chronic and concomitant immune therapy or 
hormone therapy for cancer. 
11. Other concomitant antineoplastic treatments. 
12. Clinically significant coronary artery disease or a history of 
myocardial infarction in the past 12 months or high risk of 
uncontrolled arrhythmia or uncontrolled heart failure. 
13. Chronic obstructive pulmonary disease that required ≥ 3 
hospitalisations in the previous 12 months. 
14. Uncontrolled active peptic ulcer. 
15. Presence of a psychological or medical illness that would 
prevent the patient from taking part in the study or from 
providing written informed consent. 
16. Known drug abuse (except for heavy drinking). 
17. Known allergic reaction to any of the ingredients of the study 
treatment. 
18. Previous treatment with monoclonal antibodies or other 
inhibitors of signal transduction or EGFR inhibitors. 
19. Any experimental treatment in the 30 days prior to study 
entry. 
  

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2. Index 
 
1. 
Summary ................................................................................................................. 6 
2. 
Index ...................................................................................................................... 16 
3. 
Justification and objectives .................................................................................. 18 
3.A  
Justification for cetuximab ............................................................................. 18 
3.B 
Study rationale ................................................................................................ 26 
3.C. 
 Rationale for a randomised study .................................................................. 31 
4. 
Study objectives .................................................................................................... 32 
4.A 
Primary objective ............................................................................................ 32 
4.B 
Secondary Objectives ..................................................................................... 32 
5. 
Investigational plan .............................................................................................. 33 
5.A 
Study design ................................................................................................... 33 
5.B 
Randomisation ................................................................................................ 33 
5.C 
Study design ................................................................................................... 34 
5.D 
Blinding .......................................................................................................... 38 
5.E 
Study periods .................................................................................................. 38 
6. 
Study population screening ................................................................................. 39 
6.A 
Selection criteria ............................................................................................. 39 
6.B 
Patients number .............................................................................................. 41 
6.C 
Withdrawal criteria ......................................................................................... 41 
7. 
Treatment description .......................................................................................... 43 
7.A 
Treatments administered and therapeutic regimen ......................................... 43 
7.B 
Previous and concomitant medicine ............................................................... 63 
7.C 
Material management ..................................................................................... 64 
7.D 
Assessment of treatment compliance ............................................................. 65 
8. 
Efficacy and safety measurements and study outline ....................................... 66 
8.A 
Efficacy evaluations ....................................................................................... 66 
8.B 
Description of the methods used .................................................................... 66 
8.C 
Conduct of the study ....................................................................................... 77 
9. 
Adverse events ...................................................................................................... 84 
9.A 
Brief summary of adverse events and serious adverse events ........................ 84 
9.B 
Methods of registration and evaluation of adverse events. ............................ 85 
9.C 
Procedure for reporting serious adverse events .............................................. 86 
9.D 
Monitoring of patients with adverse events .................................................... 87 
10. 
Ethical aspects ................................................................................................... 88 
10.A 
 General considerations .................................................................................. 88 
10.B 
 Patient information and informed consent..................................................... 88 
10.C 
 Confidentiality ............................................................................................... 89 
10.D 
 Patient insurance ............................................................................................ 89 
11. 
Practical considerations ................................................................................... 90 
11.A 
Participants’ responsibilities ........................................................................... 90 
11.B 
 Conditions for archiving and handling data .................................................. 91 
11.C 
 Final report and publication ........................................................................... 95 
12. 
Statistical analysis ............................................................................................. 96 
12.A 
 Efficacy and safety endpoints ........................................................................ 96 
12.B 
 Analysis populations ..................................................................................... 96 
12.C 
 Efficacy and safety analysis .......................................................................... 97 
12.D 
 Sample size .................................................................................................. 100 
12.E 
 Intermediate analysis ................................................................................... 101 

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13. 
References........................................................................................................ 102 

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3. 
Justification and objectives 
3.A  Justification for cetuximab 
As of 28 April 1999, the USAN adopted the name cetuximab for the chimeric 
monoclonal antibody C225. On 8 May 2000, cetuximab obtained the proposed 
qualifying status of the International Nonproprietary Names (INN).  
Cetuximab (Erbitux®) was developed jointly by Bristol-Myers Squibb (BMS), ImClone 
Systems Incorporated and Merck KGaA. In February 2004 the Food and Drug 
Administration (FDA) authorised in the United States of America (USA) the 
commercial use of Erbitux™ combined with irinotecan in the treatment of metastatic 
colorectal carcinoma (CRC) expressing epidermal growth factor receptor (EGFR) in 
patients refractory to irinotecan-based chemotherapy and alone for patients intolerant to 
irinotecan. In June 2004 the European Medicines Agency (EMA) approved the use of 
cetuximab (Erbitux®) in the European Union (EU) (as well as in Norway and Iceland) 
combined with irinotecan in the treatment of patients with CRC expressing EGFR after 
treatment failure with cytotoxic agents, including irinotecan. In Spain, the Spanish 
Agency of Medicines and Medical Devices (AEMPS) authorised the marketing of 
Erbitux® on 18 January 2005. On 30 November 2004, marketing authorisation for 
cetuximab (Erbitux®) was also approved in Argentina, Chile and Mexico for the 
treatment of metastatic CRC expressing EGFR in patients refractory to irinotecan, either 
alone or combined with irinotecan. 
In December 2005 cetuximab (Erbitux®) was approved for the treatment of locally 
advanced head and neck squamous cell carcinoma (HNSCC) combined with 
radiotherapy (RT), in Switzerland, and in March 2006 it was approved in the EU by the 
EMA. In Spain, the AEMPS authorised the use of Erbitux® in the treatment of head and 
neck cancers on 31 May 2006. In Argentina, the Philippines, Chile, Israel and Mexico, 
Erbitux® was also authorised as monotherapy in patients with recurrent and/or 
metastatic HNSCC where previous chemotherapy had failed. On 1 March 2006, 
Erbitux® was approved in the USA for use in combination with RT for the treatment of 
locally advanced HNSCC, and as a single agent in recurrent or metastatic HNSCC 
where platinum-based chemotherapy had failed. 
In the Investigator's Brochure, version 10.0, dated May 2004 [6] further information 
about the relevant pre-clinical pharmacological, pharmacokinetic and toxicological data 
can be found. 
3.A.1 
Epidermal growth factor receptor in cancer 
EGFR is a transmembrane glycoprotein that is expressed under normal conditions and is 
a member of the tyrosine kinase receptor family. EGFR is expressed in many human 
tissues, and the activation of the proto-oncogene, which encodes it, results in the 
overexpression seen in many types of tumour. EGFR has an extracellular domain that 
constitutes a ligand-binding site for the epidermal growth factor (EGF) and for tumour 
growth factor alpha (TGFα). After ligand-binding, the intracellular domain of EGFR is 
activated, which triggers the signal-transduction pathway of EGFR-mediated tyrosine 

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kinase, and consequently various cell mechanisms that regulate cell growth and division 
are activated [7]. 
The in vitro analysis performed with cell lines that not only express EGFR in large 
amounts but also produce a ligand for these receptors has shown that EGFR may be 
activated by an autocrine pathway, causing cell proliferation in cultures [8]. In order to 
inhibit the cell proliferation that expresses EGFR, EGFR antagonists have been 
synthesised that block the ligand-binding site. 
Table 3.1 shows the prevalence of EGFR expression in some of the most common 
tumours [9]. 
Table 3.1 Prevalence of EGFR expression in the most common tumours. 
Type of tumour 
Percentage of EGFR expression 
Oesophageal cancer 
92% 
Head and neck squamous cell carcinoma (HNSCC) 
90% 
Pancreatic cancer 
89% 
Colorectal cancer (CRC) 
82% 
Prostate cancer 
65% 
Bladder cancer 
65% 
Ovarian epithelial cancer 
60% 
Cervical cancer 
60% 
Renal cell carcinoma 
50% 
Non-small cell lung cancer (NSCLC) 
50% 
EGFR: Epidermal growth factor receptor 
3.A.1.1 
EGFR inhibition and cell cycle  
The effects of EGFR blockade on cell-cycle progression have been studied in several 
human cell lines, including the colorectal cancer cell line (DiFi), the mammary 
epithelial cell line (MCF10A), the epidermoid carcinoma cell line (A-431) and the 
prostate cancer cell line (DU145). These studies suggest that the EGFR blockade with 
monoclonal antibodies like cetuximab cause the cell cycle to stop in G1, which is 
accompanied by decreased activity of cyclin-dependent kinases (CDKs) 2 and increased 
expression of the cyclin-CDK inhibitor p27K1P1 [10,11]. In addition to stopping the G1 
phase, it has also been shown to block the EGFR that induces cell death through 
apoptosis in the DiFi human colorectal cancer cell line [12]. 
3.A.2 
Cetuximab 
Cetuximab, a chimeric antibody in subclass IgG1, was originally obtained from a mouse 
myeloma cell line. The chimerization process produces an antibody with an affinity for 
binding to EGFR that is greater than that of the natural ligand EGF [13]. Cetuximab 
blocks the binding of EGF and TGF-α to EGFR, thereby inhibiting the activation of this 
receptor tyrosine kinase caused by the ligand binding. Cetuximab also stimulates EGFR 
internalisation, thus effectively removing the cell-surface receptor and preventing it 

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from interacting with the ligand [14]. Cetuximab was created by chimerization of the 
murine monoclonal antibody (M225), developed at the University of California, San 
Diego [6]. Cetuximab was constructed genetically by cloning the heavy and light chains 
of M225 and adapting them for expression with the constant domains of the human light 
chain k and heavy chain γ 1. 
In an in vitro study to establish the biological activity of cetuximab and its specificity to 
human EGFR compared with that of a murine antibody against EGFR (M225), both 
cetuximab as well as M225 inhibited the growth of A431 cells to a similar extent, i.e. 
30% of the control [13]. 
3.A.2.1 
Binding cetuximab ligands to tissue in vitro 
In a series of immunohistochemical studies to characterise the binding of cetuximab to 
human and animal tissues, it was shown that cetuximab reacted positively and 
specifically to human placental epithelium [6]. Specific staining was also observed in 
the normal epithelia of skin, gastrointestinal tract, urogenital system and tonsillar crypts, 
and in squamous cell carcinoma and small-cell lung cancer. There was no specific 
staining in cancers in other organs, in melanomas or in lymphoid tumours. In a cross-
species study, the control human placental tissues showed positive staining for 
cetuximab; however, no staining was observed in monkey liver tissues (Cynomolgus 
and Rhesus), baboons, rodents and dogs. In the Investigator's Brochure, version 10.0, 
dated May 2004, specific details of these studies can be found [6]. 
3.A.2.2 
Criteria for dose selection and clinical pharmacokinetic parameters of 
cetuximab 
When the clinical development of cetuximab was started, the objective was to 
administer doses of the antibody which were safe and which would maintain serum 
concentrations of cetuximab above the doses needed to saturate the binding of EGFR 
associated with the tumour obtained in preclinical mouse models (approximately 20 
nM). In this early stage of clinical development, this dose-selection criterion was 
revised considering in the hypothesis that binding to EGFR not associated with the 
tumour (especially in the liver and the skin) could cause a considerable loss of 
cetuximab, which might limit the availability of antibody for the tumour-associated 
receptors. Expanding this hypothesis, it was thought that the binding of cetuximab to 
targets other than the tumour and the subsequent internalisation of the receptor 
represented a major route of elimination of cetuximab, which could theoretically 
become saturated. Thus, at some point the systemic clearance of cetuximab could 
become saturated, which might be detected by estimating serum pharmacokinetic 
parameters in subjects (total body clearance and half-life). Based on this hypothesis the 
criteria used to select the dose were revised to find the dose at which systemic clearance 
(as determined by serum pharmacokinetic parameters) becomes saturated. 
The initial clinical development programme for cetuximab was composed of 14 studies, 
13 of which contributed to the pharmacokinetic database. In dose-finding studies, where 
the dose of cetuximab was increased from 5 to 500 mg/m2, a trend towards decreased 
clearance of cetuximab was described. At doses above 200 mg/m2, cetuximab clearance 
appeared to stabilise and was maintained at approximately 0.02 L/h/m2 up to the highest 
dose studied, 500 mg/m2. The estimated mean terminal half-life of cetuximab in serum 
increased from 14 to 97 hours in the dosage range from 5 to 300 mg/m2 after which the 

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half-life seemed to stabilise. The mean of the steady-state volume of distribution (Vss) 
of cetuximab in serum was not cetuximab dose-dependent; it was from 1.96 to 2.52 
L/m2, which suggests that cetuximab is distributed in an equal or slightly higher volume 
in the vascular space. Based on the foregoing and on the finding of an increased 
incidence of skin toxicity at 500 mg/m2, the cetuximab regimen chosen for the phase II 
clinical trials was an initial dose of 400 mg/m2 followed by repeated doses every week 
of 250 mg/m2. It has been suggested that on this regimen patients might maintain EGFR 
activity and drug activity.  
When cetuximab was administered alone to subjects with solid tumours at an initial 
dose of 400 mg/m2 followed by weekly maintenance doses of 250 mg/m2 (n=7 
subjects), the mean of the maximum serum concentration (Cmax) of cetuximab at week 3 
was 153 µg/mL (range from 112 to 225 µg/mL). The mean elimination half-life at week 
3 was 119 h (range from 82 to 188 hours). The mean Vss at week 3 was 3.6 L (range 
from 2.2 to 4.5 L). Concomitant administration of irinotecan (350 mg/m2) at week 4 did 
not change the pharmacokinetic characteristics of cetuximab, given that the 
relationships (expressed as a percentage) of all the pharmacokinetic parameters of 
cetuximab at week 4 versus week 3 were from 87% to 123% (EMR 62 202-012 study 
by Merck). 
3.A.2.3 
Response of anti-cetuximab antibodies 
The presence of anti-cetuximab antibodies was evaluated in a total of 614 patients 
treated with cetuximab up to 30 November 2002, analysing the baseline and subsequent 
serum concentrations. The overall incidence of an anti-cetuximab immune response in 
these patients was 3.7%. When there was an anti-cetuximab response, in general it was 
found to be weak. The anti-cetuximab antibodies were analysed in two patients who had 
greater reactivity (4,670 and 6,516 ng/mL) in an in vitro trial to determine neutralising 
activity. The serum concentrations analysed did not interfere with the ability of 
cetuximab to inhibit proliferation in a cell line sensitive to cetuximab, thus suggesting 
that the antibodies of these sera were not neutralising. The levels of serum reactivity in 
the other subjects were not high enough to perform this kind of analysis. To determine 
the specificity of the antibody response, the sera of 15 patients who had a positive 
response to anti-cetuximab were then studied using as a competitor unlabelled 
cetuximab in an immunoradiometric double-antigen assay. This analysis showed that 
the sera of 14 of the 15 patients contained antibodies specific to anti-cetuximab. 
3.A.2.4 
Clinical experience with cetuximab 
Clinical experience with cetuximab is detailed in the Investigator's Brochure for 
cetuximab, version 10.0, dated 20 May 2004 [6]. Clinical trials with cetuximab started 
in 1994. Cetuximab has been administered in phase I-III clinical trials as a single agent 
or in combination with chemotherapy and RT. Those trials have shown anti-tumour 
activity in metastatic colorectal cancer, HNSCC, non-small cell lung cancer and 
pancreatic cancer. The clinical experience with cetuximab in head and neck cancers is 
detailed in section 3.A.2.6. 

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3.A.2.5 
Clinically significant adverse events related to cetuximab at the time of 
the study design 
The database includes safety data from 2,127 patients treated with cetuximab in 33 
clinical trials up to 30 November 2003 [6]. Adverse events (AEs) were reported in 
90.3% of patients. A total of 1,378 patients (64.8%) reported at least one AE of grade 3 
or 4. In all, 1,817 patients (85.4%) had AEs related to cetuximab. In total, 31.7% of 
patients reported cetuximab-related AEs of grade 3 or 4. The most common AE with 
cetuximab was acneiform rash. 
The Investigator's Brochure [6] summarises the safety data in table format for all phase 
I studies, by indication for phase II studies and by study for each phase III study.  
The incidence of the most common cetuximab-related AEs (all grades) is given in Table 
3.2. 
Table 3.2 Most common cetuximab-related AEs (all grades, n=2127, up to 30 November 2003). 
Adverse event 
Frequency 
 
 
 
N 
Grade ≤1 (%) 
Grade 3-4 (%) 
Skin reactiona 
1621 
76.2 
11.1 
Fatigue/Malaise/Lethargy 
640 
30.1 
4.2 
Nausea/Vomiting 
510 
24.0 
2.2 
Mucositis/Stomatitis 
372 
17.5 
2.3 
Diarrhoea 
321 
15.1 
2.4 
Nail irritation 
229 
10.8 
0.3 
Allergic reactions or hypersensitivityb 
112 
5.3 
2.4 
Data from 2127 patients in 33 trials who received cetuximab alone or in combination with chemotherapy or 
radiotherapy.  
a Includes the COSTART terms acne, rash, maculopapular rash, pustular rash, dry skin or exfoliative dermatitis. 
b Includes the COSTART terms allergic reaction or anaphylactoid reaction. 
 
Skin reactions are the most common AEs related to cetuximab (76.2% grades 1-4, 
11.1% grades 3 or 4). They usually occur as an acne-like rash or, less often, as nail 
disorders. The aetiology of acneiform rash is thought to be the result of cetuximab 
binding to the EGFR of the cells of the epidermis, thus interfering with the homeostasis 
of the epidermis, hair follicles and sebaceous glands, as well as with the regulation of 
skin inflammation. 
Acneiform rash (72.4% grades 1-4) usually occur during the first three weeks of 
treatment on the face, upper part of the chest and the back, although sometimes it 
extends to the limbs. It appears as multiple pustular or follicular lesions, histologically 
characterised as lymphocytic perifolliculitis or superficial suppurative folliculitis. It 
tends to resolve over time without after-effects after stopping treatment. In patients who 
received cetuximab in doses under 100 mg/m2, there were few cases of acneiform rash 
reported, and they were limited to grades 1 and 2. For treatment guidelines, see section 
7.A.1.4.1. 

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A clear correlation has been established between the onset of skin toxicity and the 
efficacy of treatment, both in response and in time to progression (TTP) and survival 
[15,16]. 
Nail disorders are another typical, but less common skin manifestation (10.8% grades 
1-4, 0.3% grades 3 or 4 = 0.3%) that occur at different pain levels and sensitivity, as 
does cracked skin on the distal end of the fingers and toes. These patients developed 
paronychia associated with swelling of the lateral nail folds of the fingers or toes. The 
digits most commonly affected are the big toes and the thumbs. In one patient, the 
middle finger was also affected. In some cases, swelling of the lateral nail folds was 
associated with friable pyogenic granuloma that bled but with only minor trauma. 
Cleaning and padding the areas affected provided the greatest relief from symptoms. 
From the information provided by the investigators, nail disorders have been known to 
last up to 2 months after discontinuing cetuximab. 
Allergic or hypersensitivity reactions: grade 3 or 4 reactions have been observed 
(including allergic and anaphylactic reactions), characterised by rapid onset of airway 
obstruction (bronchospasm, stridor, hoarseness), urticaria and/or hypotension, in 2.4% 
of patients treated with cetuximab. Approximately 80% of all allergic or 
hypersensitivity reactions occurred during the first infusion of cetuximab and were 
observed during the infusion or one hour after completing it. 
Before the first administration of cetuximab, patients should be pre-treated with an 
antihistamine and a corticosteroid (see section 7.A.1.3). This pretreatment is also 
recommended prior to all subsequent infusions of cetuximab, as some patients 
experienced their first serious hypersensitivity or allergic reaction during later infusions. 
To date, in studies with cetuximab, patients who experienced serious reactions received 
conventional treatment, all but one recovered without after-effects, and they were 
removed from the corresponding studies. This patient died due to angioedema after 
completion of the cetuximab infusion, which was reported because of a grade 4 
reaction. The appearance of allergic or hypersensitivity reactions does not appear to be 
related to monotherapy or combination therapy, underlying disease or previous 
exposure to murine monoclonal antibodies. 
Mild to moderate allergic or hypersensitivity reactions can usually be controlled by 
slowing the infusion rate of cetuximab (see section 7.A.1.4.2). 
After the approval of cetuximab by regulatory agencies and subsequent marketing, 
several cases of hypomagnesaemia have been reported, possibly associated with the 
administration of cetuximab, whether combined or not with chemotherapy. Most have 
been described as mild and/or moderate hypomagnesaemia, and so in general this is not 
a clinically significant finding; it is usually associated with secondary hypocalcaemia 
and/or hypokalaemia [17,18]. Preliminary data from three randomised trials (E5397, 
NCIC CO.17 and BMS CA225014) have confirmed that magnesium levels may fall in 
patients on cetuximab, whether combined or not with chemotherapy, compared with 
patients included in a control arm without cetuximab. Current data are insufficient for 
establishing the frequency of this finding. In the cases described, there was a quick 
response with magnesium supplementation, where it was considered necessary to 
replace it, and the condition was able to be reversed, as the hypomagnesaemia resolved 
within a few weeks of stopping treatment with cetuximab. 

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3.A.2.6 
Clinical experience with cetuximab in head and neck cancers 
Cetuximab has been evaluated in locally advanced disease and in metastatic and/or 
recurrent HNSCC, both in first-line and salvage therapy. 
 
3.A.2.6.1 
As salvage therapy in recurrent and/or metastatic disease  
An extensive development programme for cetuximab in HNSCC has been carried out, 
which includes several phase II studies examining the efficacy and safety of cetuximab 
combined with a platinum-based agent (cisplatin or carboplatin) or cetuximab alone in 
patients with metastatic and/or recurrent HNSCC, in whom disease progression was 
confirmed during administration of platinum-based chemotherapy [19–21]. In studies 
investigating cetuximab combined with a platinum-based agent, the overall response 
rate (ORR) was 11-13%, the disease control rate 51%, median TTP 2.2-2.8 months, and 
median survival 5.2-6 months [19,20]. In a study investigating cetuximab alone in the 
same patient population (EMR 62 202-016 study), the ORR was 13%, the disease 
control rate 45%, median TTP 2.3 months, and median survival 5.9 months [21].  
These results indicate that cetuximab given alone provides the same benefit as the 
combination of cetuximab with a platinum-based agent in patients who have progressed 
on a previous regimen of platinum-based chemotherapy. The results obtained in these 3 
studies are superior to historical results observed in these patients: 3.4% with objective 
responses and a median survival of 3.5 months [22,23]. 
3.A.2.6.2 
As first-line treatment in recurrent and/or metastatic disease  
The most extensive study in first-line treatment of recurrent and/or metastatic HNSCC 
was done by the Eastern Cooperative Oncology Group (ECOG), and it compared 
cisplatin + cetuximab versus cisplatin + placebo in 121 patients (E5397) [24]. The ORR 
was higher in the group treated with cetuximab (26.3% vs 9.8%, p=0.03), while the 
efficacy values based on time were also better in the group treated with cetuximab, 
though there were no statistically significant differences (overall survival [OS]: 9.2 
months vs 7.9 months; progression-free survival [PFS]: 4.2 months vs 2.7 months). 
Cetuximab did not change the safety profile of cisplatin. 
A phase I/II study (EMR 62 202-008) has also been conducted to investigate the 
tolerability and efficacy of the cisplatin or carboplatin regimen + 5-fluorouracil (5-FU) 
combined with cetuximab as first-line treatment for recurrent and/or metastatic HNSCC. 
The results showed that cetuximab did not alter the known safety profile of 
chemotherapy, and vice versa; full doses were therefore able to be given. The efficacy 
data were encouraging with an ORR of 36%, a disease control rate of 74%, a median 
TTP of 5.1 months and a median OS of 9.9 months [25]. 
At the 2007 American Society of Clinical Oncology (ASCO) he results of the phase III 
study (EMR 62 202-002 EXTREME) [26] were presented, in patients with recurrent 
and/or metastatic HNSCC, in which the efficacy of the combination of cetuximab was 
compared with the regimen of cisplatin or carboplatin + 5-FU in first-line treatment 
versus the same chemotherapy regimen alone. The results have shown a statistically 
significant increase in median survival, from 7.4 months in the chemotherapy-alone arm 
to 10.1 months with the chemotherapy-plus-cetuximab combination, with no major 

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changes in the toxicity profile of the platinum-based regimen. At that same ASCO, the 
Grupo Español de Tratamiento de Tumores de Cabeza y Cuello (TTCC, Spanish Group 
for Head and Neck Tumour Treatment) presented a phase II study [27] with excellent 
results in tumour response with the combination of weekly paclitaxel and cetuximab 
(60% of responses in the same population of patients with recurrent and metastatic 
disease). 
3.A.2.6.3 
As treatment combined with RT in locally advanced disease 
There are many preclinical studies showing that the cetuximab-induced inhibition of 
EGFR increases the effectiveness of RT, as it decreases the number of cells in the S 
phase and increases them in the G1 phase, facilitates apoptosis, decreases the ability of 
DNA repair, and has a clear antiangiogenic effect [28–32]. 
Based on this scientific justification, a phase Ib/IIa trial was conducted at the University 
of Alabama, Birmingham in patients with locally advanced HNSCC [33]. In this dose-
escalation trial, 8 patients were administered weekly infusions of cetuximab combined 
with normofractionated or hyperfractionated RT. Tolerance was excellent and toxicities 
associated with radiation did not increase by adding cetuximab to RT, and the full dose 
of cetuximab was therefore able to be given. Of the 15 evaluable patients in this study, 
13 (87%) complete responses were seen, based on physical and endoscopic exams. 
These results were very encouraging compared with historical controls, and so a phase 
III study was designed for patients with locally advanced HNSCC to compare the 
combination of cetuximab and RT versus RT alone, which was the standard treatment 
accepted by the FDA when the study was started in 1999 [34,35].  
In this study, 424 patients with locally advanced HNSCC were enrolled: oropharynx 
60%, larynx 25% and hypopharynx 15%. A total of 208 patients received the 
combination of cetuximab and RT (accelerated with concomitant overprint 56%; 
normofractionated 26%; hyperfractionated 18%), and 212 had RT alone (accelerated 
with concomitant overprint 56%; normofractionated 27%; hyperfractionated 17%). 
Median follow-up was 54 months. The combination of cetuximab and RT provided a 
significant improvement in survival and locoregional disease control (Table 3.3). 
Median survival was 49 months for combined and 29.3 months in the RT-alone arm 
(p=0.02). There were no significant differences in studied quality of life (QoL) 
parameters between treatment arms [34–36]. 
Table 3.3 Combined cetuximab and RT versus RT alone. 
 
Combined cetuximab 
and RT 
RT alone 
P-value 
Relative risk 
reduction 
Overall Survival 
 
 
 
 
At 2 years 
62% 
55% 
0.02 
0.74 (0.57-0.97) 
At 3 years 
55% 
45% 
0.05 
 
Locoregional control 
 
 
 
 
At 2 years 
63% 
55% 
0.02 
 
At 3 years 
50% 
41% 
<0.001 
0.68 (0.52-0.89) 

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The administration of cetuximab determined the presence of the usual related toxicity, 
but did not increase the toxicity related to RT (Table 3.4). 
Table 3.4 Most common side effects in the study.  
Toxicity 
Radiotherapy (n=212) 
Cetuximab + Radiotherapy (n=208) 
All Grades 
Grade 3-4 
All Grades 
Grade 3-4 
Acneiform rash 
10% 
1% 
87% 
17% 
Radiation 
dermatitis 
90% 
18% 
86% 
23%** 
Mucositis, 
stomatitis 
94% 
52% 
93% 
56% 
Dysphagia 
63% 
30% 
65% 
26% 
Xerostomia 
71% 
3% 
72% 
5% 
Asthenia 
49% 
5% 
56% 
4% 
Infusion-related 
reactions*** 
2% 
0% 
15%** 
3%* 
* p <0.05; ** p <0.001; *** Recorded due to relationship to cetuximab. 
The magnitude of the improvement in survival provided by the combination of 
cetuximab and RT is comparable to that associated with chemoradiotherapy treatment, 
but with much lower toxicity [35,37,38]. The multivariate analysis confirmed that the 
administration of cetuximab was an independent prognostic factor for the improvement 
in survival. 
Based on these results, the regulatory agencies authorised the use of cetuximab in the 
treatment of head and neck cancers. Since March 2006, Erbitux in combination with RT 
is indicated for the treatment of locally advanced HNSCC.  
3.B 
Study rationale 
HNSCC represent 5% of cancers diagnosed de novo in the total adult population. This is 
a potentially curable malignant neoplasia if diagnosed at an early stage, but 
unfortunately two-thirds of cases are diagnosed at an advanced locoregional stage, or 
stages III and IV M0 [39]. Despite the fact that in recent years there have been 
important advances in the treatment of HNSCC, with confirmation of the efficacy of 
radiochemotherapy programmes with cisplatin [37,38], locally advanced unresectable 
HNSCCs have a very poor prognosis, with a median survival of less than 20-24 months, 
and only 25-30% of patients living at 5 years [40–42]. Approximately 60-70% of these 
patients will develop a locoregional failure and 20-30% will develop distant metastasis.  
With these results, it is clear that an effort should be made to investigate and integrate 
the new therapeutic options available for the treatment of HNSCC, in order to try to 
improve the prognosis of patients with unresectable locally advanced HNSCC. 
3.B.1.  Induction chemotherapy with TPF (docetaxel, cisplatin, 5-fluorouracil) 
Induction chemotherapy programmes, which are basically the a continuous infusion of 
combined cisplatin and 5-FU (PF), and which during the 1990s led to the development 
of strategies for organ preservation [43,44] and reducing the incidence of distant 
metastases [45], were questioned by the meta-analysis published in 2000 (MACH-NC: 

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Meta-Analysis of Chemotherapy in Head and Neck Cancer) and updated in 2004 
[37,38]. The MACH-NC established the role of radiochemotherapy programmes with 
cisplatin as a new standard treatment for locally advanced HNSCC, because the 
improvement in survival was superior to that provided by the treatments with induction 
chemotherapy followed by RT and/or surgery [37,38]. 
A subsequent specific meta-analysis of the efficacy of induction chemotherapy with PF 
confirmed that absolute 5-year survival was active and increased by 5% [46]. Its 
efficacy was lower than radiochemotherapy programmes with cisplatin; therefore, its 
integration in sequential programmes with subsequent chemoradiotherapy should also 
be improved and studied. 
The introduction of the taxanes (docetaxel or paclitaxel) which are demonstrated to be 
active in HNSCC without presenting cross-resistance with cisplatin, and with a 
minimally-overlapping toxicity profile with PF, made it possible to design combination 
chemotherapy regimens with 3 drugs (PF + paclitaxel, PF + docetaxel). These regimens 
were shown to be highly active in the first phase I-II studies with response rates of up to 
90% and a significant percentage of complete responses [47–49]. These good results 
with an acceptable toxicity profile led to the conduct of phase III studies to compare 
these new induction chemotherapy regimens with the "classic" PF. In the past 2 years, 
results of 4 phase III studies have been presented, and these have definitively 
established the efficacy of induction docetaxel, cisplatin and 5-FU (TPF) in locally 
advanced HNSCC. 
Hitt et al. published the results of a phase III study with 382 patients with locally 
advanced unresectable and resectable HNSCC, which showed that the sequence of the 
combination of PF with paclitaxel followed by radiochemotherapy with cisplatin 
provides better survival than the PF sequence followed by chemoradiotherapy: 43 
months versus 37 months; p=0.06. In contrast to what was expected, the PF 
combination with paclitaxel was less toxic than PF [50]. 
A phase III study by the European Organization for Research and Treatment of Cancer 
(EORTC 24971) with 358 patients with unresectable advanced HNSCC was presented 
at the 2004 ASCO and was updated at the 2006 ASCO. This study showed that 
administration of 4 cycles of induction TPF followed by radical RT provides a 
significant improvement in survival compared with the PF induction sequence followed 
by radical RT: 18.6 months versus 14.2 months; hazard ratio (HR): 0.73 [0.56-0.90]; 
p=0.0052. The TPF regimen was better tolerated and provided a better QoL in all 
studied parameters, compared with the PF regimen [51–53]. 
At the 2006 ASCO, the results of two new phase III trials with TPF were presented. A 
first study included 501 patients with locally advanced resectable and unresectable 
HNSCC, 
and 
compared 
TPF 
administration 
followed 
by 
non-standard 
radiochemotherapy (normofractionated RT carboplatin, 1.5 area under the curve 
(AUC)/weekly), followed by the same radiochemotherapy regimen. With a median 
follow-up of 42 months, the TPF regimen provided a significant improvement in 
survival: +70.6 months versus 30.1 months with 62% of the patients alive after 3 years 
versus 48%, HR: 0.70 [0.54-0.90], p=0.0058 [54]. 
The second phase III study included 205 patients with carcinoma of the larynx or 
hypopharynx, who required surgical treatment involving a laryngectomy. The 

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possibility of preserving the larynx was investigated by comparing TPF versus PF 
followed by radical RT when a response was confirmed or radical surgery when no 
response was confirmed. TPF provided a high objective and complete response (CR) 
rate, greater therapeutic compliance, a higher rate of larynx preservation and larynx 
function, as well as a clear trend towards improved survival [55]. 
With the results provided by TPF in the trials described, regulatory agencies (EMA and 
FDA) have approved administration of TPF as an effective induction regimen, 
especially in patients with unresectable locally advanced HNSCC and good overall 
condition, as established at ASCO 2006 [54,55]. In Spain, the AEMPS approved 
administration of TPF for patients with unresectable locally advanced HNSCC, from 8 
June 2007. 
3.B.2.  Sequential treatment with TPF 
The first phase II studies with TPF induction chemotherapy followed with RT indicated 
that TPF was a highly active regimen that reduced the incidence of distant metastases, 
but locoregional control of disease could continue to be a problem for a group of 
patients [56]. Therefore, from a conceptual and biological perspective, following TPF 
induction, the most effective locoregional treatment possible should be offered.  
Currently, there are two studies, a randomised phase II and a randomised phase II-III 
study by the TTCC, that suggest a greater efficacy of TPF followed by standard 
chemoradiotherapy with cisplatin 100 mg/m2 than when standard chemoradiotherapy 
was administered without previous induction [57,58]. These preliminary results 
reinforce the work line of TTCC in the sense that after an effective induction 
chemotherapy the most effective locoregional treatment possible must be administered 
[48,58], in order to be able to control the metastatic spread without jeopardising the 
results of locoregional control, which can be brought about by the reduction in the 
tumour volume prior to administration of locoregional treatment. 
Thus, in unresectable disease, the combination of induction chemotherapy with TPF 
followed by the best locoregional treatment is being established as a new standard in 
order to improve poor results obtained with chemoradiotherapy alone. The results of the 
Spanish group on unresectable disease [58] showing a significant improvement in the 
TTP favouring the induction chemotherapy arms, support sequential therapy followed 
by chemoradiotherapy with cisplatin as the new standard for this group of patients. 
3.B.3.  Radiotherapy combined with cisplatin for treatment following induction 
chemotherapy with TPF 
In the 1990s, no randomised study with induction chemotherapy had demonstrated that 
it could increase the OS rate when used against a local treatment only, this being either 
surgery or RT. Only one Italian study [59] in the analysis of the subgroup with 
unresectable disease found that patients who had received 4 cycles of induction 
chemotherapy with PF at full doses had a lower rate of local and metastatic recurrence, 
resulting in increased survival.  
As well as the poor survival results in the induction regimens, the meta-analysis [37] 
was published, which suggested that the only way of increasing survival versus single 

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locoregional treatment was through the use of concomitant treatments, and several 
randomised trials were published in the same period [40,60–64] that demonstrated that 
treatment with chemoradiotherapy has much greater locoregional control and survival 
than RT alone. As a result of these events, therapeutic regimens started to be based on 
concomitant treatment. The normofractionated RT regimen (70 Gy) with cisplatin at 
doses of 100 mg/m2 on days 1, 22 and 43 of RT was chosen as the concomitant regimen 
with the best balance between acute toxicity and therapeutic efficacy, and as a result, 
since the beginning of the 2000s, it has been the standard regimen, which is still the 
case.  
At ASCO 2006, the new sequential therapeutic approach was strengthened for 
unresectable disease [55,57,58], but a major concern arose due to the toxicity of the 
administration of radiochemotherapy with cisplatin after induction chemotherapy. 
Particularly since the scientific community is aware of having underestimated the 
incidence and severity of chronic toxicity caused by radiochemotherapy programmes 
with cisplatin that can be responsible for up to 6% of deaths and a significant 
deterioration in the QoL of these patients [65,66]. In this regard a larger randomised 
study with TPF (the TAX324 study), which showed that treatment with TPF is superior 
to PF, used a sequential treatment with carboplatin radiochemotherapy, which is not a 
therapeutic programme with proven efficacy [34,35,54]. In fact, there was a phase III 
randomised study with 124 patients with locally advanced HNSCC, which compared 
normofractionated RT versus RT + cisplatin (100 mg/m2/3 weeks) versus RT + 
carboplatin (7 AUC/3 weeks): median TTP was 6.3 months versus 45.2 months versus 
17.7 months p=0.0002; and median survival of 12.2 months versus 48.6 months versus 
24.5 months p=0.0003 [67].  
When acute toxicity is analysed in randomised studies [40,60–64] which have compared 
chemoradiotherapy versus RT alone, there is only a significant increase against 
concomitant regimens, which is shown in Table 3.5. The most significant increase 
occurs in mucositis, which increases in both severity and duration. This is a key factor 
in chemoradiotherapy treatments, which results in a series of complications for patients, 
which will involve greater support requirements by hospitals where they are treated 
(over half will need enteral feeding tubes, there is a significant increase in medical and 
nursing visits, greater antibiotic treatment requirements, etc.). Due to increasing support 
requirements, HNSCC need to be restructured if they want to keep offering adequate 
treatment, a key factor in recovery.  
Table 3.5 Comparison of the increase in severe acute toxicity in concomitant chemoradiotherapy 
compared to RT alone in 6 randomised studies [40,60–64] 
Toxicity 
Increase 
Grade 3-4 mucositis 
13-30% 
Grade 3-4 Radiodermatitis 
5-10% 
Grade 3-4 vomiting 
10-15% 
Grade 3-4 neutropenia 
30-40% 
Risk of infection 
4-15% 

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Weight loss > grade 1 
10% 
Toxic mortality 
2% 
 
Although it is difficult to know the increase in chronic toxicity due to a lack of 
published data, there is indirect data that may help us to get an idea of the magnitude of 
the problem. In patients who have received chemoradiotherapy, the main cause of death 
not related to disease, during the first year, is treatment-related toxicity [65]. Argiris 
analysed the causes of death in the first few years in more than 300 patients treated at 
his institution with concomitant chemoradiotherapy, as part of clinical trials: 45% were 
due to disease progression, 15% had treatment complications (9% acute + 6% late), 9% 
to secondary neoplasias (in particular in lung cancer) and 21% for the comorbidity 
associated with these patients. It is possible that the increase in toxicity caused by more 
aggressive treatment regimens determines these high mortality rates due to the patient’s 
base co-morbidity. In this same regard, an update was presented to ASCO 2006 for the 
study of the US Intergroup trial RTOG 91-11 in the conservative treatment of the larynx 
[68]. It is supported that concomitant treatment is superior to induction chemotherapy 
with PF (and to RT alone) in locoregional control and larynx preservation rate, but this 
does not lead to an impact on survival. In fact, when the OS curve was analysed with 
close follow-up after 7 years, the curves start to be separated from the fifth year in 
favour of induction chemotherapy and while it is not yet reached a difference of 
statistical significance, the curve of concomitant treatment is clearly lowering, at the 
same level as the RT alone curve. It is interesting to note that the causes of death vary 
according to the treatment arm: patients in the RT alone arm died mainly from a 
recurrence their disease, whereas patients with concomitant chemoradiotherapy had a 
high rate of deaths unrelated to cancer. In other words, concomitant treatment with 
chemoradiotherapy in conservative treatment achieves better control of the neoplastic 
disease. However, it does not produce any impact on survival as it favours death due to 
other causes, most probably related to the impact of the increase in chronic toxicity on 
cardiovascular underlying disease in these patients.  
In conclusion, for unresectable disease, the best treatment option in terms of anti-
tumour efficacy is the combination of induction chemotherapy with TPF followed by 
chemoradiotherapy with cisplatin. However, the toxicity associated with this treatment 
regimen (assumes a total of 6 cycles of cisplatin) is making it necessary to search for 
alternative treatments that control to disease just as well, but with a lower potential 
acute and chronic toxicity profile. 
3.B.4.  Radiotherapy combined with cetuximab for treatment following induction 
chemotherapy with TPF 
The combination of cetuximab and RT is a treatment option approved by regulatory 
agencies (the FDA and EMA), which has been shown to increase locoregional control 
and survival without increasing acute and chronic toxicity. This can provide effective 
and well-tolerated treatment for patients with locally advanced HNSCC who have had 
TPF as induction treatment [34]. Its excellent tolerance allows for the maintenance of 
planned treatment times, both between induction chemotherapy and RT and during RT, 
which is essential for achieving good therapeutic outcomes. Furthermore, the 

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combination with RT does not alter the QoL parameters compared to RT alone [36]. For 
more information on this treatment arm, see section 3.A.2.6.3. 
3.C.  Rationale for a randomised study 
Despite all the therapeutic advances described, patients with unresectable locally 
advanced HNSCC continue to have a poor prognosis -18.6 months- when they are 
treated with TPF in the updated, more extensive study [50–52]. The TPF regimen must 
constitute the therapeutic basis upon which new biological treatments are added, while 
also trying to improve results without significantly increasing toxicity [53]. 
The combination of TPF induction chemotherapy followed by concomitant 
chemoradiotherapy with cisplatin currently appears to be the new standard treatment in 
unresectable cancer. However, increased acute and particularly chronic toxicity lead us 
to reconsider continuing a chemoradiotherapy regimen after induction chemotherapy. In 
particular, due to the onset of cetuximab and the finding that cetuximab has been shown 
to increase the efficacy of RT with a significant increase in locoregional disease control 
and survival in locally advanced HNSCC, without increasing the acute and/or chronic 
toxicity associated with RT (see section 3.A.2.6.3).  
This is why this phase III, randomised study has been designed. All patients with 
unresectable locally advanced HNSCC will start treatment with induction chemotherapy 
with the TPF regimen. Patients with progression in this chemotherapy regimen will be 
withdrawn from the study, as it is known that the possibility of a cure from these 
patients is practically negligible and therefore each site will decide which is the best 
therapeutic procedure for them, with the aim of not causing excessive toxicity. Patients 
with a response to induction chemotherapy or a stable disease (SD) will be randomised 
to a control arm (chemoradiotherapy with cisplatin), which is considered standard by 
the Spanish group for treatment of HNSCC, or they will be assigned the treatment arm 
receiving a treatment considered investigational (RT in combination with cetuximab). 
The study aims to evaluate the non-inferiority of the experimental arm versus the 
standard arm in terms of OS in patients with HNSCC who have responded to induction 
chemotherapy with the TPF regimen. Moreover, the acute and chronic toxicity of both 
treatment arms will be carefully compared, as well as the QoL of subjects subject to 
these treatments. 
This study will be conducted according to this protocol, the good clinical practice 
(GCP) guidelines and applicable regulations. 
 
 

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4. 
 Study objectives  
4.A Primary objective 
• To demonstrate that induction (TPF) chemotherapy followed by RT + 
Cetuximab is at least non-inferior to chemotherapy with TPF followed by RT + 
Cisplatin in terms of OS in patients with unresectable HNSCC. 
4.B Secondary Objectives  
The secondary objectives are: 
• To evaluate the activity and safety of TPF treatment. 
• To evaluate the reasons for study non-continuation (possibility of complying 
with randomisation criteria) after induction treatment with TPF. 
• To evaluate and compare efficacy in the 2 treatment groups (experimental arm 
versus standard arm): 
− Disease-free survival 
− Specific survival 
− Time to locoregional control of disease 
• To evaluate and compare the safety activity and safety profiles of the 2 treatment 
groups (experimental versus standard): 
− Response rate 
− Acute and chronic toxicity rates 
• To evaluate and compare the patient perceptions using QoL questionnaires. 
• To evaluate the treatment compliance rate with RT plus Cetuximab and RT plus 
cisplatin, after combination with induction and TPF. 
 
 
 
 

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5. 
Investigational plan 
5.A Study design 
Phase III, open-label, randomised and multicentre clinical trial in patients with 
unresectable locally advanced HNSCC.  
5.B Randomisation 
Patients will have signed the informed consent form to participate in the study at the 
time they have been recognised as candidates, following diagnosis of unresectable 
locally advanced HNSCC, and always before starting treatment with TPF induction 
chemotherapy. Patients with stage III and IV squamous cell carcinoma of the 
oropharynx, larynx, hypopharynx or oral cavity considered as unresectable by a 
committee for head and neck tumours and with no evidence of distant metastasis, will 
be eligible for the study. 
However, only those patients that present objective response or stabilization after 
induction chemotherapy with TPP, and do not have a contraindication to continue 
treatment with cisplatin, will be randomized to two groups to continue with the radical 
treatment (randomized population): 
Group A (standard): Concomitant RT with Cisplatin 
Group B (experimental): Concomitant RT with Cetuximab 
Patients will be randomized according to a scheme generated by a computer program 
that will be used to ensure that patients are distributed equally between the two 
treatment groups and will be performed after the 3 cycles of TPF, only in patients in 
response or stabilization after induction chemotherapy and who are able to continue 
receiving cisplatin. 
A stratified randomization will be performed according to the primary location of the 
disease (oral cavity, versus oropharynx, versus larynx, versus hypopharynx). Each 
stratum will be randomized in a 1:1 ratio to one of the two treatment groups, group A 
(standard RT concomitant with Cisplatin and group B (experimental: RT with 
Cetuximab). 
The randomization will be made in the DCTrials 2.5 application (electronic CRF) that 
will be used to collect the data of the patients included in the trial. DCTrials 2.5 is a 
web-based application and accessible via the Internet. 
Only the randomization of patients from authorized investigators will be accepted and 
once the list of registration criteria has been verified, which includes having received a 
minimum of 2 cycles of induction TPF, having had a stable response or disease to that 
treatment and not having a contraindication to being able to continue treatment with 
cisplatin. 
 

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Randomization: 
Randomization will be stratified according to primary location of the disease (oral 
cavity, versus oropharynx versus larynx versus hypopharynx), each stratum will be 
randomised at a 1:1 ratio to one of the two treatment groups, group A (standard 
concomitant RT with cisplatin and group B (experimental: RT with Cetuximab).  
Patients who have signed informed consent will not be randomized, will not be part of 
the main analysis of the study, although they will be followed similarly to randomized 
patients and descriptive information on their treatment and evolution will be obtained. 
5.C 
Study design 
5.C.1 
Overall design  
Patients must sign the informed consent form to participate in the study at the time they 
will be recognized as candidates, following diagnosis of unresectable locally advanced 
HNSCC, and always before starting treatment with TPF induction chemotherapy.  
All patients will start treatment with 3 cycles of induction chemotherapy with the TPF 
regimen.  
1.- Patients who progress with the treatment with TPF will be excluded from the 
study and will be treated according to each Site’s protocol. 
2.- Patients with TPF toxicity, which mean that they cannot follow a treatment that 
include cisplatin, will be excluded from the study and treated according to each 
site’s protocol and in accordance with international guidelines. 
3.- Patients who are unable to receive at least two cycles of induction will be 
excluded from the study and will be treated according to each site’s protocol and 
in accordance with international guidelines. 
4.- Patients who respond to or are stabilized with TPF and who can follow treatment 
with cisplatin, will be randomised to receive normofractionated RT plus 
cisplatin (Group A) versus the combination of cetuximab and normofractionated 
RT (Experimental Group B). Patients will be stratified by tumour location (oral 
cavity, versus oropharynx versus larynx versus hypopharynx), to ensure 
homogeneous distribution. 
As a result, there are two separate parts of the study: 
o Part 1 of the study: the period from the signing of the informed consent 
form until the response and toxicity assessment of induction 
chemotherapy with TPF (standard group) 
o Part 2 of the study: the period from randomisation following induction 
chemotherapy with TPF until the end of study (experimental group) 
The objective of the trial is to demonstrate the non-inferiority of the experimental 
arm compared to the standard arm in terms of OS, using time to death due to any 
case as the primary endpoint. 

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In the analysis of OS, which is the primary endpoint proposed in this study, the Cox 
proportional hazards regression will be used. The general formula of the hypothesis to 
at least prove non-inferiority was as follows: 
H0: HR Experimental Arm / Standard Arm ≥1.3 
H1: HR Experimental Arm / Standard Arm <1.3 
Calculation of sample size is based on an assumed exponential distribution, using the 
following parameters: 
 
Unilateral testing with an alpha of 0.05 and 80% power. 
 
A recruitment phase of 53 months. 
 
A follow-up phase of 36 months. 
 
A HR of 0.0231 for the standard arm (median PFS of 30 months). 
 
HR Experimental arms / Standard arms = 0.938 (this assumes a median of 32 months 
for the experimental arm). 
 
Competing risk of 0.01. 
The total number of randomised and evaluable patients is 398. At this size, we also have 
to add 15% of the patients who will progress with TPF or will be lost (dropouts or TPF 
toxicity that provide continued cisplatin administration), so the patients total is 469.  
5.C.2 
Study planning 
Around 43 sites from the Spanish TTCC Group will participate in the study. Patients 
with stage III and IV squamous cell carcinoma of the oropharynx, larynx, hypopharynx 
or oral cavity considered as unresectable by a committee for head and neck tumours 
and with no evidence of distant metastasis, will be eligible for the study. 
All the patients included in the study will receive a combination of TPF chemotherapy 
every 3 weeks for 3 cycles, followed by RT combined with cetuximab (experimental 
arm) or cisplatin (standard arm) depending on the randomisation arm.  
Neoadjuvant treatment will be given according to the regimen in Table 5.1. 
Table 5.1 Diagram of the induction chemotherapy combination. 
Drugs 
Daily dose 
Administration 
Days 
Docetaxel 
75 mg/m2/d 
IV 1 hour 
1 
Cisplatin  
75 mg/m2/d 
IV 1 hour 
1 
5-FU 
750 mg/m2/d 
24-hour infusion 
1-5 
Dexamethasone  
16 mg 
8 mg/12 hours 
-1, 1 and 2 
Ciprofloxacin (or equivalent) 
1 g 
500 mg/12 hours 
D 7-15 
G-CSF* 
150 µg/m2/d 
SC 
D 7-12 
IV: intravenous; SC: subcutaneous 
*Lenograstim (Granocyte®) is recommended. If another granulocyte-colony stimulating factor (G-CSF) will be used, 
it has to be administered according to the summary of product characteristics.  

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Patients who present an objective response or stabilisation to the TPF treatment, who 
receive at least 2 cycles of induction therapy and do not have any contraindications to 
continued cisplatin treatment will be randomised into 2 radical treatment groups: 
• 
Group A (standard): Concomitant RT with cisplatin: at 3-4 weeks (5 weeks at 
most) from the beginning of the 3rd TPF cycle, treatment begin with concomitant 
normofractionated RT with chemotherapy (cisplatin 100 mg/m2 IV). 
 
Drugs 
Daily dose 
Administration 
Days 
Cisplatin 
100 mg/m2/d 
IV 1 hour 
1, 22 and 43 of the RT 
- Cisplatin will be administered every three weeks from the first day of RT. 
• 
Group B (experimental): Concomitant RT with cetuximab: at 3-4 weeks (5 weeks 
at most) from the beginning of the 3rd TPF cycle, treatment begin with 
normofractionated RT. Cetuximab will have be started the week before. 
 
Drugs 
Daily dose 
Administration 
Days 
Cetuximab* 
250 mg/m2/d 
IV 1 hour 
1, 8, 15, 22, 29, 36, 43 and 50** 
*Initial dose of 400 mg/m2/day in the first infusion for 120 minutes 
** Or to the end of the RT if there is any delay 
 
- 
Cetuximab will be administered continuously weekly, from one week 
before the start of RT (loading dose). 
5.C.2.1.  Intervention due to unacceptable TPF toxicity 
If a patient has unacceptable toxicity to one of the study drugs, treatment with the drug 
will be discontinued but the patient will continue to receive the other study drugs and 
treatments. In the case of the TPF regimen, if a patient has unacceptable toxicity to two 
of the study drugs, neoadjuvant treatment will be discontinued.  
- 
If a minimum of 2 cycles was received, the response to the treatment 
will be evaluated: if a response or stabilisation and ability to be continue 
cisplatin treatment is shown, the patient will be randomised to assign 
him to the radical treatment arm.  
- 
However, if a minimum of two TPF cycles was not received or 
toxicity caused prevented the continuation of cisplatin treatment, the 
patient has to leave the study and will be treated according to the 
protocol for each site and according to international recommendations. 
5.C.2.2.  Evaluation of response to TPF 
2-3 weeks after the administration of the 3rd cycle of induction chemotherapy, a CR 
assessment study will be conducted with computed axial tomography (CAT), Positron 

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Emission Tomography and Computed Tomography (PET-CT) or magnetic resonance 
imaging (MRI) and a clinical assessment of the tumour that include direct and/or 
indirect eye exams as necessary, as well as a biopsy of suspicious areas if that would be 
accurate. 
If the investigator suspects disease progression at any time, the disease will have to be 
assessed using both clinical and imaging techniques before the indicated date. 
If disease progression is detected, the scheduled treatment will be discontinued and the 
visit after progression (VAP) will be conducted, and the patient will receive the 
treatment that the investigator considers most appropriate outside the study. From the 
trial perspective, the patients will enter into the follow-up phase and the information on 
all subsequent treatments and survival will be collected. If a patient receive any anti-
cancer treatment other than that of the study design before disease progression is 
confirmed, the patient information will be censored from this point on and the 
case will be analysed individually to establish the possibility that this is a disease 
progression. 
At 3-4 weeks (5 weeks at most) from the start of the 3rd TPF cycle, patients who have 
not progressed and have no contraindication to continue receiving treatment with 
cisplatin will receive the second part of the treatment according to randomisation: arm 
A (RT combined with cisplatin) or arm B (RT combined with cetuximab). In 
exceptional individual cases, and with prior contact with the study coordinators, a 5th 
week of delay will be permitted to start RT.  
RADIOTHERAPY REGIMEN (same for arm A and arm B) 
Radiotherapy 
Total dose 
Dose per fraction 
Normofractionated 
70 Gy 
2 Gy per fraction 
35 fractions 
1 fraction a day 
4-6 MV Lineal accelerators as well as electrons with different energy levels are 
recommended, if overprinting is necessary in some areas with tumours or those at risk. 
The total dose in the tumour and lymph node areas affected will be 70 Gy. Doses in the 
lymph node areas at high-risk of microscopic disease will be 55-60 Gy and in low-risk 
elective areas, 45-50 Gy.  
PTV1 = CTVt + CTVn + CTVn elective plus 45-50 Gy margins 
PTV11= CTVt + CTVn of maximum risk plus 60 Gy margins 
PTV111= CTVt plus 70 Gy margins 
Maximum dose in marrow 45 Gy. 
5.C.2.3.  
Evaluation of response after radical treatment 
The response in all patients will be evaluated at 6-8 weeks after completing RT 
with cisplatin or cetuximab (same for both radical treatment arms). See section 
8.B.2.2. 

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5.C.3 
Discussion of the study design  
The TPF chemotherapy regimen has been proved very effective, both in the treatment of 
squamous cell carcinomas of the head and neck as well as in gastric adenocarcinomas. 
In HNSCC it has been shown to be superior to conventional treatment with PF, and in 
unresectable disease there is evidence that using an induction chemotherapy improves 
the survival outcomes of these patients. The standard continuation of induction 
chemotherapy is concomitant RT with cisplatin. However, the total administration of 6 
cycles of cisplatin involves considerable toxicity to the patient. Moreover, cetuximab 
can be combined with RT to increase its efficacy without increasing associated toxicity, 
and so combining it with RT after 3 cycles of TPF is an interesting and promising area 
to be studied in HNSCC. The study aim to demonstrate the non-inferiority of the 
combination of RT plus cetuximab compared to the combination of RT plus cisplatin 
after 3 cycles of TPF induction chemotherapy. 
5.C.4 
End of trial 
The study duration is determined at the time when there are 282 deaths. A 53-month 
continuous recruitment period, 36-month follow-up after the inclusion of the last patient 
and also a median survival of 30 months are considered. 
5.D 
Blinding 
Not applicable. 
5.E 
Study periods 
It is planned that the deadline of the clinical phase of the study be 36 months after 
inclusion of the last patient. The planned overall duration of the study for a total of 469 
patients is 96 months (53 months for recruitment plus 36 months of follow-up since the 
last patient). 
The schedule foreseen for this study is from November 2007 to October 2015. 

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6. 
Study population screening 
6.A 
Selection criteria 
6.A.1  
Inclusion criteria 
For inclusion in the study, all of the following inclusion criteria must be met: 
1. Before beginning the specific procedures of the protocol, informed written 
consent have to be obtained and documented. 
2. Locally advanced cancer of the head and neck (oral cavity, oropharynx, larynx 
and hypopharynx), stage III-IV, with no evidence of metastasis. 
3. The tumour have to be classified as inoperable according to Northern California 
Oncology Group [5] criteria after assessment by a multidisciplinary team, which 
includes, at least, a specialist in oncological surgery from the Ears, Nose and 
Throat Department or a specialist in maxillofacial surgery (as applicable), a 
specialist in Medical Oncology and a specialist in Radiotherapy oncology. The 
reason for inoperability will be recorded on the case report form (CRF). 
NCOG inoperability criteria: 
o Technically 
nonresectable 
(includes: 
evidence 
of 
mediastinal 
dissemination; tumour fixed to the clavicle, base of the cranium or 
cervical vertebrae; involvement of the nasopharynx). 
o Medical criteria based on a low surgical curability. 
o Medical contraindication for surgery. 
4. Anatomically and pathologically proven epidermoid carcinoma. 
5. Disease measurable according to the modified RECIST 1.0 criteria. 
6. Men or women aged 18 to 70 inclusive. 
7. ECOG performance status: 0 or 1 
8. Patients in a medical condition to be able to receive induction treatment with 
TPF followed by normofractionated RT with cetuximab or cisplatin.   
9. Patients with adequate haematological function: neutrophils ≥ 2 x 109, platelets ≥ 
100 x 109, haemoglobin ≥ 9 g/dL and no symptoms related to anaemia. 
10. Adequate liver function: Bilirubin ≤ 1.5 x upper normal limit (UNL), and some 
of the following parameters: glutamic oxaloacetic transaminase (GOT) ≤ 2.5 
UNL or alanine aminotransferase (GPT) ≤ 2.5 ULN or alkaline phosphatase < 

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UNL; however, if all of these are present, their value should not exceeded the 
UNL. 
11. Adequate kidney function: serum creatinine < 1.4 mg/dL (120 µmol/L); if the 
values are > 1.4 mg/dL, creatinine clearance has to be > 60 mL/min (real or 
calculated by the Cockcroft–Gault method). 
12. Adequate nutritional status: Body mass index (BMI) > 18.5% or albumin ≥ 30 
g/L. 
13. Patients have to be accessible for treatment and follow-up. 
6.A.2 
Exclusion criteria 
Patients cannot be included in the study if they meet any of the following criteria: 
1. Metastatic disease. 
2. Previous treatment by surgery, with RT and/or chemotherapy for the disease 
being studied. 
3. Other tumour locations in the head and neck area, other than the oral cavity, 
oropharynx, larynx and hypopharynx. 
4. Stages other than stage III or IVM0. 
5. A previous and/or synchronous squamous carcinoma. 
6. Diagnosis of another neoplasia in the past 5 years except properly treated 
cervical carcinoma in situ and/or basal cell carcinoma. 
7. Active infection (infection that required intravenous antibiotics), including 
diagnosed active tuberculosis and HIV. 
8. Uncontrolled hypertension defined as systolic blood pressure ≥ 180 mmHg 
and/or diastolic blood pressure ≥ 130 mmHg at rest. 
9. Pregnancy (its absence must be confirmed by a serum β-HCG test) or lactation. 
10. Systemic, chronic and concomitant immune therapy or hormone therapy for 
cancer. 
11. Other concomitant antineoplastic treatments. 
12. Clinically significant coronary artery disease or a history of myocardial 
infarction in the past 12 months or high risk of uncontrolled arrhythmia or 
uncontrolled heart failure. 
13. Chronic obstructive pulmonary disease that required ≥ 3 hospitalisations in the 
previous 12 months. 
14. Uncontrolled active peptic ulcer. 

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15. Presence of a psychological or medical illness that would prevent the patient 
from taking part in the study or from granting informed consent. 
16. Known drug abuse (except for heavy drinking). 
17. Known allergic reaction to any of the ingredients of the study treatment. 
18. Previous treatment with monoclonal antibodies or other inhibitors of signal 
transduction or EGFR inhibitors. 
19. Any experimental treatment in the 30 days prior to study entry. 
6.B 
Patients number 
The objective of the trial is to demonstrate the non-inferiority of the experimental arm 
compared to the standard arm in terms of OS, using time to death due to any case as the 
primary endpoint. 
In the analysis of OS, which is the primary endpoint proposed in this study, the Cox 
proportional hazards regression will be used. The general formula of the hypothesis to 
at least prove non-inferiority is as follows: 
H0: HR Experimental Arm / Standard Arm ≥1.3 
H1: HR Experimental Arm / Standard Arm <1.3 
Calculation of sample size is based on an assumed exponential distribution, using the 
following parameters: 
 Unilateral testing with an alpha of 0.05 and 80% power. 
 A recruitment phase of 53 months. 
 A follow-up phase of 36 months. 
 A HR of 0.0231 for the standard arm (median PFS of 30 months). 
 HR Experimental arms / Standard arms = 0.938 (this assumes a median of 32 months for the 
experimental arm). 
 Competing risk of 0.01. 
The total number of randomised and evaluable patients is 398. At this size, we also have 
to add 15% of the patients who will progress with TPF or will be lost (dropouts or TPF 
toxicity that provide continued cisplatin administration), so the patient total is 469. 
6.C 
Withdrawal criteria 
6.C.1 
Patients withdrawal 
Patients can freely withdraw from the study at any time without having to provide any 
reason. 
Subjects have to be withdrawn from the study when any of the following situations 
occurred: 

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- 
Withdrawal of the informed consent.  
- 
Disease progression. When disease progression is detected, the patient will be 
withdrawn from the study and will receive the treatment considered most 
suitable by the investigator. 
- 
Patients who are not considered to be in a suitable condition to receive cisplatin-
based treatment at the time of randomization 
- 
Patients who have not been able to receive at least 2 cycles of induction and 
therefore whose response to it cannot be assessed. 
- 
Appearance of any exclusion criterion that is clinically relevant and that may 
affect patient safety. 
- 
If treatment is discontinued permanently without confirming disease 
progression, but the patient's investigator considers it necessary to administer a 
salvage therapy other than that envisioned in the trial. 
- 
Pregnancy. 
- 
Administration of any concomitant medication that is not permitted, as detailed 
in the section 7.B when the result described is withdrawal from the study. 
- 
Failure to fulfil the protocol. 
If a patient have not attended the scheduled study evaluations, the investigator have to 
determine the reasons and circumstances as completely and accurately as possible. 
If a patient is withdrawn early from the study, if possible all scheduled tests have to be 
performed to evaluate the tumour fully (indirect and/or direct optical exam of the 
tumour and a diagnostic imaging technique, particularly CTT and/or PET-CT and/or 
MRI). In any case, the “End of treatment sheet" section of the case report form have to 
be completed. 
If there is a medical reason for the withdrawal, the patient have to remain under the 
supervision of the investigator until the AEs will be resolved. 
A patient may be replaced by another only if the patient leaves the study before the first 
infusion of cetuximab, cisplatin or the start of the first RT fraction. 
Information will be collected on subsequent treatments administered and the survival of 
all patients, regardless of the reason for withdrawal, at the same frequency as the post-
treatment visits. 
6.C.2 
Study discontinuation 
The study may be discontinued if the principal investigator and sponsor consider it 
necessary in the following cases: 
• Medical or ethical reasons affecting the continuation of the study. 
• Difficulties in recruiting patients. 
• Ineffectiveness of the study medication. 
• Onset of adverse reactions to cetuximab that are unacceptable and unknown to 
date with regard to their nature, severity and duration; or an unexpected 
incidence of any unacceptable adverse reaction. 

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The principal investigator, the study coordinator and sponsor will supervise the drug 
safety data on a regular basis to ensure that it is appropriate to continue with the study. 
Note: Patients who have adverse reactions to TPF induction chemotherapy, which 
prevent them from continuing to receive cisplatin will not be randomised, will be 
withdraw from the study at that time although they will have similar follow-up in order 
to obtain data on their treatment and evolution, which will be treated descriptively. 
6.C.3 
Recruitment period 
The planned recruitment period is 53 months. 
 
7. 
Treatment description 
7.A 
Treatments administered and therapeutic regimen 
All the patients included in the study will receive 3 cycles of TPF chemotherapy upon 
entry and subsequently, if there is no disease progression, they will be randomised to 
receive: 
Arm A (standard): will receive conventional RT combined with cisplatin.  
No other cancer treatment will be administered before confirming disease progression 
or persistence after radical treatment. 
Arm B (experimental): will receive conventional RT combined with cetuximab.  
No other cancer treatment will be administered before confirming disease progression 
or persistence after radical treatment. 
If a patient has unacceptable toxicity to one of the study drugs during concomitant 
treatment (cisplatin or cetuximab), treatment with this drug will be discontinued but the 
patient will continue to receive the RT planned in the trial: 
Group A (standard): Cisplatin must be discontinued permanently but without 
withdrawing the patient from the study in cases of: 
• Appearance of serious AEs (SAEs) (see section 7.A.2), if the investigator and/or 
the patient want or consider withdrawal of the study medication necessary.  
The patient will finish treatment with RT alone if the investigators believe this to be 
possible. 
Group B (experimental): Cetuximab must be suspended definitively but without 
withdrawing the patient from the study in case of:  
• Repeated appearance of Grade 3 dermal toxicity in spite of an appropriate dose 
reduction (see section 7.A.3.4.1). In this situation, the investigator may consult 

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the principal investigator and/or study coordinator to assess the possibility of 
individualised measures that allow the patient to continue receiving cetuximab. 
• Grade 3-4 cetuximab-related hypersensitivity reaction. 
• Suspension of 4 consecutive cetuximab infusions. In this situation, the 
investigator may consult the principal investigator and/or study coordinator to 
consider the reasons and assess the possibility of individualised measures that 
allow the patient to continue receiving cetuximab. 
• Appearance of AEs, if the investigator and/or the patient wants or considers 
withdrawal of the study medication necessary. 
The patient will finish treatment with RT alone, if the investigators believe this to be 
possible. 
If there is a toxicity caused by the TPF regimen: 
- If the unacceptable toxicity is clearly attributable to one of the TPF drugs (docetaxel 
or 5-FU), this drug will be discontinued for the following treatment cycles (provided 
that it is not toxicity to cisplatin, which will lead to withdrawal from the study). 
- If a patient suffers unacceptable toxicity due to cisplatin or there is toxicity linked to 
least two drugs in the combination, induction treatment with TPF will be suspended, 
with matters being conducted as follows: 
1. If such toxicity occurs after then 1st cycle, the patient will be withdraw from 
the study. 
2. If this toxicity occurs after the 2nd or 3rd cycle, the patient may be randomised 
if there have been tumour response or stabilisation and, if there are no 
contraindications to treatment with cisplatin. If the patient cannot follow 
cisplatin treatment, they will be withdrawn from the study and will not be 
randomised. 
3. If the patient cannot be randomised due to toxicity preventing continued 
treatment with cisplatin, the patient will be withdrawn from the study and will 
be treated according to each site's protocol and according to international 
recommendations. 
7.A.1  
Induction treatment (Part 1): Docetaxel in combination with cisplatin and 
5-FU (TPF) 
 
7.A.1.1 
Therapeutic programme 
The patients will receive docetaxel 75 mg/m2, followed by cisplatin 75 mg/m2 on day 1. 
The 5-FU will be administered after the end of cisplatin infusion as a continuous 
infusion of 750 mg/m2/day for 5 days. 
Treatment with docetaxel 
Dose: 
 
75 mg/m2 
Route:  
 
IV infusion of 1 hour. For the first 5 minutes, the infusion will be 
administered very slowly. 
Regimen:   
Day 1 and then every 3 weeks. 
Treatment with cisplatin 
Dose:  
 
75 mg/m2 
Route:  
 
IV infusion of 1 hour. 

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Regimen:   
Day 1 and then every 3 weeks. 
Adequate hydration will be ensured during administration of cisplatin. 
Treatment with 5-FU 
Dose:  
 
750 mg/m2/day 
Route:  
 
IV continuous infusion over 24 hours for 5 days. 
Regimen:   
Days 1-5 and then every 3 weeks. 
The sequence of the drugs recommended will be the following: 
 
Day 1: 
• 
Start, t = 0 to t = 2h: Infusion of 1 L of normal saline or of 5% glucose in 
0.45% saline, con KCl (20 mmol/L) and MgSO4 (2 g/L). 
• 
From t = 2h to t = 3h: Infusion of docetaxel in 250 mL of 5% glucose or 0.9% 
NaCl. 
• 
Immediately before the infusion of cisplatin: 12.5 g mannitol in the IV bolus 
• 
From t = 3h to t = 4h: cisplatin 75 mg/m2 in 500 mL of normal saline 
• 
From t = 4h to 8h: infusion of 25 g mannitol in 1 L of normal saline or of 5% 
glucose in 0.45% saline, con KCl (20 mmol/L) and MgSO4 (2 g/L). 
• 
From t = 8h: start of continuous IV infusion of 5-FU, 750 mg/m2, using an 
infusion pump. 
Days 2, 3, 4, 5: 
• 5-FU, 750 mg/m2/day, on the following days, up to a total of 5 consecutive days 
of treatment. 
 
7.A.1.2 
Prophylactic medication of TPF 
 
7.A.1.2.1 
Antiemetic pre-medication 
All patients have to receive a prophylactic antiemetic medication that will include a 
serotonin receptor (5-HT3) antagonist, such as ondansetron or granisetron, before and 
after the administration of cisplatin. 
7.A.1.2.2 
Pre-medication with corticosteroids 
The next pre-medication will be administered to all patients to prevent a 
hypersensitivity reaction and to reduce and/or delay the presentation of skin toxicity and 
fluid retention in relation to docetaxel. 
Dexamethasone 8 mg orally with a total of 6 doses 
• The night before chemotherapy. 
• Immediately on waking up on the morning of chemotherapy. 
• One hour before the docetaxel infusion (might be IV during administration of 
the treatment) 
• The night of docetaxel. 
• The morning of the day following docetaxel. 
• The afternoon after docetaxel. 

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If dexamethasone administration is not possible, the medication equivalent to 8 mg of 
dexamethasone is: 
- 
methylprednisolone at a dose of 40 mg orally 
- 
prednisolone at a dose of 50 mg orally 
 
7.A.1.2.3 
Recombinant granulocyte colony-stimulating factor (G-CSF) 
It is necessary to administer prophylactic administration from the first cycle on. 
Dose*: Lenograstim (Granocyte) 150 µg/m2/day from day 7 until day 12. 
Route: Subcutaneous. 
Regimen: Starting after the end of chemotherapy (day 7). Lenograstim will be 
administered once a day for 6 days, i.e. from day 7 to day 12, both included. 
*Lenograstim is recommended. If another granulocyte-colony stimulating factor will be 
used, it will be administered according to the summary of product characteristics. 
7.A.1.2.4 
Prophylactic antibiotic therapy 
All patients have to be given prophylactic antibiotic therapy with ciprofloxacin at a dose 
of 500 mg orally twice daily for 9 days from day 7 of each cycle, or their equivalent (for 
example levofloxacin) according to the investigator’s normal practice. 
7.A.1.3 
Dose adjustment 
The dose will be modified in the case of severe toxic and/or non-haematological toxic 
effects. The dose adjustments will be performed according to the type of toxicity that 
showed the highest grade of toxicity. Toxic effects will be graded according to NCIC-
CTG criteria, version 3.0. 
The main toxic dose-limiting effect of docetaxel in monotherapy is neutropenia. Other 
toxic effects that can be seen are anaphylactoid-type reactions and cutaneous reactions, 
toxic effects on the digestive system (nausea, vomiting, oral mucositis, diarrhoea), 
reversible paraesthesia, alopecia, asthenia and minor local venous reactions (phlebitis) 
at the injection site and fluid retention/oedema. The standards given below show the 
dose adjustments to be adopted in the event of several of these toxic effects. 
The main toxic effects observed with cisplatin in monotherapy are nausea and vomiting, 
peripheral neuropathy, nephrotoxicity and ototoxicity. 
The main toxic effects observed with 5-FU in monotherapy are mucositis, 
myelosuppression and diarrhoea. 
If a patient experience several toxic effects and the recommendations give conflict 
with one another, the most conservative dose adjustment of those recommended 
must be followed, involving a reduction in doses that is suitable for the most severe 
toxicity. Once the doses have been reduced because of toxicity they must not be re-
escalated. 

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7.A.1.3.1 
Docetaxel dose adjustments 
Haematological toxicity and/or complications 
Fever will be classified in grades using the NCI-CTC system, version 3.0. The 
temperature reported has to be oral or equivalent. In the case of febrile neutropenia, the 
following strategy is recommended: 
• Hospitalisation 
• Pre-antibiotic evaluation 
• Complete blood count and blood cultures 
• Start of empirical antibiotic therapy 
FEBRILE NEUTROPENIA OR DOCUMENTED INFECTION 
Adverse event 
Action to be taken in subsequent cycles 
 Febrile neutropenia 
 Documented infection 
 
The first episode of febrile neutropenia and/or documented infection will 
remain with G-CSF and ciprofloxacin (or their equivalent) and the 
docetaxel dose will be reduced from 75 to 60 mg/m2. 
If a second episode occurs, the patient will remain with ciprofloxacin (or its 
equivalent) and G-CSF, and the dose of docetaxel will be reduced from 60 
to 50 mg/m2 
BLOOD COUNT ON DAY 21 
 
Action to be taken 
Neutrophils ≥1.0 × 109/L 
Platelets ≥100 x 109/L 
Treatment at the scheduled date  
Neutrophils <1.0 x 109/L 
Delay over 1 week and repetition of the complete blood count on day 28 
 If ANC ≥1.0 x 109/L, administer chemotherapy by reducing the dose of 
docetaxel from 75 to 60 mg/m2 (*). 
 In a second episode, this should be repeated and the docetaxel dose 
would be reduced to 50 mg/m2. 
 If ANC is <1.0 x 109/L. There was a new 1-week delay and repeat 
haematology count on day 35:  
- If ANC ≥1.0 x 109/L, administer chemotherapy by reducing the dose 
of docetaxel from 75 to 60 mg/m2 (*). 
In a second episode, this should be repeated and the docetaxel dose 
would be lowered to 50 mg/m2. 
- If there is no recovery by day 35 (ANC <1.0 x 109/L), the patient 
will abandon the induction chemotherapy and will be treated 
according to each site’s protocol, and in accordance with 
international recommendations. 
(*) Maintain G-CSF and ciprofloxacin (or their equivalent) according to the 
regimen defined in points 7.A.2.2.3 and 7.A.2.2.4 of the Study Protocol. 

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Platelets <100 x 109/L 
 
 
Delay over 1 week and repetition of the complete blood count on day 28 
 If the platelet count ≥100 × 109/L, administration of chemotherapy but 
the dose of docetaxel will be reduced from 75 to 60 mg/m2. In a second 
episode, this should be repeated and the docetaxel dose would be 
lowered to 50 mg/m2. 
 If platelet count <100 x 109/L. perform a complete blood count on day 
35:  
o 
If the platelet count ≥100 x 109/L, administer chemotherapy, 
reducing the dose from 75 to 60 mg/m2. In a second episode, this should 
be repeated and the docetaxel dose would be lowered to 50 mg/m2. 
o 
If there is no recovery by day 35 (platelet count <100 x 109/L), 
the patient abandon the induction chemotherapy and proceed as 
established in section 7.A for unacceptable toxicity due to the TPF 
regimen. 
Skin reactions 
Docetaxel tends to induce erythematous maculopapular rash that is sometimes itchy, 
which particularly affects hands, forearms and feet, but also on the chest and face. It 
may occur in up to 50% of patients during the first week. Hand-foot syndrome and nail 
disorders have also been reported. Skin and nail disorders are usually more prominent in 
patients treated with a high cumulative dose and/or weekly administration. Therefore, 
patients included in the trial are not expected to have extraordinary problems managing 
this toxicity. 
Grades 0, 1 and 2: no changes. 
Grade 3: delay up to ≤ 1 and treat again with a reduction in the docetaxel dose from 75 
to 60 mg/m2. If there is no recovery at grade ≤ 1 within a 2-week delay, the patient 
should discontinue treatment with docetaxel. 
Grade 4: treatment with docetaxel will be discontinued. 
Nail disorders do not change dose modification. 
Nausea and/or vomiting 
An antiemetic regimen with 5-HT3 antagonists will be administered from the first cycle 
as well as corticosteroids that will be administered for 3 days as prophylaxis for fluid 
retention, which work together to reduce the incidence and severity of emesis. Patients 
with persistent nausea and/or vomiting despite these measures will be able to receive 
other antiemetic regimens. 
Bilirubin and impaired liver function 
In case of abnormal bilirubin levels during the study, the next cycle will be delayed for 
a maximum of 2 weeks. If there is no recovery, treatment with docetaxel will be 
discontinued. 
If AST and/or ALT and/or ALP levels are altered, the following had to be performed: 
 

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AST / ALT values 
ALP values 
Dose modification 
≤1.5 x UNL 
≤5 x UNL 
No dose change 
>1.5 x UNL - ≤2.5 x UNL
≤2.5 x UNL 
No dose change 
>2.5 x UNL - ≤5 x UNL 
≤2.5 x UNL 
Reduction of docetaxel dose from 75 to 60 
mg/m2 
>1.5 x UNL - ≤5 x UNL 
>2.5 x UNL - ≤5 x UNL 
Reduction of docetaxel dose from 75 to 60 
mg/m2 
>5 x UNL                               or >5 x UNL 
Delay a maximum of 2 weeks. If recovery to 
previous values have not occurred within this 
period, docetaxel will be discontinued. 
AST: aspartate transaminase; ALP: alkaline phosphatase; ALT: alanine transaminase UNL: upper normal limit 
 
If there is a deterioration of these parameters after initial dose reduction, treatment with 
docetaxel will be definitively suspended. 
7.A.1.3.2 
Cisplatin dose adjustments 
Peripheral sensory and motor neurotoxicity 
A neurological examination will be performed before study entry, and then when the 
patient have symptoms suggestive of neuropathy and/or 2 cycles of induction TPF 
chemotherapy.  
The following dose modifications will be applied: 
Grade 0.1: 
no changes. 
Grade 2: 
cisplatin reduction to 50 mg/m2 
Grade ≥3: 
treatment with cisplatin will be discontinued 
Ototoxicity 
In the case of grade 3 or 4, treatment with cisplatin will be discontinued. 
Nephrotoxicity 
In case of elevated serum creatinine (≥ 1.5 x patient initial value) despite adequate 
hydration, creatinine clearance will be determined and the following dose reductions 
will be considered: 
• If creatinine clearance (CCl) is ≥ 60 mL/min: the full dose of cisplatin will be 
administered and CCl will repeated before each cycle. 

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• If CCl is ≥ 40 mL/min <60 mL/min: the cisplatin dose will be reduced to 50 
mg/m2 in the subsequent cycles and the CCl will be repeated in the remaining 
cycles. 
• If CCl is < 40 mL/min: cisplatin will be suspended in the remaining cycles. 
Thrombocytopenia 
If grade 4 thrombocytopenia occurs (<25 x 109/L), the dose of cisplatin will be reduced 
to 25% (from 75 to 60 mg/m2). 
7.A.1.3.3 
5-FU dose adjustment 
Mucositis 
For grade 3 mucositis, the dose of 5-FU will be reduced by 20%, from 750 to 600 
mg/m2/day. In case of grade 4 mucositis, treatment with 5-FU will be discontinued. 
Diarrhoea 
If diarrhoea is observed, maintenance therapy is allowed to be administered. If grade 3 
diarrhoea occur, the 5-FU dose will be lowered by 20% from 750 to 600 mg/m2/day. In 
case of grade 4 diarrhoea, treatment with 5-FU will be discontinued. 
7.A.1.3.4 
Other toxicities 
For the other grade 3 and 4 toxic effects not covered by the preceding sections, with the 
exception of hair loss and nail disorders, chemotherapy will be discontinued for a 
maximum of two weeks from the planned administration date until resolution to grade ≤ 
1. The possibility of administering chemotherapy again will be assessed in each case, 
with the necessary changes and modifications to the doses.  
7.A.1.4.  
Management of the specific toxic effects of docetaxel, which do not 
require dose modifications 
7.A.1.4.1.  Hypersensitivity reactions 
During the first and second infusions, the patient’s overall status will be assessed as 
well as, if possible, blood pressure and heart rate, for at least the first 10 minutes, with a 
view to immediate intervention in case of a hypersensitivity reaction. The patients 
receive the infusions in an area where resuscitation equipment and other drugs 
(adrenaline, prednisone equivalents, etc.) are available. If a hypersensitivity reaction 
occurs, it will be treated according to the best available medical practice. 
HYPERSENSITIVITY REACTIONS TO DOCETAXEL 
NCI-CTC grade, 
version 3 
Treatment 
Grade 1 
Decrease in infusion rate until the symptoms disappear, close observation of the 
patient. 
Subsequently, complete the docetaxel infusion into the initially planned rate. In 

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the following cycles, use the same pre-medication indicated in section 7.A.1.2.2. 
Grade 2 
Discontinue docetaxel infusion 
Administer antihistamines and corticosteroids intravenously 
Resume docetaxel infusion once symptoms have disappeared. In subsequent 
cycles, administer antihistamines and corticosteroids intravenously, one hour 
before the infusion as well as the pre-medication established in section 7.A.2.2.2. 
Grade 3 
Discontinue docetaxel infusion 
Administer antihistamines and corticosteroids intravenously. Add adrenaline 
and/or bronchodilators and/or fluids and/or IV macromolecules if indicated. 
Once the signs and/or symptoms of the hypersensitivity reaction have disappeared, 
you may resume the infusion of docetaxel within 24 hours of discontinuation, if 
medically suitable and possible. 
The premedication regimen described in section 7.A.2.2.2 is only recommended 
when docetaxel is reinfused over 3 hours after discontinuation. 
In subsequent cycles, dexamethasone will be administered at a dose of 20 mg 
orally in the evening before chemotherapy, the morning of chemotherapy and one 
hour before the docetaxel infusion. 
Diphenhydramine (or equivalent) will also be administered at the 50 mg IV 1 hour 
dose before the docetaxel infusion. 
If a severe reaction occurs again, docetaxel is permanently suspended. 
Grade 4 
Appropriate urgent treatment (see description in grade 3) and docetaxel suspended 
permanently. 
7.A.1.4.2.  Peripheral oedemas and/or effusions 
If there have been fluid retention during treatment despite premedication with 
corticosteroids, its symptoms and signs have to be graded according to NCIC-CTG 
criteria. Dose reduction is not planned. Weight will be recorded as often as possible to 
document a possible weight gain that may be due to oedema. 
The recommended treatment -spironolactone 100 mg/day orally- will be initiated when 
the patient develop grade 2 or 3 in an attempt to continue treatment with docetaxel.  
If symptoms may not be adequately controlled, adding furosemide at doses of 20-40 
mg/day orally will be assessed. The clinical tolerance of the patient, the overall response 
and the investigator's medical opinion determine whether it is better in the patient's 
interest to continue with docetaxel or suspend it. 
7.A.2  
Radical treatment (Part 2 – arm A): Cisplatin (during concomitant 
treatment with radiotherapy) 
Patients will receive cisplatin 100 mg/m2 on day 1, coinciding with the first day of RT, 
and subsequently on days 22 and 43 of RT: 
Dose: 100 mg/m2 
Route: IV infusion of 1 hour. 

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Regimen: Day 1 and then every 3 weeks. 
Adequate hydration will be ensured during administration of cisplatin. The sequence of 
the drugs recommended is the following: 
 
Day 1: 
• Start, t = 0 to t = 2h: Infusion of 1 L of normal saline or of 5% glucose in 
0.45% saline, with KCl (20 mmol/L) and MgSO4 (2 g/L). 
• From t = 2h to t = 3h: Infusion of docetaxel in 250 mL of 5% glucose or 0.9% 
NaCl. 
• Immediately before the infusion of cisplatin: 12.5 g mannitol in the IV bolus 
• From t = 3h to t = 4h: cisplatin 100 mg/m2 in 500 mL of normal saline 
• From t = 4h to 8h: infusion of 25 g mannitol in 1 L of normal saline or of 5% 
glucose in 0.45% saline, with KCl (20 mmol/L) and MgSO4 (2 g/L). 
7.A.2.1 
Prophylactic medication of cisplatin 
7.A.2.1.1 
Antiemetic pre-medication 
All patients have to receive a prophylactic antiemetic medication that includes a 5-HT3 
antagonist, such as ondansetron or granisetron, before and after the administration of 
cisplatin. The adjuvant use of dexamethasone is recommended. 
7.A.2.2 
Dose adjustment 
The dose will be modified in the case of severe toxic and/or non-haematological toxic 
effects. The dose adjustments are performed according to the type of toxicity that 
showed the highest grade of toxicity.  
If a patient experiences several toxic effects and the recommendations give conflict 
with one another, the most conservative dose adjustment of those recommended 
must be followed, involving a reduction in doses that is suitable for the most severe 
toxicity. Once the doses have been reduced because of toxicity they must not be re-
escalated. 
7.A.2.2.1 
Cisplatin dose adjustments 
Haematological toxicity and/or complications 
Fever will be classified in grades using the NCI-CTC system, version 3.0. The 
temperature reported will be oral or equivalent. In the case of febrile neutropenia, the 
following strategy is recommended: 
• Hospitalisation 
• Pre-antibiotic evaluation 
• Complete blood count and blood cultures 
• Start of empirical antibiotic therapy 

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FEBRILE NEUTROPENIA OR DOCUMENTED INFECTION 
Adverse event 
Action to be taken in subsequent cycles 
 Febrile neutropenia 
 Documented infection 
 
The first episode of febrile neutropenia and/or documented infection, the 
dose of cisplatin is reduced from 100 to 75 mg/m2. 
If a second episode occurs, the third dose of cisplatin is suspended. 
BLOOD COUNT ON DAY 21 
 
Action to be taken 
Neutrophils ≥ 1.0×109/L 
Platelets ≥ 100x109/L 
Treatment at the scheduled date  
Neutrophils <1.0 x 109/L 
Delay over 1 week and repetition of the complete blood count on day 28 
 If ANC ≥1.0 x 109/L, administer chemotherapy by reducing the dose of 
cisplatin from 100 to 75 mg/m2. 
 If there is a second episode, the 3rd cisplatin cycle should be 
discontinued. 
 If ANC is <1.0 x 109/L. There was a new 1-week delay and repeat 
haematology count on day 35:  
- If ANC ≥1.0 x 109/L, administer chemotherapy by reducing the dose 
of cisplatin from 100 to 75 mg/m2. 
When this happens, there is no space to administer the 3rd cycle of 
cisplatin, so this 3rd cycle is suspended. 
- If there is no recovery on day 35 (ANC <1.0 x 109/L), the patient 
will discontinue chemotherapy with cisplatin and will continue 
radiotherapy treatment. 
Platelets <100 x109/L 
 
 
Delay over 1 week and repetition of the complete blood count on day 28 
 If the platelet count ≥100 × 109/L, administer chemotherapy but the dose 
of cisplatin will be reduced from 100 to 75 mg/m2. If there is a second 
episode, the 3rd cisplatin cycle is suspended. 
 If platelet count <100 x 109/L perform a complete blood count on day 
35:  
o 
If the platelet count ≥100 x 109/L, administer cisplatin, reducing 
the dose from 100 to 75 mg/m2. If there is a second episode, treatment 
with cisplatin should be suspended. 

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o 
If there is no recovery on day 35 (Platelet count <100 x 109/L), 
the patient will discontinue chemotherapy with cisplatin and will 
continue radiotherapy treatment. 
 
Nausea and/or vomiting 
An antiemetic regimen with 5-HT3 antagonists will be administered from the first cycle 
as well as corticosteroids that will be administered for 3 days as prophylaxis for fluid 
retention, which work together to reduce the incidence and severity of emesis. Patients 
with persistent nausea and/or vomiting despite these measures will be able to receive 
other antiemetic regimens. 
Peripheral sensory and motor neurotoxicity   
A neurological examination will be performed before study entry and then when the 
patient have symptoms suggestive of neuropathy. 
The following dose modifications will be applied: 
Grade 0, 1: 
no changes. 
Grade 2: 
cisplatin reduction to 50 mg/m2 
Grade ≥ 3: 
treatment with cisplatin is suspended 
Ototoxicity 
In the case of grade 3 or 4, treatment with cisplatin will be discontinued. 
Nephrotoxicity 
In case of elevated serum creatinine (≥1.5 x patient initial value) despite adequate 
hydration, creatinine clearance have to be determined and the following dose reductions 
will be considered: 
• If CCl is ≥ 60 mL/min: the full dose of cisplatin will be administered and CCl 
will be repeated before each cycle. 
• If CCl is ≥ 40 mL/min <60 mL/min: the cisplatin dose will be reduced to 50 
mg/m2 in the subsequent cycles and the CCl will be repeated in the remaining 
cycles. 
• If CCl is < 40 mL/min: cisplatin will be suspended in the remaining cycles. 
7.A.2.2.2 
Other toxicities 
For the other grade 3 and 4 toxic effects not covered by the preceding sections, with the 
exception of hair loss and nail disorders, cisplatin will be discontinued for a maximum 
of two weeks from the planned administration date until resolution to grade ≤ 1. The 
possibility of administering cisplatin again will be assessed in each case, with the 
necessary changes and modifications to the doses.   
Under no circumstances will a dose of cisplatin be administered once RT treatment have 
been completed. If due to the successive delays of cisplatin administration, the cisplatin 

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doses that have not yet been administered coincided with the end of treatment with RT; 
these will not be recovered. 
7.A.3  
Radical treatment (Part 2 – Arm B): Cetuximab (during concomitant 
treatment with radiotherapy) Dose and fractionation 
The dose and procedure for the administration of cetuximab will be as follows: 
 The initial dose (first infusion) is 400 mg/m2 (= 80 mL/m2). For safety reasons, it 
is mandatory to treat patients with a suitable antihistamine and corticosteroid (as 
prophylactic treatment in order to reduce the risk of an allergic reaction). The 
required volume will be administered in a 2-hour period (maximum velocity of 2 
mL/min) and a saline solution (0.9%) will be used to wash the route at the end of 
the infusion. Vital signs will be checked before the administration of cetuximab 
and then during infusion and for one hour after infusing the volume.  
This initial dose or load will be administered one week before the first day of RT, 
then 2-4 weeks after the 3rd cycle of TPF. 
 The weekly dose (the remaining infusions) is 250 mg/m2 (= 50 mL/m2). Patients 
should be treated in advance with a suitable antihistamine and corticosteroid. 
The required volume will be administered in a 1-hour period (maximum velocity 
of 2 mL/min) and a saline solution (0.9%) will be used to wash the route at the 
end of the infusion. Although no vital signs checks are necessary, careful 
observation of the patient (up to one hour after infusion) is required to monitor 
the possible appearance of AEs (specifically, allergic reactions).  
The weekly dose will be maintained until the RT programme is completed. The last 
week of cetuximab coincided with the last week in which the patient received RT. 
7.A.3.1 
Dose modifications and cetuximab treatment changes 
7.A.3.1.1  Skin reaction 
If a patient experience grade 3 skin toxicity, treatment with cetuximab will be delayed. 
The investigator will be able to establish concomitant treatment with moisturising 
creams and/or oral and/or topical antibiotics and/or topical corticosteroids (a specific 
manual for the management of skin toxicity will be distributed). Treatment may only be 
resumed if the reaction is repeated to grade 2, which may be delayed by up to four 
consecutive infusions. 
If the serious skin reaction occurs for the first time, the treatment may be resumed 
without changes in the dose. If they present severe skin reactions for the second or third 
time, the treatment with cetuximab will be again discontinued and may resume with a 
lower dose (200 mg/m2 body surface area after the second time, and 150 mg/m2 days 
after the third time) only if the reaction remit to grade 2. 
If severe skin reactions occur for a fourth time, or they do not recover to grade 2 during 
treatment interruption, the treatment with cetuximab have to be suspended permanently. 

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If the patient have Grade 4 dermal toxicity, treatment with cetuximab will be 
discontinued. 
If the infusion of cetuximab will be discontinued for 4 weeks due to cetuximab toxicity 
or due to an intercurrent condition (e.g. infection) that require treatment discontinuation, 
treatment with cetuximab will be discontinued. In each case, the principal investigator 
and/or study coordinator may have assessed the possibility of the patient continuing to 
receive cetuximab (Figure 7.1). 
Figure 7.1 Adjustment of treatment in case of dermal toxicity caused by cetuximab. 
Grade 3 dermal toxicity 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Has it recovered to 
grade  
 2? 
Yes 
 
Which grade 3 toxicity 
episode is this? 
 
 
 
 
 
 
 
 
No 
 
 
 
 
 
 
 
Delay infusion  
1st week 
 
 
 
First 
250 mg/m2 dose 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Delay infusion 
2nd week 
 
 
 
Second 
Dose reduction to 200 
mg/m2 
 
consecutive 
 
 
 
 
 
 
 
 
 
 
 
 
 
Treatment 
discontinuation 
3rd week 
 
 
 
Third 
Dose reduction to 150 
mg/m2 
 
 
consecutive 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Fourth 
Treatment 
discontinuation  
 
 
 
 
 
7.A.3.1.2 Allergic reaction 
If a hypersensitivity reaction occurs, the investigator have to establish therapeutic 
measures according to the best available medical practices. Based on previous 
experience with hypersensitivity reactions, the following treatment guidelines may be 
applied (Table 7. 1): 
 

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Table 7. 1 Adjustment of treatment in case of allergic or hypersensitivity reactions caused by 
cetuximab. 
CTC grade of 
allergic reactions or 
hypersensitivity 
Treatment 
Grade 1  
Reduce the cetuximab infusion rate by 50% and closely monitor for worsening. 
The total infusion time for cetuximab should not exceed 4 hours. 
Grade 2  
 
Interrupt the infusion of cetuximab. 
Administer bronchodilators, oxygen, etc. as medically indicated. 
Resume the infusion at 50% of the previous rate after it has disappeared or 
decreased to a Grade 1 allergic/hypersensitivity reaction and closely monitor for 
worsening. 
Grade 3 or Grade 4  
Stop cetuximab infusion immediately and remove the infusion route from the 
patient. 
Administer 
adrenaline, 
bronchodilators, 
antihistamines, 
corticosteroids, 
intravenous fluids, vasopressors, oxygen, etc. when medically indicated. 
Patient treatment should immediately be discontinued and treatment with 
cetuximab should not subsequently be restarted. 
New administration of treatment after a hypersensitivity reaction 
Once the rate of infusion of cetuximab is reduced due to the onset of an allergic or 
hypersensitivity reaction, the reduction will continue for later infusions. If a subject has 
a second allergic or hypersensitivity reaction to the slower infusion rate, the treatment 
with cetuximab have to be discontinued definitively. If at any time, a patient 
experiences an allergic or hypersensitivity reaction of Grade 3 or 4, cetuximab treatment 
will be suspended. If there is any doubt as to whether the subject’s reaction is a Grade 
1-4 allergic or hypersensitivity reaction, the study coordinator and/or principal 
investigator have to be immediately contacted for consultation and for assignment of a 
grade. 
7.A.3.1.3 
Management of radiodermatitis concomitant with cetuximab-induced 
skin rash 
One of the side effects associated with RT is radiodermatitis, which occurs in head and 
neck tumours in the area of the cheek, retroauricular area and neck. In other words, it 
coincides with one of the areas with the most skin disorders caused by cetuximab. In 
patients treated with RT and concomitant cetuximab, both skin toxicities coincide 
within the irradiation field, and therefore some patients may have severe skin disorders 
in this area that require specific support measures. 
The management of this toxicity will be performed according to the grade of dermatitis 
as specified in section 8.B.7. It is summarised in the following table: 
 
 
 
 

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Grade of 
radiation 
dermatitis 
Grade 1 
Grade 2 
Grade 3 
Grade 4 
General 
measures 
The general measures are those belonging to each site. 
 
Topical application of protective substances or dressings, gels, and emulsions 
should not be applied immediately before treatment with radiotherapy, as it can 
cause a bolus effect, thus increasing the dose of radiation on the epidermis. The 
skin within the irradiation field must be cleaned and dried appropriately just before 
being irradiated. 
Measurements 
based on the 
degree of 
toxicity 
Keep the area 
irradiated clean.  
Subsequent use of 
a protective 
dressing is 
optional. 
To keep the area treated with clean, even 
when ulcerated. 
 
Check that the 
irradiation 
dose 
and distribution is 
correct. 
If anti-infectious 
measurements are 
required, anti-
infective dressings 
may occasionally 
be used (e.g. 
triclosan or 
chlorhexidine). 
When infection is not suspected, one of the 
following topical measures can be used:  
o 
Shower gels, possibly with 
the addition of antiseptics 
(e.g. 
chlorhexidine-based 
creams)  
o 
Hydrophilic dressings were 
applied after radiotherapy to 
the cleaned irradiated area, 
they may improve the topical 
symptoms.  
o 
An 
anti-inflammatory 
emulsion, 
such 
as 
triethanolamine.   
o 
Hyaluronic acid cream. 
o 
Zinc oxide paste, if it is 
considered possible to break 
them before starting each 
radiotherapy fraction.  
o 
Silver sulfadiazine or beta 
glucan cream can be used 
after radiation (preferably in 
the afternoon) after cleaning 
the irradiated area. 
It requires a 
specialised 
treatment on 
wounds with the 
support of the 
radiation 
oncologist, 
dermatologist and 
nurse, and should 
be treated 
individually.  
When infection is suspected: 
o 
The 
person 
tasked 
with 
treated the lesion must rule 
out 
the 
presence 
of 
an 
infection, if they require a 
culture 
to 
identify 
the 
infectious agent. 
o 
Topical antibiotics (they are 
not recommended to be used 
prophylactically) 
o 
Doxycycline 
is 
not 
recommended in this stage. 
Cetuximab 
Continue with 
treatment 
Continue with treatment 
 
Suspend 
radiotherapy and 
cetuximab 

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7.A.3.1.4 
Modifications or delay of cetuximab dose  
If a patient presents a concomitant condition (e.g. infection) that in the opinion of the 
investigator and/or study coordinator requires interruption of treatment, the concomitant 
condition has to be cured within a period of time that does not prevent more than four 
consecutive infusions of cetuximab from being administered. If treatment with 
cetuximab will be delayed, another loading dose will not be administered and all 
subsequent treatments will be administered at the allocated dose. If the administration of 
cetuximab suspends for a period of time, the study investigator and/or coordinator may 
assess the possibility of the patient continuing to receive cetuximab or withdrawing 
them from the study. 
7.A.4.  Radical treatment (part 2 both arms): RADIOTHERAPY 
Normofractionated RT combined with cisplatin or cetuximab 
The RT administration regimen for RT is shown in Table 7.2. It will be started at 3-4 
weeks (5 weeks at most) from the start of the administration of the 3rd cycle of 
induction chemotherapy, with the aim of minimising the effect that treatment stops have 
on the cell repopulation. In individual – exceptional – cases, and previous contact with 
the study coordinators, a 5th week of delay will be allowed for the start of RT. In no 
case there will remain weeks without treatment with cetuximab. 
The sequence, interval and hours compared to the administration of cisplatin (standard 
arm) or cetuximab (experimental arm) and RT will be the most suitable for the site and 
the patient. 
Table 7.2 Radiotherapy administration regimen for radiotherapy. 
Radiotherapy 
Total radiotherapy 
Dose per fraction 
Normofractionated 
Total 70 Gy, 
divided into 35 fractions 
2 Gy / fraction 
1 fraction per day 
35 fractions for 7 weeks 
7.A.4.1  
Planning 
Treatment planning with radiation will be done before any treatment. If there are 
anthropometric variations in the patients after having received chemotherapy, it is not 
due to a decrease in adenopathies (N3) or by weight loss; a new planning will be 
performed to adjust the dosimetry to the current volume. Re-planning will be performed 
after the third induction chemotherapy. The initial volume of the disease have to be 
what is treated. RT will be performed using three-dimensional analysis with a CAT 
scan. This will be done with contrast if possible. The distance between the cuts in the 
planning CT scan will be 5 mm. 
The patient have to be immobilised with a thermoplastic mask and carbon-fibre support, 
where possible for the use of subsequent fields.  
 

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7.A.4.2.  
Determination of volumes 
To design the volumes and the specification of the dose, it is recommended to follow 
the International Commission on Radiation Units (ICRU) 50 recommendations. To 
determine the clinical target volume (CTV) of the primary tumour, it is recommended to 
follow the general considerations published by Eisbruch et al. [1]. To determine the 
CTV of the lymph node chains, we followed the recommendations and consensus 
published by the DAHANCA, EORTC, GORTEC and RTOG for the negative lymph 
nodes, and the recommendations of Grégoire et al. [2,3] for the positive lymph nodes. 
The determination of the volumes will be always performed by taking into account the 
initial disease volume, and not just the disease that lasted after chemotherapy. This is 
intended to improve the dosimetric study of the treatment and reduce the doses in 
healthy tissues.  
The margins added to the gross tumour volume (GTV) to reach the CTV will be 5 mm 
plus the margin of organ and patient movement, and the technical inaccuracies that will 
be specific to each site.  
They defined 2 or 3 planning target volumes (PTVs) according to the initial disease, 
tumour size and lymph node extension. 
To restrict the dose to healthy tissues, the values published by Emami et al. will be used 
[4]. 
7.A.4.3.  
Method, dose and fractioning 
Accelerators with 4-6 MV as well as electrons with different energy levels are 
recommended, in case overprinting is necessary in some areas with tumours or those at 
risk. 
The total dose in the tumour and lymph node areas affected will be 70 Gy. Doses in the 
lymph node areas at high-risk of microscopic disease will be 55-60 Gy and in low-risk 
elective areas, 45-50 Gy.  
PTV1 = CTVt + CTVn + CTVn elective plus 45-50 Gy margins 
PTV11= CTVt + CTVn of maximum risk plus 60 Gy margins 
PTV111= CTVt plus 70 Gy margins 
Maximum dose in marrow 45 Gy. 
7.A.4.4.  
In the case of treatment discontinuation 
In the case of treatment, discontinuation, due either to malfunction or revision of the 
treatment machine, continued treatment have to be ensured, and so the use of another 
unit is recommended. For units that have different energy levels, it is recommended to 
perform the dosimetry on an alternative device. 
7.A.4.5.  
Check of the treatment 
In technically complex cases, treatment simulation is recommended. Testing the 
treatment will be performed by X-ray of all fields or at least portal-vision at baseline 
and technical changes. 

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A linear accelerator will be used, 4-6 MV which have different types of electrons for 
proper radiation of the posterior cervical lymph nodes. 
7.A.4.6  
Management of acute radiation toxicity 
If skin or mucosa grade 4 toxicity occurs, the possibility of temporary suspension of 
treatment is assessed. For any other degree of minor toxicity, with the necessary support 
measures have to be taken to guarantee treatment continuity. Given that it is an 
accelerated diagram, prolongation of total treatment time seems to lower the benefits of 
this type of therapeutic regimen. 
The protocol for each site will be followed in terms of prophylaxis and dental hygiene 
and management of skin and mucosal toxicity.  
Analgesics: it is recommended to use a rapid analgesic scale going through a first step 
with a non-steroidal anti-inflammatory drugs (NSAIDs) and analgesics, a second step 
with opioids, followed by a third step with morphine or fentanyl.  
Skin toxicity: it is recommended to hydrate and clean the skin. 
- 
In the case of G I dermatitis: hydration 
- 
In case of G II-III dermatitis: topical corticosteroids 
- 
In case of G-IV dermatitis: topical corticosteroids, epithelializing creams and 
dressings  
Mucositis: The following recommendations will be considered: 
- 
Analgesics: rapid escalation using the WHO cancer pain relief ladder 
- 
Nutritional support: according to the protocol of each site. Oral nutritional 
support was recommended for oral administration if there was weight loss of ≥ 
5%. If the weight loss was ≥ 10%, the use of nasogastric or gastrostomy tube is 
recommended for feeding. 
Nasogastric or gastrostomy tube for feeding: recommended to use in the following 
situations: 
1. Weight loss ≥ 10% (assess it from weight loss ≥ 5% of initial weight). 
2. Grade 3 functional mucositis 
3. Pain in oral cavity and/oropharyngeal pain poorly controlled with morphine. 
4. Risk of aspiration: appearance of cough and/or choking during intake. 
5. Swallowing disorder initially attributed to the tumour and/or spreading of the 
tumour into the supraglottis. 
Interruption of radiotherapy: it will be considered in the following clinical situations: 
1. Mucositis measured by physical examination and/or functional, grade 4. 
2. Mucositis measured by physical examination and/or functional, grade 3, when it 
is associated with weight loss ≥ 20% with respect to the initial weight or a 
decrease in Karnofsky index score ≥ 40% compared to baseline. 
3. Grade 4 Radiodermatitis 

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The discontinuation of RT due to toxicity do not prevent the treatment of RT in 8 
weeks. It is always attempted to finish within this time, if the delay requires 
finishing for the ninth week, before exceeding 8 weeks, it is required to consult the 
study coordinators whether to consider these patients as evaluable. If the 
treatment is completed after a period of 9 weeks, the patient have to be withdrawn 
from the study. 
The discontinuation of RT due to toxicity do not involve the discontinuation of 
cetuximab treatment, which continues to be administered during this interruption and 
will be suspended only if the patient withdraw from the study. 
Radiotherapy report: 
It is recommended that the following be included in the external RT report: 
 Definition of GTV, CTV, PTV and organs at risk. 
 Positioning of the patient and immobilisation. 
 Technique used: number of beams, energy of the beams. 
 Description of interruptions: number of days and cause. 
 Dose specifications: maximum and minimum dose in each PTV, mean and 
median in each PTV, dose in organs at risk 
 Toxicity: grade of epithelitis, grade of clinical and functional mucositis. 
 A copy of the complete dosimetry, including dose-volume histograms of the 
defined volumes and risk organs had to be included. 
 Provide images of the cross-sections representative of the delimited volumes as 
well as digitally reconstructed radiographic (DRR) images from each of the 
treatment fields used. 
7.A.3.4  
Cisplatin at the same time as radiotherapy (Arm A, conventional) 
Cisplatin will be administered 1st day of the RT and subsequently every 21 days (days 
22 and 43 of the RT), irrespective of the duration of the RT. The discontinuation of RT 
due to toxicity involves discontinuation of cisplatin treatment that may be restarted if it 
will be decided to continue with the RT treatment. Cisplatin will be administered while 
the patient is undergoing RT, and the last day possible will be the last day of 
administration of RT. 
7.A.3.5  
Cetuximab at the same time as radiotherapy (arm B, experimental) 
Cetuximab will be administered throughout the entire RT, regardless of its duration. 
The discontinuation of RT due to toxicity do not involve the discontinuation of 
cetuximab treatment, which continues to be administered during this interruption and 
will be suspended only if the patient withdraw from the study. Cetuximab will be 
maintained until the last week in which the patient completed RT. 
7.A.5 
Dissection of the neck after radiotherapy 
For those patients in whom a persistent cervical adenopathy is observed but with control 
of the primary tumour during the definitive treatment assessment (a complete extension 
study at 6-8 weeks after the RT has finished), it is assessed whether to carry out a neck 

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dissection. The decision on the type of neck dissection depend on the head and neck 
surgeon, and will be discussed in detail with the multidisciplinary treatment team. 
In patients where the initial lymph node condition is resectable, the type of dissection 
depends on the location, size and relationship to the cervical structures. In cases of N1 
and some cases of N2, the procedure to be performed will be a functional neck 
dissection (FND), preserving important neck structures such as the internal jugular vein, 
the spinal nerve and the sternocleidomastoid muscle. In cases where the size or location 
of the cervical adenopathies make this technique impossible, a radical FND will be 
performed - without preserving the aforementioned cervical structures. There is also the 
possibility, depending on the surgical findings, of performing a modified FND, with the 
preservation of some of the aforementioned cervical structures. The use of this 
technique depends on the surgical findings. In general, irrespective of the technique 
used, the neck dissection levels must include lymph node areas I to IV or II to IV.  
In patients whose initial lymph node condition is classified as unresectable (N3), the 
most advisable technique to be performed will be a Radical RND. 
The performance of selective FNDs, which involve the removal of one or two lymph 
node levels, without the performance of a regulated neck dissection, will be left to the 
discretion of each Tumour Committee. Its advantage comes from a lower post-operative 
morbidity; its disadvantage is that it involves the incomplete removal of all the cancer.  
Lymph node surgical rescue due to the persistence of cervical adenopathies with 
primary tumour control is considered an integral part of the therapeutic programme, 
which is why it is not considered a therapeutic failure or a serious event. 
If the lymph node persistence is accompanied by a local disease persistence, this will be 
considered a therapeutic failure, and in this case, the performance of the most suitable 
salvage therapy have to be evaluated. 
Note: Prophylactic neck surgery after the end of the complete treatment, irrespective of 
the final response to treatment, for all patients with N2/N3 initially, is optional for each 
site. 
7.B Previous and concomitant medicine 
All patients in this study will be offered supportive measures for disease-related 
symptoms and treatment-associated toxicity. Any concomitant medication (e.g. 
antibiotics, analgesics, antihistamines, anti-emetics, steroids), procedures (e.g. 
paracentesis, thoracentesis) or blood products (e.g. erythrocyte, platelet or frozen fresh 
plasma transfusions) administered during the study and in the 2 weeks prior to its start 
will be recorded the CRF, indicating the date, indication, procedure description and 
clinical observations, if any. The generic name of the medication will be specified 
together with the total daily dose and duration of the treatment. In the case of 
medications containing more than two active substances, the brand name may be used.  
The patients have to be premedicated with antihistamines and corticosteroids before 
they receive the first dose of cetuximab. Similarly, the patients also have to be 
premedicated with dexamethasone before the administration of docetaxel. It is 

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recommended that the patients be premedicated with antihistamines and corticosteroids 
before the subsequent cetuximab infusions. 
Palliative RT may not be administered for pain management or other non-curative 
purposes. 
Surgery to remove tumours is not permitted during the study. The study patient will be 
withdrawn if this surgery is carried out. If, at the end of the study, tumour persistence, 
relapse or progression (exit from the study) is observed, the investigator may obviously 
then make a decision regarding the appropriateness or not of performing rescue and/or 
palliative surgery. 
 
Permitted concomitant medication 
Sedatives, antiemetics, antibiotics, analgesics, antihistamines, steroids, red blood cell 
concentrates, erythropoietin, or fresh-frozen plasma or platelet transfusions may be 
administered to help the treatment of pain, infection or other complications of the 
neoplasia. In the case of documented febrile neutropenia or infection, IV antibiotics may 
be administered for curative purposes. Only the administration of haematopoietic 
growth factors is accepted. 
Erythropoietin is only administered in patients with a haemoglobin value below 10 g/dL 
and at the lowest possible dose to avoid a transfusion. Furthermore, the administration 
of erythropoietin will be stopped if, after 8 weeks of treatment, the patient's 
haemoglobin levels do not recover to the levels necessary or if they still require 
transfusions. 
Prophylactic treatment with an antihistamine and a corticosteroid is administered before 
the initial dose of cetuximab will be administered. Similarly, the patients have to be 
premedicated with corticosteroids before all the docetaxel doses. Prophylactic treatment 
with an antihistamine and a corticosteroid before the following weekly doses of 
cetuximab is recommended. 
Non-permitted concomitant medication 
Patients in this study may not be administered any other concomitant chronic systemic 
immunotherapies, chemotherapy not indicated in the study protocol, RT not indicated 
by the study, hormone therapy for cancer (the administration of corticosteroids at low 
doses as antiemetics and progestogens for the tumour cachexia is allowed), amifostine 
or any other investigational drugs. If it is necessary to administer a concomitant drug or 
procedure that is not permitted, the patient will be withdrawn from the study. 
7.C Material management 
The drugs in this study are approved for the study indication, and therefore, the normal 
supply methods and the handling instructions specified in their respective summaries of 
product characteristics are followed. 

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7.D Assessment of treatment compliance 
The study medication will be administered by the investigator or under their direct 
supervision. Given that the IV infusions will be administered in a hospital or in an 
outpatient environment, compliance with the treatment may be easily monitored.  
The date and the exact quantity of the drug administered at each infusion will be 
recorded in the study CRF/medication form. The date and the start and end time of the 
infusion, as well as the exact quantity of cetuximab, cisplatin and TPF administered at 
each infusion, will be recorded in the patient’s medical record. If the treatment have to 
be modified, the medical staff have to evaluate the percentage of the dose received by 
the patient and record this in the CRF. All the reasons have to be recorded. 
In the event of insufficient compliance by the patient, the principal investigator and the 
study coordinator decide together, on a case-by-case basis, on the possible withdrawal 
of the patient from the study. 

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8. 
Efficacy and safety measurements and study outline 
8.A Efficacy evaluations 
The variables of the study are shown in section 12.A. The main objective of the study is 
to determine the non-inferiority in OS of the experimental branch (TPF followed by RT 
+ Cetuximab) versus the standard branch (TPF followed by RT + cisplatin). 
8.B Description of the methods used 
The following table summarizes the evaluations to be made during the periods of 
selection, treatment and follow-up of the study. The descriptions of the methodology to 
be followed are included in the following sections.  
Table 8.1 Diagram of the valuations to be made during the study 
Assessment 
Include 
Informed consent 
• 
Written informed consent to participate in the study will be made before the 
start of induction chemotherapy with TPF. 
Register 
• 
Assignment of patient number 
Demographic data 
• 
Age (date of birth) 
• 
Sex 
• 
Ethnic origin 
Tumour diagnosis 
• 
Date of initial diagnosis  
• 
Histological type and degree of differentiation 
• 
Tumour, ganglion (node), metastasis (TNM) classification   
• 
Staging according to the American Joint Commission for Cancer (AJCC) 
criteria; 6th edition 
• 
It will be recorded if both the primary tumour and the lymph node 
involvement are resectable or unresectable 
Medical history and 
previous treatments 
• 
Malignant and non-malignant diseases of previous interest 
• 
Treatments administered in the two weeks prior to the start of the study 
Inclusion and exclusion 
criteria 
• 
Comprehensive review of all criteria 
Physical exploration 
• 
Height, weight, BMI, and body surface area (BSA) 
• 
General aspect 
• 
Cardiovascular system 
• 
Pulmonary 
• 
Neurological 
• 
Digestive system 
• 
Genitourinary device 
• 
Locomotor apparatus 
• 
Lymphatic system 
• 
Dermatological 
• 
Eyes 
• 
Extremities 
• 
Detailed physical examination of the head and neck area, to rule out a second 
neoplasia 

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Vital signs 
• 
Temperature 
• 
Resting heart rate 
• 
Blood pressure at rest (systolic and diastolic) 
Activity degree 
• 
ECOG - PS 
Dental evaluation 
• 
It is recommended to remove seriously damaged parts before therapy, trying 
to preserve or restore them when possible. 
Nutritional assessment 
• 
A minimum intake of 1700 calories per day should be guaranteed, but if it is 
possible orally, the use of nasogastric tube and/or jejunostomy will be 
assessed. 
Direct optical 
examinations of the 
tumour 
• 
It is advisable to perform a panendoscopy under general anaesthesia with the 
necessary biopsies. When this is not possible or is not considered necessary, 
an indirect laryngoscopy with an evaluation of the oropharynx, hypopharynx 
and larynx will be accepted. 
Diagnostic imaging 
techniques (within 5 
weeks before inclusion) 
• 
CT, PET-CT or head and neck nuclear magnetic resonance (NMR) 
• 
Chest X-ray 
• 
Bone scintigraphy and a bone radiology directed only in cases where bone 
metastasis is suspected 
• 
Ultrasonography or CT scan/PET-CT scan in the case of suspected liver 
metastases and/or relevant abnormalities of liver function. 
Laboratory analysis (2 
weeks before inclusion) 
• 
Haematology: haemoglobin, white blood cell count, absolute neutrophil 
count, and platelet count 
• 
Biochemistry: alanine aminotransferase [SGOT], aspartate aminotransferase 
[SGPT], lactate dehydrogenase [LDH], total protein, serum creatinine, urea, 
alkaline phosphatase, total bilirubin, albumin, and electrolytes-sodium, 
potassium, calcium, and magnesium- 
• 
Creatinine clearance, optional or if creatinine > 120 µmol/L (1.4 mg/dL) 
• 
Pregnancy test, if applicable 
Cardiovascular tests 
• 
Electrocardiogram (ECG) 
Adverse events 
• 
On all visits and according to what is specified in section 9.A.1  
Concomitant medication 
• 
On all visits and according to what is specified in section 9.A.1  
Survival and other 
antineoplastic treatments 
• 
With the same frequency as post-treatment visits 
8.B.1  
Valuations to be made during the study 
8.B.1.1 
Informed consent of the patient 
Patients must sign an informed consent before undergoing any specific protocol 
evaluation and before receiving treatment (induction chemotherapy with TPF) 
(Appendix 1). 
8.B.1.2 
Demographic data  
Demographic data should include the assigned patient number, date of birth, gender and 
ethnic origin, which will only be recorded at the baseline visit. 
8.B.1.3 
Clinic history   
The clinical history should include the date of diagnosis, the main diagnosis including 
the histological or pathological documentation of the neoplasm, other pathologies and 
the related treatments when these have been administered in the 14 days prior to the 
start of the assigned treatment. 
The clinical history will only be collected at the baseline visit. 

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8.B.1.4 
Inclusion and exclusion criteria  
To be included in the study, patients must meet all the inclusion criteria and none of 
exclusion (section 6.A). 
8.B.1.5 
Physical exploration  
The full physical examination includes height, weight, BMI, body surface area (BSA) 
and a complete evaluation of the cardiovascular, respiratory, nervous, gastrointestinal, 
hepatic, renal, and cardiovascular systems and equipment. Dermatological and 
musculoskeletal, extremities and a complete and detailed physical examination of the 
head and neck area. 
A complete physical examination will be performed at the baseline visit, at each visit 
before the administration of TPF-type chemotherapy, at each response assessment visit 
and at the post-progression visit except for the BSA, which will not be necessary to 
calculate the post-progression visit. Height will only be recorded at the baseline visit. 
8.B.1.6 
Vital signs 
Vital signs include heart rate (after 5 minutes at rest), blood pressure (systolic and 
diastolic, after 5 minutes at rest) and temperature (measured using the same method in 
the same patient). 
The vital signs will be monitored and recorded before, during, immediately after and 1 
hour after the administration of the first infusion of cetuximab. The following weekly 
visits should not be documented in the CRF unless the results are anomalous and are 
reported as an AE. 
8.B.1.7 
Dental evaluation 
It is advisable to carry out an extraction of the pieces seriously damaged before the 
therapy, trying to preserve or restore them when possible. At least a period of 10 days 
should be allowed for the healing of the gums after extraction. 
8.B.1.8 
Functional status according to the ECOG scale 
Functional status will be assessed using the ECOG scale at the baseline visit, at each 
visit and at the end of the study visit. 
8.B.1.9 
Clinical evaluation of the tumour 
The measurement of the tumour will be made through a complete physical examination 
of the oral cavity, pharynx and the cervical and supraclavicular ganglionic areas that 
will include physical measurements of the affected tumour areas, emphasizing the 
following characteristics: 
• Lesion location, size and mobility. 
• Presence of trismus or decreased mobility of the tongue. 
• Alteration of functionalism of cranial nerves V, VII, IX, X, XI and XII. 
• Number, location, size and characteristics of cervical adenopathies. 

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It is advisable to perform a panendoscopy under general anaesthesia, which allows a 
better evaluation and localization of the structures invaded by the tumour, performing 
the necessary biopsies in the correct location and ruling out the presence of second 
primary tumours. It includes therefore the evaluation of the nasopharynx, the 
oropharynx, the oral cavity, the larynx, the hypopharynx and the oesophagus. 
When this is not possible or is not considered necessary, an indirect laryngoscopy with 
an evaluation of the oropharynx, hypopharynx and larynx with the necessary biopsies 
will be accepted. 
The location and size of the primary tumour and lymph node involvement should be 
identified in representative diagrams. 
In case of skin lesions of ≥ 20 mm, clinical evaluation will be carried out by means of a 
calibrator and photographs will be taken. 
All determinations will be recorded in the metric system. 
8.B.1.10 
Evaluation by tumour image  
A computed tomography (CT) or MRI of the head and neck will be performed, allowing 
a complete study of the locoregional tumour disease and the evaluation of more 
complicated areas such as the base of the skull, the base of the tongue, the 
parapharyngeal space, the mandible and the structures cervical vessels. These baseline 
and subsequent radiological studies should be performed using identical techniques 
(type and volume of contrast, times, cuts, apparatus, etc.) to ensure the comparability of 
the images obtained and to evaluate the efficacy correctly. 
If the patient has a PET-CT scan of the head and neck, if the CT scan performed on the 
hybrid equipment (PET-CT) is low dose, it is not useful for the morphological 
measurements required by the RECIST 1.0. However, if CT is performed with contrast, 
intravenous and oral, and with adequate parameters to be of diagnostic quality, then 
PET-CT can be used in the baseline assessment and to assess response to treatment. 
A baseline chest radiograph will be performed and every 12 months thereafter, but it 
will not be necessary to perform this radiograph if the patient has a chest CT or PET-CT 
within the stipulated times for the chest radiograph. 
Only in cases where bone metastasis is suspected, a bone scan and a directed bone 
radiology, or a PET-CT, will be requested; and an abdominal ultrasound or CT 
scan/PET-CT scan in the case of suspected liver metastases and/or significant liver 
function abnormalities. 
8.B.1.11 
Safety laboratory evaluations 
Sites will have to provide a list of the normal ranges to the study promoter and the 
CRO, who should be informed of all changes in normal values that are made during the 
study. 
At the baseline visit a haematological study should be performed, which will include 
the determination of leukocytes, neutrophils, platelets, haemoglobin; and a biochemical 

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study that will include sodium, potassium, calcium, magnesium, LDH, SGOT, SGPT, 
alkaline phosphatase, total bilirubin, total proteins, albumin, creatinine and urea. 
If the creatinine values are > 120 µmol/L (1.4 mg/dL), a creatinine clearance will be 
requested. With lower values, it is optional. 
Serum pregnancy test (only in women with the possibility of pregnancy). All patients 
(men and women) must use medically accepted methods of contraception throughout 
the study and up to 6 months after the end of treatment. 
8.B.1.12 
Cardiac tests 
An electrocardiogram will be performed in the 21 days prior to the start of treatment. 
8.B.1.13 
Assignment of the stage and resectability 
With the information from sections 8.B.1.9 and 8.B.1.10 the tumour will be classified 
according to the Tumour-Ganglion-Metastasis (TGM) and a stage will be assigned 
according to the criteria of the American Joint Commission for Cancer (AJCC) 6th 
edition. 
It will be recorded in all cases if the lymph node disease is unresectable or 
unresectable (in the evaluation of the Committees of each Site); with the objective of 
facilitating the decision to perform the rescue cervical evacuation adequate for each 
case, in the event of persistence of adenopathies at 6-8 weeks after completing RT (see 
section 7.A.5). 
The criterion of surgically unresectable disease will be defined in the different 
Interdisciplinary Committees of the Head and Neck of the Institutions participating in 
the study. The tumour should be considered inoperable according to the criteria of the 
Northern California Oncology Group [5] after evaluation by a multidisciplinary team, 
which will include, at least, a specialist in oncological surgery of the O.R.L. or maxillo-
facial surgery (as appropriate), a specialist in Medical Oncology and a specialist in 
Radiation Oncology. The reason for inoperability will be noted in the CRF. 
NCOG inoperability criteria: 
1. Technically nonresectable (Includes: Evidence of mediastinal dissemination; 
tumour fixed to the clavicle, base of the cranium or cervical vertebrae; 
involvement of the nasopharynx). 
2. Medical criteria based on a low surgical curability. 
3. Medical contraindication for surgery. 
In cases considered unresectable due to the characteristics of the primary tumour, a 
ganglionic surgical rescue will be offered in the case of complete response of the 
primary tumour to treatment with persistent cervical disease. 
In cases considered unresectable due to the characteristics of both the primary tumour 
and cervical disease, a ganglionic surgical rescue will be offered in the case of complete 
response of the primary tumour to treatment with persistent cervical disease. 

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In cases considered unresectable due to the characteristics of the cervical disease, being 
the primary tumour resectable, a ganglionic surgical rescue will be offered in the case of 
complete response of the primary tumour to treatment with persistent cervical disease. 
8.B.2  
Response evaluation 
8.B.2.1  
Response evaluation after 3 cycles of TPF 
The assessment of the response to neoadjuvant treatment with the TPF will be made 2-3 
weeks after the start of the 3rd cycle of TPF. 
The assessment of the response will be based on an integrated evaluation of the 
multidisciplinary treatment team that will include: 
- 
A clinical evaluation of the tumour (see section 8.B.1.9) 
- 
An evaluation of the tumour by imaging techniques (see section 8.B.1.10) 
If the investigator suspects a progression of the disease, a clinical and imaging 
assessment should be done before the dates indicated. 
In cases where CT, PET-CT or MRI scans are not indicated for medical reasons and 
there is clear evidence of disease progression on chest radiography, optical techniques 
and/or physical examination (ie, in exceptional circumstances), documentation of 
progressive disease can be based only on chest radiography, optical techniques and/or 
physical examination. 
In case of progression of the disease, the visit after progression (VAP) visit will be 
carried out and the patient will be removed from the study. The investigator will be able 
to decide which is the most appropriate treatment strategy for the patient. 
8.B.2.2  
Response evaluation at the end of treatment (same for both arms of 
radical treatment) 
The evaluation of the response after 3 cycles of neoadjuvant treatment with the TPF 
regimen followed by concomitant RT with cisplatin or cetuximab will be carried out 6-8 
weeks post-radiotherapy. 
This assessment will be based on the integrated evaluation of the multidisciplinary 
treatment team that will include: 
- 
A clinical evaluation of the tumour (see section 8.B.1.9) 
- 
An evaluation of the tumour by imaging techniques (see section 8.B.1.10) 
From this moment, the patient will enter the follow-up phase (see section 8.C.6). 
8.B.2.3  
Response evaluation criteria 
Response will be evaluated using the modified RECIST 1.0 criteria. These criteria 
includes confirmation of tumour response in a second observation performed at least 4 
weeks after the initial assessment. In this specific trial, the responses (CR or partial 
response [PR]) observed after the third and last cycle of TPF will not be re-evaluated 4 

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weeks after assessment of the initial response, since RT begin as soon as possible after 
the end of the neoadjuvant treatment. 
The lesions will be assessed based on physical examination of the tumour and in the 
images obtained using CAT, PET-CT* or MRI scan. The same method and evaluation 
technique will be used to characterise each of the lesions identified and reported in the 
baseline period and during the study. 
* "If the CT is performed with contrast, intravenous and oral, and with the appropriate 
parameters to be of diagnostic quality". 
Lesions will be assessed at baseline and 2-3 weeks after administration of the 3rd cycle 
of TPF, at 6-8 weeks post-RT, and in the first 6 months in the first, the second, second 
and fourth year and every 12 months thereafter. If the investigator suspects disease 
progression, the disease will be assessed using both clinical and imaging techniques 
before the indicated dates. 
If a CT, PET-CT MRI scan are not indicated for medical reasons and there is clear 
evidence of disease progression on chest X-ray, optical techniques and/or physical 
examination (in other words, in exceptional circumstances), disease progression 
documentation may be based on chest X-ray, optical techniques and/or physical 
examination. 
An assessment of the disease will be carried out on the VAP visit if there is no 
documented disease progression by imaging techniques, in prior assessments. 
Local radiologists assessed the plates of the CAT scan, PET-CT or the MRI according 
to the modified RECIST 1.0 criteria. The outcome of the assessments will be carefully 
documented in the CRF and tumour progression was assessed and documented as 
described as follows: 
Definitions 
To assess the objective response, the tumour mass at the baseline visit will be estimated, 
to be compared with subsequent assessments. Tumour lesions will be classified at the 
baseline visit as follows: 
 Measurable: the lesion can be accurately measured in at least one dimension 
(the greater diameter should be measured) such as ≥ 20 mm using conventional 
techniques or as ≥ 10mm using conventional MRI or CT scan. 
 Non-measurable: the other lesions, including small lesions (longest diameter < 
20 mm using conventional techniques or < 10 mm using conventional 
MRI/spiral CT scan/PET-CT) and truly non-measurable lesions. The lesions 
considered truly non-measurable include the following: bone lesions, 
leptomeningeal disease, ascites, pleural/skin/lung/skin or abdominal masses that 
have not been confirmed or followed by imaging techniques, cystic lesions, 
pericardial effusion, inflammatory disease in the breast, and lymphangitis. 
Tumours located in pre-irradiated tumours areas are not be considered 
measurable either. 

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All the baseline assessments will be performed as close as possible to the start of 
treatment (≤ 35 days before the start of treatment).  
Lesions will be assessed based on images obtained using CAT, PET-CT or MRI. The 
same method and the same assessment technique have to be used to characterise the 
lesions identified at the baseline visit and subsequent visits. All measurements will be 
recorded using the metric system and using rulers or calibrators. 
Baseline evaluation 
All measurable lesions must be identified, up to a maximum of 10 lesions in total, as 
recorded and measured target lesions at the baseline visit. The target lesions will be 
selected for their size (lesions with the largest diameter) and suitability for repeatedly 
conducting precise measurements. These lesions have to be assigned numbers in the 
CRF that could not be changed for every patient throughout the study. The sum of all 
the largest diameters of all the target lesions will be calculated, recorded as the sum of 
largest diameters at the baseline visit. This sum of larger diameters will be used as a 
reference, used to characterise the tumour's objective responses, while progression is 
diagnosed based on the smallest sum of the smallest of the largest diameters taken 
during the study treatment. 
The rest of the lesions will be identified as non-target lesions and will also be recorded 
at the baseline visit. It is not necessary to measure these lesions, but their status will be 
monitored throughout the study. 
Evaluation of response at consecutive visits 
The overall response will be defined according to the assessment of target and non-
target lesions, also taking into account the appearance of new lesions. The definitions 
are: 
Evaluation of the target lesions: 
Complete response (CR): 
Disappearance of all target lesions 
Partial response (PR): 
Reduction of at least 30% in the sum of the largest diameter of all target 
lesions, using the sum of larger diameters at the baseline visit as a 
reference. 
Stable disease (SD): 
There is neither sufficient reduction to classify it as PR nor sufficient 
increase to classify it as DP; in other words, a decrease in the sum of the 
greatest diameter of all target lesions less than 30%, taking the baseline 
measurement as the reference or an increase of this diameter by less than 
20%, using the smallest sum of larger diameters after the start of 
treatment as the reference. 
Disease progression (DP) 
An increase of 20% or more of the sum of the largest diameter of all 
target lesions, using the smallest sum of larger diameters since the 
treatment started as the reference. 
Evaluation of non-target lesions: 
Complete response (CR): 
Disappearance of all non-target lesions 
Incomplete response (IR) 
/stable disease (SD) 
Persistence of one or more non-target lesions 
Disease progression (DP) 
Appearance of one or more new lesions and/or unequivocal progression 
of existing non-target lesions (although a clear progression of non-target 

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lesions is exceptional, in these circumstances, the physician's opinion 
must prevail). 
Patients with a global deterioration in their health that require discontinuation of 
treatment without objective evidence of disease progression at that time will be 
classified as "symptomatic deterioration". Every effort have to be made to document 
progression even after discontinuing treatment. 
The overall response will be obtained from the values taken from the target and non-
target lesions, and taking into account the appearance or lack thereof of new lesions. 
Table 8.2 shows all overall responses of potential combinations of tumour responses. 
The overall response assessments will be carried out on each visit in which a response 
evaluation is scheduled. 
Table 8.2 Assessment of overall response 
Target lesions: 
Non-target lesions. 
New lesions 
Overall response 
CR 
CR 
No 
CR 
CR 
IR/SD1 
No 
PR 
PR 
No-DP 
No 
PR 
SD 
No-DP 
No 
SD 
DP 
Any 
Yes or no 
DP 
Any 
DP 
Yes or no 
DP 
Any 
Any 
Yes 
DP 
 
Notification of results 
The investigator will check the response to the treatment in all the patients included in 
the study according to the screening visit's findings. All patients will be classified into 
one of the following groups: 
- 
Complete Response 
- 
Partial Response 
- 
Stable disease 
- 
Disease progression 
- 
Death from cancer 
- 
Early death due to toxicity 
- 
Early death due to another cause 
- 
Unknown (not assessable, data insufficient) 
Patients who die before any of the post-treatment assessments of response may be 
conducted will be considered “premature deaths”. For the response analysis, they will 
be considered to have had a “progressive disease”. 
Patients who have experienced symptomatic deterioration without objective evidence of 
progression will be classified within the “progressive disease” group. 
8.B.3 
Quality of life assessment 
The importance of evaluating the QoL in head and neck cancer, which can affect some 
of the most basic functions of life, is recognized. In the study of EORTC-24971 [53] the 

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TPF administration was shown to improve the QoL in relation to patients who had 
received FP. In this study, it is expected that the experimental arm (RT plus cetuximab) 
is superior to the control arm (RT plus cisplatin) in the reduction of acute and chronic 
adverse effects. 
For this comparative study, the QoL questionnaires of the EORTC have been chosen. 
The questionnaire QLQ-C30 version 3.0 [69] is a basic questionnaire of 30 items. The 
module QLQ-H & N35 [70], consisting of 35 items, will also be used, with the 
authorization of Kristin Bjordal. 
These questionnaires will be self-completed by the patients when they will be in the 
site. They will have to complete them before starting TPF induction chemotherapy, after 
3 cycles of TPF, just before the patient know the radical treatment arm to which they 
have been assigned, and then 6-8 weeks after completion of RT and every 6 months 
during the follow-up visits for the first and second year. If the time for completing the 
questionnaire coincide with an assessment of the tumour, the patient will fill it in before 
knowing the results of the tumour study. 
The reasons for the selection of the indicated time points are as follows: 
- 
Before induction chemotherapy: to find out the patient's baseline condition. 
- 
After 3 cycles of induction chemotherapy: to determine the changes after 
chemotherapy and just before randomisation. 
- 
6-8 weeks after finishing RT: To determine the patient's condition in light of 
recent RT and at the time the first tumour response assessment is conducted. 
- 
At 6, 12, 18 and 24 months after RT, to allow the patient to have recovered 
from the RT toxicity. 
The QoL questionnaires will be completed before the patient know the results of the 
tumour study. The patient have to complete the questionnaires themselves, in their own 
language, at the site.  
8.B.3.1.   
Quality of life dimensions 
For the QLQ-C30, 15 scales are taken from the 30 initial items: 5 functional scales 
(physical, role played, emotional, cognitive and social function), 3 symptoms scales 
(fatigue, nausea and vomiting, pain), 6 individual symptom scales (dyspnoea, insomnia, 
loss of appetite, constipation, diarrhoea and financial difficulties) and 1 overall 
health/QoL status scale. 
18 scales of the 35 initial items are taken for the QLQ-H&N35: 7 multi-item symptoms 
scales (pain, swallowing, feeling, speech, eating from a social perspective, social 
interactions and sexuality) and 11 individual symptom scales (condition of teeth, mouth 
opening, salivation, cough, sensation of illness, use of analgesic medication, nutritional 
supplements, feeding tubes, weight loss and weight gain). 
The scores for all scales are calculated according to the procedures defined in the 
EORTC Scoring Manual, ranging from 0 to 100 following linear transformation (72). 
The highest scores on the functional and overall health/QoL status scales indicate a high 
level of functioning and a better QoL, respectively, while higher scores on symptom 
scales represent a higher level of symptoms. 

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8.B.4 
TPF administration 
TPF (docetaxel, cisplatin, 5-FU) should be administered under the supervision of the 
investigator, as described in section 7.A.1. 
The date of TPF administration should be reflected in the CRF. 
8.B.5 
Administration of cisplatin concomitant with radiotherapy 
Cisplatin should be administered under the supervision of the investigator, as described 
in section 7.A.2. 
The date of cisplatin administration should be reflected in the CRF. 
8.B.6  
Administration of cetuximab concomitant with radiotherapy 
Cetuximab should be administered under the supervision of the investigator as 
described in section 7.A.3 in an area where resuscitation equipment and other drugs are 
available (adrenaline, prednisolone equivalents, etc.) 
Cetuximab will be administered from one week before starting the RT program until the 
week of its termination, or if before a progression of the disease, an unacceptable 
toxicity or withdrawal of consent by the patient is observed. 
In the CRF should be reflected the date of administration of cetuximab, the time of start 
and end of all infusions. 
8.B.7 
Adverse events 
An assessment of toxicity and/or AEs should be made at each visit. 
All AEs must be reported in the manner described in section 9.A.1 . 
All AEs related to treatment, both with induction chemotherapy (TPF) and with RT plus 
cisplatin or RT plus cetuximab, should be classified according to the following criteria: 
1. NCI CTC, version 3.0 during the induction treatment (Appendix 3) 
2. NCI common toxicity criteria (CTC), version 3.0 (Appendix 3) and CTC of the 
RTOG during Chemotherapy/RT or Cetuximab/RT and 90 days after completion 
of the RT (Appendix 4). In case of doubt, the criteria that assessed the AE to be 
the highest grade were used. 
3. Late CTC from the RTOG/EORTC from 90 days after completion of RT, which 
were basically used to gather chronic toxicity associated with radio-
chemotherapy (Appendix 5) 
Special precautions must be taken with: 
Allergic reactions 
During or after infusion with cetuximab and/or docetaxel allergic reactions may occur. 
It is therefore recommended to pre-treat patients with an adequate antihistamine (it is 

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mandatory at the visit of the first infusion). As a routine precaution, the patients 
included in this study will remain under close observation for possible AE, from the 
start of the infusion until one hour after the infusion is finished, in an area with 
resuscitation equipment and emergency agents (adrenaline, prednisone equivalents, 
etc.). 
In the event of an allergic reaction or reaction to infusion with cetuximab and/or 
docetaxel, the patient should be treated with the best available means (see section 
7.A.1.4.1). The patient should be instructed to notify the investigator immediately of 
any delayed reaction. 
Interstitial pneumonitis 
In the recent literature, severe acute interstitial pneumonitis has been described in 
patients treated with another agent against EGFR, gefitinib. In case a patient in this 
study develops a severe pulmonary toxicity that manifests with dyspnoea and/or 
hypoxia, it is advisable to consult an appropriate specialist (pulmonologist). In addition, 
the promoter must be notified through the Serious Adverse Event Alert Report Form 
(ARF) in order to make a timely decision on the case. Tests that are considered 
medically appropriate, such as a high-resolution chest CT, should be performed. If the 
result of these tests indicates interstitial disease, more tests should be seriously 
considered, if not contraindicated by the patient's condition. These tests are 
bronchoscopy with transbronchial biopsy for pathological anatomy and cultures and, if 
the bronchoscopic studies are negative, lung biopsy for pathological anatomy (for 
evidence of malignancy or infection). Patients with any severe toxicity (grade 3 or 4), 
including pulmonary toxicity, should not be re-treated with cetuximab until the severe 
toxicity is resolved. 
8.B.8 
Concomitant medication 
The concomitant medication, dosage, route of administration, start date and duration of 
all treatments should be reflected in the CRF. After the post-progression visit, only the 
subsequent treatment lines for head and neck cancer will be collected. 
8.B.9 
Survival status 
When a death occurs due to an unknown cause, the principal investigator/promoter 
recommends carrying out an autopsy in order to adequately document the cause of the 
death. 
8.C Conduct of the study 
The schedule of visits, procedures and evaluations required is described in the study 
schedule (see Appendix 2). It may be necessary to study other parameters and/or 
increase the frequency of the examinations depending on the findings discovered during 
the study. 
The methodology of the studies and activities is described in section 8.B. 

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For safety and efficacy reasons, the investigator have to comply with the schedule as 
closely as possible. 
8.C.1 
Screening/baseline visit 
The baseline visit have to be performed within 21 days prior to the scheduled start date 
of TPF induction chemotherapy treatment.  
Patients have to sign the informed consent form before carrying out the specific 
assessments of the protocol and before receiving treatment (see Appendix 2). 
The following assessments prior to treatment will be performed in the three weeks prior 
to study entry except the β-HCG pregnancy test, which will be carried out within seven 
days prior to inclusion of the patient in the study. 
The following assessments prior to treatment will be performed in the previous 3 weeks: 
• Informed consent (consent to participate in the study). 
• Diagnosis of the primary tumour. 
• Inclusion and exclusion criteria. 
• Demographic data. 
• Medical history. 
• Physical examination including weight, height, BMI and BSA. 
• Dental examination. 
• ECOG-PS Performance Status. 
• Assessment of the tumour through a complete physical examination and a direct 
visual examination, preferably via panendoscopy or direct laryngoscopy, 
(previous 28 days). A diagram of the lesions and lymph nodes will be made.  
• Radiological examinations using a CAT, a PET-CT scan or MRI scan of the 
head and neck. A chest X-ray will also be performed, which may not be 
performed if there is a chest CAT/PET-CT scan. It is accepted up to 35 days 
prior to the planned start date of treatment.  
• Definitive assignment of the stage, with description of the primary tumour and 
whether or not lymph node involvement is resectable from entry. 
• An electrocardiogram. 
• Bone scan if the alkaline phosphatase ≥ 1.5 x UNL or clinical suspicion of bone 
metastases. 
• Blood draw for haematology study, clinical chemistry. The determination of β-
hCG should be performed within 7 days prior to the inclusion of a patient of 
childbearing age in the study.  
• QoL questionnaires (QLQ-C30 and QLQ-H&N35). 
• Concomitant medication 
• Patient recruitment form. 
Based on the findings, the investigator will include patients in the study, sending an 
inclusion sheet by fax to the CRO/study coordinator. 

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8.C.2 
Evaluation visits during neoadjuvant treatment with TPF  
Visits will be made every 3 weeks during treatment with TPF, which will coincide on 
the day of the next cycle of TPF: 
• Collection of blood samples for the complete laboratory safety, haematology and 
clinical chemistry analyses every 3 weeks, coinciding with the administration of 
chemotherapy. The extraction may occur in the previous 48 hours, but the 
results will have to be available before administration of chemotherapy. 
• Physical examination including weight (this will be determined every week 
during full treatment, at the investigator's discretion), performance status based 
on ECOG - PS and calculation of BSA every 3 weeks, coinciding with the 
administration of chemotherapy. 
• Clinical assessment of the tumour to rule out progression during treatment with 
TPF. If progression is suspected, radiological assessment will be brought 
forward using CAT, PET-CT or MRI scan to document progression.  
• Documentation of AEs and concomitant treatments (weekly). 
8.C.3 
Response assessment visit after neoadjuvant treatment with TPF 
The following assessments and procedures will be performed 2-3 weeks after the 
administration of the 3rd cycle of TPF: 
• Physical examination, weight and BSA. 
• ECOG-PS performance status assessment. 
• Clinical assessment of the tumour, including direct and/or indirect optical exams 
of the tumour as considered necessary, as well as a biopsy of suspicious areas if 
that would be accurate.  
• Radiological studies using a CAT, a PET-CT or MRI scan (always the same 
technique) of the head and neck 2-3 weeks after the administration of the 3rd 
cycle of TPF. 
• Complete laboratory tests with blood count and biochemistry 
• QoL questionnaires (QLQ-C30 and QLQ-H&N35). 
• Documentation of AEs and concomitant treatments. 
When treatment will be discontinued for reasons other than disease progression, efforts 
will be made to carry out a response assessment before starting an alternative treatment 
For example, if a patient can only receive 2 cycles of TPF, the response will be assessed 
to decide whether they can be randomised. 
PATIENT RANDOMISATION: 
All patients will receive 3 cycles of induction chemotherapy with the TPF regimen. 
Treatment will be organised according to the evaluation of the response to TPF 
chemotherapy: 
1.- Patients who progressed with the treatment with TPF will be excluded from the 
study and will be treated according to each Site’s protocol. 

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2.- Patients with a response or stabilisation when treated with TPF but with toxicity 
that contraindicated the continuation of treatment with cisplatin will be excluded 
from the study and will continue treatment according to each site’s protocol and 
according to international guidelines. These patients will then analysed as a 
population with intention-to-treat (ITT). 
3.- Patients who are unable to receive at least two cycles of induction will be 
excluded from the study and will be treated according to each site’s protocol and 
in accordance with international guidelines. 
4.- Patients who respond to or are stabilised with TPF and who have not shown 
toxicity that prevented the continuation of treatment with cisplatin, will be 
randomised to receive normofractionated RT plus cisplatin (Group A - standard) 
versus the combination of cetuximab and normofractionated RT (Group B - 
experimental). 
STRATIFICATION: to ensure a homogeneous distribution, patients will be stratified 
according to: 
- 
Tumour location (oral cavity, versus oropharynx versus larynx versus 
hypopharynx). 
8.C.4 
Evaluation visits during radical treatment (concomitant radiotherapy with 
cisplatin [Arm A] or cetuximab [arm B]) 
Weekly visits will be conducted during concomitant treatment in the same way in both 
treatment arms. 
8.C.4.1. Concomitant radiotherapy with cisplatin 
• Physical examination, performance status based on ECOG–PS and weight. 
• Complete blood count and clinical chemistry profile (sodium, potassium, 
magnesium, calcium, LDH, SGOT, SGPT, alkaline phosphatase, total bilirubin, 
total proteins, albumin, creatinine and urea). This will be performed just before 
starting combined treatment and coinciding with each administration of 
cisplatin. A blood test will be repeated at 3 weeks after the last cisplatin dose 
and only if a grade 3/4 analytical alteration persists until it has resolved, or at the 
investigator's discretion. In addition, a blood count will be performed every 15 
days. 
• Documentation of AEs and concomitant treatments. 
8.C.4.2.  
Concomitant radiotherapy with cetuximab 
It will coincide with the day cetuximab is administered:  
• Administration of cetuximab 
• Physical examination, performance status based on ECOG–PS and weight. 
• Complete blood count and clinical chemistry profile (sodium, potassium, 
magnesium, calcium, LDH, SGOT, SGPT, alkaline phosphatase, total bilirubin, 
total proteins, albumin, creatinine and urea). It will be performed just before the 

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start of the combined treatment and every 3 weeks. The latest blood test will be 
performed when RT has been completed and subsequently, and only in the event 
of a grade 3/4 analytical alteration until resolution, or at the investigator's 
discretion. In addition, a blood count will be performed every 15 days. 
• Documentation of AEs and concomitant treatments. 
8.C.5 
Evaluation visit during the first 8 weeks after completion of radiotherapy 
and definitive end of the radical treatment (identical for both treatment 
arms) 
Two assessments will be conducted, one at 4 weeks and another at 6-8 weeks after 
having completed RT.  
THE EVALUATION AT 4 WEEKS will consist of a complete physical examination 
including weight, performance status according to ECOG-PS, a haematological and 
clinical chemistry profile, a clinical assessment of the tumour (which included direct 
and/or indirect optical exams of the tumour, as considered necessary) and an evaluation 
of the AEs that may appear since the completion of the RT. Due to post-RT local 
inflammatory problems, a clinical assessment of the tumour may be impossible during 
this visit. 
THE EVALUATION AT 6-8 WEEKS will be the same as that at 4 weeks but with a 
CAT scan, a PET-CT scan or MRI of the head and neck to establish the definitive 
assessment of locoregional disease control; and, if necessary, with biopsy of suspected 
disease persistence areas, and assessment of the QoL test. 
In the assessment at 6-8 weeks the decision will be made concerning the necessity of 
performing a cervical lymph node dissection (see section 7.A.5). 
8.C.6 
Evaluation visits during the follow-up period 
Table 8.5 shows the tests and assessments that should be performed on all patients 
included in the study during the follow-up period starting from 6-8 weeks after 
completion of RT. 
Patients with toxicity associated with cisplatin or cetuximab will be adequately 
monitored until the toxicity is resolved. 
An abdominal ultrasound or CAT/PET-CT scan and/or a bone scan or a PET/CT scan is 
only considered if there is suspected metastases at these sites. 
The QoL questionnaires (QLQ-C30 and QLQ-H&N35) will be undertaken every 6 
months during the follow-up visits for the first and second year. 
 
Table 8.3 Evaluations during the follow-up period 
Regimen 
During 
years 1 and 2 
During 
years 3 and 4 
During year 5 
Clinical assessment of the 
tumour* 
Every 3 months 
Every 6 months 
Every 12 months 

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Physical examination with 
weight and ECOG 
performance status 
assessments 
Every 3 months 
Every 6 months 
Every 12 months 
Assessment of late 
radiotherapy toxicity 
Every 3 months 
Every 6 months 
Every 12 months 
Complete blood count and 
clinical biochemistry 
Every 3 months 
Every 6 months 
Every 12 months 
Tumour imaging methods** 
Every 6 months*** 
Every 6 months*** 
Every 12 
months*** 
Chest X-ray 
Every 12 months*** 
Every 12 months*** 
Every 12 
months*** 
* Will include direct and/or indirect optical exams of the tumour as deemed necessary, as well as a biopsy of suspicious areas if 
accurate 
** CAT, PET-CT or MRI of the head and neck (always the same technique). 
*** Or at the time of suspected progression and/or recurrence. 
When recurrence and/or progression at any level is significant, complete the study in 
order to be able to study the therapeutic failure pattern: locoregional and/or distant. 
With this follow-up, there is a complete tumour assessment of the disease at 12 
months after starting treatment (1st cycle of TPF), at 24 months, and at 36 months. 
Follow-up after 5 years will be performed according to the protocol for each site. 
8.C.7 
Visit after progression  
Patients will be required to attend a VAP visit once DP occurred. 
The following additional procedures and tests will be performed at this visit: 
• Physical examination. 
• ECOG performance status assessment. 
• Collection of blood samples for laboratory safety analyses (haematology and 
biochemistry). 
• Assessment on the need for lymph node dissection. 
• Documentation of the AEs and concomitant medication in accordance with that 
specified in section 9.A.1 . 
• A CAT, a PET-CT or MRI scan of the head and neck when the last took place 
more than 4 weeks ago, and have not shown recurrence and/or progression.  
• Clinical assessment of the tumour (which included direct and/or indirect eye 
exams of the tumour considered as necessary), when the latter have been 
performed more than 4 weeks ago, and have not shown recurrence and/or 
progression. 
• Chest X-ray when the last have been done over 4 weeks ago, and recurrence 
and/or progression have not been demonstrated. 
• Survival status. 

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8.C.8 
Follow-up visits following the visit after progression 
After the visit after progression, data will be collected on the subsequent therapy lines 
with the same frequency as the post-treatment visits. When hospital visits are not 
required, survival data may be obtained by phone. 

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9. 
Adverse events 
9.A Brief summary of adverse events and serious adverse events 
9.A.1  
Adverse events (AE)∗ 
An AE is defined as any unfavourable medical experience that affects a patient or a 
subject that participates in a clinical investigation to which a pharmaceutical product has 
been administered, and that does not necessarily have a causal relationship with this 
treatment. Therefore, an AE can be a sign (including an anomalous laboratory data, for 
example), symptom or unfavourable and unintended disease, associated chronologically 
with the use of a pharmaceutical specialty, whether or not it is related to the 
pharmaceutical specialty. 
Due to regulatory standards, events that occur before and after the treatment period 
should also be designated as AE. Therefore, safety surveillance (notification of AEs) 
begin when the patient is included in the study (date of signing the informed consent) 
and will continue until the evaluation visit after the RT treatment has been made in 
combination with cisplatin or cetuximab. 
After 90 days post-treatment of RT in combination with cisplatin or cetuximab, only 
data on chronic toxicity associated with radio-chemotherapy will be collected and 
following the Common Criteria for Late Toxicity of the RTOG/EORTC (Appendix 5). 
This procedure complies with the requirements of the authorities and the request of the 
insurance companies of the patients. 
9.A.2 
Adverse events or serious adverse events (SAE)* 
SAEs (experiences) or severe reactions are any unfavourable medical experience that 
occurs during any phase of the study (from the inclusion of the patient to the evaluation 
visit after RT treatment in combination with cisplatin or cetuximab), at any dose of the 
product in investigation, and that it meets one or more of the following criteria: 
• Produces the death of the subject, 
• Threatens life, 
NOTE: The term "life threatening" in the definition of "serious" refers to an event in which the 
patient was at risk of death at the time of the event; it does not refer to an event that hypothetically 
could have caused death had it been more severe. 
• Requires the hospitalization of the patient or the extension of an existing income, 
• Result in a persistent or significant disability/disability 
• It is a birth defect or congenital anomaly in the offspring of the patient 
• It is an important medical event 
The medical and scientific criteria will be used to decide whether immediate notification 
is appropriate in each situation, such as important medical events that may not be 
                                                 
∗Management of clinical safety data: "Definitions and Standards for Expedited Reporting - ICH 
Topic E 2ª, 1995 

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immediately life threatening or result in death or hospitalization but may endanger the 
patient or require intervention for prevent any of the consequences mentioned in the 
previous definitions. These situations or in case of doubt will usually be considered 
serious. 
Examples of such events include intensive treatment in an emergency department or at 
home because of allergic bronchospasm; blood dyscrasias or seizures that do not 
involve hospitalization; appearance of drug dependence or drug addiction; or presence 
of malignant tumours that are anatomopathologically different from the primary tumour. 
Other events considered as SAE 
Overdose should always be considered and treated as a SAE. 
Pregnancy and breastfeeding are criteria for exclusion. In case pregnancy occurs during 
the course of the study, the patient should be withdrawn from the treatment under study 
immediately. The Promoter must be notified immediately and the patient will be 
observed throughout the pregnancy and the post-partum period. All the data of the 
mother and the new-born must be recorded, even if they are completely normal and do 
not present any adverse event. The ARF form must be used, although pregnancy is not 
considered a SAE. No "severity criteria" box should be checked. ARF is only used to 
guarantee immediate communication. 
9.A.3 
Events not considered as SAE 
The progression of the disease is not considered a SAE. Due to the seriousness of the 
disease under study, certain situations will be considered as SAEs excluded from 
immediate notification: 
• Elective hospitalization and surgery for the treatment of the disease, 
• Elective hospitalization to simplify treatment or study procedures 
• Hospitalization that is unequivocally due to disease progression 
9.B Methods of registration and evaluation of adverse events. 
All AEs must be documented in the corresponding section of the data collection 
notebook. In addition, all SAEs must be documented in the ARF (for an "initial" SAE or 
for "follow-up" information from a previous SAE). 
The following information will be recorded for each event in the CRF: 
• A description of the AE in medical terms, not as the patient refers; 
• The start date; 
• The date of recovery (end date); 
• The degree/severity according to investigator’s assessment according to the 
definitions of the following criteria: 
1. National Cancer Institute (NCI) CTC, version 3.0 during the induction 
treatment (Appendix 3) 
2. NCI CTC, version 3.0 (Appendix 3) and CTC of the Radiation Therapy 
Oncology Group (RTOG) during the treatment of QT/RT or Cetuximab/RT 

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and up to 90 days after the completion of radiation therapy (Appendix 4). 
In case of doubt, the criteria that assess the adverse event in the highest 
degree will be used. 
3. RTOG/EORTC Common Criteria for Late Toxicity from 90 days after the 
completion of RT, which will basically serve to collect the chronic toxicity 
associated with radio-chemotherapy (Appendix 5) 
• The causal relationship with the study medication according to the investigator; 
the most important factor in the documentation is the chronological relationship 
between the AE and the study medication. The following criteria should be used 
about the causal relationship of AE with the drug or study procedures: 
o Not related = there is no temporal relationship with the administration of 
the drug (too early, too late, or the study drug was not taken) or there is a 
reasonable causal relationship with another drug, breakthrough disease or 
other circumstance and the SAE. 
o Unlikely = there is a temporal relationship with the administration of the 
drug, but there is no reasonable causal relationship between the study drug 
and the SAE. 
o Possible = there is a reasonable causal relationship between the study drug 
and the SAE. There is no information about the interruption of the drug or 
it is not clear. 
o Probable = there is a reasonable causal relationship between the study drug 
and the SAE. The event responds to the interruption of the drug, it is not 
necessary to re-expose it. 
o Safe/Definitive = There is a reasonable causal relationship between the 
study drug and the SAE. The event responds to the interruption of the drug 
and reappears when it is re-exposed, if it is clinically feasible. 
• The action taken with the drug (none, interruption of the medication, reduction 
of the dose, delay of the medication, reduction of the speed of the infusion) 
• Other actions (none, concomitant medication administered new hospitalization 
or prolongation thereof, surgical intervention, etc.) 
• The result of the AE according to the following definitions: 
o Recovery with sequelae 
o Recovery without sequelae 
o Continue, without treatment 
o Continue, with treatment 
o Death 
o Change in the degree of toxicity 
• Gravity: yes or no 
If one of the patients experiences the same AE on several occasions, the AE in question 
must be documented and evaluated each time it occurs. 
9.C Procedure for reporting serious adverse events 
Any AE or abnormal value in laboratory parameters that is considered serious or 
medically significant occurred during the course of the study or during the post-
treatment period, regardless of the treatment received by the patient, should be 
immediately reported by the investigator by telephone or fax. The names, addresses and 
telephone and fax numbers are listed in the ARF. 

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After a phone notification, the information must be sent in writing by fax or mail. To 
make the written notification, the ARF must be used (for an "initial" SAE or for 
"follow-up" information from a previous SAE). 
As a general rule, the investigator must document and medically assess the AE, and 
describe its evolution, in the ARF as well as in the AE section of the CRF. When 
necessary, the ARF sent by fax must be accompanied by some relevant pages of the 
CRF, for example, clinical history, AEs and concomitant medication. 
The promoter and/or study coordinator may request additional information, if necessary, 
to ensure that the initial notification of SAE is made to the health authorities within the 
required times. For the follow-up report to the authorities, the sponsor and/or study 
coordinator may be asked to obtain more information in order to have a detailed 
description and a final evaluation of the case, including copies of hospital reports, 
autopsy reports and other relevant documents. 
If there is incomplete or inconsistent SAE information directly affecting the 
communication obligation of the promoter to the health authorities, the Corporate 
Pharmacovigilance Group can contact the investigator directly to clarify it. 
 
Investigator must notify the Clinical Research Ethics Committee (CREC), if applicable, 
in accordance with international and local laws and regulations. 
9.D Monitoring of patients with adverse events 
The following (S)AE must be notified or followed up as specified in section 9.A.1 : 
• All new AEs must be registered in the CRF. 
• All new SAEs must be notified through the ARF. 
All AEs assessed as possible, probably or definitely related to the study medication, and 
which were still present at the time of the post-progression visit, should be followed (ie, 
these AEs should be evaluated until their final evolution in the first follow-up visit of 
survival). 
It is the responsibility of the promoter and the investigator to ensure that the necessary 
additional therapeutic measures are taken, and that appropriate follow-up is carried out. 
 

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10. 
Ethical aspects 
10.A General considerations 
10.A.1 Notification to the authorities 
The study protocol and any other applicable documentation (information for the patient, 
informed consent, etc.) will be presented to the health authorities in accordance with the 
regulations in force at the time of presenting the study. 
10.A.2 Ethics committee of clinical investigation 
Before commencing the study, the protocol and other documents (patient information 
sheet and informed consent form, investigator's brochure) will be submitted to the 
corresponding Independent Ethics Committee (IEC) with the aim of obtaining a 
favourable opinion/approval. The favourable opinion/approval will be filed in the 
investigator's file, with a copy being kept in the general study file. 
The study will only be started once the favourable report/approval have been obtained 
in writing. The sponsor will request the documentation relating to the date of the IEC 
meeting, the composition of the committee and the voting members present at the 
meeting. The sponsor also will require a written approval that clearly identified the 
clinical trial, the protocol version and the consent documents that will be reviewed. As 
far as possible, a copy of the minutes of the meeting will be obtained from the meeting 
in which the protocol was evaluated. 
Any amendment to the protocol will be submitted to the IECs; they will also be 
informed of SAEs, according to current legislation. 
10.B  Patient information and informed consent 
10.B.1 
Information for the patient 
An essential requirement for a patient's participation in the clinical trial is written 
informed consent. The investigator have to provide adequate patient information before 
obtaining his/her consent. Local legislation permitting, the investigator will be able to 
designate a person to provide the information. A patient information sheet will be 
provided in the local language according to Conference on Harmonisation (ICH) GCP 
standards (ICH Topic E6, 1995). In addition to the written information, the investigator 
will inform the patient verbally. Terms will be used such that the content will be 
completely legible and understandable for the layperson. The information sheet will be 
updated whenever important new information is available that may be relevant for 
patient consent. 

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10.B.2 Patient consent 
The patient have to give written informed consent to participate in the clinical study 
before any study-related procedure will be carried out (see Appendix 1). This consent 
form will be signed and dated personally by the patient and by the investigator or the 
person designated to explain and discuss the informed consent form with the patient.  
The investigator will confirm that the patient granted his/her consent in the CRF. The 
signed and dated informed consent form will remain at the site and will be kept by the 
investigator in a safe place so that it can be available at any time for monitoring, 
inspection or audit. The patient will be given a signed and dated copy of the patient 
information and informed consent form before being included in the study. 
Illiterate patients 
If the patient or his or her legal representative cannot read, an independent and reliable 
witness have to be present, that is say, a person not related to the site or to the study, 
throughout the discussion of the informed consent form. The choice of witness have to 
not affect the right to patient confidentiality. Family members and friends will be 
considered suitable independent witnesses. Once the patient or his or her legal 
representative have consented verbally and signed, if able, the witness signed and dated 
the consent form personally, thus attesting that the information is accurate and that the 
patient or his or her legal representative have fully understood the content of the 
agreement in the informed consent form and that consent will be actually granted. 
10.C 
Confidentiality 
See section 11.B.1. 
10.D 
Patient insurance 
The promoter will provide mandatory insurance coverage for all patients participating in 
the study from the time of their inclusion in the study (ie date of patient consent). The 
insurance coverage will comply with the legal requirements and GCP guidelines and in 
accordance with Spanish regulations. In the file of the investigator of each site, a 
certificate of the insurance policy must be kept together with the insurance conditions. 
 

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11. 
Practical considerations 
11.A Participants’ responsibilities 
11.A.1 Administrative structure of the study 
The study will be monitored through regular visits and telephone calls to the 
investigator. During visits to the site, the monitor should review the patients' original 
records, medication stock records, and document preservation. In addition, the monitor 
should evaluate the study procedures and discuss any problems with the investigator. 
During the course of the study, audits can be carried out in the participating sites. The 
investigator will allow direct access to the source data/documents for the tasks of 
monitoring, auditing, review of the CREC and inspection by the health authorities. 
11.A.2 Investigator's responsibilities 
The investigator will be responsible for ensuring that the study is being conducted in 
accordance with the protocol, the Declaration of Helsinki and in accordance with the 
Standards of GCP (CPMP/ICH/135/95) approved on July 17, 1996, as well as to the 
relevant legal requirements. These documents explain that informed consent of patients 
is an essential condition for participation in the clinical trial. 
11.A.3 Monitoring, quality assurance and inspections by the authorities 
This study will be conducted in accordance with the Standards of GCP 
(CPMP/ICH/135/95) dated July 17, 1996. The clinical monitor of the study will arrange 
visits with certain regularity in the sites of the study to verify the development of the 
same one. 
During monitoring visits, the monitors will: 
- Help solve any problem 
- Examine all the CRFs to check if there are data that have been omitted, as well as 
compliance with the protocol and possible AEs 
- Discuss the inconsistencies of the study data 
- Ensure that all study material is properly stored and is properly dispensed 
- Check the compliance of the investigator's obligations 
- Review the consents of the patients, in particular the date and the signature of the 
consent. 
- Complete the Verification of Original Data record as described below 
According to the International ICH guidelines on PCBs, monitoring will include 
verification of the data collected in the CRF against the original records of patients. This 
verification will be done through direct access to the patient's medical history. It is 
guaranteed that the patient's confidentiality will be respected at all times. Participation 
in the study will be interpreted as an acceptance to allow verification of the original 
data. 

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The promoter and/or principal investigator may decide to conduct audits to verify the 
validity of the study data. 
11.A.4 Modifications to the study protocol 
Changes in the study protocol should be made in the form of modifications to the 
written protocol. These will need the approval of all signatories on page 2 of the final 
version of the protocol. The signature of the modification of the study protocol by the 
principal investigator will be considered sufficient if it has authorization on behalf of 
the other investigators. 
Any amendment to the protocol that could affect the patient, for example, changes in 
procedures/evaluations or issues related to patient safety, will require a favourable 
report/approval of the CREC of each site, before its implementation. Purely 
administrative changes should be notified to the CREC, but do not require formal 
approval. Any amendment that affects patients requires an additional informed consent 
for each patient before its implementation. 
11.A.5 Study protocol deviations 
Deviations from the protocol are not allowed -especially the prescription of doses not 
programmed in the protocol-, other forms of administration, other indications or 
treatment periods longer than those established. 
11.B  Conditions for archiving and handling data 
11.B.1  
Handling of the Data Record Collection 
An electronic CRF (eCRF) will be created on-line in which investigators will record the 
integrity of the data directly through a web page. 
The eCRF will be developed based on a standard application: DCTrials 2.5. This is a 
web-based application and accessible via the Internet through browsers: Internet 
Explorer 5.0 or higher and Netscape 8.0 or higher. 
DCTrials 2.5 includes the functionalities module of the investigator and module of the 
monitor/study manager. 
A data management plan will be made before the start of the study. A validation of the 
functions of the eCRF application will be performed by entering simulated data prior to 
the start of the data entry process. 
11.B.1.1  
Data accessibility 
Access to the database will be restricted to the system administrator (design and data 
entry), to the Data Manager, who will be the investigators who will perform the data 
transcription (data entry) and the monitors (reading data and editing queries). Any entry 
in the database must be registered, identified and dated. Any modification of the data 
will be traceable (registered, identified, dated and the old value retained). 

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At user level: security is guaranteed by the application, which encrypts communications 
between the server and the user. 
11.B.1.2 
Security 
At user level: security is guaranteed by the application that encrypts communications 
between the server and the user. 
At server level: the current legislation in relation to the control and restriction of 
physical access to the data is applied. 
11.B.1.3  
Password Management 
It is guaranteed that the only person with access to a password is its owner: 
• Any password transmission is done through a secure environment. 
• At the beginning of the study, the user will be assigned a temporary password. 
When accessing the application for the first time, you will be obliged to modify 
this password and enter a password of 5 characters or more. 
• In case of loss of password, the user must inform the help desk service of the 
study and the latter will provide another temporary password that must be 
modified the first time he/she returns to access the application. 
This guarantees, at a technical level, the security of the access codes. 
11.B.1.4  
Data management 
The data will be entered by the same investigator, connecting to a portal that will give 
access to an on-line database, through a user and its corresponding exclusive password, 
to ensure the confidentiality and security of the data. 
In order to guarantee the confidentiality of the data of the patients participating in the 
study, only the investigator and his team of collaborators will have access to them, the 
representative of the promoter who will perform the monitoring tasks, the auditor in 
case the study was subject to an audit, the CREC and the Health Authorities. 
The content of the electronic records of data collection, as well as the documents 
generated during the study, will be protected against use by people outside the research, 
will be considered strictly confidential and will not be disclosed to third parties except 
those specified in the previous section. The treatment of the personal data required in 
this study is governed by the Organic Law 15/1999. 
Prior to the declaration of the definitive database, a verification of the consistency of the 
values of the inclusion/non-inclusion criteria, of the clinical evaluations, of the results 
of complementary explorations, of the dates of visit, of compliance, of concomitant 
medication, AEs, information about dropouts and evaluation of efficacy. A queries 
management will be carried out, to clarify the inconsistencies. 
The queries management allows the user to identify possible omissions or errors in the 
entered data. 

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The queries system requires the definition of the conditions of data entry and indicate 
the mandatory data. 
The application will identify on the data entry forms the fields that have some incidence 
and that the user must resolve. 
The user can consult the list of queries in their cases and directly access the data form to 
make the necessary corrections. 
Any subsequent change in the database will be done leaving a traceable record of it 
(Audit Trail). The Audit Trail (or audit of modifications) will record all operations 
performed on the database: 
• Connections (correct and incorrect) 
• Data query 
• High cases 
• Cases modifications 
• Etc... 
In addition, the user will be registered and the date and time in which a certain operation 
was performed. So that it is possible to fully monitor the evolution of the database. 
The Audit Trail will also incorporate a recovery system that allows restoring a previous 
state of the database eliminating all the modifications made from a certain date. 
The content of the eCRF database will be transferred to SAS data sets for statistical 
analysis. All statistical analyses will be performed using the statistical package SAS® 
system version 8.2 for Windows 2000 or later available. 
11.B.2 Original data and patient file 
The investigator must keep a file of each patient who participates in the study either on 
paper or electronically. In this patient file, the demographic and medical information 
available must be recorded, in particular the following information: name, date of birth, 
sex, height, weight, patient's history, concomitant diseases and concomitant medication 
(including changes during the study), report of inclusion in the study, identification of 
the study, date of informed consent, date of all study visits, explorations made and 
clinical findings, AEs observed (if applicable), and, if applicable, the reasons for the 
withdrawal of the study. With the data available in this file, it should be possible to 
verify the inclusion and exclusion criteria of the study. 
It should be possible to identify all the patients in the study using this file. 
In addition, any other document that contains original data, especially the reports 
generated by technical devices, must be archived. All these documents must have at 
least the identification of the patient and the date printed by the registration device, to 
indicate to which patient and to which study procedure that document belongs. 
The printed copies of the patient files that are computerized must be signed and dated 
by the investigator, endorsed by the monitor and stored in the patient's medical record as 
a source document. 

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The medical information relevant to the evaluation of efficacy and safety will be 
transcribed to the e-CRF specifically designed for the study and collected in the clinical 
history. 
During the monitoring visits, the consistency between the patient's medical records and 
the e-CRF data, that is, the verification of the original data will be checked. 
The e-CRF data that come from original documents should be consistent with them, in 
case there is any discrepancy should be justified. 
The study will be carried out in accordance with the Organic Law of Protection of 
Personal Data 15/1999 and RD 994/99 of security measures for automated files 
containing personal data. 
11.B.3 Investigator's file, data conservation and record handling 
The investigator will be provided with a study file at the beginning of the study. This 
file contains all the relevant documents necessary to carry out the study. Once the study 
is finished, this file should be kept in a safe place. 
It is the responsibility of the investigator to ensure that the patient's identification sheets 
are kept for at least 15 years after the end of the clinical trial. The original files of 
patients should be kept for as long as possible allowed by the regulations of the hospital, 
research institute or the doctor in question. If the file cannot be kept at the site, the 
investigator must notify the promoter. 
The data required for the analysis will be recorded and electronically transferred to a 
central database, through an electronic data report collection (eCRF). The system works 
on the Internet, with a system of data recording in real time (online). The data, 
introduced by investigators, are transferred directly via the Internet to a central database, 
without being registered on the investigator's local computer. 
High security standards for the transfer and storage of study data are guaranteed by the 
use of technologies such as an encrypted data transfer, firewall and a daily backup to 
protect centrally stored data. Write access to the system will be limited to authorized 
personnel, and the system will automatically maintain a trail for the audit of all entries 
and corrections of the eCRF. 
The electronic report collection is operated under an electronic signature, which consists 
of the combination of an identification code and a password. Each investigator will be 
provided with these codes of strictly personal and non-transferable use. Investigator can 
change his access password as many times as he wishes. The codes will be used to 
enter, modify or visualize the study data. 
It is the responsibility of the investigators to keep their passwords secret, that is, not to 
reveal them to third parties. 
Once the study in the sites is finished, the database will be sent to the biometrics 
department of the company TFS, responsible for the statistical analysis of the same. 
Before carrying out any analysis, the populations in a meeting between the promoter 
and TFS (Clean File Meeting) will be defined and all the populations and deviations 

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will be reflected in a report to be signed by the promoter and the persons responsible for 
TFS (Clean File Protocol). 
11.B 4  Quality control 
During the course of the study, the monitor will be responsible for ensuring that the 
study will be conducted in compliance with GCP and the current legislation. Verifying, 
among other procedures, the informed consent of all patients will be obtained correctly, 
that study procedures will be followed as detailed in the protocol and that data 
collection will be conducted accurately, for which purpose they will compare the 
information available in medical records (source documents) with the data recorded in 
the e-CRF. 
In case of lack of information or partial or imprecise information, discrepancy reports 
will be generated by the data-handling department of TFS responsible for this task so 
that the investigator can resolve them. 
The data generated in this clinical trial will be handled in accordance with the standard 
operating procedures of the company TFS, which is responsible for data handling. 
11.C 
Final report and publication 
TTCC undertakes to comply with current Spanish legislation on clinical trials, and 
specifically article 38 of Royal Decree 223/2004, which establishes the obligation to 
publish the results, both positive and negative, in scientific journals, with mention to the 
CREC that approved the study, and to the funding source. By signing this protocol, 
principal investigator accepts the terms of the TTCC’s publication policy and 
undertakes to respect them as a member of the Spanish Treatment Group of Head and 
Neck Tumours. 

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12. 
Statistical analysis 
12.A 
Efficacy and safety endpoints 
The study's primary endpoint is OS defined as time between the start of treatment 
with TPF and death due to any cause. 
The secondary endpoints of the study are: 
- 
ORR (according to the modified RECIST 1.0 criteria), will be measured for 
induction chemotherapy and also for both radical treatment arms after TPF (RT 
+ Cisplatin and RT + Cetuximab). 
- 
Incidence and time when dose reductions or suspensions will be carried out (rate 
of compliance with the protocol in both treatment arms). 
- 
PFS.  
- 
Specific survival. 
- 
Time to locoregional control of disease. 
- 
Satisfaction with treatment. Analysis of QoL in both treatment arms. 
12.B  Analysis populations 
The assignment of patients to any of the populations mentioned below will be made 
before closing the database. 
Part I of the study (period between the signature of the informed consent form until the 
evolution of the response and toxicity to induction chemotherapy with TPF) 
A. Safety population 1 (SP 1): all patients who have signed the informed consent 
form and who received at least one dose of chemotherapy with TPF. 
B. Intention-to-treat population 1 (ITT 1): all patients enrolled who have signed the 
informed consent form and who have received at least one dose of TPF 
chemotherapy. 
Part II of the study (period from randomisation after induction chemotherapy with TPF 
and until the end of the study) 
A. Safety population 2 (SP 2): all randomised patients who have initiated the 
assigned radical treatment. 
B. Intention-to-treat population 2 (ITT 2): all randomised patients who have at least 
started the assigned radical treatment. 

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12.C 
Efficacy and safety analysis 
12.C.1 Primary efficacy analysis: overall survival 
OS is defined as: the time from the start of induction chemotherapy with TPF to death 
due to any cause or to the last check-up in the case of living patients. 
The study’s primary analysis will be performed on the ITT population that will be 
randomised into the standard arm or the experimental arm. It will be tested using the 
following hypotheses, if the experimental treatment group is, at least, non-inferior to the 
standard group: 
 
H0: HR Experimental arm / Standard arm ≥1.3. 
 
H1: HR Experimental arm / Standard arm <1.3 
The one-sided alpha level specified in the study protocol is 0.05. Thus, non-inferiority 
can be concluded if the upper limit of the two-sided 90% CI for the HR is below 1.3. 
Patients who have signed an informed consent form but have not been randomised will 
not be included in the primary study primary analysis, although they will be monitored 
in a similar way to randomised patients and descriptive information will be taken from 
their treatment and evolution. 
12.C.2 Secondary analysis  
12.C.2.1 
Overall Survival  
OS is defined as: the time from the start of induction chemotherapy with TPF to death 
due to any cause or to the last check-up in the case of living patients. 
The analysis will be performed on the ITT population of part 2 and ITT of part 1. 
The results of a proportional hazards regression model, which includes the factors used 
for stratification and/or prognostic factors in this disease, will also be presented in the 
ITT populations, in order to evaluate the sensitivity of the main analysis. 
In addition to the risk reasons and their corresponding one-sided 95% CIs, the results of 
these analyses will be summarised for each treatment group, with data in the form of 
Kaplan-Meier graphs and median survival rates at 2, 3 and 5 years, with the 
corresponding 95% unilateral CI. 
12.C.2.2 
Overall response rate  
The ORR is defined as the response rate (CR + PR) measured using the RECIST 1.0 
method. 
The populations analysed will be in part 1 after induction therapy, ITT population, and 
in part 2 also the ITT PP population.  
The results on part 1 will be presented in absolute and relative frequency tables and the 
corresponding 95% CI. 

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The results from part 2, as well as the absolute and relative frequency tables with a 95% 
CI for each treatment group, the response rates will be compared using the chi-squared 
test (or the corresponding non-parametric test) with a 95% CI.   
Using the ITT population 1, exploratory analyses will be performed to search for 
prognostic factors in the response rate. 
12.C.2.3 
Adverse events rate and laboratory parameters    
All the AEs that appear will be recorded in the case report form according to the 
following criteria: 
1. NCI CTC, version 3.0 during the induction treatment (Appendix 3) 
2. NCI CTC, version 3.0 (Appendix 3) and CTC of the RTOG during 
Chemotherapy/RT or Cetuximab/RT and 90 days after completion of the RT 
(Appendix 4). In case of doubt, the criteria that assessed the AE to be the highest 
grade will be used. 
3. Late CTC from the RTOG/EORTC from 90 days after completion of RT, which 
will be basically used to gather chronic toxicity associated with radio-
chemotherapy (Appendix 5) 
AEs will be presented in the form of lists and summarised by absolute and relative 
frequency tables. A table for part 1 (induction therapy) and another for the part 2 
treatment assigned by the randomisation group will be presented. In both the AEs will 
be separated according to whether they are related to the study medication or not. When 
classification of the relationship with the study medication will be lacking, it will be 
deemed to be related to the study medication. 
Laboratory data will be presented by the incidence of toxicities according to the 
corresponding criteria and changes from the baseline to the highest degree of toxicity, 
according to the given criteria, as described during treatment. 
All abstracts and lists of AEs and laboratory data will be based on the safety population.  
12.C.2.4 
Early withdrawals from the study   
The main reason for withdrawal from the study will be recorded in the case report form. 
Lists and summary tables will be provided, giving the reason for the end of the study 
and when it occurred. 
These summaries and lists will be based on the safety population. Part 2 of the study 
will be separated by assigned treatment arm. 
12.C.2.5 
Incidence and time when dose reductions or suspensions were carried 
out   
Details and summary tables will be provided, providing the incidence of reductions or 
treatment discontinuations and giving the reason. 
These summaries and lists will be based on the safety population. Part 2 of the study 
will be separated by assigned treatment arm. 
12.C.2.6 
Progression-free survival 
For the PFS analysis, we defined TTP as the time since the start date of treatment with 
TPF induction chemotherapy until the time when DP occurred or death occurred due to 
any cause. Patients who show no progression or die will be censored on the date of the 
last check-up. Patients for whom no tumour assessments are available after the baseline 

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evaluation will be censored on day 1. Patients who show no progression and begin a 
cancer treatment other than that of the study will be censored on the start date of the 
other treatment.   
This analysis will be performed on the ITT populations in both parts of the study. 
In part 2, the study have no power to show statistical differences or equivalences 
between the two treatment groups after randomisation. Using the Cox proportional 
hazards regression, the risk ratio will be presented together with its 95% CI, as well as 
the Kaplan-Meier estimations of the survival curves for each treatment group (including 
and survival rates and medians at 2, 3 and 5 years, with their corresponding 95% CI). 
The regression model will also include the factors used for stratification and/or 
prognostic factors of this disease in order to assess the robustness of the primary 
analysis. 
12.C.2.7 
Disease-free specific survival 
For the disease-specific survival analysis, we defined TTP as time elapsed from the start 
date of treatment with TPF induction chemotherapy to date of death due to disease or 
related to the treatment of the disease. Deaths caused by other reasons will be 
considered "censored" data on the date of death. Patients who do not die will be 
censored on the date of the last check-up.  
This analysis will be performed on the ITT populations in both parts of the study. In 
part 2, the study have no power to show statistical differences or equivalences between 
the two treatment groups after randomization. Using the Cox proportional hazards 
regression, the risk ratio will be presented together with its 95% CI, as well as the 
Kaplan-Meier estimations of the survival curves for each treatment group (including 
and survival rates and medians at 2, 3 and 5 years, with their corresponding 95% CI). 
The regression model will also include the factors used for stratification and/or 
prognostic factors of this disease in order to assess the robustness of the primary 
analysis. 
12.C.2.8 
Time to locoregional control of disease 
Locoregional control: defined as permanent and complete resolution of the disease in 
terms of its initial site and lymph nodes (T and N). If the disease lasts (regardless of 
size) or the tumour recur or a second tumour appear in the field RT, it will be recorded 
as a therapeutic failure. This allows for surgical rescue on the lymph nodes if after the 
evaluation at the end of RT the cervical adenopathy will remain but the primary tumour 
will be under control (indicated as part of the first treatment). Locoregional failure will 
be considered in cases of patients who have rescue surgery on the primary tumour (T 
surgery) because of its persistence. Lymph node recurrence after a complete cervical 
lymph node remission will also be considered a therapeutic failure. In some cases, 
residual tumours may persist, consisting of areas of fibrosis or scarring, which may 
remain stable or resolved gradually over time and which is not accompanied by 
evidence of locoregional disease progression or clinical deterioration.  
We define disease locoregional control time as time from the start of TPF induction 
chemotherapy to tumour recurrence or the appearance of a second tumour within the RT 
field. Patients who do not achieve complete remission at any of the points of the 
analysis will be considered therapeutic failures from day 1 (start of TPF chemotherapy). 
This analysis will be performed on the ITT populations in both parts of the study. 

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In part 2, the study have no power to show statistical differences or equivalences 
between the two treatment groups after randomisation. Using the Cox proportional 
hazards regression, the risk ratio will be presented together with its 95% CI, as well as 
the Kaplan-Meier estimations of the survival curves for each treatment group (including 
and survival rates and medians at 2, 3 and 5 years, with their corresponding 95% CI). 
The regression model will also include the factors used for stratification and/or 
prognostic factors of this disease in order to assess the robustness of the primary 
analysis. 
12.C.2.9 
Satisfaction with treatment. Quality-of-life analysis in both treatment 
arms 
EORTC QoL questionnaires are chosen for this study. QLQ-C30 version 3.0 [1], which 
is a basic questionnaire with 30 items and the QLQ-H&N35 module [2], which is made 
up of 35 items. 
These questionnaires will be self-completed by the patients when they will be in the 
site. They have to complete them before starting TPF induction chemotherapy, after 3 
cycles of TPF, just before the patient knew the radical treatment arm to which they have 
been assigned, and then 6-8 weeks after completion of RT and every 6 months during 
the follow-up visits for the first and second year. If the time for completing the 
questionnaire coincide with an assessment of the tumour, the patient will fill it in before 
knowing the results of the tumour study.  
Overall scores and those per field in the total population and per treatment group will be 
described. A comparative analysis will be performed on the different scales according to 
the treatment assigned by the randomisation. The QoL population (patients who 
complete the questionnaires) that is explained in section 12.B will be used for these 
analyses. 
12.C.2.10 Other endpoints 
Continuous variables will be summarised using descriptive statistics, i.e. the mean, 
median, standard deviation, minimum, and maximum and two-sided 95% CI, when 
appropriate. The qualitative variables will be summarised using counts and percentages 
and 95% two-sided CI, when appropriate. The differences between means or 
percentages will be accompanied by 95% two-sided CI or will be compared using the 
corresponding statistical test.   
12.D 
Sample size 
The calculation of the sample size will be performed on the primary objective of 
determining non-inferiority in terms of OS of the experimental arm (TPF followed by 
RT + Erbitux) compared to the control arm (TPF followed by RT + cisplatin). 
Calculation of sample size will be based on an assumed exponential distribution, using 
the following parameters: 
• Unilateral testing with an alpha of 0.05 and 80% power. 
• A recruitment phase of 53 months. 
• A follow-up phase of 36 months. 
• A risk rate for the standard 0.0231 arm (median OS of 30 months) 

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• A HR Experimental arm/Standard arm = 0.938 (this assumes a median of 32-months for the 
experimental arm). 
• Competing risk of 0.01. 
The total number of randomised and evaluable patients will be 398. We also have to add 
the 15% of patients who will progress with TPF or will be lost to this total number. 
Total number of patients: 469. 
The study duration will be determined at the time when there will be 282 deaths. A 53-
month continuous recruitment period, 36-month follow-up after the inclusion of the last 
patient and also a median survival of 30 months will be considered. 
12.E  Intermediate analysis 
A review committee will perform periodic analyses to monitor the safety of both 
treatment branches and the evaluability of the patients included. 

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