Conditions: Carcinoma, Squamous Cell of Head and Neck
Keywords: tomuzotuximab cetuximab SCCHN
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 240
Healthy volunteers: no

Brief summary:
The aim of the study is to evaluate the efficacy of CetuGEX™ for the treatment of patients with stage III/IV recurrent and/or metastatic SCCHN as compared to cetuximab (both in combination with platinum-based chemotherapy) in terms of progression-free survival (PFS).

Detailed description:
Indication: First line systemic treatment for stage III/IV recurrent and/or metastatic squamous cell carcinoma of the head and neck (SCCHN)

Primary Objective:

To evaluate the efficacy of CetuGEX™ for the treatment of patients with stage III/IV recurrent and/or metastatic SCCHN as compared to cetuximab (both in combination with platinum-based chemotherapy) in terms of progression-free survival (PFS).

Secondary Objectives:

To evaluate further efficacy criteria, safety and quality of life (QoL) of patients with stage III/IV recurrent and/or metastatic SCCHN treated with CetuGEX™ as compared to cetuximab (both in combination with platinum-based chemotherapy).

To assess pharmacokinetic (PK) parameters and profiles of CetuGEX™. To assess efficacy and safety based on genetic markers for immune response (Fc-gamma receptor \[FcγR\] allotypes) and biomarkers (exploratory only).

Arms:
arm 1: 720 mg weekly administration arm 2: 250 mg/m2 weekly administration

Interventions: intervention 1: CetuGEX™ intervention 2: Cetuximab intervention 3: Chemotherapy
Intervention descriptions: intervention 1: 60 mg/day 0, 930 mg/day 1, followed by 720 mg i.v. weekly administration intervention 2: 400 mg/sqm body surface area (BSA) on day 1, followed by 250 mg/sqm BSA i.v. weekly administration intervention 3: Combination of Cisplatin and 5-Fluorouracil (Carboplatin may substitute Cisplatin following the 1st cycle of therapy in case of toxicity)

Protocol document:
Prot_000.pdf: 
Study Protocol 
 
 
Randomized, controlled, open label, multicenter, phase II study to evaluate the efficacy 
and safety of CetuGEX™ plus chemotherapy in comparison to cetuximab plus 
chemotherapy for the treatment of patients with stage III/IV recurrent and/or 
metastatic squamous cell carcinoma of the head and neck 
 
(The “RESGEX” Study) 
 
PROTOCOL DATE:  
February 06, 2015 
 
ClinicalTrials.gov Identifier: NCT02052960 
 


 
 
 
 
 
PROTOCOL 
 
Randomized, controlled, open label, multicenter, phase II study to evaluate the 
efficacy and safety of CetuGEX™ plus chemotherapy in comparison to cetuximab 
plus chemotherapy for the treatment of patients with stage III/IV recurrent and/or 
metastatic squamous cell carcinoma of the head and neck 
 
(The “RESGEX” Study) 
 
 
PRODUCT NAME/NUMBER: 
CetuGEX™ 
PROTOCOL NUMBER: 
GEXMab52201 
EUDRACT NUMBER: 
2013-003695-13 
IND NUMBER: 
118026 
DEVELOPMENT PHASE: 
Phase II 
PROTOCOL DATE: 
Final Version 4.0, 06 February 2015 
SPONSORED BY: 
Glycotope GmbH 
Robert-Rössle-Str. 10 
D-13125 Berlin, Germany 
Phone: +49 30 9489 2600 
Fax: +49 30 9489 2609 
COORDINATING 
INVESTIGATOR 
 
 
 
 
 
CONTRACT RESEARCH 
ORGANIZATION: 
  
 
 
 
This study will be performed in compliance with Good Clinical Practices (GCP) and applicable regulatory 
requirements, including the archiving of essential documents. Information contained in this protocol is 
confidential in nature, and may not be used, divulged, published or otherwise disclosed to others except to 
the extent necessary to obtain approval of the Institutional Review Board or Independent Ethics Committee, 
or as required by law. Persons to whom this information is disclosed should be informed that this 
information is confidential and may not be further disclosed without the express permission of Glycotope 
GmbH.


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1 
APPROVAL SIGNATURES 
 
PROTOCOL NUMBER: 
GEXMab52201 
PROTOCOL TITLE: 
Randomized, controlled, open label, multicenter, 
phase II study to evaluate the efficacy and safety of 
CetuGEX™ plus chemotherapy in comparison to 
cetuximab plus chemotherapy for the treatment of 
patients with stage III/IV recurrent and/or metastatic 
squamous cell carcinoma of the head and neck. (The 
“RESGEX” Study) 
I, the undersigned, have read this protocol and confirm that to the best of my knowledge 
it accurately describes the planned conduct of the study. 
 
 
 
 
 
 
 
 
 
 
 
 
Date 
 
 
 
  
 
 
 
Date 
 
 
 
 
 
 
 
Date 
 
 
  
 
Date 


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2 
SYNOPSIS 
 
PRODUCT 
NAME/NUMBER 
CetuGEX™ 
PROTOCOL NUMBER 
GEXMab52201 
EUDRACT NUMBER 
2013-003695-13 
IND NUMBER 
118026 
DEVELOPMENT 
PHASE 
Phase II 
PROTOCOL TITLE 
Randomized, controlled, open-label, multicenter, phase II study to evaluate the 
efficacy and safety of CetuGEX™ plus chemotherapy in comparison to 
cetuximab plus chemotherapy for the treatment of patients with stage III/IV 
recurrent and/or metastatic squamous cell carcinoma of the head and neck. 
(The “RESGEX” Study) 
INDICATION 
First line systemic treatment for stage III/IV recurrent and/or metastatic 
squamous cell carcinoma of the head and neck (SCCHN) 
SPONSOR 
Glycotope GmbH 
Robert-Rössle-Str. 10 
D-13125 Berlin, Germany 
COORDINATING 
INVESTIGATOR 
 
OBJECTIVES 
Primary: 
To evaluate the efficacy of CetuGEX™ for the treatment of patients with 
stage III/IV recurrent and/or metastatic SCCHN as compared to cetuximab 
(both in combination with platinum-based chemotherapy) in terms of 
progression-free survival (PFS). 
Secondary: 
To evaluate further efficacy criteria, safety and quality of life (QoL) of 
patients with stage III/IV recurrent and/or metastatic SCCHN treated with 
CetuGEX™ as compared to cetuximab (both in combination with platinum-
based chemotherapy). 
To assess pharmacokinetic (PK) parameters and profiles of CetuGEX™. 
To assess efficacy and safety based on genetic markers for immune response 
(Fc-gamma receptor [FcγR] allotypes) and biomarkers. 
STUDY DESIGN 
Randomized, controlled, multicenter, phase II study with first line treatment 
(six cycles of 5-fluorouracil and cisplatin in combination with CetuGEX™ vs. 
combination with cetuximab) followed by single-agent maintenance therapy 
(CetuGEX™ or cetuximab respectively). Following the first cycle, 
substitution of cisplatin by carboplatin is allowed in case of toxicity. 
Randomization to CetuGEX™ vs. cetuximab will be performed using a 1:1 
ratio.  
Randomization will be stratified by: 
 
FcγRIIIa status (FF or FV or VV) 
 
Oral cavity and oropharynx vs. other locations 
 
Locally recurrent vs. metastatic disease 


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 
Epidermal growth factor receptor (EGFR) treatment naïve vs. EGFR 
treatment as part of multimodal therapy. 
DATA SAFETY 
MONITORING 
BOARD 
As soon as at least 10 patients per treatment arm have completed the second 
cycle of combination therapy, patient safety data will be reviewed by an 
independent data safety monitoring board (DSMB). After this, regular 6-
monthly meetings will be scheduled until all ongoing patients have been 
treated for at least 6 months. For important reasons additional meetings may 
be scheduled by sponsor, medical monitor, coordinating investigator or 
DSMB as long as patients are at risk.    
PLANNED NUMBER 
OF PATIENTS 
A total of approximately 240 randomized patients. 
STUDY ENTRY 
CRITERIA 
Inclusion criteria: 
1. Patients with histologically confirmed recurrent and/or metastatic 
SCCHN not eligible for local treatment. 
2. Patients with measurable disease according to Response Evaluation 
Criteria in Solid Tumors (RECIST) 1.1. 
3. Patients aged at least 18 years at screening. 
4. Eastern Cooperative Oncology Group (ECOG) performance status of 
0 or 1. 
5. Minimum life expectancy of 3 months. 
6. Tissue samples available for specific disease and therapy related 
biological assessments. 
7. If female and of childbearing potential, is non-lactating and has 
negative pregnancy test results at screening and prior to 
randomization. 
8. If female, is either not of childbearing potential (defined as 
postmenopausal for at least 1 year or surgically sterile [bilateral tubal 
ligation, bilateral oophorectomy, or hysterectomy]) or willing to use 
highly effective contraceptives during study participation until 6 
months after last administration of any study medication, particularly 
cisplatin or carboplatin, with a failure rate < 1% according to the 
Note for Guidance on non-clinical safety studies for the conduct of 
human clinical trials and marketing authorization for pharmaceuticals 
(CPMP/ICH/286/95) of the European Medicines Agency (EMA).
 
  
Male patients who have partners of childbearing potential have to 
confirm adequate use of highly effective contraceptives during study 
participation until 6 months after last administration of any study 
medication, particularly cisplatin or carboplatin, as well. 
9. Willing and able to comply with the protocol. 
10. Willing and able to provide written informed consent. 
Exclusion criteria: 
1. Prior systemic chemotherapy, except if given as part of a multimodal 
treatment for locally advanced disease which was completed more 
than 6 months prior to randomization. 
2. Cetuximab or other EGFR targeting agent treatment, except if given 
as part of a multimodal treatment for locally advanced disease which 
was completed more than 6 months prior to randomization. 
3. Surgery (other than minor interventions like diagnostic biopsy or 
intravenous port implantation) or irradiation within 30 days before 
randomization. 


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4. Concomitant anti-tumor therapy or concomitant immunotherapy, live 
vaccines including yellow fever vaccination (as per cisplatinum 
Summary of Product Characteristics [SmPC]). 
5. Concomitant corticosteroid treatment unless specified within the 
protocol. 
6. Clinical evidence of brain metastasis or leptomeningeal involvement. 
7. Patients with nasopharyngeal tumors. 
8. Concomitant malignant disease, except for adequately treated tumors 
with high likelihood of being cured (e.g., basal cell cancer of the 
skin, cervical cancer or breast cancer in situ). Patients with other 
previous malignancies but without evidence of disease for at least 5 
years will be allowed to enter the study. 
9. Patients with renal or hepatic impairment (serum creatinine and 
bilirubin > 1.5 fold above the upper limit of normal ranges, creatinine 
clearance < 60 ml/min, and transaminase > 5 fold above the upper 
limit of normal ranges) and patients with hematology parameters 
outside the normal ranges (hemoglobin < 9 g/dl, absolute neutrophil 
count < 1500/mm3 and platelet count < 105/mm3) at screening as well 
as patients with impaired auditory function or platinum-related 
neuropathy. 
10. Clinically active infections ≥ Grade 2 using National Cancer Institute 
(NCI) Common Terminology Criteria for Adverse Events (CTCAE) 
version 4 and/or requiring intravenous antibiotics. 
11. Known active hepatitis B or C. 
12. Known human immunodeficiency virus (HIV) infection. 
13. Myocardial infarction within 6 months prior to screening. 
14. Symptomatic congestive heart failure (New York Heart Association 
[NYHA] Grade 3 or 4), unstable angina pectoris within 6 months 
prior to screening, significant cardiac arrhythmia, history of stroke or 
transient ischemic attack within 1 year prior to screening. 
15. History of keratitis requiring medical interventions within the last 
5 years or interstitial lung disease. 
16. Patients with any other disorder that, in the opinion of the 
investigator, might interfere with the conduct of the study. 
17. Patients with an unstable condition (e.g., psychiatric disorder, a 
recent history of drug or alcohol abuse, interfering with study 
compliance, within 6 months prior to screening) or otherwise thought 
to be unreliable or incapable of complying with the requirements of 
the protocol. 
18. Patients institutionalized by official means or court order. 
19. Receipt of any other investigational medicinal product within the last 
30 days before randomization or any previous CetuGEX™ 
administration.  
20. Prior allergic reaction to a monoclonal antibody, grade 3 infusion 
related reaction (IRR) or any grade 4 reaction to a monoclonal 
antibody. 
21. Known sensitivity to any component of the investigational medicinal 
product (IMP) and medication used in this study. 
INVESTIGATIONAL 
PRODUCT 
Active substance: CetuGEX™, a chimeric monoclonal immunoglobulin G 
(IgG) antibody binding to the EGFR which is glyco-optimized and fully 
human glycosylated with an enhanced antibody-dependent cell-mediated 


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cytotoxicity (ADCC) activity against tumor cells. 
Dose, route, frequency: Solution for infusion, to be administered once weekly.
The initial dose will be 990 mg; subsequent doses will be 720 mg once 
weekly. The initial dose will be given as split-dose over 2 days with a priming 
dose of 60 mg on Day 0 and the remaining dose of 930 mg on Day 1. 
REFERENCE 
PRODUCT 
Active substance: cetuximab, a chimeric monoclonal IgG antibody binding to 
the EGFR. 
Dose, route, frequency: Solution for infusion, to be administered once weekly.
The initial dose will be 400 mg/m2 body surface area (BSA), subsequent doses 
will be 250 mg/m2 BSA each. The maximum infusion rate for the initial dose 
must not exceed 5 mg/min. The maximum infusion rate for subsequent doses 
must not exceed 10 mg/min. 
NON-
INVESTIGATIONAL 
PRODUCTS 
Active substance: 5-Fluorouracil (5-FU) 
Dose, route, frequency: Solution for intravenous injection. Doses of 
1000 mg/m2 BSA per day will be administered every 3 weeks (1 cycle of 
cisplatin or carboplatin treatment) as continuous intravenous infusion on 
Days 1-4 of each cycle. 
Active substance: Cisplatin 
Dose, route, frequency: Solution for infusion. Doses of 100 mg/m2 BSA will 
be administered every 3 weeks (1 cycle), on Day 1 of each cycle. 
Active substance: Carboplatin 
Carboplatin may substitute cisplatin following the first cycle of therapy in 
case of toxicity. 
Dose, route, frequency: Solution for infusion, to be administered at an area 
under the curve (AUC) of 5 mg/mL/min (using the Calvert formula for 
calculation) as a 1-hour intravenous infusion every 3 weeks (1 cycle), on 
Day 1 of each cycle. As per SmPC, carboplatin may not be used in patients 
with bleeding tumors. 
 
Cisplatin (which is allowed to be substituted by carboplatin following the first 
cycle in case of toxicity) in combination with 5-FU will be administered for a 
maximum 
of 
6 cycles, 
starting 
approximately 
1 hour 
after 
CetuGEX™/cetuximab infusion on Day 1 of each cycle. 
TREATMENT 
REGIMENS 
Combination treatment phase: 
Eligible patients will be randomized to receive as first line treatment either 
CetuGEX™ or cetuximab in combination with chemotherapy (5-FU and 
cisplatin) for the maximum duration of 6 cycles of combined treatment. In 
case of toxicity, chemotherapy can be dose reduced, discontinued or, if later 
than the first cycle, switched to carboplatin. If corticosteroids are required, 
e.g., as premedication to prevent infusion related reactions, dexamethasone is 
to be used (unless contraindicated). If chemotherapy is discontinued earlier for 
any other reason apart from progression, patients will start the maintenance 
phase at that time.  
Single-agent maintenance phase: 
After completion or discontinuation of combination chemotherapy for any 
other reason apart from progression, the treatment will be followed by 
maintenance therapy receiving single agent CetuGEX™ or cetuximab, 
respectively. Single-agent maintenance therapy will be continued until 
progression of disease.  
Follow-up:  


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A Safety Visit must be performed 28 (+2) days after the last administration of 
the study drug for all randomized patients. In case of treatment discontinuation 
due to reasons other than disease progression, patients will stay on the regular 
study schedule until disease progression is documented and will then attend a 
Final Examination Visit. In case of regular treatment discontinuation due to 
disease progression, the Safety Visit is identical to the Final Examination 
Visit. 
After the Final Examination, patients will be followed-up by quarterly phone 
calls until death or for a maximum duration of 24 months after randomization 
of the last patient for assessment of overall survival. 
PLANNED STUDY 
SITES 
Approximately 40 study sites in Europe and the USA. 
CRITERIA FOR 
EVALUATION 
Primary efficacy endpoint: 
Progression-free survival (PFS) as assessed by the investigator. 
Secondary endpoints 
Efficacy endpoints: 
 
PFS as assessed by independent centralized reading 
 
Objective response rate (ORR; i.e., complete response [CR] + partial 
response [PR]) at the end of combination treatment 
 
Best overall response rates (including maintenance therapy treatment) 
 
Clinical benefit rate (CBR; i.e., CR + PR + stable disease [SD]) 
 
Duration of response 
 
Overall survival (OS) 
 
Time to treatment failure (TTF) 
 
QoL scores as assessed by European Oncology Research Trials 
Committee 
(EORTC) 
quality 
of 
life 
questionnaires 
(QLQ) 
EORTC-QLQ-C30 and EORTC-QLQ-H&N35. 
In addition, PFS and all secondary efficacy endpoints listed above will be 
analyzed by FcγRIIIa-allotype subgroups (i.e., FF, FV, and VV), by p16 
status, by EGFR status, and other potential parameters, unless the sample sizes 
in subgroups are too low. 
Pharmacokinetic endpoints:  
Antibody trough levels and PK profiles of CetuGEX™ will be assessed 
throughout the study.  
Safety endpoints: 
 
Incidence of adverse events (AEs) and serious AEs, including incidence 
of target/class-specific side effects (skin reactions, diarrhea) 
 
IRRs 
 
Physical and laboratory assessments 
 
Vital signs 
 
Electrocardiogram (ECG) 
In addition, the incidence of AEs will be analyzed by FcγRIIIa-allotype 
subgroups (FF, FV, VV). 
Exploratory endpoints: 
 
Immunogenicity: incidence of anti-drug antibodies (ADAs) 
 
Immunological parameters: cytokine levels and immune cell status. 


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STATISTICAL 
METHODS 
Analysis Populations 
 
Intention-to-treat (ITT) population – all randomized patients  
 
Safety Population – all patients having received treatment at least once. 
 
Per-protocol (PP) Population – all patients in the ITT population and who 
have received treatment at least once without major protocol deviations as 
defined in the statistical analysis plan and finally decided in a Data 
Review Meeting before data base lock. 
 
Pharmacokinetic Population – all randomized patients including the 
subset of patients who had blood samples collected for PK non-
compartmental profiling, who had at least one measureable CetuGEX™ 
antibody concentration. 
Efficacy Analyses 
Primary endpoint of the trial is PFS defined as time from randomization until 
disease progression (as assessed by the investigator) or death of any cause. If 
the patient is alive and without progression at the last time of observation, the 
PFS time will be censored at the time of the last tumor assessment. 
The primary efficacy analysis for PFS will be based on the ITT population. A 
log-rank test will be used to test the null hypothesis of equal treatment effects 
at an overall significance level of 0.05. The primary efficacy analysis will not 
be stratified by the factors used for stratification at randomization in order to 
preserve the estimated power considering the high number of strata. As a 
sensitivity analysis, a proportional hazards regression model will be applied 
and the effects of the stratification factors, the p16 status, and the EGFR status 
will be estimated. 
The Kaplan-Meier method will be used to estimate the survival functions. 
Median survival times together with their 95%-confidence intervals will be 
retrieved from the survival functions.  
The analysis will be repeated for the PP population as a sensitivity analysis. 
A Chi-squared test will be performed to evaluate the effects of treatment on 
response rates according to RECIST. A logistic regression model will be fit to 
estimate odds ratios for the association of stratification factors, the p16 status, 
and the EGFR status with response categories. 95%-confidence intervals will 
be calculated for the treatment differences in response rates. 
Overall survival and TTF will be analyzed analogously to PFS on an ITT 
basis.  
If subgroup sample sizes allow, analyses of the primary and secondary 
efficacy endpoints will be repeated for the FcγRIIIa-allotype subgroups (i.e., 
FF, FV, and VV), the p16 status subgroups as well as the EGFR status 
subgroups s, omitting the FcγRIIIa factor, the p16 status and the EGFR status 
factor, respectively.  
Pharmacokinetic Analyses 
A population PK analysis will be performed with samples from all patients. In 
addition, non-compartmental analyses to evaluate the PK profile will be 
performed for a subgroup of approximately 30 patients. 
Safety Analyses 
All AEs will be coded using Medical Dictionary for Regulatory Activities 
(MedDRA) and analyzed on Preferred Term (PT) and System Organ Class 
(SOC) level.  
Treatment emergent adverse events (TEAEs) are defined as any AE which 
started or deteriorated at or after start of treatment. Incidences for TEAE will 
be calculated on PT level, on SOC level and globally by treatment group. On 


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each analysis level, a patient will be counted only once. Frequencies for TEAE 
will also be given for causality and severity graded according to Common 
Toxicity Criteria (NCI-CTC; AE criteria Version 4.0). In addition, toxicity as 
evaluated via incidence of AEs will be analyzed by Fc-gamma receptor 
allotype subgroups (FF, FV, VV) The incidences of ADA will be summarized 
in frequency tables per treatment arm. 
For biomarkers as well as hematology and biochemistry laboratory variables, 
descriptive summaries of observed values and changes from baseline will be 
presented by treatment arm. The assessments of laboratory variables 
concerning reference ranges and clinical relevance will be tabulated by visit 
for each clinical laboratory parameter by treatment arm (frequency tables). 
Additionally, for each laboratory parameter, shifts in assessments from 
baseline to the last on-study value will be presented by treatment arm (shift 
tables). 
Descriptive summaries of observed values and changes from baseline will be 
calculated for vital signs. These summaries will be presented by visit and 
treatment arm. 
Descriptive summaries of observed values and changes from baseline will be 
calculated for ECG variables. QT will be corrected according to Bazett. 
Frequency and shift tables will be presented for the classified values of QTc as 
given by the International Conference on Harmonisation (ICH)-E14, as well as 
for the overall clinical assessment. 
Finding in post-baseline physical examinations will be documented as AE and 
analyzed as part of the general AE analysis. 
SAMPLE SIZE 
DETERMINATION 
The log-rank test will be used to test the hypothesis that patients assigned to 
the CetuGEX™ arm have increased PFS compared to patients assigned to the 
control arm. The sample size calculation is based on the following 
assumptions: 
 
 
The median PFS in the control arm is expected to be 5.6 months post 
randomization. 
 
It is expected that the median PFS in the CetuGEX™ arm can be 
increased to 8.4 months corresponding to a hazard rate of 0.67. 
 
The anticipated recruitment time is 24 months, anticipated time until PFS 
events are reached is 12 months after randomization of the last patient, 
follow-up for OS for at least 24 months after randomization of the last 
patient. 
 
Drop-outs are expected to occur at times following an exponential 
distribution and resulting in a drop-out rate of 10% at the cut-off for PFS 
analysis.  
 
Patients will be randomized in a 1:1 ratio. 
 
The overall two-sided significance level will be 0.05 and the power to be 
maintained 80%. 
 
Based on these assumptions, approximately 240 patients have to be 
randomized to observe the required overall number of 192 events. 
Assuming a corresponding effect on OS (hazard ratio 0.67) and a median 
overall survival of 10.6 months in the control group the number of survival 
events to be observed after a 24 months follow-up for survival will be 183. 
STUDY AND 
TREATMENT 
The overall study duration is expected to be approximately 48 months, 
assuming 24 months for recruitment and follow-up of the patients for at least 


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DURATION 
24 months after randomization of the last patient). 
The sequence and maximum duration of the study periods and treatment for 
each patient will be as follows: 
1. Screening: to be performed within 28 days prior to first infusion to assess 
general eligibility for this study. 
2. Combination treatment phase: maximum of 6 treatment cycles of 
combination treatment. 
3. Single-agent maintenance treatment: until disease progression. 
4. Follow-up: at least 24 months after randomization of the last patient. 
The patients will be treated until disease progression. 
 


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3 
TABLE OF CONTENTS 
 
1 
APPROVAL SIGNATURES ...................................................................................... 2 
2 
SYNOPSIS .................................................................................................................. 3 
3 
TABLE OF CONTENTS .......................................................................................... 11 
List of Tables ............................................................................................................. 16 
List of Figures ............................................................................................................ 16 
4 
LIST OF ABBREVIATIONS .................................................................................... 17 
5 
INTRODUCTION ..................................................................................................... 19 
5.1 
Background ...................................................................................................... 19 
5.1.1 Study Drug – Mode of Action .............................................................. 19 
5.1.2 GlycoExpress™ (GEX™) .................................................................... 20 
5.2 
Clinical Experience .......................................................................................... 21 
5.3 
Summary of Potential Risks and Benefits ........................................................ 21 
5.4 
Rationale .......................................................................................................... 22 
6 
OBJECTIVES ............................................................................................................ 23 
6.1 
Primary Objective ............................................................................................ 23 
6.2 
Secondary Objectives ....................................................................................... 23 
7 
STUDY DESIGN ...................................................................................................... 23 
7.1 
Overall Study Design and Plan ........................................................................ 23 
7.1.1 Overview .............................................................................................. 23 
7.1.2 Endpoints .............................................................................................. 25 
7.2 
Discussion of Study Design ............................................................................. 26 
7.3 
Study Site(s) ..................................................................................................... 26 
7.4 
Point of Contact................................................................................................ 26 
8 
PATIENT POPULATION ......................................................................................... 27 
8.1 
Selection of Study Population and Diagnosis .................................................. 27 
8.2 
Study Entry Criteria ......................................................................................... 27 
8.2.1 Inclusion Criteria .................................................................................. 27 
8.2.2 Exclusion Criteria ................................................................................. 28 
8.3 
Premature Patient Withdrawal ......................................................................... 29 
8.4 
Replacement of Withdrawn Patients ................................................................ 30 
9 
TREATMENTS ......................................................................................................... 30 
9.1 
Identification of Investigational Medicinal Products (IMPs) ........................... 30 


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9.1.1 Investigational Medicinal Products ...................................................... 30 
CetuGEX™ ............................................................................................... 30 
Cetuximab ................................................................................................. 30 
9.1.2 Non-Investigational Medicinal Products .............................................. 31 
9.2 
Labeling and Packaging ................................................................................... 31 
9.2.1 Labeling ................................................................................................ 31 
9.2.2 Packaging ............................................................................................. 31 
9.3 
Treatments Administered ................................................................................. 31 
9.4 
Dispensing and Storage .................................................................................... 34 
9.5 
Method of Assigning Patients to Treatment Groups ........................................ 35 
9.6 
Blinding and Unblinding Treatment Assignment ............................................ 35 
9.7 
Selection of Doses in the Study ....................................................................... 35 
9.8 
Selection of Timing of Dose for Each Patient ................................................. 35 
9.9 
Dose Adjustment Criteria ................................................................................. 36 
9.9.1 CetuGEX™ .......................................................................................... 37 
9.9.2 Cetuximab ............................................................................................ 38 
9.9.3 Cisplatin ................................................................................................ 40 
9.9.4 5-Fluorouracil ....................................................................................... 41 
9.10 Drug Accountability ......................................................................................... 41 
9.11 Treatment Compliance ..................................................................................... 42 
9.12 Concomitant and Prohibited Therapies ............................................................ 42 
9.12.1 Concomitant Therapies ......................................................................... 42 
9.12.2 Prohibited Therapies ............................................................................. 42 
9.13 Treatment After End of Study .......................................................................... 42 
10 STUDY PROCEDURES ........................................................................................... 43 
10.1 Study Periods and Schedule of Visits .............................................................. 43 
10.1.1 Screening Visit ..................................................................................... 43 
10.1.2 Randomization ...................................................................................... 44 
10.1.3 Combination Treatment Phase ............................................................. 44 
10.1.4 Single Agent Maintenance Phase ......................................................... 50 
10.1.5 Follow-Up Phase .................................................................................. 51 
10.2 Study Duration ................................................................................................. 53 
10.3 Assessments ..................................................................................................... 53 
10.3.1 Efficacy ................................................................................................ 53 
10.3.1.1 Assessment of Primary Endpoint ............................................. 53 
10.3.1.2 Assessment of Secondary Efficacy Endpoints ......................... 54 


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10.3.2 Quality of Life Measures ...................................................................... 55 
10.3.3 Pharmacokinetics .................................................................................. 55 
10.3.3.1 Pharmacokinetics Blood Samples Collection .......................... 55 
10.3.3.2 Pharmacokinetic Blood Sample Handling ............................... 56 
10.3.4 Pharmacogenomics ............................................................................... 56 
10.3.5 Immunogenicity and Immunological Parameters ................................. 57 
10.3.5.1 Immunogenicity (Antibody Testing) ........................................ 57 
10.3.5.2 Cytokine Release and Immune Cells Status ............................. 57 
10.3.6 Safety .................................................................................................... 58 
10.3.6.1 Laboratory Safety Assessments ............................................... 58 
10.3.6.2 Clinical Examinations .............................................................. 59 
10.3.6.3 Adverse Events ......................................................................... 60 
11 ADVERSE EVENTS ................................................................................................. 61 
11.1 Definitions ........................................................................................................ 61 
11.1.1 Adverse Events ..................................................................................... 61 
11.1.2 Adverse Drug Reaction ........................................................................ 61 
11.1.3 Unexpected Adverse Event/Adverse Drug Reaction ........................... 61 
11.1.4 Serious Adverse Events/Drug Reaction ............................................... 62 
11.1.5 Significant Adverse Events .................................................................. 63 
11.1.6 Treatment-Emergent Adverse Events................................................... 63 
11.2 Management of Adverse Events ...................................................................... 63 
11.2.1 Collection ............................................................................................. 63 
11.2.2 Evaluation ............................................................................................. 63 
11.2.2.1 Severity of Adverse Events ...................................................... 63 
11.2.2.2 Seriousness ............................................................................... 64 
11.2.2.3 Action(s) Taken ........................................................................ 64 
11.2.2.4 Outcome at the Time of Last Observation ............................... 65 
11.2.2.5 Adverse Event Relationship to Investigational Product ........... 65 
11.2.3 Documentation ..................................................................................... 66 
11.2.4 Treatment of Adverse Events ............................................................... 66 
11.2.5 Follow-up ............................................................................................. 66 
11.2.6 Notification ........................................................................................... 67 
11.2.6.1 Serious Adverse Events ............................................................ 67 
11.2.6.2 Adverse Drug Reactions .......................................................... 68 
11.2.6.3 Non-serious Adverse Events .................................................... 68 
11.3 Special Considerations ..................................................................................... 68 


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11.3.1 Other Adverse Events for Immediate Reporting .................................. 68 
11.3.2 Pregnancies ........................................................................................... 69 
11.3.3 Overdose ............................................................................................... 69 
12 DATA SAFETY MONITORING BOARD .............................................................. 69 
13 STATISTICS ............................................................................................................. 70 
13.1 Study Endpoints ............................................................................................... 70 
13.1.1 Primary Endpoint ................................................................................. 70 
13.1.2 Secondary Endpoints ............................................................................ 71 
13.1.3 Pharmacokinetic Endpoints .................................................................. 71 
13.1.4 Safety Endpoints ................................................................................... 72 
13.1.5 Exploratory Endpoints .......................................................................... 72 
13.2 Sample Size Determination .............................................................................. 72 
13.3 Analysis Populations ........................................................................................ 73 
13.4 Statistical Analyses .......................................................................................... 74 
13.4.1 General Methods .................................................................................. 74 
13.4.2 Study Patients and Demographics ........................................................ 74 
13.4.2.1 Disposition and Withdrawals ................................................... 74 
13.4.2.2 Demographics and Other Baseline Characteristics .................. 74 
13.4.3 Efficacy Analyses ................................................................................. 74 
13.4.3.1 Primary Analysis ...................................................................... 74 
13.4.3.2 Secondary Analyses ................................................................. 75 
13.4.3.3 Pharmacokinetics ..................................................................... 75 
13.4.4 Safety and Tolerability Analyses.......................................................... 76 
13.4.4.1 Adverse Events ......................................................................... 76 
13.4.4.2 Clinical Laboratory Evaluations .............................................. 76 
13.4.4.3 Vital Signs ................................................................................ 77 
13.4.4.4 Electrocardiograms and Echocardiograms ............................... 77 
13.4.4.5 Physical Examination Findings ................................................ 77 
13.4.5 Interim Analysis ................................................................................... 77 
14 STUDY CONDUCT .................................................................................................. 77 
14.1 Sponsor and Investigator Responsibilities ....................................................... 77 
14.1.1 Sponsor Responsibilities ...................................................................... 77 
14.1.2 Investigator Responsibilities ................................................................ 78 
14.2 Site Initiation .................................................................................................... 78 
14.3 Study Documents ............................................................................................. 79 
14.3.1 Site Documents ..................................................................................... 79 


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14.3.2 Case Report Forms ............................................................................... 79 
14.3.3 Source Documents ................................................................................ 79 
14.4 Data Quality Control ........................................................................................ 80 
14.4.1 Monitoring Procedures ......................................................................... 80 
14.4.2 Data Management ................................................................................. 80 
14.4.3 Quality Assurance/Audit ...................................................................... 81 
14.5 Study Termination ............................................................................................ 81 
14.5.1 Regular Study Termination .................................................................. 81 
14.5.2 Premature Study Termination .............................................................. 81 
14.6 Study Site Closure ............................................................................................ 82 
14.6.1 Record Retention .................................................................................. 82 
14.6.2 Sample Retention ................................................................................. 82 
14.7 Changes to the Protocol ................................................................................... 83 
14.8 Use of Information and Publication ................................................................. 83 
15 FINAL CLINICAL STUDY REPORT ..................................................................... 83 
16 ETHICAL AND LEGAL CONSIDERATIONS ....................................................... 84 
16.1 Declaration of Helsinki and Good Clinical Practice ........................................ 84 
16.2 Patient Information and Informed Consent ...................................................... 84 
16.3 Approval by Independent Ethics Committee/Institutional Review Board ....... 85 
16.4 Finance and Insurance ...................................................................................... 85 
17 REFERENCES .......................................................................................................... 86 
18 ATTACHMENTS ...................................................................................................... 88 
18.1 Schedule of Events ........................................................................................... 88 
18.2 Investigator’s Agreement ................................................................................. 92 
APPENDICES .................................................................................................................. 93 
A. 
ECOG Performance Status ............................................................................... 94 
B. 
Time Schedule for Pharmacokinetics Blood Sampling ................................... 95 
C. 
Response Evaluation Criteria in Solid Tumors ................................................ 96 
Measurable Lesions: ......................................................................................... 96 
Non-Measurable Lesions ................................................................................. 96 
New Lesions ..................................................................................................... 97 
Methods of Measurement ................................................................................. 97 
Baseline Documentation of Target and Non-Target Lesions ........................... 97 
Response Criteria According to Adapted Immune-Related RECIST 1.1 ........ 98 
Evaluation of Best Overall Response According to Adapted Immune-Related 
RECIST 1.1 .......................................................................................... 99 


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Duration of Response ..................................................................................... 100 
D. 
Regulations and Good Clinical Practice Guidelines ...................................... 101 
1. 
Regulations ......................................................................................... 101 
2. 
Good Clinical Practice Guidelines ..................................................... 101 
E. 
SmPC for Cetuximab (Erbitux®) .................................................................... 102 
F. 
SmPC for Cisplatin ........................................................................................ 103 
G. 
SmPC for 5-FU .............................................................................................. 104 
H. 
SmPC for Carboplatin .................................................................................... 105 
 
List of Tables 
Table 9-1:  
CetuGEX™ Infusion Scheme and Dosage ........................................... 33 
Table 9-2: 
Treatment Adjustment in the Event of CetuGEX™ Caused 
Allergic/Hypersensitivity Reaction ........................................................................... 38 
Table 9-3: 
Treatment Adjustment in the Event of Cetuximab Caused 
Allergic/Hypersensitivity Reaction ........................................................................... 39 
Table 10-1: 
Ideal treatment schedule – combination treatment phase ..................... 46 
 
List of Figures 
Figure 9-1: 
Treatment Modification in the Event of Grade 3 Skin Toxicity 
Considered to be Related to Weekly Administration of CetuGEX™/Cetuximab. .... 36 
 


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4 
LIST OF ABBREVIATIONS 
 
ADA
Anti-drug antibody
ADCC
Antibody dependent cell cytotoxicity
ADR
Adverse drug reaction
AE
Adverse event
AUC
Area under the curve
BMI
Body mass index
BSA
Body surface area
BUN
Blood urea nitrogen
CBR
Clinical benefit response
CR
Complete response
CRA
Clinical research associate
CSR
Clinical study report
CT
Computed tomography
CTC
Common Toxicity Criteria
DSMB
Data safety monitoring board
ECG
Electrocardiogram
ECHO
Echocardiogram
eCRF
Electronic case report form
EDC
Electronic data capture
EGFR
Epidermal growth factor receptor
EORTC
European Oncology Research Trials Committee
FcγR
Fc-gamma receptor 
FDA
Food and Drug Administration
GCP
Good Clinical Practice
GMP
Good Manufacturing Practice
HIV
Human immunodeficiency virus
IB
Investigator’s Brochure
IgG
Immunoglobulin G
ICF
Informed consent form
ICH
International Conference on Harmonisation
IEC
Independent Ethics Committee
IMP
Investigational medicinal product
IND
Investigational New Drug
IRB
Institutional Review Board
IRR
Infusion-related reaction
irRC
Immune-related response criteria
ITT
Intention-to-treat
IWRS
Interactive web response system
KRAS
Kirsten rat sarcoma viral oncogene
MedDRA
Medical Dictionary for Regulatory Activities
MRI
Magnetic resonance imaging
MUGA
Multiple gated acquisition scan


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nIMP
Non-investigational medicinal product
NCI
National Cancer Institute
NYHA
New York Heart Association
ORR
Objective response rate
OS
Overall survival
PD
Progression disease
PFS
Progression-free survival
PK
Pharmacokinetic
PP
Per-protocol
PR
Partial response
QLQ
Quality of life questionnaire
QoL
Quality of life
RECIST
Response evaluation criteria in solid tumors
SAE
Serious adverse event
SAF
Safety population
SAP
Statistical analysis plan
SCCHN
Squamous cell carcinoma of the head and neck
SD
Stable disease
SmPC
Summary of product characteristics
TEAE
Treatment emergent adverse event
TTF
Time to treatment failure
UADR
Unexpected adverse drug reaction
5-FU
5-fluorouracil
 
 


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5 
INTRODUCTION 
5.1 
Background 
Cetuximab (Erbitux®) is a chimeric immunoglobulin G (IgG) 1 mouse-human antibody 
targeted against the extracellular domain of the epidermal growth factor receptor (EGFR) 
with high specificity and affinity and is produced in the murine myeloma cell line SP2/0. 
Cetuximab is approved and marketed for clinical use as a single agent or in combination 
with chemotherapy for the treatment of EGFR-expressing, KRAS-non mutated, 
metastatic colorectal cancer. Cetuximab is also approved for use in combination with 
radiation therapy for treating squamous cell carcinoma of the head and neck (SCCHN) or 
in combination with platinum-based chemotherapy and 5-fluorouracil (5-FU) for the 
treatment of recurrent and/or metastatic SCCHN.  
CetuGEX™ is an improved second-generation antibody, designed to fully retain the 
antigen binding properties of cetuximab, e.g., affinity, specificity and EGFR inhibition, 
and is improved by fully human glycosylation and glycosylation optimization in its anti-
tumor efficacy mediated by antibody dependent cell cytotoxicity (ADCC) and its lack of 
potentially immunogenic carbohydrate chains in order to improve drug efficacy and to 
reduce side effects. To obtain the fully human and optimized glycosylation, CetuGEX™ 
is produced in a cell line of the GlycoExpress™ system. Improvement of ADCC-
mediated anti-tumor efficacy against EGFR positive tumor cells was demonstrated in in 
vitro studies in comparison to cetuximab. Adverse effects are likely to be reduced since 
non-human carbohydrate structures of cetuximab which result from its rodent cell based 
production system do not occur on CetuGEX™. The Gal-Gal carbohydrate and also other 
non-human structures present on cetuximab such as the neuraminic acid NeuGc are 
potentially immunogenic and known to be responsible for hypersensitivity reactions 
following cetuximab therapy.  
Glycotope GmbH intends to develop CetuGEX™ in various tumor indications, based on 
target expression and patient experience starting in patients with recurrent/metastatic 
SCCHN.  
5.1.1 
Study Drug – Mode of Action 
CetuGEX™ specifically binds to the EGFR and acts as a competitive antagonist at the 
ligand binding site of EGFR. The antigen specificity is exactly the same as for cetuximab. 
An increasing body of data from various anti-tumor antibodies, such as rituximab 
(MabThera®), trastuzumab (Herceptin®) and cetuximab, indicates that the ADCC activity 
is the key mode of action of therapeutic anti-tumor antibodies in patients. Glycosylation 
structure especially the absence of core fucose and the presence of bisecting GlcNAc 
within the antibody Fc part are known key structures for an increased ADCC activity. 
Core fucose is present and bisecting GlcNAc absent on the Fc part glycans produced in 
rodent systems such as CHO and SP2/0 as it is the case for cetuximab. Therefore, 
CetuGEX™ was glyco-optimized to contain bisecting GlcNAc and largely reduced core 
fucose of Fc glycans in order to achieve improved ADCC activity in a fully human 


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glycosylation setting. In vitro assays show that glyco-optimization of CetuGEX™ leads 
to a higher binding affinity of the molecule to the Fc-gamma receptor IIIa (FcγRIIIa) on 
natural killer cells, thereby enhancing ADCC activity and probably broadening the 
subpopulations per indication benefitting from such an antibody. 
Two allotypes of this receptor are known which have different affinities to human IgG1 
depending on the glycosylation of the Fc tail of IgG1. While antibodies with core fucose 
such as rituximab, trastuzumab and cetuximab bind to the V allotype inducing some 
ADCC activity in homozygous patients, they show a strongly reduced binding to the F 
allotype with little or no ADCC activity in homozygous (FF) or heterozygous (FV) 
patients. Addition of bisecting GlcNAc and/or reduction of core fucose at the Fc part 
glycan results in an increase of the binding affinity to the FcγRIIIa and an increase in 
ADCC activity. This increase is most pronounced for F allele types thereby broadening 
the patient coverage for the ADCC-mediated anti-tumor effect of antibodies1, 2, 3, 4. This is 
also reflected by studies showing that patients with the higher affinity FcγRIIIa V 
allotype (VV) have a better clinical outcome than those with the lower affinity FcγRIIIa F 
allotype5, 6, 7, 8.  
The key mode of action of ADCC-mediated killing is improved for CetuGEX™ 
compared to cetuximab as tested in human assay systems. The degree of ADCC increase 
depends on the FcγRIIIa polymorphism status of the effector cells. The ADCC increase 
compared to cetuximab is higher for effector cells from donors comprising the FcγRIIIa F 
variant (~50-fold on FF, ~20-fold on FV) than for effector cells being homozygous for 
the V variant (~10-fold on VV). By achieving a ~10-fold improvement of anti-tumor 
ADCC activity with homozygous FcγRIIIa V alleles (the one best working for 
cetuximab) CetuGEX™ even reaches comparable absolute tumor cell killing rates with 
all receptor variants including the F allotypes. Thereby, the suitable patient spectrum is 
potentially broadened by making effective anti-tumor ADCC activities available also for 
the 80% of the patients bearing the lower affinity FcγRIIIa (FV and FF). 
It is expected that due to improved ADCC activity for all FcγRIIIa allotypes CetuGEX™ 
will show comparable anti-tumor activity against tumor cells largely independent on 
KRAS status (KRAS wild types and mutants) because the downstream effector 
mechanisms mediated by EGFR are less relevant for the therapeutic effect. 
5.1.2 
GlycoExpress™ (GEX™) 
The anti-tumor activity of cetuximab was improved manifold by glycolization-
optimization using the proprietary production system GlycoExpress™ (GEX™). 
GlycoExpress™ is a toolbox consisting of a series of newly developed human 
glyco-engineered cell lines biotechnologically optimized not only for product 
optimization but also for high yield protein expression and fully reproducible quality 
from batch to batch. The GlycoExpress™ system is fully serum and virus free and well 
documented, rendering it suitable for pharmaceutical production. Three antibodies and 
1 non-antibody manufactured using GlycoExpress™ are currently being tested in human 
clinical studies. 


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5.2 
Clinical Experience 
A phase 1 study has been performed at 5 sites in Germany, Italy and Switzerland. This 
was a dose escalation, multicenter study evaluating the safety, tolerability and 
pharmacokinetics of CetuGEX™ after intravenous administration in patients with locally 
advanced and/or metastatic solid cancers. The effect of CetuGEX™ on the development 
of anti-drug antibodies and on tumor response was also evaluated. This was an open-
label, dose-escalation study in a 3 + 3 design, in which 3 to 6 eligible patients were 
enrolled into each of the sequential ascending dosing cohorts. CetuGEX™ was 
administered in 500 ml physiologic saline solution by intravenous infusion over a 2 or 3 
hour-period, later amended to a more complex scheme. 
Until the relevant cut-off date for the clinical study report, 40 patients were treated on a 
weekly (8 dose levels from 12 to 1370 mg flat dose), or once-every-two-weeks (990 mg 
flat) schedule. Twenty-four patients had received at least 8 weekly doses and were thus 
evaluable for activity. The most frequently observed related treatment-emergent adverse 
events (TEAEs), all grades, apart from infusion related reactions (IRRs), were acneiform 
dermatitis (25%), skin rash (28%), asthenia (15%), fatigue (13%) and nausea (10%). 
Observed IRRs, all grades, (70%), virtually restricted to the first infusion and most of 
mild or moderate grade, were associated with cytokine secretion: IL-6, IL-8, TNFα, IFNγ 
and IP-10 as marker of macrophage activation. An optimized infusion scheme and 
premedication reduced the incidence of IRRs. Activity was seen over all dose levels. One 
patient with non-small cell lung cancer achieved a complete response. Another 2 patients 
with esophageal and gastric cancer without measurable disease at study entry had marked 
improvement of symptoms and normalization of tumor markers. Additional 15 patients 
had stable disease lasting from 8 weeks to over a year, including several minor responses, 
leading to a clinical benefit rate of 45% (18/40) in the overall and 75% (18/24) in the PP 
population. Pharmacokinetics (PK) supports weekly and bi-weekly dosing. One 
additional patient was included into the study after the cut-off date and results of this 
patient are not yet included within the summary presented above. 
5.3 
Summary of Potential Risks and Benefits 
As an optimized (bio-superior) second-generation antibody of the marketed product 
cetuximab, CetuGEX™ has the potential to become a considerably more active 
anti-EGFR antibody due to its significantly higher tumor-specific ADCC activity caused 
by the humanized and optimized glycosylation in the production process. At the same 
time the removal of non-human immunogenic Gal-Gal carbohydrate structures is 
expected to avoid the severe hypersensitivity reactions reported to be caused by non-
human carbohydrate structures of cetuximab (in some geographical regions in about 22% 
of patients treated with cetuximab). Furthermore, CetuGEX™ opens the chance of 
therapeutic activity in otherwise unsuitable patients. As the key anti-tumor mode of 
action, ADCC is expected to be not only pronounced in patients with FcγRIIIa receptor 
allele status VV (8 - 27 % of the population) but also in those with FF and FV allotypes 
(73 - 92 % of the population), while the latter show no or very low anti-tumor ADCC 
activity with cetuximab. Therefore extended patient populations may benefit from the 
potential anti-tumor activity of CetuGEX™ in the clinic. The well-known cutaneous 


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toxicity occurring in up to 90% of patients treated with the approved anti-EGFR 
antibodies cetuximab and panitumumab (Vectibix®) is clearly linked to the EGFR 
inhibition in the skin and correlates with the anti-tumor efficacy of the antibody. This was 
also observed in the patients treated with CetuGEX™, although from first evidence with 
lower incidence and grade. The phase 1 study showed reasonable tolerability with an 
expected high incidence of IRRs (mostly grades 1 and 2, few grade 3 and no grade 4) in 
conjunction with a considerable activity, given the far advanced cancer population. 
Immediate allergic infusion reactions are unlikely; however IRRs of low grade were very 
common with this compound. As in general, although it didn’t happen in the reported 
study, any infusion reaction has the potential to occur as life threatening severe reaction 
like a hypertensive crisis associated with neurologic signs and symptoms, wheezing, 
oxygen desaturation, chest pain, headaches, rigors, and diaphoresis, cardiac emergencies, 
anaphylaxis, cytokine release syndrome, convulsions, or hypotension, monitoring for 
these events will be cautiously undertaken. 
In conclusion, the benefit-risk balance is deemed positive. 
5.4 
Rationale 
Cancers of the head and neck, primarily tumors of the oral cavity, pharynx and larynx, 
account for > 5% of all malignancies. Most head and neck cancers, approximately 90% in 
Western societies, are SCCHN. Tobacco and alcohol use are the most important risk 
factors for the development of head and neck cancers. Beside cigarette smoke, chewing 
of tobacco increases the risk for cancers of the oral cavity. Smoking pipes may lead to 
cancer of the lip and tongue. The detrimental effect of tobacco is further enhanced by 
alcohol abuse and by poor oral hygiene. Further risk factors are virus infections caused by 
Epstein-Barr virus and human papilloma viruses. Due to the drinking and smoking habits, 
many patients also suffer from concomitant diseases such as coronary artery disease, 
chronic bronchitis or liver cirrhosis. 
Treatment of head and neck cancer varies depending on localization, spread and 
histological subtype. The primary therapy option is surgery with excision of the primary 
tumor combined with extensive neck dissection. For advanced-stage disease, surgery and 
radiotherapy are often combined with chemotherapy usually delivered postoperatively. 
For unresectable disease, combined chemotherapy and radiotherapy has become the 
standard of care. The majority of patients presenting in a more advanced disease stage 
will eventually relapse either loco regional and/or at distant sites9,10. Patients with 
recurrent and/or metastatic disease who are not candidates for local therapies are usually 
offered chemotherapy, with the goal of prolonging survival and controlling symptoms. 
Platinum based chemotherapy is the current standard of care in patients with recurrent 
and/or metastatic SCCHN and since 2008 a new targeted therapy, cetuximab, showed 
benefit by prolonging overall survival in addition to platinum-based chemotherapy and 
5-FU without modifying the characteristic AE profile of platinum-based chemotherapy 
and without negative impact on quality of life (QoL). Platinum based chemotherapy plus 
cetuximab is the current standard of care in patients with recurrent and/or metastatic 
SCCHN9. Recurrent and metastatic SCCHN still carries a poor prognosis. The median 


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survival of patients with recurrent and/or metastatic SSCHN is 6-9 months and the 1-year 
survival is 20-40%9. 
The clinical conduct of this study is planned in accordance to the guidance document of 
the International Conference of Harmonization (ICH) on Good Clinical Practice (GCP) 
and study design is chosen in accordance with the published guidelines on the clinical 
investigation of human normal immunoglobulin for intravenous administration (IVIgs) 
(EMA/CHMP/BPWP/94033/2007), on similar biological medicinal products containing 
monoclonal 
antibodies 
– 
non-clinical 
and 
clinical 
issues 
(EMA/CHMP/BMWP/403543/2010) and on the evaluation of anticancer medicinal 
products in man (CHMP/EWP/205/95).  
6 
OBJECTIVES 
6.1 
Primary Objective 
The primary objective of the study is to evaluate the efficacy of CetuGEX™ for the 
treatment of patients with stage III/IV recurrent and/or metastatic SCCHN as compared to 
cetuximab (both in combination with platinum-based chemotherapy) in terms of PFS. 
6.2 
Secondary Objectives 
Secondary objectives are as follows: 
1. To evaluate further efficacy criteria, safety and QoL of patients with stage III/IV 
recurrent and/or metastatic SCCHN treated with CetuGEX™ as compared to 
cetuximab (both in combination with platinum-based chemotherapy). 
2. To assess PK parameters and profiles of CetuGEX™. 
3. To assess efficacy and safety based on genetic markers for immune response 
(FcγR allotypes) and biomarkers. 
7 
STUDY DESIGN 
7.1 
Overall Study Design and Plan 
7.1.1 
Overview 
This is a phase II, randomized, controlled, multicenter study with first line treatment 
(6 cycles of 5-FU and cisplatin in combination with CetuGEX™ vs. combination with 
cetuximab) followed by single-agent maintenance therapy (CetuGEX™ or cetuximab, 
respectively). 
The randomization to CetuGEX™ vs. cetuximab will be performed using a 1:1 ratio and 
will be stratified by: 
 FcγRIIIa status (FF or FV or VV) 
 Oral cavity and oropharynx vs. other locations 


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 Locally recurrent vs. metastatic disease 
 EGFR treatment naïve vs. EGFR treatment as part of multimodal therapy.  
The study will include 3 separate study periods following screening: 
Combination treatment phase: 
Eligible patients will be randomized to receive as first line treatment either CetuGEX™ 
or cetuximab in combination with chemotherapy (5-FU and cisplatin) for the maximum 
duration of 6 cycles of combined treatment. In case of toxicity, chemotherapy can be dose 
reduced, discontinued or, if later than the first cycle, switched to carboplatin. If 
discontinued earlier for any other reason apart from progression, patients will start the 
maintenance phase at that time. 
As soon as at least 10 patients per treatment arm have completed the second cycle of 
combination therapy, patient safety data will be reviewed by an independent data safety 
monitoring board (DSMB). 
Single-agent maintenance phase: 
After completion or discontinuation of combination chemotherapy for any other reason 
apart from progression, the treatment will be followed by maintenance therapy with 
CetuGEX™ alone or cetuximab alone, respectively. Single-agent maintenance therapy 
will be continued until progression of disease or limiting toxicity.  
Follow-up:  
A Safety Visit must be performed 28 (+2) days after the last administration of the study 
drug for all randomized patients. In case of treatment discontinuation due to reasons other 
than disease progression, patients will stay on the regular study schedule until disease 
progression is documented and will then attend a Final Examination Visit. In case of 
treatment discontinuation due to disease progression, the Safety Visit is identical to the 
Final Examination Visit.  
After the Final Examination, patients will be followed-up by quarterly phone calls until 
death or for a maximum duration of 24 months after randomization of the last patient for 
assessment of overall survival. 
An overview on the duration of each study period as well as the overall study duration is 
provided in Section 10.2.  


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7.1.2 
Endpoints 
The primary efficacy endpoint is the progression-free survival (PFS) as assessed by the 
investigator. 
Secondary endpoints are: 
Efficacy endpoints: 
 PFS as assessed by independent centralized reading 
 Objective response rate (ORR; i.e., complete response [CR] + partial response 
[PR]) at the end of combination treatment 
 Best overall response rates (including maintenance therapy treatment) 
 Clinical benefit rate (CBR; i.e., CR + PR + stable disease [SD])   
 Duration of response 
 Overall survival (OS) 
 Time to treatment failure (TTF) 
 
QoL scores as assessed by European Oncology Research Trials Committee 
(EORTC) 
QoL 
questionnaires 
(QLQ) 
EORTC-QLQ-C30 
and 
EORTC-QLQ-H&N35. 
In addition, PFS and all secondary efficacy endpoints listed above will be analyzed by 
FcγRIIIa-allotype subgroups (i.e., FF, FV and VV), by p16 status, by EGFR status, and 
other potential parameters, unless the sample sizes in subgroups are too low. 
Pharmacokinetic endpoints:  
Antibody trough levels and PK profiles of CetuGEX™ will be assessed throughout the 
study. 
Safety endpoints are: 
 Incidence of AEs and serious AEs, including incidence of target/class-specific side 
effects (skin reactions, diarrhea) 
 IRRs 
 Physical and laboratory assessments 
 Vital signs 
 Electrocardiogram (ECG) 
In addition, the incidence of AEs will be analyzed by FcγRIIIa-allotype subgroups (FF, 
FV, VV). 
Exploratory endpoints are: 
 Immunogenicity: incidence of anti-drug antibodies (ADAs) 
 Immunological parameters: cytokine levels and immune cell status. 


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7.2 
Discussion of Study Design 
The study is designed as a 2-arm study in patients with SCCHN to assess the efficacy and 
safety of CetuGEX™ as compared to cetuximab, both in combination with platinum-
based chemotherapy and thereafter as single-agent maintenance therapy until progression 
of disease (PD) in patients with recurrent or metastatic SCCHN.  
Cetuximab as well as CetuGEX™ are chimeric monoclonal IgG antibodies binding to the 
EGFR, which is overexpressed in more than 95% of SCCHN patients. Both cetuximab 
and CetuGEX™ are acting as competitive agonists at the ligand-binding site of EGFR 
and thus interrupt the signaling pathways and induce apoptotic cell death to EGFR 
expressing tumor cells. Cetuximab has received marketing authorization for the treatment 
of patients with SCCHN, either in combination with radiation therapy for locally 
advanced disease or in combination with platinum-based chemotherapy for patients with 
recurrent or metastatic SCCHN and therefore was selected as active control treatment in 
this study. 
Antibody dependent cellular cytotoxicity, one of the main antitumor mechanisms of 
monoclonal antibodies of the IgG1 class, is mediated by surface receptors on immune-
effector cells belonging to the FcγR family. The activity of cetuximab is strongly related 
to the V allotype of the FcγRIIIa and most prevalent when homozygously expressed (VV 
allotype). CetuGEX™ does not show this dependency on FcγRIIIa phenotypes from pre-
clinical experience and may as well be effective in patients with FF and FV-allotypes. 
This is most probably depending on the glycosylation status of the Fc part of the 
antibody, which has been improved for CetuGEX™ in contrast to cetuximab. One goal of 
this study is to confirm this pre-clinically observed independency on FcγRIIIa phenotypes 
in clinical practice. 
Eligible study population are patients aged at least 18 years at screening, with metastatic 
and/or recurrent, stages III or IV SCCHN, not eligible for local treatment.  
7.3 
Study Site(s) 
The study will take place at approximately 40 sites in Europe and the USA. Each site is 
anticipated to screen a sufficient number of patients to be able to randomize a total of 
approximately 240 patients.  
7.4 
Point of Contact 
A point of contact will be identified to provide information to patients about where to 
obtain information on the study, the rights of the patient, and whom to contact in case of 
study-related injury. This information will be provided in the patient information and 
informed consent form (ICF). 


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8 
PATIENT POPULATION 
8.1 
Selection of Study Population and Diagnosis 
It is planned to randomize approximately 240 adult patients with stage III/IV recurrent 
and/or metastatic SCCHN. An enrollment log of enrolled patients must be maintained at 
each study site. 
8.2 
Study Entry Criteria 
8.2.1 
Inclusion Criteria 
A patient will be eligible for study participation if the patient meets all of the following 
criteria: 
1. Patients with histologically confirmed recurrent and/or metastatic SCCHN not 
eligible for local treatment. 
2. Patients with measurable disease according to Response Evaluation Criteria in 
Solid Tumors (RECIST) 1.1. 
3. Patients aged at least 18 years at screening. 
4. Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1. 
5. Minimum life expectancy of 3 months. 
6. Tissue samples available for specific disease and therapy related biological 
assessments. 
7. If female and of childbearing potential, is non-lactating and has negative 
pregnancy test results at screening and prior to randomization. 
8. If female, is either not of childbearing potential (defined as postmenopausal for at 
least 1 year or surgically sterile [bilateral tubal ligation, bilateral oophorectomy, 
or hysterectomy]) or willing to use highly effective contraceptives during study 
participation until 6 months after last administration of any study medication, 
particularly cisplatin or carboplatin, with a failure rate < 1% according to the Note 
for Guidance on non-clinical safety studies for the conduct of human clinical trials 
and marketing authorization for pharmaceuticals (CPMP/ICH/286/95) of the 
European Medicines Agency (EMA).  
 
Male patients who have partners of childbearing potential have to confirm 
adequate use of highly effective contraceptives during study participation until 6 
months after last administration of any study medication, particularly cisplatin or 
carboplatin, as well. 
9. Willing and able to comply with the protocol. 
10. Willing and able to provide written informed consent. 


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8.2.2 
Exclusion Criteria 
A patient will be excluded from the study if the patient meets any of the following 
criteria: 
1. Prior systemic chemotherapy, except if given as part of a multimodal treatment 
for locally advanced disease which was completed more than 6 months prior to 
randomization.  
2. Cetuximab or other EGFR targeting agent treatment, except if given as part of a 
multimodal treatment for locally advanced disease which was completed more 
than 6 months prior to randomization. 
3. Surgery (other than minor interventions like diagnostic biopsy or intravenous port 
implantation) or irradiation within 30 days before randomization. 
4. Concomitant anti-tumor therapy or concomitant immunotherapy, live vaccines 
including yellow fever vaccination (as per cisplatinum Summary of Product 
Characteristics [SmPC, Appendix F]). 
5. Concomitant corticosteroid treatment unless specified within the protocol. 
6. Clinical evidence of brain metastasis or leptomeningeal involvement. 
7. Patients with nasopharyngeal tumors. 
8. Concomitant malignant disease, except for adequately treated tumors with high 
likelihood of being cured (e.g., basal cell cancer of the skin, cervical cancer or 
breast cancer in situ). Patients with previous malignancies but without evidence of 
disease for at least 5 years will be allowed to enter the study. 
9. Patients with renal or hepatic impairment (serum creatinine and bilirubin > 1.5 
fold above the upper limit of normal ranges, creatinine clearance < 60 ml/min, and 
transaminase > 5 fold above the upper limit of normal ranges) and patients with 
hematology parameters outside the normal ranges (hemoglobin < 9 g/dl, absolute 
neutrophil count < 1500/mm3 and platelet count < 105/mm3) at screening as well 
as patients with impaired auditory function or platinum-related neuropathy. 
10. Clinically active infections ≥ Grade 2 using National Cancer Institute (NCI) 
Common Terminology Criteria for Adverse Events (CTCAE) version 4 and/or 
requiring intravenous antibiotics. 
11. Known active hepatitis B or C. 
12. Known human immunodeficiency virus (HIV) infection. 
13. Myocardial infarction within 6 months prior to screening. 
14. Symptomatic congestive heart failure (New York Heart Association [NYHA] 
Grade 3 or 4), unstable angina pectoris within 6 months prior to screening, 
significant cardiac arrhythmia, history of stroke or transient ischemic attack 
within 1 year prior to screening. 
15. History of keratitis requiring medical interventions within the last 5 years or 
interstitial lung disease. 


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16. Patients with any other disorder that, in the opinion of the investigator, might 
interfere with the conduct of the study. 
17. Patients with an unstable condition (e.g., psychiatric disorder, a recent history of 
drug or alcohol abuse, interfering with study compliance, within 6 months prior to 
screening) or otherwise thought to be unreliable or incapable of complying with 
the requirements of the protocol. 
18. Patients institutionalized by official means or court order. 
19. Receipt of any other investigational medicinal product within the last 30 days 
before randomization or any previous CetuGEX™ administration. 
20. Prior allergic reaction to a monoclonal antibody, grade 3 IRR or any grade 4 
reaction to a monoclonal antibody. 
21. Known sensitivity to any component of the investigational medicinal product 
(IMP) and medication used in this study.  
8.3 
Premature Patient Withdrawal 
All patients will be advised that they are free to withdraw from participation in this study 
at any time, for any reason, and without prejudice. Every reasonable attempt should be 
made by the investigator to keep patients in the study; however, patients must be 
withdrawn from the study if they withdraw consent to participate. Investigators must 
attempt to contact patients who fail to attend scheduled visits by telephone or other means 
to exclude the possibility of an AE being the cause of withdrawal. Should this be the 
cause, the AE must be documented, reported, and followed as described in Section 11.2. 
The sponsor reserves the right to request the withdrawal of a patient due to protocol 
violations or other reasons. 
The investigator also has to withdraw patients from the study at any time for the 
following reasons: 
 Unacceptable toxicity 
 More than 3 weeks delay of scheduled infusion of CetuGEX™/cetuximab (i.e., 
missing more than 2 consecutive infusions) 
 Intercurrent illness interfering with study procedures 
 Noncompliance with study procedures, or 
 Pregnancy.  
If a patient is withdrawn from treatment prior to PD due to unacceptable toxicity or any 
other reasons as detailed above except noncompliance with study procedures, the patient 
will remain on regular study schedule until progression of disease unless this might 
interfere with the patient's best interest. 


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If a patient is withdrawn from the complete study before documented progressive disease, 
the reason for withdrawal and the date of discontinuation will be recorded on the 
appropriate electronic case report form (eCRF). Whenever possible, the evaluations that 
were to be conducted at the Final Examination should be performed at the time of 
premature discontinuation. 
8.4 
Replacement of Withdrawn Patients 
No replacement procedure of withdrawn patients is planned or accepted for this study. 
9 
TREATMENTS 
9.1 
Identification of Investigational Medicinal Products (IMPs) 
Investigational medicinal products (IMPs) of this study are CetuGEX™ and the active 
comparator cetuximab. 
In addition to CetuGEX™ or cetuximab, all patients will receive 5-FU and cisplatin or, in 
case of unacceptable toxicity, carboplatin. These drugs are non-investigational medicinal 
products (nIMPs) in this study and will be used according to general standard of care. 
9.1.1 
Investigational Medicinal Products  
CetuGEX™ 
CetuGEX™ is a chimeric monoclonal glyco-optimized IgG antibody with fully human 
glycosylation. CetuGEX™ binds to the EGFR and shows an enhanced ADCC activity 
against tumor cells. 
Name of the drug:
CetuGEX™
Active substance:
Chimeric monoclonal IgG antibody
Dosage form:
Solution for intravenous infusion, provided in single-use vials
Strength:
240 mg
Volume:
48 mL
Excipients: 
Sodium citrate, sodium chloride, Tween 80, glycine, water for 
solution for infusion
CetuGEX™ will be manufactured in accordance with Good Manufacturing Practice 
(GMP) requirements by Glycotope Biotechnology, Heidelberg, Germany. 
Cetuximab  
Cetuximab, a chimeric monoclonal IgG antibody binding to the EGFR, will be the 
reference drug used in this study. The authorized product will be sourced from the 
European or US market as applicable and will be provided by Glycotope GmbH or its 
delegate for the European sites.  


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Name of the drug:
Cetuximab 
Active substance:
Chimeric monoclonal IgG antibody
Dosage form: 
Solution for infusion, 2 mg/mL or 5mg/mL in vials with 
volumes as applicable for the corresponding market.
For more detailed information, please refer to the Summary of Product Characteristics 
(SmPC) for cetuximab11. 
9.1.2 
Non-Investigational Medicinal Products  
5-Fluorouracil 
The chemotherapy drug 5-FU, a thymidylate synthase inhibitor, will be administered to 
all patients for the first line treatment phase (a maximum of 6 cycles).  
Cisplatin (or, in case of unacceptable toxicity, Carboplatin) 
The platinum-salt that will be used in this study is cisplatin. It will be administered as 
intravenous infusion for the first line treatment phase (maximum of 6 cycles) according to 
the routine standard of care at each site, avoiding corticosteroids as far as possible. If 
corticosteroids are required, dexamethasone is to be used (unless contraindicated). 
Carboplatin may be administered in the same fashion in case cisplatin is not tolerated and 
dose reduction of cisplatin is not deemed to be the appropriate measure. However, 
cisplatin is mandatory for the first therapy cycle. 
9.2 
Labeling and Packaging 
9.2.1 
Labeling 
The medication labels for the IMPs and nIMPs will comply with the requirements of 
local laws and regulations as well as with GMP Annex 13 and ICH-GCP. Master labels 
will be filed within the Trial Master File (TMF). 
9.2.2 
Packaging  
The packaging and supply to the study sites of CetuGEX™ and cetuximab will be 
performed by Glycotope GmbH or a delegate company contracted and authorized by 
Glycotope GmbH.  
9.3 
Treatments Administered 
The treatment period will consist of a first line treatment phase followed by maintenance 
therapy. CetuGEX™, cetuximab, 5-FU, cisplatin and carboplatin must be administered 
under the supervision of an investigator experienced in the use of antineoplastic 
medicinal products. Close monitoring is required during the infusion and for at least 
1 hour after the end of the infusion. Availability of resuscitation equipment must be 
ensured.  
Prior to the first infusion of cetuximab, patients must receive premedication with an 
antihistamine and dexamethasone (or another corticosteroid if dexamethasone is 


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contraindicated). According to the SmPC11 this premedication is recommended prior to 
all subsequent infusions of cetuximab.  
Prior to the first two infusions of CetuGEX™ (Day 0 and Day 1 of 990mg initial loading 
dose) patients must receive premedication consisting of paracetamol (acetaminophen) 1 g 
per os (PO) the evening before the infusion as well as paracetamol 1g PO, dexamethasone 
(or another corticosteroid if dexamethasone is contraindicated) and antihistamines 
approximately 60 minutes before the start of infusion. Premedication should be avoided 
during subsequent cycles. However, premedication might be applied after the occurrence 
of an IRR in relation to the previous infusion. 
During administration of CetuGEX™/cetuximab, IRRs might occur. For a more detailed 
description of possible IRRs and dose adjustment procedures to be followed in case of 
IRRs, please refer to Section 9.9.  
Combination Treatment Phase 
Patients who fulfill all inclusion criteria and do not meet any of the exclusion criteria will 
be randomized in a 1:1 ratio to receive either CetuGEX™ or cetuximab in combination 
with 5-FU and cisplatin (or carboplatin later than the first cycle, in case of unacceptable 
toxicity), for a maximum of 6 chemotherapy cycles.  
During the combination treatment phase, even if the chemotherapy is delayed for any 
reason (e.g., see Sections 9.9.3 and 9.9.4), the IMP (CetuGEX™ or cetuximab) 
administration may not be withheld and needs to be continued with weekly infusions as 
scheduled. 
CetuGEX™ 
The study drug CetuGEX™ will be administered as infusion to all patients randomized to 
the CetuGEX™ arm, once weekly, starting with Day 0. Starting with the second infusion 
(Day 8 of Cycle 1), a time window of ± 1 day will be allowed for the weekly infusions 
(calculated from the previous infusion). 
The initial dose will be 990 mg and subsequent doses will be 720 mg once weekly. The 
initial loading dose will be given as split-dose over 2 days with a priming dose of 60 mg 
on Day 0 diluted to a total volume of 100 mL (administered over 2 hours with a 30-
minute break) and the remaining dose of 930 mg on Day 1 diluted to a total volume 
500 mL (the intravenous infusion will last for approximately 4 hours). Infusion on Day 1 
should be started within 24 ± 2 hours after start of infusion on Day 0. The exact timing, 
total volumes of infusions, steps for increasing infusion flow rates and duration of each 
flow rate for first and subsequent infusions can be found in Table 9-1. If clinically 
indicated, timely discontinuation of the infusion will be possible in order to prevent 
serious side effects. 
 


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Table 9-1:  
CetuGEX™ Infusion Scheme and Dosage 
Infusion/Timing
Dose [mg] 
(Total 
Volume) 
Duration 
[min] 
Flow rate 
[(mL/h] 
Dose in 
mg/h 
Infusion 1 (Cycle 1) 
990
Day 0
60 
(100 mL) 
60
35
21
Break (30)
NA
60
65
39
Day 1
930 
(500 mL) 
30
20
37
60
40
74
≈ 164
165
306
Infusion 2* (Day 8 of Cycle 1)
720 
(500 mL) 
60
30
43
60
55
79
≈ 116
215
310
Infusion 3* (Day 15 of Cycle 1) 
and subsequent weekly infusions  
720 
(500 mL)
90 
333 
480 
* Starting with the second infusion (Day 8 of Cycle 1), a time window of ± 1 day will be allowed for the 
weekly infusions (calculated from the previous infusion). 
Cetuximab 
Cetuximab will be administered once weekly as infusion to all patients randomized to the 
cetuximab arm. Starting with the second infusion (Day 8 of Cycle 1), a time window of 
± 1 day will be allowed for the weekly infusions (calculated from the previous infusion). 
The initial dose will be 400 mg/m2 body surface area (BSA) and each subsequent dose 
will be 250 mg/m2 BSA. The maximum infusion rate for the initial dose must not exceed 
5 mg/min. The maximum infusion rate for subsequent doses must not exceed 10 mg/min. 
The BSA will be calculated using the Mosteller formula: 
 
BSA [m2] = (Weight [kg] × Height [cm]/3600)1/2 
The following information related to the infusion of CetuGEX™ and cetuximab will be 
recorded for each infusion: 
 Infusion start time 
 Infusion stop time 
 Time, duration and reason of any infusion interruptions, if applicable 
 Adjustments to infusion rate, if applicable 
Concomitant Platinum-based Chemotherapy 
During the combination treatment phase, all randomized patients will receive 5-FU as 
continuous intravenous infusion, in combination with cisplatin (or carboplatin in case of 
required substitution of cisplatin in further cycles). This platinum-based chemotherapy 
will be administered for a maximum of 6 cycles of 3 weeks each, starting approximately 
1 hour after CetuGEX™/cetuximab infusion on Day 1 of each cycle. If the 
CetuGEX™/cetuximab infusion is administered in the afternoon, the concomitant 


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platinum-based chemotherapy may be administered the next morning; however, all drugs 
should be given within 24 hours. 
5-fluorouracil will be administered in doses of 1000 mg/m2 BSA per day every 3 weeks 
(one cycle of cisplatin or carboplatin treatment) as continuous intravenous infusion on 
Days 1 to 4 of each cycle.  
Cisplatin will be administered as a dose of 100 mg/m2 BSA by infusion every 3 weeks, 
on Day 1 of each cycle, according to current standards and prescribing guidelines 
including hydration before and after cisplatin treatment, as required (please refer to the 
instructions in the corresponding SmPC [Appendix F]). In case cisplatin has to be 
replaced by carboplatin for toxicity reasons, Carboplatin will be administered at an area 
under the curve (AUC) of 5 mg/mL/min (using the Calvert formula for calculation12) as a 
1-hour intravenous infusion every 3 weeks, on Day 1 of each cycle. As per SmPC 
(Appendix H), carboplatin may not be used in patients with bleeding tumors. 
In case of related relevant toxicity, each compound of the chemotherapy treatment can be 
discontinued prior to completion of 6 cycles of chemotherapy, and patients will continue 
with the remaining compounds of the combination therapy. After all chemotherapy has 
been discontinued, irrespective if the 6 cycles are completed or discontinued prematurely 
for any other reason apart from progression, patients will directly enter the maintenance 
phase.   
Single-Agent Maintenance Treatment Phase 
After completion or discontinuation of chemotherapy for any other reason apart from 
progression, the treatment will be followed by maintenance therapy receiving 
CetuGEX™ alone or cetuximab alone, respectively. Single-agent maintenance therapy 
will be continued with unchanged dosing schedule until progression of disease or limiting 
toxicity. 
9.4 
Dispensing and Storage 
The IMPs and nIMPs supplied by Glycotope GmbH are to be used exclusively in the 
clinical study according to the instructions of this protocol. The investigator and the 
dispensing study team member(s) are responsible for dispensing the study medications 
according to the dosage scheme and for ensuring proper storage of the IMPs and nIMPs. 
The study medication and the nIMPs will be administered at the study site, under strict 
surveillance of experienced study team members.  
All study medication must be stored in accordance with the manufacturer's instructions 
and separately from normal hospital/practice stocks in a securely locked area, only 
accessible to authorized study personnel.  
CetuGEX™ and cetuximab have to be stored by 2-8°C and should not be frozen. 
5-fluorouracil and cisplatin have to be stored at 15-25°C and protected from light. 
Carboplatin has to be stored not exceeding 25°C and protected from light. 
Dispensing will only be performed by authorized study team members and according to 
the interactive web response system (IWRS) for randomization. IWRS will be performed 


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by Perceptive. Receipt and dispensing of study medication must be recorded by an 
authorized person at the investigator´s site. 
Detailed instructions concerning the storage, preparation and administration of IMPs and 
nIMPs will also be described in a separate Drug Handling Manual. 
All unused study medication should be returned to Glycotope GmbH or its designee for 
destruction or can be destroyed at the study site upon sponsor's request after the drug 
accountability check has been performed. 
9.5 
Method of Assigning Patients to Treatment Groups 
Patients eligible for study participation will be randomized using a 1:1 ratio to either the 
CetuGEX™ or cetuximab arm. The randomization may take place within 3 days prior to 
Day 0 of the first treatment cycle for the patients randomized in CetuGEX™ arm or prior 
to Day 1 of the first treatment cycle.  
Randomization will be stratified by: 
 FcγRIIIa status (FF or FV or VV) 
 Oral cavity and oropharynx vs. other locations 
 Locally recurrent vs. metastatic disease 
 EGFR treatment naïve vs. EGFR treatment as part of multimodal therapy 
A centralized randomization procedure the IWRS will be used assigning a unique 
randomization number to each patient. 
9.6 
Blinding and Unblinding Treatment Assignment 
Blinding at the level of study treatment does not apply since the study will be open label. 
9.7 
Selection of Doses in the Study 
Doses for cetuximab, 5-FU, cisplatin and carboplatin are chosen based on routine 
standard of care and according to the instructions of the corresponding SmPCs and 
product information leaflets for the treatment of SCCHN. 
The dosage of CetuGEX™ has been chosen based on the results of former studies and PK 
simulations, indicating that an initial dose of 990 mg followed by subsequent infusions of 
720 mg are well tolerated and safe.  
9.8 
Selection of Timing of Dose for Each Patient 
Timing of dose for each patient has been chosen according to current standard of care and 
based on the instructions in the corresponding SmPCs and product information leaflets. 
According to the instructions for treatment of recurrent or metastatic SCCHN, platinum-
based chemotherapy in combination with 5-FU should not start prior to 1 hour after end 
of cetuximab. The same timing has been chosen for CetuGEX™. The platinum-based 
chemotherapy 
should 
be 
given 
within 
24 hours 
after 
the 
infusion 
of 


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CetuGEX™/cetuximab. Administration of 5-FU should be started within 24 hours after 
the infusion of CetuGEX™/cetuximab. 
9.9 
Dose Adjustment Criteria 
Adjustment of the study drug doses is performed according to the rules described in this 
section. 
Mild or moderate IRRs are very common comprising symptoms such as fever, chills, 
dizziness, or dyspnea that occur in a close temporal relationship mainly to the first 
CetuGEX™/cetuximab infusion.  
Severe IRRs also may commonly occur, in rare cases with fatal outcome. 
In case of IRRs requiring dose adjustment, this should be performed as described in 
following sections. 
The dose of CetuGEX™/cetuximab will be adjusted for CetuGEX™/cetuximab-related 
grade 3 skin toxicities only as displayed in Figure 9-1 and described in sections 9.9.1 and 
9.9.2. CetuGEX™/cetuximab therapy will not be withheld for chemotherapy-related 
toxicities.  
Figure 9-1: 
Treatment Modification in the Event of Grade 3 Skin Toxicity 
Considered 
to 
be 
Related 
to 
Weekly 
Administration 
of 
CetuGEX™/Cetuximab. 
 
yes
yes
Grade 3 
skin toxicity
Delay infusion
for 1 week
Discontinue
treatment
Delay infusion
for 1 week
Resolved to
grade < 2
2nd consecutive week
3rd consecutive week
no
Grade 3 
skin toxicity
Skip
for 1 week
Discontinue
treatment
Skip infusion
for 1 week
Resolved to
grade < 2
2nd consecutive week
3rd consecutive week
no
Dose at 250 mg/m
2
Reduce dose to 150 mg/m
2
1st occurrence
Which grade 3
occurrence ?
Initial dose 
Reduce dose to 600 mg 
(CetuGEX™)/200 mg/m2 
(Cetuximab) 
1st occurrence
2nd occurrence
3rd occurrence
4th occurrence
Which grade 3
occurrence ?
Discontinue treatment
Reduce dose to 480 mg 
(CetuGEX™)/150 mg/m2 
(Cetuximab) 


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9.9.1 
CetuGEX™ 
There were no severe IRRs in the Phase 1 study of CetuGEX™. It was also noted that 
decreasing the infusion rate did not influence the symptom control of mild to moderate 
IRRs. At this time it is recommended that CetuGEX™ infusions should be temporarily 
interrupted where necessary until improvement. 
Whilst no severe IRRs have occurred to date in early clinical trials with CetuGEX™, it 
should be noted that severe IRRs may occur, in rare cases with fatal outcome, and 
investigators should be vigilant of similar reactions like observed for cetuximab (see 
Section 9.9.2).  
In case of a severe IRR, the CetuGEX™ infusion needs to be discontinued immediately, 
and infusion tubing has to be disconnected from the patient. Emergency treatment 
(epinephrine, broncho-dilators, antihistamines, glucocorticoids, intravenous fluids, 
vasopressor agents, oxygen, etc., as medically indicated) might be necessary.  
Patients must be withdrawn immediately from the treatment and must not receive 
any further CetuGEX™ treatment. 
Skin toxicities: If a patient experiences a grade 3 skin toxicity (as defined in the US NCI-
CTC, Version 4.0), CetuGEX™ therapy may be skipped for up to two consecutive 
infusions without changing the dose level. Patients with grade ≥3 reactions should be 
referred to the dermatologist for advice and management. If the toxicity resolves to 
grade 2 or less by the following treatment period, treatment may resume. With the second 
and third occurrences of grade 3 skin toxicity, CetuGEX™ therapy may again be skipped 
for up to two consecutive infusions, with concomitant dose reductions to 600 mg and 
480 mg, respectively. CetuGEX™ dose reductions are permanent. Patients should 
discontinue CetuGEX™ if more than two consecutive infusions are withheld or a fourth 
occurrence of grade 3 skin toxicity occurs despite appropriate dose reduction. 
 


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Table 9-2: 
Treatment Adjustment in the Event of CetuGEX™ Caused 
Allergic/Hypersensitivity Reaction 
 
CTC Grade 
Allergic/ 
Hypersensitivity 
Reaction
Treatment CetuGEX™ 
Grade 1 
Infusions should be temporarily interrupted where necessary until 
improvement of mild IRRs. 
Grade 2 
Infusions should be temporarily interrupted where necessary until 
improvement of moderate IRRs. 
Grade 3 or  
Grade 4 
Stop the CetuGEX™ infusion immediately and disconnect infusion 
tubing from the patient. Administer epinephrine, broncho-dilators, 
antihistamines, glucocorticoids, intravenous fluids, vasopressor agents, 
oxygen, etc., as medically indicated.  
Patients must be withdrawn immediately from the treatment and 
must not receive any further CetuGEX™ treatment. 
 
9.9.2 
Cetuximab 
In case of mild to moderate IRRs, the infusion rate of cetuximab might be decreased and 
it is recommended to maintain the reduced infusion rate for all subsequent infusions.  
During treatment with cetuximab, severe IRRs usually develop during or within 1 hour of 
the initial infusion, but may occur after several hours or with subsequent infusions. 
Although the underlying mechanism has not been identified, some of these reactions may 
be anaphylactoid/anaphylactic in nature and may include symptoms such as 
bronchospasm, urticaria, increase or decrease in blood pressure, loss of consciousness or 
shock. In rare cases, angina pectoris, myocardial infarction or cardiac arrest have been 
observed.  
In case of severe IRRs (grade 3 and 4), the cetuximab infusion requires immediate and 
permanent discontinuation and emergency treatment might be necessary.  
Skin toxicities: In case of skin toxicities like grade 1 or 2 acne –like rash, pruritus or dry 
skin due to cetuximab treatment, events should be treated according to the instructions 
given in the cetuximab SmPC (Appendix E). If a patient experiences a grade 3 skin 
toxicity (as defined in the US NCI-CTC, Version 4.0), cetuximab therapy may be skipped 
for up to two consecutive infusions without changing the dose level. Patients with grade 
≥3 reactions should be referred to the dermatologist for advice and management.  
With the second and third occurrences of grade 3 skin toxicity, cetuximab therapy may 
again be skipped for up to two consecutive infusions (one infusion during maintenance) 
with concomitant dose reductions to 200 mg/m2 and 150 mg/m2 respectively. Cetuximab 


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dose reductions are permanent. Patients should discontinue cetuximab if more than two 
consecutive infusions are withheld or a fourth occurrence of grade 3 skin toxicity occurs 
despite appropriate dose reduction (see Figure 9-1). 
Allergic/hypersensitivity reactions: In each case of allergic/hypersensitivity reaction, 
the investigator should implement treatment measures according to the best available 
medical practice. Based on previous experience with cetuximab allergic/hypersensitivity 
reactions, the treatment guidelines as described in Table 9-3 may be applicable. 
 
Table 9-3: 
Treatment Adjustment in the Event of Cetuximab Caused 
Allergic/Hypersensitivity Reaction 
CTC Grade  
Allergic/ 
Hypersensitivity Reaction 
Treatment 
Grade 1 
Decrease the cetuximab infusion rate by 50% and monitor 
closely for any worsening.  
The total infusion time for cetuximab should not exceed 4 
hours.
Grade 2 
Stop cetuximab infusion. 
Administer bronchodilators, oxygen, etc. as medically 
indicated. 
Resume 
infusion 
at 
50% 
of 
previous 
rate 
once 
allergic/hypersensitivity reaction has resolved or decreased to 
Grade 1 in severity, and monitor closely for any worsening
Grade 3 or Grade 4 
Stop the cetuximab infusion immediately and disconnect 
infusion tubing from the patient.  
Administer epinephrine, broncho- dilators, antihistamines, 
glucocorticoids, intravenous fluids, vasopressor agents, 
oxygen, etc., as medically indicated.  
Patients must be withdrawn immediately from the 
treatment and must not receive any further cetuximab 
treatment.
 
Retreatment following allergic/hypersensitivity reactions: Once a cetuximab infusion 
rate has been decreased due to an allergic/hypersensitivity reaction, it will remain 
decreased 
for 
all 
subsequent 
infusions. 
For 
patients 
having 
a 
second 
allergic/hypersensitivity reaction with the slower infusion rate, the infusion should be 
stopped, and the patients should be removed from the study. If a patient experiences a 
Grade 3 or 4 allergic/hypersensitivity reactions at any time, cetuximab should be 
discontinued. 


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If therapy must be withheld for a longer period of time than defined above, the patient 
will be removed from the study treatment. In special cases, the investigator may request 
that the patient continues to receive cetuximab (the investigator must ask permission from 
the legal representative of the sponsor). 
9.9.3 
Cisplatin 
Prior to each cisplatin infusion the following criteria should be fulfilled:  
 Leucocytes >3.5 x 109/L or neutrophils ≥1.5 x 109/L 
 Platelets >100 x 109/L 
 Creatinine ≤1.5 mg/100ml 
 Urea <25mg/100ml 
If the above mentioned criteria are not fulfilled at the planned day of infusion, 
chemotherapy will be delayed until the criteria are fulfilled. If the chemotherapy is 
delayed, the IMP (CetuGEX™ or cetuximab) administration may not be withheld and 
needs to be continued with weekly infusions as scheduled. If chemotherapy is delayed for 
more than 3 weeks (i.e., more than 6 weeks between 2 consecutive Day 1 platinum-based 
chemotherapy infusions), the chemotherapy will be stopped and the patient will continue 
with the single-agent maintenance therapy.  
The patient’s subsequent chemotherapy doses will all be reduced to 75 % of the initial 
dose if any of the following toxicity occurs at any time during a chemotherapy cycle: 
 Febrile neutropenia (ANC <1.0 x 109/L, fever >38.5°C) 
 ANC <0.5 x 109/L 
 Platelets <25 x 109/L 
 Non-hematological toxicity grade 3 (NCI-CTC version 4.0): dose may be reduced 
at the discretion of the investigator 
Once a chemotherapy dose modification has occurred, the dosage may not be re-escalated 
for this patient. 
Patients with febrile neutropenia or a delay in therapy due to myelosupression will be 
treated with G-CSF on subsequent cycles. 
Switching from cisplatin to carboplatin has to be considered if the following toxicity 
occurs at any time during a chemotherapy cycle: 
 Creatinine increase > Grade 1 (NCI-CTC version 4.0)  
 Ototoxicity > Grade 2 (NCI-CTC version 4.0) 
 Sensory neuropathy > Grade 2 (NCI-CTC version 4.0) 
If any of the above mentioned occurs again under carboplatin, chemotherapy has to be 
discontinued and the patient will enter the single-agent maintenance phase. 


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For more detailed information, please refer to the SmPCs for cisplatin (Appendix F) and 
carboplatin (Appendix H). 
9.9.4 
5-Fluorouracil 
Prior to each 5-fluorouracil infusion the following criteria should be fulfilled:  
 Leucocytes >3.5 x 109/L or neutrophils ≥1.5 x 109/L 
 Platelets >100 x 109/L 
If the above mentioned criteria are not fulfilled at the planned day of infusion, 
chemotherapy will be delayed until the criteria are fulfilled. If the chemotherapy is 
delayed, the IMP (CetuGEX™ or cetuximab) administration may not be withheld and 
needs to be continued with weekly infusions as scheduled. If chemotherapy is delayed for 
more than 3 weeks (i.e., more than 6 weeks between 2 consecutive Day 1 platinum-based 
chemotherapy infusions), the chemotherapy will be stopped and the patient will continue 
with the single-agent maintenance therapy.  
Diarrhea: For patients with grade 3 diarrhea for several days, a reduction to 80% of the 
initial dose of 5-FU is required. If grade 3 diarrhea does recur on a subsequent cycle, 
then a further reduction of 20% in the 5-FU dose is recommended. 
Mucositis: For patients with the first episode of mucositis grade 3 lasting several days, a 
reduction of the daily dose to 80% of the initial dose of 5-FU is required. If grade 3 
mucositis does recur on a subsequent cycle, then no further cycle of 5-FU will be given. 
Once a chemotherapy dose modification has occurred, the dosage may not be re-escalated 
for this patient. 
For more detailed information, please refer to the SmPC for 5-FU (Appendix G). 
9.10 
Drug Accountability 
Shipment of study medication will be performed by Glycotope GmbH or an authorized 
delegate including a shipment record and approval form. Each delivery of study 
medication must be inspected and acknowledged by an authorized team member of the 
study personnel and must be kept in a secure locked location only accessible by 
authorized study personnel. 
Clinical supplies are to be dispensed only in accordance with the study protocol. 
Dispensing of study medication to the patients must be recorded on drug accountability 
logs and in the eCRF.  
The inventory will be available to the monitor to verify the drug accountability during the 
study. Any unused bottles will be returned to Glycotope GmbH or its designee or can be 
destroyed at the study site upon sponsor's request after the drug accountability check has 
been performed. Empty or partially used bottles must not be returned and should be 
destroyed at the study site following local policies, after the monitor has reviewed the 
remaining volumes versus the eCRF and accountability records. 


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9.11 
Treatment Compliance 
Treatment compliance will be confirmed by maintenance and close reviews of the drug 
accountability records. 
9.12 
Concomitant and Prohibited Therapies 
9.12.1 
Concomitant Therapies 
All concomitant medications used (including over-the-counter medications and herbal 
supplements) will be recorded in the source document and in the eCRF. Furthermore, 
each change in concomitant medication (e.g., new treatment, discontinuation of 
treatment, change in dosage/route, etc.) during the study should be documented in the 
same way. Previous medication taken within the last 6 months prior to screening has to 
be recorded as well.  
If patients received any previous treatment which is part of an exclusion criterion (for 
details, please refer to Section 8.2.2) they will not be eligible for study participation. 
Patients on ongoing treatment with phenytoin will be closely monitored (blood plasma 
level) due to the drug-drug interaction with cisplatin and 5-FU. 
9.12.2 
Prohibited Therapies 
The following co-medication/therapies are not allowed during participation in the study:  
 EGFR targeting agents apart from randomly assigned study medication until end 
of treatment. 
 Any other immunotherapy until end of treatment. 
 Any anti-cancer treatment other than described in this protocol until end of 
treatment. 
 Ongoing regular doses of hydrocortisone and steroids (except for topical/inhaled) 
other than corticosteroids used for precaution of IRR. 
 Immunosuppressive agents until end of treatment. 
 Radiation therapy (except palliation of existing bone metastasis pain). 
 Erythropoietin (Epo). 
 Other medications that are contraindications to 5-FU and cisplatin or carboplatin 
respectively as per SmPC 4.3 “Contraindications” and 4.5 “Interaction with other 
medicinal products and other forms of interaction” (see Appendices F, G, H). 
9.13 
Treatment After End of Study 
After the end of the study, i.e., in case of progression of disease or if other withdrawal 
criteria are met, patients will be treated by their physician according to most appropriate 
and best supportive standard of care. 


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10 
STUDY PROCEDURES 
Patients will provide written informed consent before any study-related procedures are 
initiated, including the cessation of prohibited concomitant therapy. 
For an overview on the timing of assessments and procedures throughout the study, refer 
to the schedule of events (Section 18.1). Throughout the study, every reasonable effort 
should be made by study personnel to follow the timing of assessments and procedures in 
the schedule of events for each patient.  
10.1 
Study Periods and Schedule of Visits 
10.1.1 
Screening Visit 
The patient must be screened within 28 days prior the day of first infusion.  
The following records and assessments will be performed at screening: 
 Obtain written informed consent. 
 Contact the IWRS to obtain patient identification number. 
 Check of inclusion/exclusion criteria. 
 Check availability of pre-existing tumor tissue sample for EGFR and p16 status 
assessment. 
 Demographic information (including age, race, smoking status and alcohol 
consumption). 
 Diagnosis of SCCHN, including oncological information, previous chemotherapy 
and radiotherapy and other oncological regimens.  
 Medical history apart from SCCHN, including current therapies (e.g., prescription 
and non-prescription medication). 
 Record ECOG performance status. 
 Physical examination including underlying disease, weight, height and BMI. 
 Vital signs (blood pressure, heart rate and body temperature). 
 12-lead ECG.  
 Echocardiogram (ECHO)/Multiple Gated Acquisition (MUGA) scan for 
confirmation of eligibility (exclusion criterion 13). 
 Evaluation of tumor size by computed tomography (CT) or magnetic resonance 
imaging (MRI) (head and neck region, chest, and abdomen). 
 Blood and urine sampling for safety laboratory (hematology, coagulation panel, 
blood chemistry and urinalysis). Please note that creatinine clearance needs to be 
assessed at screening unless previous results not older than 6 weeks are available. 


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 Blood sampling for genotyping (FcγRIIIa status; only in case the patient will enter 
the study, the blood sample might also be used at a later time point for further 
analyses like FcγRII status). 
 Recording of previous and concomitant medication. 
10.1.2 
Randomization  
If the patient is eligible to participate in this study (i.e., if all inclusion criteria are met and 
no exclusion criteria apply), the investigator will contact the IWRS for randomization 
information within 1 to 3 days prior to the next scheduled visit of the corresponding 
patient. The patient will be randomly assigned to receive either CetuGEX™ or cetuximab 
by receiving a unique randomization number (as detailed in Section 9.5). The patients do 
not need to visit the study site for this procedure but can be informed by phone. 
Additionally, the pre-existing tissue sample will be sent to the central laboratory for the 
following analyses: 
 EGFR expression by immunohistochemistry at a central laboratory. Further 
immunohistochemical assessments may be performed on the tumor sample if 
deemed necessary by the sponsor, e.g. tissue micro arrays to further characterize 
the tumor.  
 p16 tumor suppressor gene status, indicative for high risk of Human Papilloma 
Virus (HPV) in the tumor (remaining tissue needs to be stored for further analysis 
in case of eligibility). 
 Assessment of HPV status at a central laboratory. 
These analyses may be performed at a later time point during the study. 
10.1.3 
Combination Treatment Phase 
During the combination treatment phase, the patients will receive the study medication 
(CetuGEX™ or cetuximab) in combination with chemotherapy (cisplatin and 5-FU) for a 
maximum of 6 cycles of combined treatment. In case of toxicity of cisplatin, carboplatin 
may substitute cisplatin, but after completion of the first cycle at the earliest. 
During the combination treatment phase, even if the chemotherapy is delayed for any 
reason (e.g., see Sections 9.9.3 and 9.9.4), the IMP (CetuGEX™ or cetuximab) 
administration may not be withheld and needs to be continued with weekly infusions as 
scheduled. Additionally, all assessments related to the weekly administration of 
CetuGEX™/cetuximab should be performed as scheduled (see *). Only assessments 
relevant for the determination of whether the patient is eligible to continue the 
chemotherapy treatment (i.e., vital signs measurements and safety laboratory tests) have 
to be repeated in relation to the next administration of chemotherapy (see also Schedule 
of Events, Section 18.1). 
If the administration of CetuGEX™ or cetuximab is skipped for any reason (see 
Sections 9.9.1 and 9.9.2), e.g., on Day 8, all assessments scheduled for this study visit 


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day are to be performed as planned (i.e., including collection of blood samples for the 
determination of ADA and pre-dose samples for PK). 
Table 10-1 displays the ideal treatment schedule for the combination treatment phase.  


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Table 10-1: Ideal treatment schedule – combination treatment phase 
Treatment cycle 
Week 
Chemotherapy a 
IMP b,c 
 
1 
Week 1
D1 d
D1
 
D2 – D4
 
Week 2
D8
 
Week 3
D15
2 
Week 4
D1 d
D1
 
D2 – D4
 
Week 5
D8
 
Week 6
D15
3 
Week 7
D1 d
D1
 
D2 – D4
 
Week 8
D8
 
Week 9
D15
4 
Week 10
D1 d
D1
 
D2 – D4
 
Week 11
D8
 
Week 12
D15
5 
Week 13
D1 d 
D1
 
D2 – D4
 
Week 14
D8
 
Week 15
D15
6 
Week 16
D1 d
D1
 
D2 – D4
 
 
Week 17
D8
Start of maintenance phase 
 
Week 18
D15
a) If the chemotherapy is delayed, the IMP (CetuGEX™ or cetuximab) administration needs to be 
continued with weekly infusions as scheduled. 
b) Starting with the second IMP infusion (Day 8 of Cycle 1), a time window of ± 1 day will be allowed for 
the weekly infusions (calculated from the previous infusion). 
c) If the administration of CetuGEX™ or cetuximab is skipped for any reason (see Sections 9.9.1 and 
9.9.2), e.g., on Day 8, all assessments scheduled for this study visit day are to be performed as planned (i.e., 
including collection of blood samples for the determination of ADA and PK). 
d) The platinum-based chemotherapy should be given within 24 hours after the infusion of 
CetuGEX™/cetuximab. Administration of 5-FU should be started within 24 hours after the infusion of 
CetuGEX™/cetuximab. 
D = day, W = week 
 


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Day 0, Cycle 1 (Week 1) 
On Day 0 of Cycle 1, eligible patients randomized to receive CetuGEX™ will visit the 
study site to receive their unique randomization number and perform baseline 
assessments as listed below and to receive a priming dose of 60 mg on this visit, after all 
baseline/safety assessments have been performed. The Day 0 visit is not applicable for 
patients randomized to receive cetuximab. General baseline assessments scheduled for 
Day 0 will be performed on Day 1 for those patients randomized to cetuximab. 
The following assessments will be performed on Day 0 for patients in the CetuGEX™ 
treatment arm: 
 Confirmation of inclusion/exclusion criteria. 
 Physical examination. 
 Vital signs (blood pressure, heart rate and body temperature), body weight and 
BMI. 
 12-lead ECG, if not done within 7 days prior start of study medication 
administration during screening phase. 
 Record ECOG performance status. 
 Blood and urine sampling for safety laboratory (hematology, coagulation panel, 
blood chemistry and urinalysis). 
 Pregnancy test for female patients of childbearing potential. 
 Quality of life questionnaires EORTC-QLQ-C30 and EORTC-QLQ-H&N35 (to be 
performed prior to any other assessments). 
 Recording of concomitant medication. 
 Assessment of AEs. 
 Blood sampling for ADA testing. 
 Blood sampling for PK assessments prior to the start of infusion and after the end 
of infusion. 
 Blood sampling for assessment of cytokines and other relevant blood proteins (to 
be performed pre-dose, one hour after start of infusion and at the end of infusion). 
 Blood sampling for assessment of immune status (to be performed pre-dose). 
 Infusion of 60 mg CetuGEX™ priming dose. 
Day 1, Cycle 1 (Week 1) 
Day 1 of Cycle 1 will be the first treatment day for patients randomized to receive 
cetuximab. For those patients randomized to receive CetuGEX™ Day 1 of Cycle 1 
should be performed within 24 hours after Day 0. 


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Day 1 (of each treatment cycle) 
On Day 1 of each treatment cycle, the following assessments will be performed: 
 Confirmation of inclusion/exclusion criteria (to be performed only for patients 
receiving cetuximab). 
 Physical examination. 
 Vital signs (blood pressure, heart rate and body temperature), body weight and 
BMI. 
 Record ECOG performance status (to be performed in Cycle 1 only for patients 
receiving cetuximab and for all patients in every following cycle). 
 12-lead ECG (to be performed pre-dose, in Cycles 3 and 5 only; in Cycle 1 to be 
performed only for patients receiving cetuximab and only if not done within 7 days 
prior start of study medication administration during screening phase; to be 
performed). 
 Evaluation of tumor size by CT or MRI (to be performed pre-dose, in Cycles 3 and 
5 only; same equipment and type of imaging as used at Screening is required 
throughout the study). Assessment of the head, neck, and chest; assessments of the 
abdomen will only be performed if at baseline metastases were confirmed or if 
clinical evidence suggests new lesions in these regions. 
 Blood and urine sampling for safety laboratory (hematology, coagulation panel, 
blood chemistry and urinalysis) (to be performed pre-dose, in Cycle 2 and every 
following cycle; in Cycle 1 to be performed only for patients receiving cetuximab).  
 Pregnancy test for female patients of childbearing potential (in Cycle 1 only; to be 
performed only in patients receiving cetuximab). 
 Blood sampling for assessment of cytokines and other relevant blood proteins* (to 
be performed only in a subset of approximately 30 patients per treatment arm; in 
Cycles 1 and 2 only: Cycle 1: pre-dose, at the start of the highest IMP infusion 
rate, 1 hour after start of the highest infusion rate and at the end of infusion; Cycle 
2: pre-dose, 1 hour after start of infusion and at the end of infusion). 
 Blood sampling for assessment of immune status* (to be performed only in a 
subset of approximately 30 patients per treatment arm; pre-dose on Day 1 of Cycle 
1 for patients receiving cetuximab). 
 Blood sampling for ADA testing* (to be performed only for patients receiving 
CetuGEX™; pre-dose on Day 1 of Cycle 2 and Cycle 4 only). 
 Blood sampling for PK assessments* (only for patients receiving CetuGEX™; to 
be performed prior to start of infusion and at the end of infusion in Cycles 1 to 4 
only).  
 Blood sampling for additional PK assessments* (only for a subgroup of 
approximately 30 patients receiving CetuGEX™; to be performed 5 (± 5 min) and 
7 (± 15 min) hours after start of infusion on Cycles 1 and 4 only). 


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 QoL questionnaires EORTC-QLQ-C30 and EORTC-QLQ-H&N35* (to be 
performed prior to any other assessments; to be performed in Cycles 3 and 5 only; 
in Cycle 1 to be performed only for patients receiving cetuximab). 
 Study drug administration (CetuGEX™ according to infusion scheme as provided 
in Section 9.3 or cetuximab according to standard of care). Except for Day 1 of 
Cycle 1 a time window of ± 1 day will be allowed for the weekly infusions 
(calculated from the previous infusion). 
 Administration of cisplatin (or carboplatin) and 5-FU (to be started not sooner than 
1 hour after end of CetuGEX™/cetuximab infusion). The platinum-based 
chemotherapy should be given within 24 hours after the infusion of 
CetuGEX™/cetuximab. Administration of 5-FU should be started within 24 hours 
after the infusion of CetuGEX™/cetuximab. Cisplatin is mandatory in Cycle 1 and 
can be replaced with carboplatin in case of unacceptable toxicity in the subsequent 
cycles. 
 Drug accountability. 
 Recording of concomitant medication. 
 Assessment of AEs.  
Days 2 to 4 (of each treatment cycle) 
Visits on Days 2 to 4 are only obligatory for patients who may not have a transportable 
pump for 5-FU administration on Days 2 to 4 and/or who are included in the subgroup of 
30 CetuGEX™ patients for additional PK assessments.  
On Day 2, Day 3 and Day 4 of each treatment cycle, the following assessments will be 
performed for patients visiting the site: 
 Vital signs (blood pressure, heart rate and body temperature). 
 Blood sampling for PK assessments*, for a subgroup of 30 CetuGEX™ patients 
only, and only during Cycles 1 and 4: 
 24 ± 1 hours after start of infusion (Day 2) 
 48 ± 2 hours after start of infusion (Day 3) 
 72 ± 2 hours after start of infusion (Day 4). 
 Administration of 5-FU (if not automatically performed by transportable pump).  
 Drug accountability. 
 Recording of concomitant medication. 
 Assessment of AEs. 


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Days 8 and 15 (of each treatment cycle) 
On Day 8 and Day 15 of each cycle of the combination treatment phase, the following 
assessments will be performed: 
 Physical examination. 
 Vital signs (blood pressure, heart rate and body temperature), body weight and 
BMI. 
 Record ECOG performance status. 
 Blood sampling for assessment of cytokines and other relevant blood proteins*, (to 
be performed only in a subset of approximately 30 patients per treatment arm; pre-
dose, 1 hour after start of infusion and at the end of infusion in Cycle 1 only). 
 Blood sampling for assessment of immune status* (to be performed only in a 
subset of approximately 30 patients per treatment arm; pre-dose on Day 8 of Cycle 
2 only). 
 Blood sampling for ADA testing* (to be performed only for patients receiving 
CetuGEX™; pre-dose on Day 8 of Cycle 1 only). 
 Blood sampling for PK assessments* (only for patients receiving CetuGEX™; to 
be performed prior to start of infusion and at the end of infusion, in Cycles 1 to 3 
only). 
 Blood sampling for additional PK assessments* (only for a subgroup of 
approximately 30 patients receiving CetuGEX™; to be performed prior to start of 
infusion, on Day 8 of Cycle 4 only). 
 Administration of CetuGEX™/cetuximab.  
 Drug accountability. 
 Recording of concomitant medication. 
 Assessment of AEs. 
It will be accepted that assessments of Days 8 and 15 will be performed one day before 
the infusion. 
10.1.4 
Single Agent Maintenance Phase 
After completion of 6 cycles of combination chemotherapy cycles or after discontinuation 
of the chemotherapy for any other reason apart from progression, the patients will 
continue to receive CetuGEX™ alone or cetuximab alone, respectively. Single-agent 
maintenance therapy will be continued until progression of disease or limiting toxicity. 
On Day 1 of each week of the single-agent maintenance phase, the following will be 
performed or assessed: 
 Physical examination. 


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 Vital signs (blood pressure, heart rate and body temperature) and body weight and 
BMI. 
 12-lead ECG (every 6 weeks after randomization). 
 Record ECOG performance status. 
 Evaluation of tumor size by CT or MRI (to be performed pre-dose, every 6 weeks 
within the first 18 weeks after randomization, and every 8 weeks thereafter; same 
equipment and type of imaging as used at Screening is required throughout the 
study).  
 Blood and urine sampling for safety laboratory (hematology, coagulation panel, 
blood chemistry and urinalysis; to be performed every 6 weeks after 
randomization).  
 QoL questionnaires EORTC-QLQ-C30 and EORTC-QLQ-H&N35 (to be 
performed prior to any other assessments; to be performed 18 weeks after date of 
randomization. In case of premature discontinuation of combination treatment, 
also to be performed 6 weeks and 12 weeks after randomization, as applicable). 
 Pregnancy test for female patients of childbearing potential (will be performed 
only on the first week of maintenance therapy pre-dose). 
 Blood sampling for ADA testing (only for patients receiving CetuGEX™; only to 
be performed 1, 3 and 9 weeks after randomization, pre-dose, if chemotherapy was 
discontinued prematurely). 
 Blood sampling for PK assessments (only for patients receiving CetuGEX™; only 
to be performed until the 10th infusion of CetuGEX™, if chemotherapy was 
discontinued prematurely). 
 Blood sampling for additional PK assessments (only for a subgroup of 
approximately 30 patients receiving CetuGEX™; only to be performed until the 
11th infusion of CetuGEX™ [pre-dose], if chemotherapy was discontinued 
prematurely). 
 Administration of CetuGEX™/cetuximab (time window for infusion: ± 1 day 
calculated from the previous infusion).  
 Drug accountability. 
 Recording of concomitant medication. 
 Assessment of AEs. 
10.1.5 
Follow-Up Phase 
Safety Visit (28 + 2 Days After Last Infusion) 
Four weeks (28 + 2 days) after the last administration of the study drug, a Safety Visit 
must be performed for all patients. During this visit, the following assessments will be 
carried out: 


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 Physical examination. 
 Vital signs (blood pressure, heart rate and body temperature), body weight and 
BMI. 
 12-lead ECG 
 Record ECOG performance status. 
 Blood and urine sampling for safety laboratory (hematology, coagulation panel, 
blood chemistry and urinalysis). 
 Blood sampling for assessment of immune status (only in a subset of 
approximately 30 patients per treatment arm). 
 Blood sampling for ADA testing (only for patients receiving CetuGEX™). 
 Blood sampling for PK assessments (only for patients receiving CetuGEX™). 
 QoL questionnaires EORTC-QLQ-C30 and EORTC-QLQ-H&N35 (to be 
performed prior to any other assessments). 
 Pregnancy test for female patients of childbearing potential. 
 Recording of concomitant medication. 
 Assessment of AEs. 
The Safety Visit is identical to the Final Examination Visit for those patients who 
received treatment until progression of disease. 
Final Examination 
As soon as progression of disease is detected, a Final Examination Visit must be 
performed for all patients who prematurely discontinued study treatment for any other 
reason except progression of disease.  
In case of complete study withdrawal before documented progressive disease, a Final 
Examination Visit should be performed at the time of premature discontinuation.  
The following assessments will be performed: 
 Vital signs (blood pressure, heart rate and body temperature). 
 Record ECOG performance status. 
 Recording of concomitant medication. 
 Assessment of AEs. 
For patients discontinuing study medication due to progressive disease, the 28-day Safety 
Visit will constitute the Final Examination. 
After the Final Examination, patients will be followed-up by quarterly phone calls until 
death or for a maximum duration of 24 months after randomization of the last patient for 
assessment of overall survival. Apart from post-PD anti-tumor therapies, no concomitant 
medications and no AEs will be recorded after the Final Examination. 


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10.2 
Study Duration 
The overall study duration is expected to be approximately 48 months (including 
24 months of active enrollment, a treatment phase until the respective number of PFS 
events is reached of approximately 12 months after the date of randomization and 
ongoing follow-up for overall survival for 24 months after randomization of the last 
patient). 
The sequence and maximum duration of the study periods and treatment for each patient 
will be as follows: 
 Screening: to be performed within 28 days prior to randomization to assess general 
eligibility for this study. 
 Combination treatment phase: maximum of 6 treatment cycles of combination 
treatment. 
 Single-agent maintenance phase: until disease progression. 
 Follow-up: at least 24 months after the date of randomization of the last patient. 
All patients will be treated until disease progression, unacceptable toxicity or any other 
withdrawal criterion is met. 
10.3 
Assessments 
10.3.1 
Efficacy 
10.3.1.1 Assessment of Primary Endpoint  
The primary endpoint of the study is the PFS, defined as the time from randomization 
until disease progression or death, whichever occurs first.  
Disease will be evaluated by immune-related response criteria based on the RECIST 1.1 
criteria13 and adapted according to Wolchok et al14 (modified irRC). Disease progression 
is defined as a 20% increase in tumor burden, taking as reference the smallest tumor 
burden recorded since the treatment started (details in Appendix C).  
Date of disease progression is defined as the date of imaging showing disease progression 
or death, whichever occurs first. 
Tumor assessments will be performed by the investigator and independent centralized 
reading during the combination treatment phase and single-agent maintenance phase 
based on CT or MRI of the head and neck region, chest, and abdomen. Subsequent 
assessments will include head, neck and chest; assessments of the abdomen will only be 
performed if at baseline metastases were confirmed or if clinical evidence suggests new 
lesions in these regions. Additional regions might be included if clinically indicated.  
Tumor assessments in both study arms will be performed at Screening, every 6 weeks 
after day of randomization until Week 18 and every 8 weeks thereafter. The tumor 
evaluation will be performed pre-dose. 


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Results of the assessments performed at Screening will be considered baseline values. 
The same type of imaging as for baseline assessments should be maintained throughout 
the study.  
Tumor images to determine PFS will be evaluated based on the RECIST version 1.1 
adapted according to Wolchok et al14. 
Patients with measurable disease at baseline may be included into study. Measurable 
disease is defined as the presence of at least one measurable lesion. A measurable tumor 
lesion is a lesion that can be accurately measured in at least one dimension (longest 
diameter in the plane of measurement is to be recorded) with a minimum size of 10 mm 
by CT scan or MRI scan. To be considered pathologically enlarged and measurable, a 
lymph node must be at least 15 mm in short axis when assess by CT scan. A detailed 
description of measurable and non-measurable lesions can be found in RECIST version 
1.1 immune-related response criteria provided in Appendix C. 
For the evaluation of the primary efficacy endpoint PFS, assessments performed by the 
investigator will be taken into account.  
10.3.1.2 Assessment of Secondary Efficacy Endpoints 
Tumor assessments performed by the investigator and by independent centralized reading 
as described in detail above will also be used for evaluation of secondary efficacy 
endpoints. 
Progression-free Survival assessed by Centralized Read 
Tumor images to determine PFS as assessed by independent centralized reading will be 
evaluated as described in detail in Section 10.3.1.1. 
Objective Response Rate and Duration of Response 
Objective response rate is the portion of patients with a tumor size reduction of a 
predefined amount for a minimum time period and it is defined as the sum of partial 
responses and complete responses. Response duration is measured from the time of initial 
response until documented tumor progression. 
The investigator and independent centralized reader will evaluate whether complete 
response (CR), partial response (PR), stable disease (SD) or progressive disease (PD) has 
occurred, according to the criteria presented in Appendix C: 
Best Overall Response Rate 
The best overall response rate is the best response (CR, PR or SD) recorded per patient 
from the start of the treatment until disease progression/recurrence. Separate rates per 
CR, PR or SD as best response will be evaluated. 
Clinical Benefit Rate 
The clinical benefit rate is the portion of patients with an objective response or stable 
disease. 


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Overall Survival 
The overall survival is defined as the duration of time from randomization to the time of 
death. The patients will be followed up by monthly phone calls until death or for a 
maximum duration of 24 months after randomization of the last patient for assessment of 
OS. 
Time to Treatment Failure 
Time to treatment failure is defined as the time from randomization to treatment 
discontinuation for any reason, including disease progression, treatment toxicity, patient 
preference, or death. 
10.3.2 
Quality of Life Measures 
To assess the QoL of each patient, patient-reported disease-related symptoms and health 
related QoL will be measured using the EORTC-QLQ-C30 questionnaire and the head 
and neck module (H&N35; according to the availability of the validated translations). 
Patients will be required to complete the questionnaires prior to any other assessments on 
Day 0 (CetuGEX™ patients only) and Day 1 of Cycle 1 (cetuximab patients only), 
respectively, as well as on Day 1 of Cycles 3 and 5 (i.e., 6 weeks and 12 weeks after 
randomization), 18 weeks after randomization and 28 (+ 2) days after last treatment 
administration (Safety Visit).  
10.3.3 
Pharmacokinetics  
10.3.3.1 Pharmacokinetics Blood Samples Collection 
Blood sampling for antibody trough levels and PK profiles assessments will be performed 
throughout the study for the patients randomized to the CetuGEX™ treatment group at 
several timepoints, as detailed in Appendix B. 
For all patients randomized to the CetuGEX™ treatment group, blood sampling for PK 
trough levels will be performed at the following time points: 
 Week 1, Cycle 1, Day 0: Before start and at the end of the 1st infusion. 
 Week 1, Cycle 1, Day 1: Before start and at the end of the 1st infusion 
continuation.  
 Week 2, Cycle 1, Day 8: Before start and at the end of the 2nd infusion. 
 Week 3, Cycle 1, Day 15: Before start and at the end of the 3rd infusion. 
 Week 4, Cycle 2, Day 1: Before start and at the end of the 4th infusion. 
 Week 5, Cycle 2, Day 8: Before start and at the end of the 5th infusion. 
 Week 6, Cycle 2, Day 15: Before start and at the end of the 6th infusion. 
 Week 7, Cycle 3, Day 1: Before start and at the end of the 7th infusion. 
 Week 8, Cycle 3, Day 8: Before start and at the end of the 8th infusion. 


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 Week 9, Cycle 3, Day 15: Before start and at the end of the 9th infusion. 
 Week 10, Cycle 4, Day 1: Before start and at the end of the 10th infusion. 
 Safety Visit: 28 + 2 days after last infusion. 
Additionally, for a subgroup of approximately 30 patients receiving CetuGEX™, blood 
samples for assessment of PK profiles will be taken on Cycles 1and 4 at the following 
timepoints: 
 Week 1, Cycle 1, Day 1: 5 hours ± 5 min and 7 hours ± 15 min hours after start of 
the 1st infusion. 
 Week 1, Cycle 1, Days 2, 3 and 4: 24 ± 1, 48 ± 2 and 72 ± 2 hours after start of the 
1st infusion on Day 1. 
 Week 2, Cycle 1, Day 8: 7 days (168 ± 2 hours) after start of the 1st infusion on 
Day 1, before start of the 2nd infusion; identical to the pre-dose sampling for all 
patients). 
 Week 10, Cycle 4, Day 1: 5 hours ± 5 min and 7 hours ± 15 min after start of the 
10th infusion. 
 Week 10, Cycle 4, Days 2, 3 and 4: 24 ± 1, 48 ± 2 and 72 ± 2 hours after start of 
the 10th infusion. 
 Week 11, Cycle 4, Day 8: 7 days (168 ± 2 hours) after start of the 10th infusion, 
before start of the 11th infusion). 
If a patient discontinues early the chemotherapy in the first-line treatment phase, blood 
samples for PK assessments will be collected on the first day of each week of the 
maintenance phase, but only until the 10th study drug infusion after randomization or, if 
the patient is participating in the subgroup analysis, in accordance with the additional PK 
blood sampling schedule until the start of the 11th study drug infusion (pre-dose). 
10.3.3.2 Pharmacokinetic Blood Sample Handling 
Serum samples for pharmacokinetic analysis will be handled and stored at -20°C or 
below at the study site until shipment on dry ice to an external analytical laboratory. At 
the analytical laboratory, the samples will also be stored at - 20°C or below until analysis. 
Detailed instructions for handling of serum samples will be provided in the laboratory 
specific documentation. Pharmacokinetic sample assessment will be performed at a 
central laboratory. 
In addition, the residual blood samples drawn for PK analysis may be stored and 
optionally be used at a later time point for the analysis of potential pharmacodynamics 
markers, as applicable. Potential pharmacodynamics markers to be assessed may include, 
but are not limited to, EGFR-pathway related markers.  
10.3.4 
Pharmacogenomics 
Patients will consent to genotype testing of blood for a more detailed characterization of 
the patient population to enable a stratified randomization procedure with regard to 


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FcγRIIIa status. The stratified randomization is chosen to highlight the population that 
would benefit most from treatment with CetuGEX™. 
At Screening, a blood sample for genotyping analyses will be taken. Samples will be 
shipped to the central laboratory where they will be shipped to the genomics laboratory 
for genotyping analysis of the patient's FcγRIIIa status.  
Additionally, FcγRIIa status may be determined as further potential biomarker but not as 
a stratification factor. 
Handling of blood samples will be performed according to the laboratory instructions and 
as outlined in Section 10.3.6.1. 
10.3.5 
Immunogenicity and Immunological Parameters 
10.3.5.1 Immunogenicity (Antibody Testing) 
Blood samples for CetuGEX™ antibody testing (ADA) will be taken pre-dose at the start 
of treatment (Day 0), on Day 8 of Cycle 1, Day 1 of Cycles 2 and 4 and 28 + 2 days after 
last infusion (Safety Visit). Incidence of ADA will be tested in a central laboratory using 
validated assays. 
Blood samples drawn for ADA assessments will be frozen for storage. Sampling, storage 
and shipment of samples will be performed according to the laboratory instructions and 
as outlined in Section 10.3.6.1. 
10.3.5.2 Cytokine Release and Immune Cells Status 
Cytokine release and immune cell status will be assessed only in a subset of 
approximately 30 patients per treatment arm. Blood samples for the assessment of 
cytokines and other relevant blood proteins will be collected throughout the study 
according to the schedule presented as follows:  
 Day 0: before first infusion, at 1 hour after start of the infusion and at the end of 
the first infusion (only for a subset of approximately 30 CetuGEX™ patients). 
 Cycle 1, Day 1: before infusion, at the start of the highest infusion rate, at 1 hour 
after start of the highest infusion rate and at the end of infusion. 
 Cycle 1, Days 8 and 15: before infusion, at 1 hour after start of the infusion and at 
the end of the infusion. 
 Cycle 2, Day 1: before infusion, 1 hour after start of the infusion and at the end of 
the infusion. 
Blood samples drawn for the assessment of cytokines and other relevant blood proteins 
will be frozen for storage. Sampling, storage and shipment of samples will be performed 
according to the laboratory instructions and as outlined in Section 10.3.6.1. 
At selected sites blood samples will be taken from a subset of approximately 30 patients 
per treatment arm to perform a FACS analysis to determine the immune status of the 
patients using selected cluster of differentiation (CD) markers such as CD3, CD16, 


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CD19, CD56, CD4, CD8, and CD14. Blood samples for assessment of the immune cell 
status will be collected throughout the study according to the schedule presented as 
follows:  
 Cycle 1, Day 0 (for patients receiving CetuGEX™)/Day 1 (for patients receiving 
cetuximab): before first infusion.  
 Cycle 2, Day 8: before infusion.  
 28 + 2 days after last infusion (Safety Visit). 
10.3.6 
Safety 
Safety assessments will include the evaluation of standard laboratory assessments, vital 
signs, electrocardiograms, physical examinations and occurrence of AEs and IRRs. 
10.3.6.1 Laboratory Safety Assessments 
Samples for the following laboratory tests will be collected at the time points specified in 
the schedule of events (Section 18.1). 
Standard Laboratory Assessments 
Hematology 
White blood cell (WBC) with differential (neutrophils, 
lymphocytes, monocytes, eosinophils and basophils), 
hematocrit, hemoglobin, mean corpuscular volume, platelet 
count, red blood cell (RBC) count 
Blood Chemistry 
Albumin, 
total 
bilirubin, 
total 
protein, 
alanine 
aminotransferase (ALT), aspartate aminotransferase (AST), 
glucose, sodium, potassium, chloride, calcium, magnesium, 
creatinine, creatinine clearance, lactate dehydrogenase 
(LDH), gamma-glutamyl transferase (GGT), alkaline 
phosphatase (AP), urea/blood urea nitrogen (BUN) 
Coagulation Panel 
Prothrombin time (PT), partial thromboplastin time (PTT), 
fibrinogen 
Urinalysis 
pH, blood, glucose, protein, ketones 
EGFR 
EGFR expression from pre-existent tumor tissue sample 
p16 
p16 tumor suppressor gene status, indicative for high risk of 
HPV in the tumor (from pre-existing tumor tissue sample) 
Pregnancy Test (serum 
or urine) 
Females of childbearing potential only 
 


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The safety laboratory tests as mentioned above will be performed at the study site (local 
laboratory). The assessment of EGFR expression and HPV and p16 status will be 
performed at the central laboratory. The pre-existing tissue sample will be sent to the 
central laboratory once the patient was randomized. The analysis of the status will be 
performed during the conduct of the study, but is no requirement for patient inclusion or 
randomization. Storage and shipment of tumor tissue samples will be performed 
according to the instructions of the laboratory. 
Blood samples will be taken in accordance with local laboratory standard procedures and 
as detailed in the laboratory manual where applicable. 
Specimen Handling Requirements 
The transmission of infectious agents may occur through contact with contaminated 
needles and blood or blood products. Consequently, appropriate blood and body fluid 
precautions should be employed by all study personnel involved in the collection of blood 
and handling of specimens in both the clinic and laboratory settings. Refer to current 
recommendations of the appropriate authorities. 
In addition to appropriate handling of patient samples, specific regulations exist regarding 
the shipment of biologic/etiologic samples. Procedures and regulations for the packaging 
and shipping of infectious samples are outlined in the study laboratory manual. The 
investigator is responsible for ensuring that all study samples that are to be transported to 
another location are appropriately packed and shipped according to the applicable 
regulations.  
Evaluation of Laboratory Values 
All laboratory assessments regardless whether performed locally at the study site or at the 
central laboratory will be performed using established methods. Laboratory values will be 
recorded and assessed by the investigator as normal value, abnormal values or clinically 
significant abnormal values, based on the reference ranges and units of measurement 
provided by the corresponding laboratories or investigators. Changes as compared to 
baseline will be recorded. Any changes to clinically significant abnormal values should 
be reported as AEs as outlined in Section 11. 
10.3.6.2 Clinical Examinations 
Clinical examinations will be performed at different time points as outlined in the 
previous sections and in the schedule of visits (see Sections 10.1 and 18.1). 
Vital Signs 
Vital signs, including heart rate, diastolic and systolic blood pressure and body 
temperature, will be measured at every study visit prior to infusion after the patient has 
been at rest in a sitting position for at least 5 minutes. 


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Eastern Cooperative Oncology Group Performance Status 
The ECOG performance status will be recorded at each visit where study medication was 
administered, during combination treatment phase and single agent maintenance phase, at 
the Safety Visit and at the Final Examination. The performance status grades and 
corresponding descriptions are given in Appendix A. 
Electrocardiogram 
A standard 12-lead ECG will be performed at scheduled time points after the patient has 
been supine for at least 5 minutes. The QT interval (defined as the time period from 
earliest onset of the QRS complex to the latest offset of the T wave in the same lead; the 
lead with the longest QT interval should be selected) has to be exactly measured. All 
ECG recordings will be identified with the patient number, date and time of the recording 
and data including 3 selected consecutive QT intervals will be entered into the patient’s 
eCRF. Original ECG records will be kept in the patient's file. Copies will be filed in the 
Investigator's File. 
In case of any clinically relevant abnormalities, these should be reported as AEs (see 
Section 11). 
ECHO/MUGA 
An echocardiogram or a MUGA scan will be performed at screening. All the recordings 
will be identified with the patient number, date and time of the recording and data will be 
entered into the patient’s eCRF. Original records will be kept in the patient's file. Copies 
will be filed in the Investigator's File. 
Physical Examination 
A complete physical examination will be performed at screening, at each day of study 
drug administration, and at the Safety Visit, based on the following body systems: general 
appearance, 
head 
(eyes/ears/nose/throat), 
respiratory, 
cardiovascular, 
abdomen, 
urogenital, musculoskeletal, neurological, lymph nodes and skin. 
Body weight, height and BMI will be measured as part of the demography assessments, 
and body weight will also be measured on further scheduled time points for safety 
assessments. 
10.3.6.3 Adverse Events 
Adverse events will be recorded at every visit and severity has to be assessed and 
documented by the investigator. The definitions and management of and special 
considerations for AEs are provided in Section 11. 
As part of the AEs, IRRs and skin toxicities will be identified and recorded accordingly. 


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11 
ADVERSE EVENTS 
11.1 
Definitions 
11.1.1 
Adverse Events 
An AE is defined as any untoward medical occurrence in a patient or clinical 
investigation subject administered a pharmaceutical product that does not necessarily 
have a causal relationship with the product. An AE can therefore be any unfavorable and 
unintended sign (including a new, clinically important abnormal laboratory finding), 
symptom, or disease, temporally associated with the product, whether or not related to the 
product. 
Pre-existing diseases or conditions will not be considered AEs unless there is an increase 
in the frequency or severity, or a change in the quality, of the disease or condition. 
(Worsening of a pre-existing condition is considered an AE.) 
Events occurring in patients during study drug treatment free periods of the study 
(i.e., follow-up phase) are also considered AEs.  
Note: Tumor progression is part of the primary endpoint and is not to be considered an 
SAE in this study. 
11.1.2 
Adverse Drug Reaction 
All noxious and unintended responses to an investigational product related to any dose 
should be considered adverse drug reactions (ADRs). 
The phrase “responses to an investigational product” means that a causal relationship 
between an investigational product and an AE is at least a reasonable possibility, i.e., the 
relationship cannot be ruled out. All AEs judged by either the reporting investigator or 
the sponsor as having a reasonable causal relationship to an investigational product 
qualify as ADRs. 
All AEs for which the judgment of relationship to IMP is “possible” or higher will be 
considered ADRs. If a relationship to IMP is not given, then the AE must be treated as if 
the relationship to IMP were “possible.” 
11.1.3 
Unexpected Adverse Event/Adverse Drug Reaction 
An expected AE or ADR is one for which the nature or severity is consistent with the 
known AE profile of the product. For an IMP, the known information is contained in the 
Investigator’s Brochure (IB). For a marketed product, the known information is contained 
in the current package insert for the product. 
An unexpected adverse event (UAE) or unexpected adverse drug reaction (UADR) is one 
for which the specificity or severity is not consistent with the current IB. For example, 
hepatic necrosis would be unexpected (greater severity) if the IB only listed elevated 
hepatic enzymes or hepatitis. Likewise, cerebral thromboembolism and cerebral vasculitis 
would be unexpected (greater specificity) if the IB only listed cerebral vascular accidents. 


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Furthermore, reports that add significant information on specificity or severity of a 
known, already documented adverse reaction constitute unexpected events. Examples 
would be (a) acute renal failure as an expected adverse reaction with a subsequent new 
occurrence of interstitial nephritis (interstitial nephritis would be unexpected) and (b) 
hepatitis with a first occurrence of fulminant hepatitis (fulminant hepatitis would be 
unexpected.) 
11.1.4 
Serious Adverse Events/Drug Reaction 
A serious adverse event (SAE) is any untoward medical occurrence that at any dose: 
 results in death 
 is life-threatening 
 
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 which hypothetically might have caused death if it were more severe. 
 
requires inpatient hospitalization or prolongation of existing hospitalization 
NOTE: Inpatient hospitalization is defined as 24 hours in a hospital or an overnight 
stay. An elective hospital admission to treat a condition present before exposure to 
the test drug, or a hospital admission for a diagnostic evaluation of an AE, does not 
qualify the condition or event as an SAE. Further, an overnight stay in the hospital 
that is only due to transportation, organization, or accommodation problems and 
without medical background or due to local requirements for administration of the 
study treatment does not need to be considered an SAE. 
 results in persistent or significant disability/incapacity 
 
is a congenital anomaly 
 
NOTE: A congenital anomaly in an infant born to a mother who was exposed to the 
IMP during pregnancy is an SAE. However, a newly diagnosed pregnancy in a 
patient that has received an IMP is not considered an SAE unless it is suspected 
that the IP(s) interacted with a contraceptive method and led to the pregnancy.  
 
is an important medical event  
NOTE: Medical and scientific judgment should be exercised in deciding whether it 
is appropriate to consider other situations serious, such as important medical 
events that may not be immediately life-threatening or result in death or 
hospitalization but may jeopardize the patient or may require intervention to 
prevent one of the other outcomes listed in the definition above. Examples of such 
events are intensive treatment in an emergency room or at home for allergic 
bronchospasm, blood dyscrasias or convulsions that do not result in 
hospitalization, or development of drug dependency or drug abuse. The occurrence 
of malignant tumors other than those resulting from underlying study diagnosis is 
also to be considered serious. 


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11.1.5 
Significant Adverse Events 
Other significant AEs are defined as marked hematological and other laboratory 
abnormalities (other than those meeting the definition of serious) and any events that led 
to an intervention, including withdrawal of test drug, dose reduction, or significant 
additional concomitant therapy. 
11.1.6 
Treatment-Emergent Adverse Events 
An AE is defined as treatment emergent (TEAE) if the first onset or worsening is after 
the first administration of IMP (CetuGEX™ or cetuximab) and within 28 days after last 
administration. 
11.2 
Management of Adverse Events 
Adverse events will be collected from the time of signing the ICF through the Safety 
Follow-Up Visit which should be performed for all patients at 28 days (+ 2 days) after the 
last dose administered. In case patients have discontinued prematurely due to AE, this AE 
has to be followed-up for a maximum of 28 days after last IMP dose to a satisfactory 
resolution as described in Section 11.2.5. Drug related AEs must be followed until they 
are resolved. Related SAEs can be reported at any time post therapy. 
11.2.1 
Collection 
The investigator is responsible for the detection and documentation of events meeting the 
criteria and definition of an AE or SAE described previously. At each visit, the patient 
will be allowed time to spontaneously report any issues since the last visit or evaluation. 
The investigator will then monitor and/or ask about or evaluate AEs using non-leading 
questions, such as 
 “How are you feeling?” 
 “Have you experienced any issues since your last visit?” 
 “Have you taken any new medications since your last visit?” 
Any clinically relevant observations made during the visit will also be considered AEs. 
11.2.2 
Evaluation 
11.2.2.1 Severity of Adverse Events 
The clinical severity of an AE will be graded using the NCI CTCAE v4.0 
(http://ctep.cancer.gov/reporting/ctc.html). For those AEs not listed in the CTCAE, the 
following grading system should be employed: 
Mild (CTCAE grade 1): 
Transient symptoms, awareness of sign/symptom, but 
easily tolerated and no interference with patient’s daily 
activities.
Moderate (CTCAE grade 2): 
Marked signs/symptoms that interfere with patient’s 
usual activities, but still acceptable.


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Severe (CTCAE grade 3) 
Incapacitating 
signs/symptoms, 
which 
cause 
considerable interference with the patient’s daily 
activities, unacceptable.
Life-threatening  
(CTCAE grade 4)
Life-threatening or disabling adverse event. 
Death (CTCAE grade 5) 
Death-related adverse event. See CTCAE Guidelines 
for assigning grade 5
It is important to distinguish between severe AEs and SAEs. Severity is a classification of 
intensity whereas an SAE is an AE that meets serious criteria, as described in 
Section 11.1.4. 
11.2.2.2 Seriousness 
The investigator is to evaluate whether the AE meets serious criteria, as described in 
Section 11.1.4. 
11.2.2.3 Action(s) Taken 
Allowed action(s) taken for IMPs and nIMPs may consist of: 
No action taken
An indication that a medication schedule was maintained.
Drug 
interrupted/infusion 
rate reduced
An indication that a medication schedule was modified by 
temporarily terminating a prescribed regimen of IMPs or 
nIMPs.
Dose adjustment 
An indication that adjustment of dose for either IMPs or 
nIMPs was performed as described in detail in Section 9.9.
Drug withdrawn 
An indication that a medication schedule was modified 
through termination of a prescribed regimen of IMPs or 
nIMPs.


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11.2.2.4 Outcome at the Time of Last Observation 
The outcome at the time of last observation will be classified as 
 Recovered/resolved 
 Recovered/resolved with sequelae 
 Recovering/resolving 
 Not recovered/not resolved 
 Death* 
 Unknown 
*Although “death” is usually an event outcome, events such as sudden death or 
unexplained death should also be reported as SAEs. 
11.2.2.5 Adverse Event Relationship to Investigational Product 
The investigator must make an assessment of each AE’s relationship to the IP. The 
categories for classifying the investigator’s opinion of the relationship are listed below. 
 
Not related 
An AE with sufficient evidence to accept that there is no causal 
relationship 
to 
IMP 
administration 
(e.g., 
no 
temporal 
relationship to drug administration, because the drug was 
administered after onset of event; investigation shows that the 
drug was not administered; another cause was proven.)
Unlikely related 
An AE, including laboratory test abnormality, with a temporal 
relationship to IMP administration that makes a causal 
relationship improbable, and in which other drugs, events or 
underlying disease provide plausible explanations.
Possibly related 
An AE with a reasonable time sequence to administration of the 
IP, but which could also be explained by concurrent disease or 
other drugs or events. Information on drug withdrawal may be 
lacking or unclear.
Related 
An AE occurring in a plausible time relationship to IMP 
administration, and which cannot be explained by a concurrent 
disease or other drugs or events. The response to withdrawal of 
the drug (de-challenge) is clinically reasonable.


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11.2.3 
Documentation 
All AEs occurring within the period of observation for the study must be documented in 
the eCRF with the following information, where appropriate. (The period of observation 
for the study is described in Section 11.2.) 
 AE name or term 
 When the AE first occurred (start date and time) 
 When the AE stopped (stop date and time or an indication of “ongoing”) 
 Severity of the AE 
 Seriousness (hospitalization, death) 
 Action(s) taken 
 Outcome 
 Investigator opinion regarding the AE relationship to the IMP(s) 
11.2.4 
Treatment of Adverse Events 
Adverse events that occur during the study will be treated, if necessary, by established 
standards of care. If such treatment constitutes a deviation from the protocol, the patient 
might be withdrawn from the study at the discretion of the investigator. In such case, the 
reason must be documented in the eCRF. The decision about whether the patient may 
continue in the study will be made by the sponsor after consultation with the investigator 
and/or medical monitor. 
If AEs occur in a patient that are not tolerable, or for which continued administration of 
IMP is not reasonable in view of the potential benefit to patient, the investigator must 
decide whether to stop the study and/or treat the patient. Special procedures may be 
recommended for the specific IMP, such as the collection of a serum sample for blood 
concentrations of IP, specific tapering procedures, or treatment regimens, as appropriate. 
11.2.5 
Follow-up 
Any AE will be followed up to a maximum of 28 days after the last dose of study 
medication to a satisfactory resolution, until it becomes stable, or until it can be explained 
by another known cause(s) (i.e., concurrent condition or medication) and clinical 
judgment indicates that further evaluation is not warranted.  
An outcome of “unknown” is not considered to be an acceptable final outcome. An 
outcome of “not resolved” is an acceptable final outcome for non-serious AEs at the end 
of a patient’s participation in the study. SAEs should be followed up until resolution, or - 
if resolution becomes unlikely - until stabilization, or until death. An outcome of “not 
resolved” for SAEs at data lock is not acceptable. 
All findings relevant to the final outcome of an AE must be reported in the patient’s 
medical record and recorded on the appropriate eCRF. 


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11.2.6 
Notification 
11.2.6.1 Serious Adverse Events 
The investigator or designee must report all SAEs promptly to xxxxxxxxxxxxxxxx within 
24 hours of first becoming aware of the event either by phone, by email or by completing 
the SAE Report Form and faxing/emailing it to the fax number/email address designated 
in the study specific Safety Management Plan.  
European contact details for 24-hours immediate reporting: 
 
xxxxxxxxxxxxxxxx Global Pharmacovigilance 
Fax: +xxxxxxxxxxxxxxx 
Email: GlycotopeSafety@xxxxxxxxxxxxxxxx.com
 
US contact details for 24-hours immediate reporting: 
 
xxxxxxxxxxxxxxxx Global Pharmacovigilance 
Fax: xxxxxxxxxxxxxx 
Email: GlycotopeSafety@xxxxxxxxxxxxxxxx.com
 
 
At the time of first notification, the investigator or designee should provide the following 
information, if available: 
 Protocol number 
 Reporter (study site and investigator) 
 Patient’s study number 
 Patient’s year of birth 
 Patient’s gender 
 Date of first dose of IMP(s) 
 Date of last dose of IMP(s), if applicable 
 Adverse event term 
 Time and date of occurrence of the event 
 A brief description of the event, outcome to date, and any actions taken 
 The seriousness criteria(on) that were met 


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 Concomitant medication at onset of the event 
 Relevant past history information 
 Relevant laboratory test findings 
 Investigator’s opinion of the relationship to IMP(s). (“Is there a reasonable 
possibility that the IMP caused the SAE? Yes or No?”) 
Within 24 hours of the initial telephone notification, the investigator must fax a written 
SAE Report Form that describes the SAE to the recipient(s) of the initial information, 
who will forward the information to the sponsor within one working day. The 
investigator must also immediately deliver any available supporting information 
requested on the SAE Report Form or by the sponsor. 
Any missing or additional relevant information concerning the SAE should be provided 
to the recipient(s) of the initial information in a written, follow-up SAE Report Form. 
Ensure that any additional information requested about the event (e.g., hospital reports, 
autopsy reports) is provided to the designated individual(s) as soon as it is available. 
The investigator is required to comply with applicable regulations (including local laws 
and guidances) regarding the notification of his/her health authorities, Independent Ethics 
Committee (IEC) and Institutional Review Board (IRB), principal and coordinating 
investigators, other study investigators, and institutions. The detailed reporting duties and 
division of responsibilities between Glycotope GmbH and xxxxxxxxxxxxxxxx will be 
provided in a separate document (see Safety Management Plan). Each investigator is 
obligated to learn about the reporting requirements for investigators in her/his country. 
The study monitor may be able to assist with this. 
11.2.6.2 Adverse Drug Reactions 
All ADRs related to the IMP will be reported by xxxxxxxxxxxxxxxx to the relevant 
authorities and institutions: serious unexpected ADRs will be reported immediately, 
serious expected ADRs will be reported annually within Development Safety Update 
Reports (DSURs) and non-serious ADRs will be reported after completion of the study. 
Suspected sADRs must be reported to the sponsor immediately, regardless of the time 
which has elapsed since the end of the period of observation. 
11.2.6.3 Non-serious Adverse Events 
Non-serious AEs will be recorded in the eCRF and reported by xxxxxxxxxxxxxxxx to 
Glycotope according to instructions given in the project operation manual (POM) and/or 
the safety monitoring plan (SMP) of this study. 
11.3 
Special Considerations 
11.3.1 
Other Adverse Events for Immediate Reporting 
In addition to SAEs, events, such as overdose and severe IRRs will require immediate 
reporting. 


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For documentation of overdose, please refer to Section 11.3.3.  
Documentation of AEs leading to any of the above mentioned significant intervention 
must be reported promptly to xxxxxxxxxxxxxxxx within 24 hours of first becoming 
aware of the event either by phone, by email or by completing a specific AE report form 
and faxing/emailing it to the fax number/email address designated in the study specific 
Safety Management Plan. 
11.3.2 
Pregnancies 
All women of childbearing potential and all male patients with a partner of childbearing 
potential who participate in the study should be counseled on the need to practice 
adequate birth control and on the importance of avoiding pregnancy (of the partner, as 
applicable) during study participation until 6 months after last administration of any study 
medication, particularly cisplatin or carboplatin. Women should be instructed to contact 
the investigator or study staff immediately if pregnancy occurs or is suspected. 
Pregnancy testing will be conducted at randomization, prior to administration of IMP, at 
the beginning of single-agent maintenance phase of the study and at the Safety Visit on 
every woman of childbearing potential. A woman who is found to be pregnant at 
randomization will be excluded from the study and considered to be a screening failure. 
Female patients who become pregnant during treatment period and 4 weeks after last 
dose of IMP in the study must be withdrawn from the study. 
The investigator must report the pregnancy as if it were an SAE within 24 hours of 
learning of the pregnancy. The investigator should contact the designated individual(s) 
who receive SAE notification and record information related to the pregnancy on a 
Pregnancy Data Collection Form provided by Glycotope or its designee. 
The pregnancy should be followed up to determine outcome, including spontaneous or 
voluntary termination, details of birth, and the presence or absence of any birth defects or 
congenital abnormalities or maternal and newborn complications. Every infant has to be 
followed up for 2 months after delivery. 
11.3.3 
Overdose 
The maximal dose of CetuGEX™ or cetuximab treatment should not be exceeded during 
the study. 
Overdose that occurs during the study will be treated and documented as an AE, 
regardless of whether the overdose results in symptoms of an AE. Overdose should be 
reported in written form to the designated individual(s) who receive SAE notification. 
The information contained therein should include study site identification, reporter 
identification, patient identification, IMP, dose, action taken (e.g., administration of 
antidote or supportive measures or therapy), and any comments. 
12 
DATA SAFETY MONITORING BOARD 
Xxxxxxxxxxxxxxxx will establish an independent DSMB, whose task is to review 
periodically the relevant safety data and provide advice on the continuation, modification 


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or termination of the study. The DSMB will be comprised of 3 members, 2 of them being 
oncologists and one of them statistician. A study specific charter will define in detail the 
composition, responsibilities and procedures of the DSMB. 
As soon as at least 10 patients per treatment arm have completed the second cycle of first 
line treatment, a first meeting of DSMB will be scheduled to review the patient safety 
data. After this, regular 6-monthly meetings will be scheduled until all ongoing patients 
have been treated for at least 6 months. Starting at the second DSMB meeting, in addition 
to review of patient safety data a descriptive analysis on progression and survival will be 
included to monitor a potential detrimental effect of the IMP. For important reasons 
additional meetings may be scheduled by the coordinating investigator, sponsor, medical 
monitor or DSMB members as long as patients are at risk. 
13 
STATISTICS 
This section presents a summary of the planned statistical analyses. A statistical analysis 
plan (SAP) describing in detail the analyses to be conducted will be prepared as a 
separate document. 
The main statistical analysis will be performed when 192 PFS events have been observed. 
Based on the statistical assumptions as described in Section 13.2 this is expected to occur 
after 36 months of study duration (24 months recruitment + 12 months follow up). The 
result of a prolonged follow-up for OS will be analyzed and reported in an amendment to 
the main analysis. 
13.1 
Study Endpoints 
13.1.1 
Primary Endpoint 
Primary endpoint of the trial is PFS defined as time from randomization until disease 
progression or death of any cause. Date of disease progression is defined as the date of 
imaging showing disease progression, assessed by the investigator according to adapted 
immune-related RECIST 1.1 (modified irRC). 
The PFS time will be censored at the time of the last tumor assessment if the patient is 
alive and without progression at the last time of observation. 


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13.1.2 
Secondary Endpoints 
Secondary efficacy endpoints include: 
 PFS as assessed by independent centralized reading according to modified irRC. 
 Objective response rate (ORR, i.e., CR + PR) according to modified irRC at the 
end of combination treatment. 
 Best overall response rates (CR, PR, SD) according to modified irRC including 
maintenance therapy treatment. 
 Clinical benefit rate (CBR, i.e., CR + PR + SD) according to modified irRC. 
 Overall survival (OS) defined as time from randomization until death of any cause. 
 Time to treatment failure (TTF), as defined in Section 10.3.1.2. 
 QoL scores assessed using EORTC-QLQ-C30 and EORTC-QLQ-H&N35H. 
In addition, PFS and all secondary efficacy endpoints listed above will be analyzed by 
FcγRIIIa-allotype subgroups (i.e., FF, FV and VV), by p16 status, by EGFR status, and 
other potential parameters, unless the sample sizes in subgroups are too low. 
13.1.3 
Pharmacokinetic Endpoints 
The PK samples for determining CetuGEX™ antibody concentrations will only be 
collected for the first-line treatment, according to the schedule presented in Appendix B. 
No PK samples will be collected during the single-agent maintenance therapy, unless 
combination therapy has been prematurely terminated. There are 2 different groups of PK 
samples being collected during the first-line treatment. 
For all patients randomized to CetuGEX™ treatment group for the first-line treatment, 
blood sampling for PK trough and maximum levels will be performed during Cycles 1, 2, 
3 and 4. Blood samples will be collected before and at the end of each infusion on Day 1, 
8, and 15 for Cycles 1, 2 and 3. On Cycle 4, blood samples will be collected before and at 
the end of each infusion but only on Day 1. Since the first dose of Cycle 1 will be split, 
there will also be blood samples collected before and at the end of the infusion on Day 0 
(first infusion day of Cycle 1). Pre-infusion samples should be collected within 30 
minutes prior to the start of the infusion. Post-infusion samples should be collected within 
10 minutes following the end of the infusion and within 5 minutes would be ideal. 
For a subset of patients, additional blood sampling will be collected on first infusion of 
Cycle 1 and Cycle 4 to more fully PK profile the first infusions from both of these cycles. 
The full profile of Cycles 1 and 4 PK blood samples will include pre- and post-infusion 
blood samples and 5 hour ± 5 min, 7 hours ± 15 min (Day 1), 24 ± 1 hour (Day 2), 48 ± 2 
hours (Day 3), 72 ± 2 hour (Day 4), and 7 days (168 ± 2 hours; Day 8) after the start of 
the infusion on Day 1. In addition, since the first infusion on Cycle 1 will be split 
between Day 0 and Day 1, PK samples will be available for pre- and post-infusions on 
Day 0. 


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13.1.4 
Safety Endpoints 
The safety endpoints are: 
 Incidence of AEs and SAEs, including incidence of target/class-specific side 
effects (skin reactions, diarrhea).  
 IRRs. 
 Physical assessments. 
 Laboratory assessments. 
 Vital signs. 
 ECG. 
 
In addition, the incidence of AEs will be analyzed by FcγRIIIa-allotype subgroups (FF, 
FV and VV). 
13.1.5 
Exploratory Endpoints 
The exploratory endpoints in this study are: 
 Immunogenicity: incidence of ADAs. 
 Immunological parameters: cytokine levels and immune cell status. 
13.2 
Sample Size Determination 
The log-rank test will be used to test the hypothesis that patients assigned to the 
CetuGEX™ arm have increased PFS compared to patients assigned to the control arm. 
The sample size calculation is based on the following assumptions: 
 The median PFS in the control arm is expected to be 5.6 months15 post 
randomization. 
 It is expected that the median PFS in the CetuGEX™ arm can be increased to 
8.4 months corresponding to a hazard ratio of 0.67. 
 The overall trial duration will be approximately 48 months with an anticipated 
recruitment time of 24 months, anticipated treatment phase until PFS events are 
reached of approximately 12 months after randomization of the last patient (data 
cut-off for main analysis) and ongoing follow-up for overall survival for at least 24 
months after randomization of the last patient. 
 Drop-outs are expected to occur at times following an exponential distribution and 
resulting in a drop-out rate of 10% at the cut-off for PFS analysis.  
 Patients will be randomized in a 1:1 ratio. 
 The overall two-sided significance level will be 0.05 and the power to be 
maintained 80%. 


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Based on these assumptions, approximately 240 patients have to be randomized to 
observe the required overall number of 192 events. 
Assuming a corresponding effect on OS (hazard ratio 0.67) and a median overall survival 
of 10.6 months in the control group the number of survival events to be observed after a 
24 months follow-up for survival will be 183. 
13.3 
Analysis Populations 
The analysis populations include the following: 
 The intention-to-treat (ITT) population will consist of all randomized patients. The 
ITT population is the primary population for the efficacy analysis. 
 The safety population (SAF) will include all patients who received at least 
one dose of trial medication. This population will be used for safety analyses. 
 The per-protocol (PP) population will consist of all ITT patients who received at 
least one dose of trial medication and without major protocol deviations as defined 
in the statistical analysis plan and finally decided in a Data Review Meeting before 
database lock. This population will be utilized to evaluate the sensitivity of the 
primary efficacy analysis.  
 The pharmacokinetic (PK) population will consist of all randomized patients 
including the subset of patients who had blood samples collected for PK 
noncompartmental profiling, who had at least one measureable CetuGEX™ 
antibody concentration. 
In the event that a patient is randomized incorrectly or is administered the incorrect study 
medication, analyses of the ITT population will be based on the assigned treatment 
whereas all other analyses will be based on the actual treatment. 


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13.4 
Statistical Analyses 
13.4.1 
General Methods 
For dichotomous and categorical variables, absolute and relative frequencies (counts and 
percents) will be calculated. For continuous variables, comprehensive data summaries 
will be presented with sample characteristics (n, arithmetic mean, standard deviation, 
minimum, lower quartile, median, upper quartile and maximum) by treatment. Where 
data are collected over time, both the observed data and the change from baseline will be 
summarized at each visit. 
13.4.2 
Study Patients and Demographics 
13.4.2.1 Disposition and Withdrawals 
The numbers of patients randomized, completing, and withdrawing, along with reasons 
for withdrawal, will be tabulated overall and by treatment group. The number of patients 
in each analysis population will be reported. This analysis will be based on all patients. 
13.4.2.2 Demographics and Other Baseline Characteristics 
Demographic variables will include age, race, weight, BMI, smoking status and alcohol 
consumption.  
Other baseline characteristics will include: 
 Tumor specific medical history (time since first diagnostic, tumor pre-treatment, 
tumor grading) 
 FcγRIIIa status 
 General medical history 
 Prior and concomitant medications will be summarized by treatment group and by 
the number and percentage of patients taking each medication, classified using 
World Health Organization Drug Dictionary (WHO-DD). 
These analyses will be conducted for the safety population. 
13.4.3 
Efficacy Analyses 
13.4.3.1 Primary Analysis 
Primary endpoint of the trial is PFS defined as time from randomization until disease 
progression (assessed by the investigator) or death of any cause. The PFS time will be 
censored at the time of the last tumor assessment if the patient is alive and without 
progression at the last time of observation. 
The primary efficacy analysis for PFS will be based on the ITT population. A log-rank 
test will be used to test the null hypothesis of equal treatment effects at an overall 
significance level of 0.05. The primary efficacy analysis will not be stratified by the 


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factors used for stratification at randomization in order to preserve the estimated power 
considering the high number of strata. As a sensitivity analysis, a proportional hazards 
regression model will be applied and the effects of the stratification factors, the p16 
status, and the EFGR status will be estimated: 
 FcγRIIIa status (FF or FV or VV), 
 p16 status (+/-), 
 EGFR status (+/-), 
 Oral cavity and oropharynx vs. other locations,  
 Locally recurrent vs. metastatic disease. 
 EGFR treatment naïve vs. EGFR treatment as part of multimodal treatment. 
The Kaplan-Meier method will be used to estimate the survival functions. Median 
survival times together with their 95%-confidence intervals will be retrieved from the 
survival functions.  
The analysis will be repeated for the PP population as a sensitivity analysis. 
13.4.3.2 Secondary Analyses 
A Chi-squared test will be performed to evaluate the effects of treatment on response 
rates as defined in Section 13.1.2. A logistic regression model will be fit to estimate odds 
ratios for the association of stratification factors, the p16 status, and the EGFR status with 
response categories. Corresponding 95%-confidence intervals will be calculated for the 
treatment differences in response rates. 
Overall survival and TTF will be analyzed analogously to PFS on an ITT basis. 
Additional models will be applied to evaluate the impact of second line treatments on OS. 
Details will be given in the SAP. 
If subgroup sample sizes allow, analyses of the primary and secondary efficacy endpoints 
will be repeated for the FcγRIIIa-allotype subgroups (i.e., FF, FV, VV), the p16 status 
subgroups as well as the EGFR status subgroups, omitting the FcγRIIIa factor, the p16 
status and the EGFR status factor, respectively. 
13.4.3.3 Pharmacokinetics 
The PK samples will consist of 2 groups; samples from the PK profile group and samples 
from all patients of the CetuGEX™-arm before and at the end of each infusion (up to the 
10th infusion). The samples from the PK profile group will be used for non-
compartmental analyses. All samples will be pooled for a population PK analysis 
estimating clearance and volume of distribution. Both results from PK methods of 
analysis will be reported as they have different strengths and weaknesses. 
The population PK analysis will be described in a separate population PK plan that 
follows recommendations from regulatory guidance from FDA (Guidance for Industry – 
Population Pharmacokinetics) and EMA (Guideline on reporting the results of population 
pharmacokinetic analyses CHMP/EWP/185990/95, June 2007). These regulatory 


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guidance will also be followed for conduct of the population PK analysis with validation 
by boot-strapping techniques and reporting results. Population PK analysis will be 
conducted using Pharsight Phoenix NLME® software or other established population PK 
software such as NONMEM®. 
These analyses will be conducted for the PK population. 
13.4.4 
Safety and Tolerability Analyses 
The safety analysis will be performed for the safety population. 
13.4.4.1 Adverse Events 
Adverse Events will be coded using the Medical Dictionary for Regulatory Activities 
(MedDRA). Summaries of incidence rates (frequencies and percentages) of individual 
TEAEs by MedDRA System Organ Class and Preferred Term will be prepared. Such 
summaries will be displayed for all TEAEs, TEAEs by maximum intensity and TEAEs 
by strongest relationship to study treatment. 
Treatment emergent adverse events (TEAEs) are defined as any AE which started or 
deteriorated at or after start of treatment. Incidences for TEAE will be calculated on 
Preferred Term level, on System Organ Class level and globally by treatment group. On 
each analysis level, a patient will be counted only once. Frequencies for TEAE will also 
be given for causality and severity graded according to NCI-CTC (AE criteria Version 
4.0).  
In addition, toxicity as evaluated via incidence of AEs will be analyzed by FcγRIIIa 
allotype subgroups (FF, FV and VV).  
The incidences of ADA will be summarized in frequency tables per treatment arm. 
13.4.4.2 Clinical Laboratory Evaluations 
For hematology and biochemistry variables, descriptive summaries of observed values 
and changes from baseline will be presented by treatment arm.  
Each abnormal value will be flagged to show whether it is a value below or above the 
reference range. For the assessment of laboratory variables, 5 categories will be used that 
take into account the investigator’s assessment of clinical relevance: "clin. rel., above", 
"non-clin. rel., above", "within", "non clin. rel., below", "clin. rel., below". 
The assessments of laboratory variables concerning reference ranges and clinical 
relevance will be tabulated by visit for each clinical laboratory parameter by treatment 
arm (frequency tables). Additionally, for each laboratory parameter, shifts in assessments 
from baseline to the last on-study value will be presented by treatment arm (shift tables). 
Laboratory values that are outside the reference range will also be flagged in the data 
listings, along with corresponding reference ranges. 
The assessment of categorical urinalysis variables will be tabulated by visit for each urine 
parameter by treatment arm (frequency tables). Additionally, for each of these urine 


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parameter shifts in assessments from baseline the last on-study value will be presented for 
each treatment arm (shift tables). 
13.4.4.3 Vital Signs 
Descriptive summaries of observed values and changes from baseline will be calculated 
for vital signs. These summaries will be presented by visit and treatment arm. 
13.4.4.4 Electrocardiograms and Echocardiograms 
Descriptive summaries of observed values and changes from baseline will be calculated 
for ECG variables. QT will be corrected according to Bazett. Frequency and shift tables 
will be presented for the classified values of QTc as given by the International Conference 
on Harmonisation (ICH)-E14, as well as for the overall clinical assessment. 
For ECHO/MUGA assessments, descriptive values of observed values at baseline 
(“Normal”/”Abnormal [not] clinically significant”) will be presented by treatment arm. 
13.4.4.5 Physical Examination Findings 
Findings in post-baseline physical examinations will be documented as AE and analyzed 
as part of the general AE analysis. 
13.4.5 
Interim Analysis 
No formal interim analysis will be performed. Descriptive summaries of PFS and OS 
events, including point estimates and 95% confidence intervals of the hazard ratios, will 
be provided to the DSMB at all meetings starting from the second meeting 
(approximately 9 months after start of enrollment) in order to monitor potential 
detrimental effects of the investigational compound. 
14 
STUDY CONDUCT 
Steps to ensure the accuracy and reliability of data include the selection of qualified 
investigators and appropriate study sites, review of protocol procedures with the 
investigator and associated personnel prior to the study, periodic monitoring visits, and 
meticulous data management. 
14.1 
Sponsor and Investigator Responsibilities 
14.1.1 
Sponsor Responsibilities 
The Sponsor is obligated to conduct the study in accordance with strict ethical principles 
(Section 16). The sponsor reserves the right to withdraw a patient from the study 
(Section 8.3), to terminate participation of a study site at any time (Section 14.6), and/or 
to discontinue the study (Section 14.5.2). 
Glycotope GmbH agrees to provide the investigator with sufficient material and support 
to permit the investigator to conduct the study according to the study protocol. 


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14.1.2 
Investigator Responsibilities 
By signing the Investigator’s Agreement (Section 18.2), the investigator indicates that 
she/he has carefully read the protocol, fully understands the requirements, and agrees to 
conduct the study in accordance with the procedures and requirements described in this 
protocol. 
The investigator also agrees to conduct this study in accordance with all laws, 
regulations, and guidelines of the pertinent regulatory authorities, including and in 
accordance with the July 2002 ICH Guidance for Industry E6 Good Clinical Practice 
(GCP) and in agreement with the 2008 Version of the Declaration of Helsinki. While 
delegation of certain aspects of the study to sub-investigators and study coordinators is 
appropriate, the investigator will remain personally accountable for closely overseeing 
the study and for ensuring compliance with the protocol and all applicable regulations 
and guidelines. The investigator is responsible for maintaining a list of all persons that 
have been delegated study-related responsibilities (e.g., sub-investigators and study 
coordinators) and their specific study-related duties. 
Investigators should ensure that all persons who have been delegated study-related 
responsibilities are adequately qualified and informed about the protocol, IMPs, and their 
specific duties within the context of the study. Investigators are responsible for providing 
Glycotope GmbH with documentation of the qualifications, GCP training, and research 
experience for themselves and their staff as required by Glycotope GmbH and the 
relevant governing authorities. 
To ensure compliance with the guidelines, the study will be audited by an independent 
person. The investigator agrees, by written consent to this protocol, to cooperate fully 
with compliance checks by allowing access to all study documentation by authorized 
individuals. 
14.2 
Site Initiation 
Study personnel may not screen or enroll patients into the study until after receiving 
notification from Glycotope GmbH or its designee that the study can be initiated at the 
study site. The study site will not be authorized for study initiation until: 
1. The conduct of the study has been approved by the corresponding competent 
authority. 
2. The study site has received the appropriate IEC/IRB approval for the protocol and the 
appropriate ICF. 
3. All GCP documents have been submitted to and approved by Glycotope or its 
designee. 
4. The study site has a Clinical Trial Agreement in place. 
5. Study site personnel, including the investigator, have participated in a study initiation 
meeting. 


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14.3 
Study Documents 
All documentation and material provided by Glycotope GmbH for this study are to be 
retained in a secure location and treated as confidential material. 
14.3.1 
Site Documents 
Site specific documents according to regulatory and GCP requirements must be received 
from the investigator and reviewed and approved by Glycotope GmbH or its designee 
before the study site can initiate the study and before Glycotope GmbH will authorize 
shipment of IMP to the study site. Copies of the investigator’s documents must be 
retained at the study site in a secure location. Additional documents, including a copy of 
the protocol and applicable amendment(s), the IB, eCRF completion guidelines, copies of 
regulatory references, copies of IEC/IRB correspondence, and IMP accountability records 
should also be retained as part of the investigator’s site documents. It is the investigator’s 
responsibility to ensure that copies of all required documents are organized, current, and 
available for inspection. 
14.3.2 
Case Report Forms 
By signing the Investigator’s Agreement (Section 18.2), the investigator agrees to 
maintain accurate eCRFs and source documentation as part of the case histories for all 
patients who sign an ICF. 
Case Report Forms are considered confidential documents and should be handled and 
stored accordingly. The sponsor or its designee will provide the necessary training on the 
use of the specific eCRF used during the study to ensure that the study information is 
captured accurately and appropriately. 
To ensure data accuracy, eCRF data for individual patient visits should be completed as 
soon as possible after the visit. All requested information must be entered in the 
electronic data capture (EDC) system according to the completion guidelines provided by 
Glycotope or its designee. 
The eCRFs may be signed by the investigator or a sub-investigator. These signatures 
serve to attest that the information contained in the eCRF is accurate and true. 
14.3.3 
Source Documents 
All information recorded in the EDC system must be supported by corresponding source 
documentation. Examples of acceptable source documentation include, but are not 
limited to, hospital records, clinic and office charts, laboratory notes, and recorded data 
from automated instruments, memoranda, and pharmacy dispensing records. 
Before the study starts, a list identifying any data to be recorded directly on the eCRFs 
(i.e., no prior written or electronic record of data) and considered to be source data will be 
provided. 


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Clinical laboratory data required by the protocol will be electronically transferred from 
the central laboratory to Glycotope GmbH or its designee. The results of the FcγRIIIa 
status assessment will be provided to the study site and should be retained with each 
patient’s source data. 
14.4 
Data Quality Control 
Glycotope GmbH and its designees will perform quality control checks on this clinical 
study. 
14.4.1 
Monitoring Procedures 
Glycotope GmbH and/or designee will conduct site visits to monitor the study and ensure 
compliance with the protocol, GCP, and applicable regulations and guidelines. The 
assigned clinical research associate(s) (CRA[s]) will visit the investigator and study site 
at periodic intervals and maintain periodic communication. The investigator agrees to 
allow the CRA(s) and other authorized Glycotope GmbH personnel access. The CRA(s) 
will maintain current personal knowledge of the study through observation, review of 
study records and source documentation, and discussion of the conduct of the study with 
the investigator and staff. While on site, the CRA(s) will review documents and 
procedures as outlined in the Monitoring Plan. 
The CRA will ask for clarification and/or correction of any noted inconsistencies. 
Procedures for correcting eCRF are described in the study manual. As representatives of 
Glycotope, CRAs are responsible for notifying project management of any noted protocol 
deviations. 
By signing the Investigator’s Agreement (Section 18.2), the investigator agrees to meet 
with the CRA(s) during study site visits; to ensure that study staff is available to the 
CRA(s) as needed; to provide the CRA(s) access to all study documentation, to the 
clinical supplies dispensing and storage area; and to assist the monitors in their activities, 
if requested. Further, the investigator agrees to allow Glycotope GmbH or designee 
auditors or inspectors from regulatory agencies to review records and to assist the 
inspectors in their duties, if requested. 
14.4.2 
Data Management 
Glycotope GmbH or designee will be responsible for activities associated with the data 
management of this study. The standard procedures for handling and processing records 
will be followed per GCP and xxxxxxxxxxxxxxxxxx standard operating procedures 
(SOPs). A comprehensive data management plan (DMP) will be developed including a 
data management overview, database contents, annotated eCRF, pre-entry review list, 
self-evident correction conventions, query contacts, and consistency checks. 
Study site personnel will be responsible for providing resolutions to all data queries. The 
investigator will be required to document electronic data review to ensure the accuracy of 
the corrected and/or clarified data. Procedures for soliciting and documenting resolution 
to data queries are described in the study manual. 


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14.4.3 
Quality Assurance/Audit 
This study will be subject to audit by Glycotope GmbH or designee. The audits will be 
undertaken to check compliance with GCP guidelines.  
Glycotope GmbH or designee may conduct additional audits on a selection of study sites, 
requiring access to patient notes, study documentation, and facilities or laboratories used 
for the study. 
The study site, facilities, all data (including source data), and documentation will be made 
available for audit by quality assurance auditors and for IEC/IRB or regulatory authorities 
according to GCP guidelines. The investigator agrees to cooperate with the auditor during 
the visit and will be available to supply the auditor with eCRFs or other files necessary to 
conduct that audit. Any findings will be strictly confidential. 
If a regulatory authority informs the investigator that it intends to conduct an inspection, 
the investigator shall notify Glycotope GmbH immediately. 
14.5 
Study Termination 
The study may be terminated at Sponsor’s discretion at any time and for any reason. 
14.5.1 
Regular Study Termination 
The end of this study is defined as the date when:  
 The number of PFS events required for analysis are reached,  
 all patients have discontinued medication, and 
 a relevant number of deaths have occurred to obtain information on overall survival. 
Within 90 days of the end of the clinical study, Glycotope GmbH or designee will notify 
the IEC/IRBs and regulatory authorities on the regular termination of the study as 
required according to national laws and regulations. 
14.5.2 
Premature Study Termination 
The study may be terminated prematurely for any reason and at any time by Glycotope 
GmbH, IEC/IRBs, regulatory authorities, respective steering committees, or the 
coordinating investigator. A decision to prematurely terminate the study is binding to all 
investigators of all study sites. 
Reasons for premature study termination may be: new toxicological or pharmacological 
findings or safety issues invalidate the earlier positive benefit-risk ratio, the sponsor 
decides to stop the study because of failure to meet expected goals, or the development of 
the IMP is discontinued. 
Within 15 days of premature termination of a clinical study, Glycotope GmbH or 
designee will notify the IEC/IRBs and regulatory authorities on the premature termination 
as required according to national laws and regulations. Glycotope GmbH or designee 
must clearly explain the reasons for premature termination. 


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If the study is terminated prematurely, all investigators have to inform their patients and 
take care of appropriate follow-up and further treatment of the patients to ensure 
protection of the patients’ interests. Study sites may be asked to have all patients 
currently participating in the study complete all of the assessments for the Final 
Examination Visit. 
14.6 
Study Site Closure 
At the end of the study, all study sites will be closed. Glycotope GmbH may terminate 
participation of a study site at any time. Examples of conditions that may require 
premature termination of a study site include, but are not limited to, the following: 
 Noncompliance with the protocol and/or applicable regulations and guidelines 
 Inadequate patient enrolment 
14.6.1 
Record Retention 
After completing the study, Glycotope GmbH will receive the original eCRFs or at least a 
legible copy and retain the documents at least 10 years after the completion of the study. 
One copy will remain with the investigator. The investigator shall arrange for the 
retention of the patient identification codes, patient files and other source data until at 
least 5 years after the last approval of a marketing application in an ICH region and until 
there are no pending or contemplated marketing applications in an ICH region, or until at 
least 2 years have elapsed since the formal discontinuation of the clinical development of 
the product. These documents need to be retained for a longer period of time if required 
by applicable regulatory authorities or by agreement with Glycotope. 
At the end of such period, the investigator shall notify Glycotope GmbH in writing of 
her/his intent to destroy all such material. Glycotope GmbH shall have 30 days to respond 
to the investigator’s notice, and shall have a further opportunity to retain such materials at 
the sponsor’s expense. 
Copies of these study records (and all study-related documents, including source data) 
shall be kept by the investigator for the maximum period of time permitted by the 
hospital, institution, or private practice. 
14.6.2 
Sample Retention 
Samples may be used for purposes related to this research. The samples will be stored 
until Glycotope GmbH has determined that specimens are no longer needed and the 
decision has been made that none of the samples needs to be reanalyzed. In addition, 
identifiable samples can be destroyed at any time at the request of the patient. 


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14.7 
Changes to the Protocol 
This protocol cannot be altered or changed except through a formal protocol amendment, 
which requires the written approval of Glycotope GmbH. The protocol amendment must 
be signed by the investigator and approved by the IEC/IRB before it may be 
implemented. Protocol amendments will be filed with the appropriate regulatory 
agency(s) having jurisdiction over the conduct of the study. 
14.8 
Use of Information and Publication 
All information concerning CetuGEX™, Glycotope GmbH operations, patent 
applications, formulas, manufacturing processes, basic scientific data, and formulation 
information supplied by Glycotope GmbH or designee to the investigator and not 
previously published, is considered confidential and remains the sole property of 
Glycotope GmbH. Case report forms also remain the property of Glycotope GmbH. The 
investigator agrees to use this information for purposes of study execution through 
finalization and will not use it for other purposes without the written consent of 
Glycotope GmbH. 
The information developed in this study will be used by Glycotope GmbH in connection 
with the continued development CetuGEX™ and thus may be disclosed as required to 
other clinical investigators or government regulatory agencies. 
The information generated by this study is the property of Glycotope GmbH. Publication 
or other public presentation of CetuGEX™ data resulting from this study requires prior 
review and written approval of Glycotope GmbH. Abstracts, manuscripts, and 
presentation materials should be provided to Glycotope GmbH for review and approval at 
least 90 days prior to the relevant submission deadline. Data from individual study sites 
must not be published separately. 
It is agreed that the results of the study will not be submitted for presentation, abstract, 
poster exhibition or publication by the investigator until Glycotope GmbH has reviewed 
and consented on such a presentation or manuscript for publication. 
15 
FINAL CLINICAL STUDY REPORT 
Glycotope GmbH will retain ownership of the data. 
The final clinical study report (CSR) will be written within one year of completion of the 
clinical part of the study. This report will include a summary of the study results based on 
a statistical evaluation and clinical assessment of the protocol-defined endpoints. 
The final CSR will be submitted to the regulatory authorities according to local 
requirements. 


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16 
ETHICAL AND LEGAL CONSIDERATIONS 
16.1 
Declaration of Helsinki and Good Clinical Practice 
This study will be conducted in compliance with the July 2002 ICH Guidance for 
Industry E6 GCP (including archiving of essential study documents), the 2008 Version of 
the Declaration of Helsinki, the applicable regulations of the countries in which the study 
is conducted, and with the Commission Directives 2001/20/EC and 2005/28/EC. 
See Appendix D for regulation and guidelines. 
16.2 
Patient Information and Informed Consent 
According to the Declaration of Helsinki and ICH GCP, patients must provide their 
written informed consent prior to enrolment in a clinical study and before any protocol-
specified procedures are performed. Patients must declare their consent by personally 
signing and dating the ICF. The written ICF will embody the elements of informed 
consent as described in the Declaration of Helsinki and will also comply with local 
regulations.  
Each patient should be made aware by the investigator of the nature of the study 
(objectives, methods, and potential hazards and benefits) and the procedures involved, 
using the information on the ICF. Information should be given in both oral and written 
form whenever possible and deemed appropriate by the IEC/IRB. Patients must be given 
ample opportunity to inquire about details of the study.  
Patient information and the ICF must be in a language fully comprehensible to the 
prospective patient. The written information must be provided to the patient to give 
him/her sufficient time to understand the information and to prepare questions before 
being asked for his/her consent. The investigator must confirm that the text was 
understood by the patient. The patient will then sign and date the IEC/IRB-approved 
consent form indicating that he/she has given his/her consent to participate in the study. 
The signature confirms the consent is based on information that has been understood. The 
form will also be signed by the investigator obtaining the consent and annotated with the 
study patient number. Each patient’s signed ICF must be kept on file by the investigator 
for possible inspection by regulatory authorities, Glycotope GmbH and/or xxxxxxx 
xxxxxxxx personnel. Collection of informed consent must be documented on the eCRF. 
Furthermore, the patient will be informed that if he/she wishes to drop-out or withdraw 
(see Section 8.3) at any time during the study, this will not have any negative 
consequences. Patients may be withdrawn by the investigator if any change related to 
safety or ethics precludes further participation in the study. Patients will be asked to agree 
to a final assessment in the event of an early termination of the study. 
Patients will be informed that data from their case may be stored in a computer without 
inclusion of their name and such data will not be revealed to any unauthorized third party. 
Data will be reviewed by the monitor, an independent auditor, and possibly by 
representatives of regulatory authorities and/or IEC/IRBs. The terms of the local data 
protection legislation will be applied as appropriate. 


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16.3 
Approval by Independent Ethics Committee/Institutional Review Board 
For Investigational New Drug (IND) studies, the minimum standards of conduct and 
requirements for informed consent are defined in the FDA regulations. 
A valid IEC/IRB and competent authorities must review and approve this protocol before 
study initiation. Written notification of approval is to be submitted by xxxxxxxxxxxxxxx 
to Glycotope GmbH before shipment of investigational drug supplies, and will include 
the date of the committee’s approval and the chairperson’s signature.  
Until written approval by the IEC/IRB has been received by the investigator, no patient 
may undergo any study-related procedure. 
Protocol amendments must also be reviewed and approved by the IEC/IRB and 
competent authority. Written approval from the IEC/IRB, or a designee, must be received 
by Glycotope GmbH and by the investigator before implementation of the amendment. 
16.4 
Finance and Insurance 
Details on finance and insurance will be provided in a separate agreement between the 
investigator and Glycotope GmbH or designee. 


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17 
REFERENCES 
 
 
 
 
1 Umana P, Jean-Mairet J, Moudry R, Amstutz H, Bailey JE. Engineered glycoforms of 
an antineuroblastoma IgG1 with optimized antibody-dependent cellular cytotoxic 
activity. Nat Biotechnol. 1999;17:176 – 180. 
2 Suzuki E, Niwa R, Saji S, et al. A nonfucosylated anti-HER2 antibody augments 
antibody-dependent cellular cytotoxicity in breast cancer patients. Clin Cancer 
Res.2007;13:1875-1882. 
3 Shields RL, Lai J, Keck R, et al. Lack of fucose on human IgG1 N-linked 
oligosaccharide improves binding to human Fcgamma RIII and antibody-dependent 
cellular toxicity. J Biol Chem.2002;277:26733-26740. 
4 Shinkawa T, Nakamura K, Yamane N, et al. The absence of fucose but not the presence 
of galactose or bisecting N-acetylglucosamine of human IgG1 complex-type 
oligosaccharides shows the critical role of enhancing antibody-dependent cellular 
cytotoxicity. J Biol Chem. 2003;278: 3466-3473. 
5 Bibeau F, Lopez-Crapez E, Di Fiore, F, et al. Impact of FcgammaRIIa-FcgammaRIIIa 
polymorphisms and KRAS mutations on the clinical outcome of patients with 
metastatic colorectal cancer treated with cetuximab plus irinotecan. J Clin Oncol. 
2009; 27:1122-1129. 
6 Musolino A, Naldi N, Bortesi B, et al. Journal of Clinical Oncology 2008; 26:1778-
1780. 
7 Weng WK, Levy R. Two immunoglobulin G fragment C receptor polymorphisms 
independently predict response to rituximab in patients with follicular lymphoma. J 
Clin Oncol.2003; 21:3940-3947. 
8 Zhang W, Gordon M, Schultheis AM, et al. FCGR2A and FCGR3A polymorphisms 
associated with clinical outcome of epidermal growth factor receptor expressing 
metastatic colorectal cancer patients treated with single-agent cetuximab. J Clin 
Oncol.2007; 25:3712-3718. 
9 Vermorken JB. Medical treatment in head and neck cancer. Ann Oncol 16 (Suppl. 2). 
2005, ii: 258-264 
10 Colevas AD. Chemotherapy options for patients with metastatic or recurrent squamous   
cell carcinoma of the head and neck. J Clin Oncol 2006; 24 (17): 2644-2652 
11 EMA, SmPC for Erbitux® 
(http://www.ema.europa.eu/ema/index.jsp?curl=pages/medicines/human/medicines/0
00558/human_med_000769.jsp&mid=WC0b01ac058001d124) 
12 Calvert AH, Newell DR, Gumbrell LA, et al. Carboplatin dosage: prospective 
evaluation of a simple formula based on renal function. J Clin Oncol 1989; 7: 1748-
1756  
13 Eisenhauer EA, Therasse P, Bogaerts J, et al. New response evaluation criteria in solid 
tumours: revised RECIST guideline (version 1.1). Eur J Cancer 2009; 45:228-247 


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14 Wolchok JD, Hoos A, O’Day S, et al. Guidelines for the evaluation of immune therapy 
activity in solid tumors: immune-related response criteria. Clin Cancer Res 2009; 15 
(23): 7412-7420. 
15 Vermorken JB, Mesia R, Rivera F, et al. Platinum-based chemotherapy plus cetuximab 
in head and neck cancer. N Engl J Med 2008; 359:1116-1127 


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18 
ATTACHMENTS 
18.1 
Schedule of Events 
 
Screening 
(within 28 
days 
prior first 
infusion)
Random-
ization 
(1-3 d 
before 
first 
infusion) 
Day 0*
Combination treatment phase 
(max. 6 cycles of chemotherapy) 
Single-agent 
maintenance 
therapy 
Safety 
Visit1
(28 + 2 
days 
after 
last 
dose) 
FE 
Visit2 
Follow
-up3 
D1 
D2 
D3 
D4 
D8 
D15 
D1 of each 
week 
± 1 day 
W1 
W2 
W3 
Written informed consent
X
Inclusion/exclusion criteria
X
X4 
X4,5
Check availability of pre-existing tumor 
tissue sample
X 
 
 
 
 
 
 
 
 
 
 
 
 
Assign identification number (IWRS)
X
Assign randomization number (IWRS)
 
X6
Demographics
X
SCCHN diagnosis and history
X
Medical history apart SCCHN
X
Physical examination
X36
X20
X
X
X
X
X
ECOG performance status
X
X4
X7
X
X
X
X
X
Vital signs 38
X
X4 
X4 
X34
X34
X34
X
X
X
X
X
Height, weight, and BMI8
X
X4 
X4 
X
X
X
X
12-lead electrocardiogram
X
X9
X5,10
X10 
X
ECHO/MUGA 
X
Evaluation of tumor size by CT or MRI 
X 41
X10, 41
X11, 41 
Clinical laboratory tests 38 (hematology, 
coagulation panel, chemistry, urinalysis)
X33 
 
X4 
X4,7
 
 
 
 
 
X12 
X 
 
 
EGFR expression
X13 
 
p16 tumor suppressor gene status 
 
X13
 
HPV status
 
X32
 
Cytokine release14, 39 
X15,20 
X16
X17 
X17
 


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Screening 
(within 28 
days 
prior first 
infusion)
Random-
ization 
(1-3 d 
before 
first 
infusion) 
Day 0*
Combination treatment phase 
(max. 6 cycles of chemotherapy) 
Single-agent 
maintenance 
therapy 
Safety 
Visit1
(28 + 2 
days 
after 
last 
dose) 
FE 
Visit2 
Follow
-up3 
D1 
D2 
D3 
D4 
D8 
D15 
D1 of each 
week 
± 1 day 
W1 
W2 
W3 
Immune status14, 39 
X4,20 
X18
X19 
X
Anti-Drug-Antibody testing (ADA)20, 39 
X4 
X21
X22 
X35 
X
Genotyping (Fcγ receptors status)23 
X
Pregnancy test for female subjects
X4 
X5 
X24 
X
PK blood sample collection20, 39 
 
 
X25 
X25,2
6 
X26
X26
X26
X27 
X28 
X26,29 
X 
 
 
Quality of Life questionnaires 39
X4 
X5,10
X30
X
Administer study drug (CetuGEX™ or 
cetuximab) 40
 
 
X20 
X37
 
 
 
X37
X37
X37 
 
 
 
Administer cisplatin/carboplatin
X31
Administer 5-FU (continuous 
administration)
 
 
 
X 
X34
X34
X34
 
 
 
 
 
 
Drug accountability
X
X34
X34
X34
X
X
X
Concomitant medications
X
X4
X
X34
X34
X34
X
X
X
X
X
Adverse events
X4
X
X34
X34
X34
X
X
X
X
X
Record of post-PD tumor therapies 
X
Abbreviations: BMI = body mass index, CT = computed tomography, ECHO = echocardiogram, ECOG = Eastern Cooperative Oncology Group, EGFR = 
epidermal growth factor receptor, FE = Final Examination, HPV = human papilloma virus, IWRS = interactive web response system, MRI = magnetic resonance 
imaging, MUGA = Multiple Gated Acquisition, PK = pharmacokinetics, SCCHN = squamous cell carcinoma of the head and neck, 5-FU = 5-fluorouracil, 
W = week. 
* 
Day 0 only applies for patients randomized to receive CetuGEX™. 
1 
The Safety Follow-Up Visit constitutes the Final Examination Visit for the patients treated with study medication until progression of disease. 
2 
As soon as progression of disease is detected, FE assessments will be performed for all patients who prematurely discontinued study treatment. For patients 
withdrawing prematurely from the complete study, the Final Examination will be performed at the date of withdrawal. 
3 
Will be performed quarterly by phone calls for at least 24 months after randomization of last patient. 
4 
To be performed pre-dose, as applicable. 
5 
To be performed only for patients receiving cetuximab, only on Day 1 of Cycle 1. 
6 
The investigator may contact the IWRS for randomization within 1 to 3 days prior to first infusion. 


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7 
To be performed in Cycle 2 and every following cycle; To be performed in Cycle 1 only for patients receiving cetuximab. 
8 
Height will be measured only at screening.  
 
9 
Only to be performed, if not done within 7 days prior randomization. 
10 To be performed every 6 weeks after randomization (i.e., Day 1 of Cycles 3 and 5, and every 6 weeks thereafter). 
11 To be performed every 6 weeks within the first 18 weeks after randomization, and every 8 weeks thereafter. 
12 To be performed every 6 weeks after randomization. 
13 Pre-existing tumor-tissue samples will be sent to laboratory once patient was randomized; remaining tumor-tissue needs to be stored for further analysis 
14 To be performed only in a subset of approximately 30 patients per treatment arm.  
15 To be performed pre-dose, 1h after start of infusion and at the end of the first infusion.  
16 To be performed pre-dose, at the start of the highest infusion rate, 1 h after start of the highest infusion rate and at the end of infusion on Day 1 of Cycle 1; 
pre-dose, 1 h after start of infusion and at the end of infusion on Day 1 of Cycle 2. 
17 To be performed pre-dose, 1 h after start of infusion and at the end of infusion on Cycle 1, only. 
18 To be performed pre-dose, only on Day 1 of Cycle 1 for patients receiving cetuximab. 
19 To be performed pre-dose, only on Day 8 of Cycle 2. 
20 To be performed only for patients receiving CetuGEX™. 
21 To be performed pre-dose, on Day 1 of Cycles 2 and 4 only. 
22 To be performed pre-dose, on Day 8 of Cycle 1 only. 
23 Only in case the patient will enter the study, this blood sample might be used at a later time point for further analyses like FCγRII status. 
24 To be performed pre-dose, only on the first week of maintenance therapy. 
25 Blood sampling for PK prior to the start of infusion and at the end of infusion, on Day 1 of Cycles 1 to 4, only. 
26 For a subgroup of approximately 30 patients only: Additional blood sampling for PK as detailed in Appendix B. 
27 Blood sampling for PK prior to start of infusion and after the end of infusion: in Cycles 1 to 3 for all patients; in Cycle 4 only for a subgroup of 
approximately 30 patients, prior to start of infusion; all PK samplings as detailed in Appendix B. 
28 Blood sampling for PK prior to start of infusion and at the end of infusion, only in Cycle 1 to 3, for all patients. 
29 Blood sampling for PK prior to start of infusion and after the end of infusion until 10th infusion after randomization, if combination therapy was discontinued 
prematurely. 
30 To be performed 18 weeks after randomization. In case combination therapy was discontinued prematurely, also 6 and 12 weeks after randomization, as 
applicable. 
31 For Cycle 1, cisplatin is mandatory. Change to carboplatin in subsequent cycles might be accepted in case of toxicity of cisplatin. 
32 HPV status will be assessed at a central laboratory, either at randomization or at a later time point. A tumor-tissue sample provided will be used for 
evaluation. 
33 Please note that creatinine clearance needs to be assessed at screening unless previous results not older than 6 weeks are available. 
34 Site visits on days 2 to 4 are only obligatory for patients either included in the PK subgroup or if they have no transportable pump for 5-FU administrations. 
Assessment of vital signs and records of drug accountability, adverse events, and concomitant medication will only be performed for patients visiting the 
site. 
35 
To be performed pre-dose, 1, 3 and 9 weeks after randomization, if combination therapy was discontinued prematurely. 
36 
Including underlying disease condition. 


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37 
Except for Day 1 of Cycle 1 a time window of ± 1 day will be allowed for the weekly infusions (calculated from the previous infusion). 
38 
If chemotherapy administration is delayed for any reasons, assessments should be repeated in relation to the chemotherapy administration. 
39 
Assessments to be done in relation to administration of CetuGEX™/cetuximab (also in case of delay in chemotherapy administration). 
40 
If the administration of CetuGEX™/cetuximab is skipped for any reason, all assessments scheduled for this study visit day are to be performed as planned. 
41 
Screening: head and neck region, chest, and abdomen. Subsequent assessments: head, neck, and chest; assessments of the abdomen will only be performed 
if at baseline metastases were confirmed or if clinical evidence suggests new lesions in these regions.  


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18.2 
Investigator’s Agreement 
 
PROTOCOL NUMBER: 
GEXMab52201 
PROTOCOL TITLE: 
Randomized, controlled, open-label, multicenter, phase 
II study to evaluate the efficacy and safety of 
CetuGEX™ plus chemotherapy in comparison to 
cetuximab plus chemotherapy for the treatment of 
patients with stage III/IV recurrent and/or metastatic 
squamous cell carcinoma of the head and neck (The 
“RESGEX” Study) 
FINAL PROTOCOL: 
Final Version 4.0, 06 February 2015 
 
I have read this protocol and agree to conduct this clinical trial as outlined herein. I will 
ensure that all sub-investigators and other study staff members have read and understand 
all aspects of this protocol. I agree to cooperate fully with Glycotope GmbH and xxxxxxx 
xxxxxxxx during the study. I ensure that this study will be conducted in accordance with 
the revised Declaration of Helsinki 2008, ICH-GCP and the local laws and regulations 
relevant to the use of new therapeutic agents. 
Principal Investigator: 
 
 
Printed Name:
 
 
 
 
Signature:
 
 
 
 
Date:
 
 
 
 
 


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APPENDICES 
A.  ECOG Performance Status  
B. Time Schedule for PK Blood Sampling 
C. Response Evaluation Criteria in Solid Tumors 
D. Regulations and Good Clinical Practice Guidelines 
E. SmPC for Cetuximab (Erbitux®) 
F. SmPC for Cisplatin 
G. SmPC for 5-FU 
H. SmPC for Carboplatin 
 


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A. 
ECOG Performance Status 
 
ECOG Performance Status* 
Grade
Description
0 
Asymptomatic (Fully active, able to carry on all pre-disease 
performance without restriction). 
1 
Symptomatic but completely ambulatory (Restricted in physically 
strenuous activity, but ambulatory and able to carry out work of a light 
or sedentary nature (e.g., light housework, office work).
2 
Symptomatic, in bed <50% of the time (Ambulatory and capable of all 
self-care, but unable to carry out any work activities. Up and about 
more than 50% of waking hours).
3 
In bed >50% of the time. Capable of only limited self-care, confined to 
bed or chair more than 50% of waking hours.
4 
100% bedbound. Completely disabled. Cannot carry on any self-care. 
Totally confined to bed or chair. 
5
Dead
*As published in Am. J. Clin. Oncol.: Oken, M.M., Creech, R.H., Tormey, D.C., Horton, J., Davis, T.E., 
McFadden, E.T., Carbone, P.P.: Toxicity And Response Criteria Of The Eastern Cooperative Oncology 
Group. Am J Clin Oncol 5:649-655, 1982. 
 
 


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B. 
Time Schedule for Pharmacokinetics Blood Sampling 
 
 
 
Treatment Cycle 1 
(Infusions 1-3) 
Treatment Cycle 2 / 
Treatment Cycle 3 
(Infusions 4-9) 
Treatment Cycle 4 
(Infusions 10) 
/    FE 
Total Number of Samples 
Visit*
Day 0 
Day 1 
(Inf. 1) 
Day 2 to 
Day 4 
Day 8 
(Inf. 2)
Day 
15 
(Inf. 3) 
Day 1
(Inf. 
4/7) 
Day 8
(Inf. 
5/8) 
Day 15
(Inf. 
6/9) 
Day 1 
(Inf. 10) 
Day 2 to 
Day 4 
Day 8 
SV   
W1 
W2 
W3 
W4/ 
W7 
W5/ 
W8 
W6/ 
W9 
W10 
W11 
W12 
Timing
Prior infusion 
At end of inf. 
Prior infusion 
At end of inf. 
After start  
of inf. 
After start  
of inf. 
Prior infusion (168 ± 2 h after 
start of 1st infusion on Day 1)
At end of inf. 
Prior infusion 
At end of inf. 
Prior infusion 
At end of inf. 
Prior infusion 
At end of inf. 
Prior infusion 
At end of inf. 
Prior infusion 
At end of inf. 
After start  
of inf. 
After start  
of inf. 
Prior inf. (168  ± 2 h after start 
of 10th infusion)
28 days after last inf. 
0 h 
0 h 
5 h ± 5 min 
7 h ± 15 min 
24 ± 1 h 
48 ± 2 h 
72 ± 2 h 
0 h 
0 h 
0 h 
0 h 
0 h 
0 h 
5 h ± 5 min  
7 h ± 15 min 
24 ± 1 h 
48 ± 2 h 
72 ± 2 h 
All Patients 
(CetuGEX™ arm) 
X 
X 
X 
X 
 
 
 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
 
 
 
 
X 
23 
Selected Subset
X
X
X
X
X
X
X
X
X
X
X
11 
If the administration of CetuGEX™/cetuximab is skipped for any reason, the pre-dose blood sample scheduled for this study visit day is to be taken as planned. 
* In case of premature discontinuation of chemotherapy cycles, please refer to the corresponding CetuGEX™ infusion numbers for scheduling PK assessments. 
W = Week


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C. 
Response Evaluation Criteria in Solid Tumors 
 
The criteria below are based on RECIST 1.1 criteria as described by Eisenhauer et al. 
(2009) and adapted according to immune-related response criteria (irRC) as defined by 
Wolchok et al. (2009). The adapted immune-related RECIST 1.1 (modified irRC) criteria 
are used in order to permit physicians to continue treatment in spite of the appearance of 
small new lesions and/or transient increases in tumor burden, as these may be 
manifestations of an anti-tumoral inflammatory response in a therapeutic setting which 
involves immunological mechanism of action. 
Measurable Lesions: 
The tumor lesion must be accurately measured in at least one dimension (longest 
diameter in the plane of measurement will be recorded) with a minimum size of: 
• 
10 mm by CT scan (CT scan slice thickness no greater than 5 mm) 
• 
20 mm by chest x-ray 
Measurable malignant lymph node: 
To be considered pathologically enlarged and measurable, a lymph node must be at least 
15 mm in short axis when assessed by CT/MRI scan (CT/MRI scan slice thickness 
recommended to be no greater than 5 mm). At baseline and in follow-up, only the short 
axis will be measured and followed. Nodes with a short axis >10 and <15 mm will be 
considered pathologically enlarged but non-measurable (see below). 
Lytic bone lesions or mixed lytic-blastic lesions with identifiable soft-tissue components 
will be considered measurable if the soft-tissue component can be evaluated by cross-
sectional imaging (i.e., CT scan) and meets the general definition of measurability. 
A lesion located in a previously irradiated area, or an area previously subjected to any 
locoregional therapy, will be considered measurable only if there has been a documented 
increase in lesion size subsequent to prior treatment but before study entry.  
Non-Measurable Lesions  
Non-measurable lesions are all other lesions, including small lesions (longest diameter 
smaller than 10 mm or pathological lymph nodes with ≥ 10 to < 15 mm short axis) as 
well as truly non-measurable lesions. Legions considered truly non-measurable are: 
leptomeningeal disease, ascites, pleural or pericardial effusion, inflammatory breast 
disease, lymphangitic involvement of skin or lung, abdominal masses/abdominal 
organomegaly identified by physical exam that is not measurable by reproducible 
imaging techniques. 
Simple cysts will not be considered malignant lesions, and will be neither measurable nor 
non-measurable. Cystic lesions believed to be metastases may be considered measurable 
if they meet the general definition of measurability, but non-cystic lesions are preferred 
as target lesions. 


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New Lesions 
The definition of measurable and non-measurable lesions also applies to new lesions to 
be included in the assessments for adapted immune-related RECIST 1.1. 
Methods of Measurement 
All measurements must be recorded in metric notation, using a ruler or calipers. All 
baseline evaluations must be performed as close as possible to the treatment start and 
never more than 4 weeks before the beginning of the treatment. 
The same method of assessment and the same technique must be used to characterize 
each identified and reported lesion at baseline and during follow-up. Imaging based 
evaluations should always be done rather than clinical examination unless the lesion(s) 
being followed cannot be imaged but are assessable by clinical exam. 
Clinical lesions will only be considered measurable when they are superficial and at least 
10 mm as assessed using calipers (e.g., skin nodules, palpable lymph nodes). In the case 
of skin lesions, documentation by color photography including a ruler to estimate the size 
of the lesion is suggested. 
Lesions on chest x-ray may be considered measurable if they are clearly defined and 
surrounded by aerated lung. However, CT scan is preferred. 
CT scans and MRI are the best currently available and reproducible methods to measure 
lesions selected for response assessment.  
Ultrasound is not useful in assessment of lesion size and should not be used as a method 
of measurement. Ultrasound examinations cannot be reproduced in their entirety for 
independent review at a later date and, because they are operator dependent, it cannot be 
guaranteed that the same technique and measurements will be taken from one assessment 
to the next. 
Endoscopy and laparoscopy: the use of these techniques for objective tumor evaluation is 
not advised. However, they can be useful to confirm complete pathological response 
when biopsies are obtained. 
Tumor markers alone cannot be used to assess response. If markers are initially above the 
upper normal limit, they must normalize for a patient to be considered in complete 
clinical response. 
Cytology and histology can be used to differentiate between PR and CR in rare cases (for 
example, residual lesions in tumor types such as germ cell tumors, where known residual 
benign tumors can remain). 
Baseline Documentation of Target and Non-Target Lesions 
When more than 1 measurable lesion is present at baseline all lesions up to a maximum 
of 5 lesions total (and a maximum of 2 lesions per organ) representative of all involved 
organs should be identified as target lesions and will be recorded and measured at 
baseline (this means in instances where patients have only 1 or 2 organ sites involved a 
maximum of 2 and 4 lesions respectively will be recorded). 


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Target lesions should be selected on basis of their size (lesions with the longest diameter), 
be representative of all involved organs, but in addition should be those that lend 
themselves to reproducible repeated measurements. 
Lymph nodes merit special attention since they are normal anatomical structures which 
may be visible by imaging even if not involved by tumor. As previously mentioned, 
pathological nodes defined as measurable must meet the criterion of a short axis of at 
least 15 mm by CT/MRI scan to be identified as target lesions. Only the short axis of 
these nodes will contribute to the baseline sum. All other pathological nodes (those with 
short axis ≥ 10 mm but < 15 mm) should be considered non-target lesions. Nodes that 
have a short axis less than 10 mm are considered non-pathological and should not be 
recorded or followed. 
A sum of the diameters (longest for non-nodal lesions, short axis for nodal lesions) for all 
target lesions will be calculated and reported as the baseline sum diameters. The baseline 
sum diameters will be used as reference to further characterize the objective tumor 
response. 
All other lesions (or sites of disease) including pathological lymph nodes should be 
identified as non-target lesions and should also be recorded at baseline. Measurements are 
not required but the presence or absence of each should be noted throughout follow-up. 
Response Criteria According to Adapted Immune-Related RECIST 1.1 
In this study, disease progression using adapted immune-related RECIST 1.1 as 
determined by the investigator will serve to determine discontinuation from study 
treatment. New lesions will be measured and incorporated into the tumor assessment. 
Tumor diameter will be treated as a continuous variable and new lesion diameter will be 
added to the diameter of existing target diameter sum.  
The response assessment in this study is based on total measurable tumor burden adapted 
from Wolchok et al. (2009). Selected target lesions and measurable new lesions occurring 
after start of study treatment are incorporated into the tumor burden. Up to 2 measurable 
new lesions per organ are added together with the sum of diameters of the target lesions 
to provide the total tumor burden. 
Evaluation of target lesions 
1. Complete Response (CR): Disappearance of all non-nodal target lesions. Any 
pathological lymph nodes (whether target or non-target) must have reduction in 
short axis to < 10 mm. 
2. Partial Response (PR): At least a 30% decrease in the tumor burden (sum of the 
longest lesion diameter (LD) of target lesions (including the short axes of any 
target lymph nodes plus measurable new lesions), taking as reference the baseline 
sum diameters. 
3. Progressive Disease (PD): At least a 20% increase in the tumor burden (including 
the short axes of any target lymph nodes plus measurable new lesions), taking as 
reference the smallest tumor burden recorded since the treatment started. 


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4. Stable Disease (SD): Neither sufficient shrinkage to qualify for PR nor sufficient 
increase to qualify for PD, taking as reference the smallest tumor burden since the 
treatment started. 
Evaluation of non-target lesions 
1. Complete Response (CR): Disappearance of all non-target lesions and 
normalization of tumor marker level. All lymph nodes must be non-pathological in 
size (< 10 mm short axis). 
2. Non-CR/Non-Progressive Disease (-PD): Persistence of one or more non-target 
lesions. 
3. PD: Unequivocal progression of existing non-target lesions. To achieve 
“unequivocal PD”, there must be an overall level of substantial worsening in non-
target disease that is of a magnitude that, even in the presence of SD or PR in 
target lesion, the treating physician would feel it important to change therapy. 
Although a clear progression of “non-target” lesions only is exceptional, in such 
circumstances, the opinion of the treating physician should prevail, and the progression 
status should be confirmed at a later time by the review panel (or study chair). 
Evaluation of Best Overall Response According to Adapted Immune-Related 
RECIST 1.1 
The best overall response is the best response recorded from the start of the treatment 
until disease progression/recurrence (taking as reference for PD the smallest 
measurements recorded since the treatment started). The patient's best response 
assignment will depend on the achievement of measurement criteria. 
 


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Measurable 
response 
Non-measurable response    
 
 
Overall Response
 
Target and new, 
measurable lesions 
(tumor burden), % 
Non-target lesions 
New, non-measurable 
lesions  
Using irRECIST 
↓100 
CR 
Absent 
irCR 
↓100 
Stable 
Any 
irPR 
↓100 
Unequivocal 
progression
Any 
irPD 
↓≥30* 
Absent/Stable 
Any 
irPR 
↓≥30* 
Unequivocal 
progression
Any 
irPD 
↓<30 to <20↑ 
Absent/Stable 
Any 
irSD 
↓<30 to <20↑ 
Unequivocal 
progression
Any 
irPD 
≥20 
Any 
Any 
irPD 
*Decrease assessed relative to baseline, including measurable lesions only (≥10mm longest diameter). 
 
Duration of Response 
Duration of Overall Response 
The duration of overall response is measured from the time measurement criteria are met 
for CR or PR (whichever is first recorded) until the first date that recurrent or PD is 
objectively documented (taking as reference for progressive disease the smallest 
measurements recorded since the treatment started). 
The duration of overall CR is measured from the time measurement criteria are first met 
for CR until the first date that recurrent disease is objectively documented. 
Duration of Stable Disease 
Stable disease is measured from the start of the treatment until the criteria for progression 
are met, taking as reference the smallest measurements recorded since the treatment 
started. 
 


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D. 
Regulations and Good Clinical Practice Guidelines 
1. 
Regulations 
Refer to the following United States Code of Federal Regulations (CFR) and European 
Directives: 
 FDA Regulations 21 CFR, Parts 50.2 – 50.27 
 
Subpart B – Informed Consent of Human Subjects 
 FDA Regulations 21 CFR, Parts 56.107 – 56.115 
 
Part 56 – Institutional Review Boards 
 
Subpart B – Organization and Personal 
 
Subpart C – IRB Functions and Operations  
Subpart D – Records and Reports 
 FDA Regulations 21 CFR, Parts 312.50 – 312.70 
 
Subpart D – Responsibilities of Sponsors and Investigators 
 European Directive 2001/20/EC and related guidance documents 
 Relevant local laws and regulations  
 
2. 
Good Clinical Practice Guidelines 
ICH GCP guidelines can be found at the following URL: 
http://www.ich.org/LOB/media/MEDIA482.pdf 


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E. 
SmPC for Cetuximab (Erbitux®) 
 
(An English version and a version translated to local language of the SmPC will be 
attached as separate documents.) 


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F. 
SmPC for Cisplatin 
 
(An English version and a version translated to local language of the SmPC will be 
attached as separate documents.) 


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G. 
SmPC for 5-FU 
 
(An English version and a version translated to local language of the SmPC will be 
attached as separate documents.) 


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H. 
SmPC for Carboplatin 
 
(An English version and a version translated to local language of the SmPC will be 
attached as separate documents.) 
 
 

SAP_001.pdf: 
Statistical Analysis Plan 
 
 
Randomized, controlled, open label, multicenter, phase II study to evaluate the efficacy 
and safety of CetuGEX™ plus chemotherapy in comparison to cetuximab plus 
chemotherapy for the treatment of patients with stage III/IV recurrent and/or 
metastatic squamous cell carcinoma of the head and neck 
 
(The “RESGEX” Study) 
 
SAP DATE:  
December 21, 2016 
 
ClinicalTrials.gov Identifier: NCT02052960 
 
 


+ 
  
STATISTICAL ANALYSIS PLAN
 
Protocol Title: 
Randomized, controlled, open label, multicenter, phase II study 
to evaluate the efficacy and safety of CetuGEX™ plus 
chemotherapy in comparison to cetuximab plus chemotherapy 
for the treatment of patients with stage III/IV recurrent and/or 
metastatic squamous cell carcinoma of the head and neck 
Protocol Number: 
GEXMab52201 (Final Version 4.0 06-Feb-2015) 
EudraCT Number: 
2013-003695-13 
IND Number: 
118026 
Compound: 
CetuGEX™ 
Phase: 
II 
Sponsor: 
Glycotope GmbH 
Robert-Rössle-Str. 10 
D-13125 Berlin, Germany 
 
SAP Author: 
 
 
 
 
 
Germany 
SAP Version: 
Final Version 1.0 
SAP Date: 
21-Dec-2016 
 
CONFIDENTIAL 


Protocol: GEXMab 52201 
 
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Statistical Analysis Plan Final Version 1.0 
 
CONFIDENTIAL 
 
21-DEC-2016 
  
STATISTICAL ANALYSIS PLAN DOCUMENT HISTORY 
 
Version 
Date 
Author 
Description 
Final Version 1.0 
21-Dec-2016 
 
Original 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


Protocol: GEXMab 52201 
 
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Statistical Analysis Plan Final Version 1.0 
 
CONFIDENTIAL 
 
21-DEC-2016 
  
SIGNATURE PAGE AND APPROVALS 
 
 
 
 
 
 
 
Date 
 
 
 
 
 
 
Date 
 
 
 
 
 
 
Date 
 
 
 
 
 
 
Date 
 


Protocol: GEXMab 52201 
 
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Statistical Analysis Plan Final Version 1.0 
 
CONFIDENTIAL 
 
21-DEC-2016 
  
TABLE OF CONTENTS 
 
1. 
SYNOPSIS ..............................................................................................................9 
2. 
STUDY OBJECTIVES AND ENDPOINTS ........................................................9 
2.1 
Study Objectives ..........................................................................................9 
2.1.1 Primary Objective ............................................................................9 
2.1.2 Secondary Objectives.....................................................................10 
2.2 
Efficacy and Safety Endpoints (Target Variables) ....................................10 
2.2.1 Efficacy Variables ..........................................................................10 
2.2.2 Safety Variables .............................................................................11 
2.2.3 Pharmacokinetic Variables ............................................................11 
2.2.4 Exploratory Variables ....................................................................12 
3. 
STUDY METHODS.............................................................................................12 
3.1 
Overall Study Design and Plan ..................................................................12 
3.2 
Selection of Study Population ....................................................................13 
3.3 
Method of Treatment Assignment and Randomization .............................13 
3.4 
Treatment Masking (Blinding) ..................................................................13 
4. 
ANALYSES AND REPORTING .......................................................................13 
4.1 
Interim Analyses ........................................................................................13 
4.2 
Final Analysis ............................................................................................14 
4.3 
Pharmacokinetic Analysis ..........................................................................14 
5. 
SAMPLE SIZE DETERMINATION .................................................................14 
6. 
ANALYSIS POPULATIONS .............................................................................15 
7. 
GENERAL ISSUES FOR STATISTICAL ANALYSIS ..................................16 
7.1 
General Statistical Methodology................................................................16 
7.2 
Derived and Computed Variables ..............................................................16 
8. 
STUDY PATIENTS AND DEMOGRAPHICS .................................................20 
8.1 
Disposition of Patients and Withdrawals ...................................................20 
8.2 
Protocol Violations and Deviations ...........................................................20 
8.3 
Demographics and Other Baseline Characteristics ....................................21 
8.4 
Analysis of Exposure .................................................................................23 
9. 
EFFICACY ANALYSIS ......................................................................................24 
9.1 
Primary Efficacy Analysis .........................................................................24 
9.2 
Secondary Efficacy Analysis .....................................................................25 
9.3 
Explorative Efficacy Analysis ...................................................................26 
10. 
SAFETY AND TOLERABILITY ANALYSES ................................................27 
10.1 
Adverse Events ..........................................................................................27 


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10.1.1 Adverse Events Leading to Withdrawal of Study Drug, Drug 
Interruption or Dose Adjustments ..................................................29 
10.1.2 Serious Adverse Events .................................................................29 
10.2 
Clinical Laboratory Evaluations ................................................................30 
10.3 
Vital Signs ..................................................................................................31 
10.4 
Electrocardiogram ......................................................................................31 
10.5 
ECOG Performance Status ........................................................................32 
11. 
OTHER PLANNED ANALYSES ......................................................................32 
11.1 
Comparison of Investigator and Centralized Tumor Response 
Assessments ...............................................................................................32 
11.2 
Anti-drug Antibodies .................................................................................32 
11.3 
Hospitalization ...........................................................................................32 
11.4 
Cytokines Release and Immune Cell Status ..............................................32 
11.5 
Pharmacokinetic Analysis ..........................................................................32 
11.6 
Quality of Life Analysis.............................................................................33 
12. 
CHANGES COMPARED TO THE CLINICAL TRIAL PROTOCOL ........35 
13. 
REPORTING CONVENTIONS.........................................................................35 
13.1 
General Reporting Conventions .................................................................35 
13.2 
Population Summary Conventions ............................................................36 
14. 
REFERENCES .....................................................................................................38 
15. 
TABLES, LISTINGS, AND FIGURES .............................................................39 
15.1 
Planned Table Descriptions .......................................................................39 
15.2 
Planned Listing Descriptions .....................................................................61 
15.3 
Planned Figure Descriptions ......................................................................64 
 


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CONFIDENTIAL 
 
21-DEC-2016 
  
ABBREVIATIONS 
ABBREVIATION 
DEFINITION OR DESCRIPTION 
5-FU 
5-fluorouracil 
ADA 
Anti-drug antibody 
ADR 
Adverse drug reaction 
AE 
Adverse Event 
AJCC 
American Joint Committee on Cancer 
ATC 
Anatomical Therapeutic Chemical 
AUC 
Area under the curve 
AUC0-t 
Area under the concentration-time curve from zero up to a 
time t 
AUC0-∞ 
Area under the concentration-time curve from zero up to ∞ w 
AUC%extrap 
Area under the concentration-time curve extrapolated in % of 
the total AUC 
AUC0-tau 
Area under the concentration-time curve from zero up to the 
last concentration ≥ BLQ 
BLQ 
Below limit of quantification 
AUC 
Area under the curve 
BMI 
Body Mass Index 
BO(R) 
Best overall response (rates) 
BSA 
Body surface area 
CB(R) 
Clinical benefit (rate) 
Cavr 
Average serum concentration  
CL 
Clearance 
Cmax 
Maximum serum concentration  
Cmin 
Minimum serum concentration  
CR 
Complete response 
CRF 
Case report form 
CSR 
Clinical Study Report 
CT 
Computed tomography 
CTC 
Common Toxicity Criteria 
CTCAE 
Common Terminology Criteria for Adverse Events 
DSMB 
Data Safety Monitoring Board 
ECG 
Electrocardiogram 
ECHO 
Echocardiogram 


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ECOG 
Eastern Cooperative Oncology Group 
eCRF 
Electronic case report form 
EGFR 
Epidermal growth factor receptor 
EMA 
European Medicines Agency 
EORTC 
European Oncology Research Trials Committee 
EOS 
End of study 
FcγR 
Fc-gamma receptor 
FDA 
Food and Drug Administration 
HIV 
Human immunodeficiency virus 
HPV 
Human Papilloma Virus 
ICH 
International Conference on Harmonization 
IMP 
Investigational medicinal product 
IRR 
Infusion related reaction 
irRC 
Immune-related response criteria 
ITT 
Intention-to-treat 
IWRS 
Interactive web response system 
MedDRA 
Medical Dictionary for Regulatory Activities 
MRI 
Magnetic resonance imaging 
MUGA 
Multiple gated acquisition scan 
NCI 
National Cancer Institute 
NYHA 
New York Heart Association 
OR(R) 
Objective response (rate) 
OS 
Overall survival 
PD 
Progressive disease 
PFS 
Progression-free survival 
PK 
Pharmacokinetic 
PP 
Per-protocol 
PR 
Partial response 
PT 
Preferred term 
QLQ 
Quality of life questionnaire 
QoL 
Quality of life 
QTc 
QT-interval for ECG corrected for heart rate 
RECIST 
Response evaluation criteria in solid tumors 
SAE 
Serious adverse event 
SAF 
Safety population 


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SAP 
Statistical Analysis Plan 
SCCHN 
Squamous cell carcinoma of the head and neck 
SD 
Stable disease 
SOC 
System Organ Class 
SOP 
Standard Operating Procedure 
TEAE 
Treatment-emergent Adverse Event 
t1/2 
Terminal half-live 
Tmax 
Time of maximum serum concentration 
TTF 
Time to treatment failure 
UICC 
Union for International Cancer Control 
ULN 
Upper limit of normal 
Vz 
Volume of distribution during terminal phase 
Vss 
Apparent volume of distribution at equilibrium 
WHO 
World Health Organization 
 


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Statistical Analysis Plan Final Version 1.0 
 
CONFIDENTIAL 
 
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1. SYNOPSIS 
This Statistical Analysis Plan (SAP) describes the planned analysis and reporting for 
Glycotope protocol GEXMab52201 (Randomized, controlled, open label, multicenter, 
phase II study to evaluate the efficacy and safety of CetuGEX™ plus chemotherapy in 
comparison to cetuximab plus chemotherapy for the treatment of patients with stage 
III/IV recurrent and/or metastatic squamous cell carcinoma of the head and neck), version 
4.0 dated 06-Feb-2015. 
This phase II study is being conducted to assess the efficacy, safety, tolerability, 
pharmacogenomics and pharmacokinetics of CetuGEX™. 
The structure and content of this SAP provides sufficient detail to meet the requirements 
identified by the Food and Drug Administration (FDA), European Medicines Agency 
(EMA), and International Conference on Harmonization (ICH) of Technical 
Requirements for Registration of Pharmaceuticals for Human Use: Guidance on 
Statistical Principles in Clinical Trials (ICH-E9) [1]. All work planned and reported in 
this SAP will follow internationally accepted guidelines, published by the American 
Statistical Association [2] and the Royal Statistical Society, for statistical practice [3]. 
The planned analyses identified in this SAP may be included in clinical study reports 
(CSRs), regulatory submissions, or future manuscripts. Also, post-hoc exploratory 
analyses not necessarily identified in this SAP may be performed to further examine 
study data. Any post-hoc, or unplanned, exploratory analyses performed will be clearly 
identified as such in the final CSR. 
The following documents were reviewed in preparation of this SAP: 
 Clinical Research Protocol GEXMab52201 Final Version 4.0 dated 06-Feb-2015 
 Electronic Case report forms (eCRFs) for Protocol GEXMab52201 Final Version 
4.0, dated 14-May-2015 
 ICH Guidance on Statistical Principles for Clinical Trials (E9) 
 EORTC QLQ-C30 Scoring Manual and head and neck cancer module 
QLQ-H&N35 documentation 
The reader of this SAP is encouraged to also read the clinical protocol and other 
identified documents, for details on the planned conduct of this study. Operational 
aspects related to collection and timing of planned clinical assessments are not repeated 
in this SAP unless relevant to the planned analyses. 
 
2. STUDY OBJECTIVES AND ENDPOINTS 
2.1 
Study Objectives 
2.1.1 
Primary Objective 
The primary objective is to evaluate the efficacy of CetuGEX™ for the treatment of 
patients with stage III/IV recurrent and/or metastatic squamous cell carcinoma of the 


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head and neck (SCCHN) as compared to cetuximab (both in combination with platinum-
based chemotherapy) in terms of progression-free survival (PFS). 
2.1.2 
Secondary Objectives 
The secondary study objectives are: 
 To evaluate further efficacy criteria, safety and quality of life (QoL) of patients 
with stage III/IV recurrent and/or metastatic SCCHN treated with CetuGEX™ as 
compared to cetuximab (both in combination with platinum-based chemotherapy) 
 To assess pharmacokinetic (PK) parameters and profiles of CetuGEX™ 
 To assess efficacy and safety based on genetic markers for immune response (Fc-
gamma receptor [FcγR] allotypes) and biomarkers 
2.2 
Efficacy and Safety Endpoints (Target Variables) 
2.2.1 
Efficacy Variables 
Primary efficacy endpoint 
The primary efficacy endpoint is PFS as assessed by the investigator. 
PFS is defined as time from randomization until disease progression or death of any 
cause. Date of disease progression is defined as the date of imaging showing disease 
progression, as assessed by the investigator according to adapted immune-related 
RECIST 1.1 (modified irRC) [5]. The PFS time will be censored at the time of the last 
tumor assessment if the patient is alive and without progression at the last time of 
observation.  
Secondary efficacy endpoints 
If not otherwise specified, all response related secondary efficacy endpoints will derived 
according to the assessments of the investigator (modified irRC) as well as according to 
the independent centralized reading assessments (modified irRC and RECIST 1.1). 
 PFS, as assessed by independent centralized reading  
 Best overall response rates by response category (complete response [CR], partial 
response [PR], stable disease [SD] or progression [PD]) at the end of combination 
treatment 
 Best overall response rates by response category (CR, PR, SD or PD) including 
maintenance therapy treatment 
 Objective response rate (ORR; i.e., CR + PR) at the end of combination treatment 
 Objective response rate (ORR; i.e., CR + PR) including maintenance therapy 
treatment 
 Clinical benefit rate (CBR; i.e., CR + PR + SD) at the end of combination 
treatment 


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 Clinical benefit rate (CBR; i.e., CR + PR + SD) including maintenance therapy 
treatment 
 Duration of response  
 Overall survival (OS) defined as time from randomization until death of any cause 
 Time to treatment failure (TTF)  
 QoL as assessed by European Oncology Research Trials Committee (EORTC) 
QoL questionnaires (QLQ) EORTC-QLQ-C30 and EORTC-QLQ-H&N35 
 Relationship of stratification factors, p16, epidermal growth factor receptor 
(EGFR) intensity and FcγRIIa allotypes to efficacy endpoints 
2.2.2 
Safety Variables 
The safety endpoints are: 
 Incidence of adverse events (AEs) and serious AEs (SAEs), including incidence 
of target/class-specific side effects (skin reactions, hypomagnesemia, neutropenia, 
gastrointestinal AEs, liver enzymes increases, conjunctivitis, mucositis) 
 Infusion related reactions (IRRs) 
 Physical assessments 
 Laboratory assessments 
 Vital signs 
 Electrocardiogram (ECG) 
 Relationship of FcγRIIa and FcγRIIIa-allotypes, occurrence of ADAs and PK 
parameters to safety endpoints 
2.2.3 
Pharmacokinetic Variables 
Antibody trough levels and PK profiles of CetuGEX™ will be assessed throughout the 
study. 
The PK samples for determining CetuGEX™ antibody concentrations will only be 
collected for the first-line treatment. No PK samples will be collected during the single-
agent maintenance therapy, unless combination therapy has been prematurely terminated. 
There are 2 different groups of PK samples being collected during the first-line treatment. 
For all patients randomized to CetuGEX™ treatment group for the first-line treatment, 
blood sampling for PK trough and maximum levels will be performed during Cycles 1, 2, 
3 and 4. Blood samples will be collected before and at the end of each infusion on Day 1, 
8, and 15 for Cycles 1, 2 and 3. On Cycle 4, blood samples will be collected before and at 
the end of each infusion but only on Day 1. Since the first dose of Cycle 1 will be split, 
there will also be blood samples collected before and at the end of the infusion on Day 0 
(first infusion day of Cycle 1). Pre-infusion samples should be collected within 30 
minutes prior to the start of the infusion. Post-infusion samples should be collected within 
10 minutes following the end of the infusion and within 5 minutes would be ideal.  


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For a subset of patients, additional blood sampling will be collected on first infusion of 
Cycle 1 and Cycle 4 to gain a more fully PK profile for the first infusions from both of 
these cycles. The full profile of Cycles 1 and 4 PK blood samples will include pre- and 
post-infusion blood samples at 5 hour ± 5 min, 7 hours ± 15 min (Day 1), 24 ± 1 hour 
(Day 2), 48 ± 2 hours (Day 3), 72 ± 2 hours (Day 4), and 7 days (168 ± 2 hours; Day 8) 
after the start of the infusion on Day 1.  
2.2.4 
Exploratory Variables 
Further exploratory variables include: 
 Immunogenicity: incidence of anti-drug antibodies (ADAs) 
 Immunological parameters: cytokine levels and immune cell counts 
 FcγRIIa allotypes 
 EGFR intensity and EGFR stained cancer cells 
 
3. STUDY METHODS 
3.1 
Overall Study Design and Plan 
This is a Phase 2, randomized, controlled, multicenter (approximately 40 sites in Europe 
and the USA) study with first line treatment (6 cycles of 5-FU and cisplatin in 
combination with CetuGEX™ vs. combination with cetuximab) followed by single-agent 
maintenance therapy (CetuGEX™ or cetuximab, respectively). 
The study will include 3 separate study periods following screening: 
Combination treatment phase 
Eligible patients will be randomized to receive as first line treatment either CetuGEX™ 
or cetuximab in combination with 5-FU and cisplatin for the maximum duration of 6 
cycles. In case of toxicity, the chemotherapy dose can be reduced, discontinued or, if later 
than the first cycle, switched to carboplatin. If discontinued earlier for any other reason 
apart from progression, patients will start the maintenance phase at that time. 
As soon as at least 10 patients per treatment arm have completed the second cycle of 
combination therapy, patient safety data will be reviewed by an independent data safety 
monitoring board (DSMB). 
Single-agent maintenance phase 
After completion or discontinuation of combination chemotherapy for any other reason 
than progression, the treatment will be followed by maintenance therapy with 
CetuGEX™ alone or cetuximab alone, respectively. Single-agent maintenance therapy 
will be continued until progression of disease or limiting toxicity. 
Follow-up 
A Safety Visit must be performed 28 (+2) days after the last administration of the study 
drug for all randomized patients. In case of treatment discontinuation due to reasons other 


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than disease progression, patients will stay on the regular study schedule until disease 
progression is documented and will then attend a Final Examination Visit. In case of 
treatment discontinuation due to disease progression, the Safety Visit is identical to the 
Final Examination Visit. 
After the Final Examination, patients will be followed-up by quarterly phone calls until 
death or for a maximum duration of 24 months after randomization of the last patient for 
assessment of overall survival. 
3.2 
Selection of Study Population 
Patients aged at least 18 years at screening with stage III/IV recurrent and/or metastatic 
SCCHN will be enrolled. Inclusion and exclusion criteria are given in sections 8.2.1 and 
8.2.2 of the protocol. 
3.3 
Method of Treatment Assignment and Randomization 
Patients eligible for study participation will be randomized using a 1:1 ratio to either the 
CetuGEX™ or cetuximab arm. Randomization will be stratified by: 
 FcγRIIIa status (FF or FV or VV) 
 Oral cavity and oropharynx vs. other locations 
 Locally recurrent vs. metastatic disease 
 EGFR treatment naïve vs. EGFR treatment as part of multimodal therapy 
A centralized randomization procedure, the interactive web response system (IWRS), will 
be used to assign a unique randomization number to each patient. 
3.4 
Treatment Masking (Blinding)  
Blinding at the level of study treatment does not apply since the study is open label. 
 
4. ANALYSES AND REPORTING 
4.1 
Interim Analyses 
No formal interim analysis will be performed. An independent DSMB will periodically 
review the relevant safety data and provide advice on the continuation, modification or 
termination of the study. The DSMB will be comprised of 3 members, 2 of them being 
oncologists and one of them statistician. A study specific charter will define in detail the 
composition, responsibilities and procedures of the DSMB. 
As soon as at least 10 patients per treatment arm have completed the second cycle of first 
line treatment, a first meeting of DSMB will be scheduled to review the patient safety 
data. After this meeting, regular 6-monthly meetings will be scheduled until all ongoing 
patients have been treated for at least 6 months. Starting at the second DSMB meeting, in 
addition to review of patient safety data a descriptive analysis on progression and 
survival, including point estimates and 95% confidence intervals of the hazard ratios, will 
be included to monitor a potential detrimental effect of the investigational compound. For 


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important reasons additional meetings may be scheduled by the coordinating investigator, 
sponsor, medical monitor or DSMB members as long as patients are at risk. 
4.2 
Final Analysis 
No database may be locked or analyses completed until this SAP has been approved.  
The database cut–off for the statistical analysis will be set to not earlier than 12 months 
after randomization of the last patient.  
The efficacy analysis will be performed for all patients, regarding the patients still under 
observation as censored and applying the same rules as defined for missing assessments 
and loss to follow-up. 
At this time, the safety analysis will be performed on all available data, including patients 
still under treatment.  
All statistical results will be made available to Glycotope following database cut-off and 
compiled into the CSR. Final results accociated with OS will be added to the CSR after 
completion of follow-up for OS which is planned for 24 months after the last patient has 
been randomized. 
Any post-hoc, exploratory analyses completed to support planned study analyses, which 
were not identified in this SAP, will be documented and reported in appendices to the 
CSR. Any results from these unplanned analyses (post-hoc) will also be clearly identified 
in the text of the CSR. 
4.3 
Pharmacokinetic Analysis 
The PK samples will consist of 2 groups; samples from the PK profile group and samples 
from all patients of the CetuGEX™-arm before and at the end of each infusion (up to the 
10th infusion).  
The samples from the PK profile group will be used for noncompartmental analyses. 
Samples taken from all patients will be described by sampling time point. Further details 
are given in Section 11.5. 
5. SAMPLE SIZE DETERMINATION 
Approximately 240 patients will be randomized in this study. 
The log-rank test will be used to test the hypothesis that patients assigned to the 
CetuGEX™ arm have increased PFS compared to patients assigned to the control arm. 
The sample size calculation is based on the following assumptions: 
 The median PFS in the control arm is expected to be 5.6 months post 
randomization. 
 It is expected that the median PFS in the CetuGEX™ arm can be increased to 8.4 
months corresponding to a hazard ratio of 0.67. 
 The overall trial duration will be approximately 36 months with an anticipated 
recruitment time of 24 months, anticipated treatment phase until PFS events are 
reached of approximately 12 months after randomization of the last patient (data 


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cut-off for main analysis) and ongoing follow-up for overall survival for at least 
24 months after randomization of the last patient. 
 Drop-outs are expected to occur at times following an exponential distribution 
and resulting in a drop-out rate of 10% at the cut-off for PFS analysis. 
 Patients will be randomized in a 1:1 ratio. 
 The overall two-sided significance level will be 0.05 and the power to be 
maintained 80%. 
Based on these assumptions, approximately 240 patients have to be randomized to 
observe the required overall number of 192 events. 
If the required number of events is not reached as planned after 12 months from last 
patient randomized, the main analysis will be postponed to obtain more events but not 
more than additional 6 months. 
Assuming a corresponding effect on OS (hazard ratio 0.67) and a median overall survival 
of 10.6 months in the control group the number of survival events to be observed after a 
24-months follow-up for survival will be 183. 
 
6. ANALYSIS POPULATIONS 
The analysis populations will include the following: 
 The intention-to-treat (ITT) population will consist of all randomized patients. 
The ITT population will be the primary population for the efficacy analysis. 
 The safety population (SAF) will include all patients who received at least one 
dose of trial medication. This population will be used for safety analyses. 
 The per-protocol (PP) population will consist of all ITT patients who received at 
least one dose of trial medication and without major protocol deviations as 
defined in this SAP and finally decided in a Data Review Meeting before database 
lock. 
 For PK analyses done in all patients the pharmacokinetic (PK) population will 
consist of all randomized patients who have at least one evaluable post dose 
concentration. For the PK profile analyses patients in the PK profile group will be 
included in the PK profile population who had blood samples collected for PK 
noncompartmental profiling and who had at least one measureable CetuGEX™ 
antibody concentration. 
In the event that a patient is randomized incorrectly or is administered the incorrect study 
medication, analyses of the ITT population will be based on the assigned treatment 
whereas all other analyses will be based on the actual treatment. 
 


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7. GENERAL ISSUES FOR STATISTICAL ANALYSIS 
7.1 
General Statistical Methodology 
Descriptive summaries will be provided where appropriate for each of the study 
variables. In general, disposition summaries will be completed for all patients; summaries 
of protocol violations will be presented for the ITT population. Analyses of demography 
and baseline variables, and all efficacy analyses will be performed on the ITT and PP 
population. Safety and exposure analyses will be done on the SAF. All summaries will be 
presented for each treatment arm and for the total population, unless otherwise specified. 
Where data are collected over time, both the observed data and the change from baseline 
will be summarized at each visit. 
Continuous variable summaries will include the number of patients with non-missing 
values (N), mean, standard deviation, median, minimum and maximum, 1st and 3rd 
quartile. 
Categorical variable summaries will include the frequency and percentage of patients 
who are in the particular category. In general the denominator for the percentage 
calculation will be based upon the total number of patients in the study population for the 
treatment arm, unless otherwise specified. 
Any patient who does not complete the study per protocol will be included in the analysis 
with the data available. Response and benefit rates will be based on the observed 
assessments and the number of patients in the respective population as the denominator, 
assuming no response/benefit for patients without sufficient data. Other imputation of 
missing values will not be performed, unless specified in the relevant sections of the 
SAP. 
The last pre-administration observation will be used as the baseline value for calculating 
post-administration changes from baseline. All data obtained on the eCRF and entered 
into the database will be provided in separate data listings showing individual patient 
values. 
Free text specifications (“other”) of multiple choice items will be detailed in the listings, 
in the tables the frequency of “other” will be displayed. 
All analysis will be performed using SAS® Software version 9.3 or later. 
7.2 
Derived and Computed Variables 
The following derived and computed variables have been initially identified as important 
for the analysis of the primary and secondary target variables. It is expected that 
additional variables will be required. The SAP will not be amended for additional 
variables that are not related to the primary target or key secondary target variables. Any 
additional derived or computed variables will be identified and documented in the SAS 
programs that create the analysis files. If the SAP is not amended, further derivations 
required to support the analyses of primary and secondary target variables will be 
described in the CSR. 
Disease will be evaluated by the investigator (modified irRC) and by independent 


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centralized reading (modified irRC and RECIST 1.1) and classified as complete response 
(CR), partial response (PR), stable disease (SD) or progressive disease (PD). 
Tumor assessments will be performed by the investigator and independent centralized 
reading during the combination treatment phase and single-agent maintenance phase 
based on computed tomography (CT) or magnetic resonance imaging (MRI) of the head 
and neck region, chest, and abdomen. Subsequent assessments will include head, neck 
and chest; assessments of the abdomen will only be performed if at baseline metastases 
were confirmed or if clinical evidence suggests new lesions in these regions. Additional 
regions might be included if clinically indicated. 
Tumor assessments in both study arms will be performed at Screening, every 6 weeks 
after day of randomization until Week 18 and every 8 weeks thereafter. The tumor 
evaluation will be performed pre-dose. Results of the assessments performed at Screening 
will be considered baseline values. The same type of imaging as for baseline assessments 
should be maintained throughout the study. 
For time durations in days that need to be converted to months, the number of days will 
be divided by factor 30.4375. For time durations in days that need to be converted to 
years, the number of days will be divided by factor 365.25. 
The following table describes the derivation of the primary and secondary efficacy 
variables related to response and survival in detail. 


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Response Based Variables 
Computation methods described below will be applied simultaneously to response criteria modified irRC 
(site, central review) and RECIST (central review) 
Variable 
Name 
Computation Methods, Notes, or Equation(s) 
PFSp 
= Earliest date of progression or death - date of randomization + 1  
The earliest date of PD will be used irrespective of PD confirmation  
(primary 
definition) 
  
Finding 
Date of PD of Censoring 
Outcome 
No PD or death  
 
 
 
 
 
 
 
Progression/death documented after 
a new anticancer treatment has 
started
Pre and post-baseline 
imaging done: Date of last 
imaging 
 
No baseline or no post-
baseline imaging done: Date 
of randomization 
 
Date of last imaging prior to 
new anticancer treatment 
Censored 
 
 
 
Censored 
 
 
 
Censored 
PD at scheduled visit 
 
PD between scheduled visits 
Date of imaging 
 
Date of imaging 
Event 
 
Event 
PFSs 
= Earliest date of progression or death - date of randomization + 1  
The earliest date of PD will be used irrespective of PD confirmation 
(sensitivity 
definition) 
  
Finding 
Date of PD of Censoring 
Outcome 
No PD or death 
Pre and post-baseline 
imaging done: Date of last 
imaging 
 
No baseline or no post-
baseline imaging done: Date 
of randomization 
Censored 
 
 
 
Censored 
 
Progression/death documented after 
a new anticancer treatment has 
started  
 
PD at scheduled visit 
Date of last imaging prior to 
new anticancer treatment. 
 
 
Date of imaging 
Censored 
 
 
 
Event 
PD between scheduled visits* 
Date of next scheduled visit 
Event 
PD after 2 or more missing 
scheduled visits 
Date of last imaging prior to 
first missing visit. 
Censored 
Death up to 16 weeks (112 days) 
after last imaging 
Date of death 
Event 
Death later than 16 weeks (112 
days) after last imaging 
Date of last imaging 
Censored 
Best overall 
response 
Best modified irRC classification (CR, PR or SD) as assessed by the investigator or 
by the independent centralized review


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(rates) 
(BO(R))
SD: follow-up measurements must have met the SD criteria at least once after 
randomization at a minimum interval of 8 weeks.
Objective 
response (rate) 
(OR(R))
Best response of CR or PR  
Clinical benefit 
(rate) 
(CB(R))
Best response of CR or PR or SD. 
SD: follow-up measurements must have met the SD criteria at least once after 
randomization at a minimum interval of 8 weeks
Duration of 
response  
= Date of first progression or death after initial response - date of first response + 1  
Date of disease progression is defined as the date of imaging showing disease 
progression. Date of response is defined as the first date of imaging showing CR or 
PR. 
If no progression or death is observed after initial response, the duration of response 
will be censored at the last date of tumor assessment. 
Duration of 
CR 
= Date of first progression or death after initial response - date of first CR + 1  
Date of disease progression is defined as the date of imaging showing disease 
progression. Date of CR is defined as the first date of imaging showing CR. 
If no progression or death is observed after initial CR, the duration of CR will be 
censored at the last date of tumor assessment. 
Other variables 
Overall 
survival (OS) 
Date of death – date of randomization + 1 
If no death is observed, OS will be censored at the last date known to be alive. 
Time to 
treatment 
failure (TTF) 
Date of treatment discontinuation for any reason (including disease progression) as 
assessed by investigator, treatment toxicity, patient preference, or death) – date of 
randomization 
If no treatment discontinuation is observed, TTF will be censored at the date of last 
study treatment. 
Body surface 
area (BSA) 
 
BSA [m2] = SQRT((weight [kg] × height [cm]/3600)) 
Number of 
combination 
treatment cycles
Number of treatment cycles with full combination treatment (3 doses of 
CetuGEX™/cetuximab, one dose of cisplatin/carboplatin, 4 doses of 5-FU) 
Only cycles in which all planned medication has been given will be counted as a full 
cycle. Dose reductions will however not prevent a cycle to be counted as full. 
Overall 
treatment 
duration 
[weeks] 
 
(Date of last treatment administration – date of first treatment administration) + 1 for 
CetuGEX™/cetuximab 
Treatment 
duration 
[weeks] during 
combination 
treatment 
 
(Date of  last treatment administration within a combination cycle – date of first 
treatment administration) + 1 for CetuGEX™/cetuximab 
Treatment 
duration 
[weeks] in 
maintenance 
phase 
 
(Date of last treatment administration – date of first treatment administration after last 
Day 15 administration in combination treatment phase) + 1 for CetuGEX™/cetuximab


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Total doses 
[mg] 
Sum of actual doses administered for CetuGEX™/cetuximab cisplatin/carboplatin and 
5-FU 
* Scheduled visits are expected to be performed every 6 weeks after day of randomization until Week 18 
and every 8 weeks thereafter. An assessment is considered “between scheduled visits” if it is performed 
more than 7 days before the next scheduled visit. 
 
The following variable will be derived with respect to hospitalization: 
Variable 
Name 
Computation Methods, Notes, or Equation(s) 
Percentage of 
days in hospital 
(Number of days of hospitalization (sum of all: discharge date [or death date if died 
in hospital] – admission date +1) divided by number of days from randomization to 
EOS visit) * 100%
 
8. STUDY PATIENTS AND DEMOGRAPHICS 
8.1 
Disposition of Patients and Withdrawals 
All patients who provide informed consent will be accounted for in this study. 
Descriptive summaries of population data will include 
 the frequency and percentage of patients in each study population, overall and by 
center 
 the disposition of patients, including number of patients who gave informed 
consent for screening, number of screening failures, number of patients 
randomized, number of patients completing the clinical phase (EOS visit after 
observed progression), number of patients discontinuing treatment without 
preceding progression, reason for discontinuation from treatment 
 study withdrawals by reason of withdrawal 
 the frequency and percentage of patients in cross-sectional subgroups defined by 
the stratification factors at randomization 
o FcγRIIIa status (FF, FV or VV) 
o Oral cavity and oropharynx vs. other locations 
o Locally recurrent vs. metastatic disease 
o EGFR treatment naïve vs. EGFR treatment as part of multimodal therapy 
and will be presented for all randomized patients, unless otherwise specified. Subgroups 
will also be detailed for the PP population. 
8.2 
Protocol Violations and Deviations 
Clinical data will be checked for potential protocol violations before database lock in 
order to define the analysis populations. A data review meeting will be held after 
database soft lock. Cases and frequency of patients violating the criteria listed below will 
be analyzed and categorized as minor or major protocol violations. Patients with one or 


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more major protocol violation will be excluded from the PP population, patients with 
only minor or no violations will be included. 
Violations of the following criteria may constitute a major protocol violation. Final 
decisions will however be made at a blinded data review meeting prior to data base lock: 
 histologically confirmed recurrent and/or metastatic SCCHN not eligible for local 
treatment 
 measurable disease according to RECIST 1.1 
 at least 18 years of age at screening 
 Eastern Cooperative Oncology Group (ECOG) at Screening ≤ 1 
 negative pregnancy test at screening/prior to randomization (if female and of 
childbearing potential) 
 no clinical evidence of brain metastasis or leptomeningeal involvement 
 no nasopharyngeal tumors 
 no myocardial infarction within 6 months prior to screening 
 no symptomatic congestive heart failure (NYHA Grade 3 or 4), no unstable 
angina pectoris within 6 months prior to screening, no significant cardiac 
arrhythmia, no history of stroke or transient ischemic attack within 1 year prior to 
screening 
 no prior allergic reaction to a monoclonal antibody, no grade 3 IRR or any grade 4 
reaction to a monoclonal antibody 
 no pregnancy during study 
 treatment as randomized 
Other issues which become obvious during data review may be considered as potential 
major violations as well. 
Furthermore, data listings will be reviewed for prohibited previous and concomitant 
therapies (as defined in protocol sections 8.2.2 and 9.12.2). 
Major and minor protocol violations will be summarized by type of violation and by 
treatment group for the ITT population. Individual patients with major protocol 
deviations will be listed. 
8.3 
Demographics and Other Baseline Characteristics 
Descriptive summaries of the demographic and other baseline characteristics will be 
completed for the ITT and PP population. 
Descriptive summaries of demographic and other baseline conditions will include: 
 Demographics and baseline data (age, sex, race, height, weight, BMI, body 
surface area (BSA), smoking status, alcohol consumption, ECOG performance 
status) 


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 Tumor specific baseline characteristics: FcγRIIa allotypes, FcγRIIIa allotypes, 
p16 status, HPV status, EGFR expression, tumor location (oral cavity and 
oropharynx vs. other locations), stage of disease (locally recurrent vs. metastatic 
disease), EGRF pre-treatment (EGFR treatment naïve vs. EGFR treatment as part 
of multimodal treatment) 
 SCCHN diagnosis and history 
 Prior anti-cancer therapies (drug therapies, radiotherapy, surgeries) 
 Echocardiogram (ECHO)/multiple-gated acquisition scan (MUGA) assessment 
 Baseline physical examination 
 General medical history 
 Baseline signs and symptoms 
 Prior medication 
 Concomitant medication (at baseline / started after baseline / taken during study) 
 Premedication 
Baseline physical examination: Incidence of abnormalities will be summarized by body 
system. 
Medical History: Medical history will be coded using the Medical Dictionary for 
Regulatory Activities (MedDRA Version 16 or newer). Incidences of findings in medical 
history will be summarized by system organ class (SOC) and preferred term. 
SCCHN diagnosis and history: Months since initial diagnosis, months since most recent 
recurrent/metastatic diagnosis, American Joint Committee on Cancer (AJCC)/Union for 
International Cancer Control (UICC) staging at initial diagnosis, location of primary 
squamous cell carcinoma, metastatic disease and TNM classification at initial diagnosis 
will be displayed. 
If the reported diagnosis dates are incomplete (year or year and month only), intervals 
will be calculated using the midpoint of the described period (15th in case of missing day 
only, 1st of July in case of missing day and month). 
Baseline signs and symptoms: The number and percentage of patients with at least one 
baseline sign/symptom. Further details of the respective signs and symptoms will be 
listed. 
Prior anti-cancer therapies: The number and percentage of patients with at least one 
prior therapy by type of therapy.  
Prior and concomitant medication: All medication will be coded using the WHO-DRUG 
dictionary September 2013 edition (or newer). Incidences of prior and concurrent 
medications will be summarized by ATC level 2 and ATC level 4 if applicable.  
Concomitant medication is defined as a medication other than study drug that was 
administered during the treatment period. The treatment period is defined as the time 
from day of first treatment to the EOS visit. Medication that has been classified as 


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premedication will be analyzed separately. Additionally the number of corticosteroids 
applications per patient will be analyzed. 
Prior medication is defined as medication which was discontinued before start of study 
treatment. Medication which was started after the treatment period will be listed but not 
analyzed otherwise. 
If the start date and stop date of medication are partially or completely missing, a 
medication will be assumed to be concomitant if it cannot be definitely shown that the 
medication was not administered during the treatment period. Missing dates will not be 
replaced. 
Thus, the following approach will be taken for exclusion from concomitant medication 
because of discontinuation before start of treatment: 
 If stop day is missing but month is complete, medication will only be excluded 
from concomitant medication if stop month is before month of treatment start. 
 If stop day and month are missing but year is complete, medication will only be 
excluded from concomitant medication if stop year is before year of treatment 
start. 
 If stop date is completely missing, medication will not be excluded. 
For exclusion from concomitant medication because of late start after end of treatment 
period: 
 If start day is missing but month is complete, medication will only be excluded 
from concomitant medication if start month is after end month of treatment 
period. 
 If start day and month are missing but year is complete, medication will only be 
excluded from concomitant medication if start year is after end year of treatment 
period. 
 If start date is completely missing, medication will not be excluded from 
concomitant medication. 
8.4 
Analysis of Exposure 
The following variables will be summarized descriptively for the SAF population. 
 Number of combination treatment cycles 
 Number of infusions of CetuGEX™/cetuximab 
 Overall treatment duration [weeks] for CetuGEX™/cetuximab 
 Treatment duration [weeks] during combination treatment for 
CetuGEX™/cetuximab 
 Treatment duration [weeks] in maintenance phase for CetuGEX™/cetuximab 
 Total dose [mg] for CetuGEX™/cetuximab, cisplatin/carboplatin and 5-FU 
 Dose changes/reductions: Number and percentage of dose reductions and reasons 


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per patient and per administration for CetuGEX™/cetuximab,  
cisplatin/carboplatin and 5-FU  
 Dosing delays: Number and percentage of delays and reasons per patient and per 
administration for CetuGEX™/cetuximab,  cisplatin/carboplatin and 5-FU  
 Dosing interruptions: Number and percentage of interruption and reasons 
(AE/per-protocol/other) per patient and per administration for 
CetuGEX™/cetuximab, cisplatin/carboplatin and 5-FU 
 Infusion rate changes: Number and percentage of infusions rate changes and 
reasons (AE/per-protocol/other) per patient and per administration for 
CetuGEX™/cetuximab 
 Switches to carboplatin by reason for switch (AE/PI discretion) and first cycle of 
switch 
Furthermore, details of study treatment termination will be tabulated, including reason for 
discontinuation of treatment and reason for chemotherapy termination and discontinued 
agent. 
 
9. EFFICACY ANALYSIS 
Efficacy analyses will be performed based on the treatment group the patient was 
randomized to unless otherwise specified. 
9.1 
Primary Efficacy Analysis 
The primary efficacy analysis for PFS as assessed by the investigator will be based on the 
ITT population using the PFSp definition as described in Section 7.2. 
A two-sided log-rank test will be used to test the null hypothesis of equal treatment 
effects at an overall significance level of 0.05. The Kaplan-Meier method will be used to 
estimate the survival functions. Median survival times together with their 95%-
confidence intervals will be retrieved from the survival functions. PFS rates at 6, 12, 15 
and 18 months and associated 95%-confidence intervals and graphs of the Kaplan-Meier 
curves by treatment arm will also be presented. 
The primary efficacy analysis will not be stratified by the factors used for stratification at 
randomization in order to preserve the estimated power considering the high number of 
strata.  
To investigate the influence of the stratification factor on the primary endpoint a Cox 
regression model will be applied as a sensitivity analysis based on the ITT population. 
This model will include the treatment effect and the stratification factors  
o FcγRIIIa allotypes (FF, FV or VV)  
o Oral cavity and oropharynx vs. other locations 
o Locally recurrent vs. metastatic disease 
o EGFR treatment naïve vs. EGFR treatment as part of multimodal 
treatment  


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The hazard ratios, the corresponding 95% confidence intervals and the p-values of the 
Wald test (using adjustment for ties according to Efron) will be presented for all factors. 
The Kaplan-Meier analyzes will be repeated separately within the subgroups formed by 
the stratification factors. Corresponding figures will combine the curves for all treatment 
group/factor level combinations on one page per factor. Factor levels maybe combined if 
the sample size per level is < 15. 
Further sensitivity analyses will be done as follows 
 The analyses will be repeated using the PFSs definition as described in Section 
7.2 
 The analyses will be repeated for the PP Population 
 It has been recognized that not all sites had strictly applied modified irRC for 
response assessment. To investigate the influence of deviating response criteria on 
PFS a log rank test will performed stratifying sites according to strict adherence to 
modified irRC (yes/no). 
9.2 
Secondary Efficacy Analysis 
Secondary efficacy analyses will be based on the ITT and PP population.  
9.2.1 Progression-free Survival Based on Independent Central Review 
PFS as assessed by independent centralized reading (irRC and RECIST 1.1) will be 
analyzed based on the PFSp definition applying a not stratified log rank test. Kaplan-
Meier estimates will be presented and Cox regression models be applied as described in 
Section 9.1. 
9.2.2 Tumor Response Rates 
ORR and CBR according to different criteria (irRC, RECIST) and sources (investigator, 
central review) will be analyzed using Chi-square tests to evaluate the effects of 
treatment on ORR and CBR for the combination treatment period as wells for the entire 
treatment period including maintenance treatment. 95%-confidence intervals will be 
calculated for the rates and their treatment differences based on normal approximation. 
Logistic regression models will be used to investigate the influence of the stratification 
factors on the response variables. These models will include the treatment effect and the 
randomization stratification factors. The odds ratios, the corresponding 95% confidence 
intervals and the p-values of the Wald test will be presented for all factors.  
Absolute and relative frequencies of tumor response categories will be tabulated by time 
point and for the best response. Waterfall plots to illustrate individual maximum 
percentage change of target lesion size form baseline will be presented by treatment 
group. 
Duration of response will be analyzed by Kaplan-Meier methods. Duration of CR will be 
described case by case. 


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9.2.3 Time to Treatment Failure 
TTF will be analyzed applying a not stratified log rank test. Kaplan-Meier estimates will 
be presented and Cox regression models be applied as described in Section 9.1. 
9.2.4 Overall Survival 
OS will be analyzed applying a not stratified log rank test and a proportional hazards 
regression model including the stratification factors in addition to the study treatment 
Kaplan-Meier estimates will be presented as described in Section 9.1 factor. Survival 
rates at 12, 18 and 24 months and associated 95%-confidence intervals will be presented. 
A further proportional hazards regression model will be applied including the study 
treatment factor, the stratification factors and a dichotomous variable for second line 
treatment. This model maybe further modified or supplemented to account for different 
classes of second line treatments. 
9.3 
Explorative Efficacy Analysis 
9.3.1 Landmark Analyses  
To explore the effect of the single-agent maintenance treatment on PFS a landmark 
analysis will be performed based on the primary endpoint definition. The landmark will 
be set to the start of the maintenance therapy. Only ITT patient still at risk for progression 
and death at this time point will be used for the analysis. The landmark PFS will be 
calculated from the start of maintenance treatment using the PFSp definition accordingly. 
Cox regression model will be applied including the treatment effect and the stratification 
factors. Kaplan-Meier analyzes will be presented. 
Corresponding landmark analyses will be presented for OS. 
9.3.2 
Influence of Baseline Tumor Characteristics on Treatment Effects 
To investigate the influence of covariables on treatment effects as assessed by the 
primary PFS endpoint Cox regression models will be applied including the covariable in 
addition to the treatment and the stratification factors based on the ITT and PP 
population. The following prognostic variables will be investigated 
o FcγRIIa allotype (HH, HR, RR) 
o p16 status (+/-) 
o EGFR intensity 
o EGFR stained cancer cells (%, continuous) 
Classes may be combined if the number of patients within a class is lower than 15. The 
hazard ratios, the corresponding 95%-confidence intervals and the p-values of the Wald 
test will be presented for all factors. Kaplan-Meier analyzes will be repeated separately 
within the subgroups formed by discrete factors. Corresponding figures will combine the 
curves for all treatment group/factor level combinations on one page per factor. 
Corresponding analyses will be performed for OS. 


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Similarly logistic models will be applied including the covariable in addition to the 
treatment and the stratification factors based on the ITT and PP population to evaluate the 
effects of treatment on CBR. 
9.3.3 
Correlation of Pharmacokinetic Parameters with PFS and CBR  
The following PK parameters of CetuGEX™ serum concentrations will be investigated 
concerning their impact on efficacy outcomes in the subgroup of patients who were 
treated with CetuGEX™ 
 Trough levels after 1st, 2nd and 3rd infusion  (= pre-infusion concentrations at 2nd, 
3rd and 4th infusion) 
 Post-infusion concentration after 1st, 2nd and 3rd infusion. 
Cox regression models including the PK parameter as continuous covariable will be fit to 
the primary PFS endpoint. Separate analyses will be performed for each of the 6 PK 
parameters. Hazard ratios, the corresponding 95%-confidence intervals and the p-values 
of the Wald test will be presented. A forest-plot will be provided to illustrate the hazard 
ratios and confidence interval for all 6 PK parameters in one figure. 
Logistic regression models including the PK parameters as continuous covariable will be 
fitted to the CBR as assessed by the central review (RECIST). Separate analyses will be 
performed for each of the 6 PK parameters. Odds ratios, the corresponding 95%-
confidence intervals and the p-values of the Wald test will be presented. Moreover, 
sample statistics of the PK parameters grouped by CB response (yes/no) will be presented 
including p-values of the Wilcoxon rank test. A forest-plot will be provided to illustrate 
the odd ratios and confidence interval for all 6 PK parameters in one figure. 
These analyses will be based on PK population. 
10. SAFETY AND TOLERABILITY ANALYSES 
The safety analysis will be performed for the SAF population. 
The analysis of safety assessments in this study will include summaries of the following 
categories of safety and tolerability data: 
 AEs (including IRRs) 
 Clinical laboratory investigations (biochemistry, hematology, urinalysis) 
 Vital signs 
 ECG investigations 
 ECOG performance status 
Findings in post-baseline physical examinations will be documented as AE and analyzed 
as part of the general AE analysis. 
10.1 
Adverse Events 
Adverse Events will be coded using MedDRA version 16 or newer. 


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An AE is defined as treatment emergent (TEAE), if the first onset or worsening is at or 
after the first administration of IMP (CetuGEXTM or cetuximab) and within 28 days after 
last administration. 
If the start date or time of an AE is partially or completely missing, the AE will be 
assumed to be treatment-emergent if it cannot be definitely shown that the AE did not 
occur or worsen during the treatment emergent period (worst case approach). Missing 
dates and times will not be replaced for display in listings and further calculations.  
Thus, the following approach will be taken: 
 If the start time of an AE is missing, but the start date is complete, an AE will 
only be excluded from treatment-emergent AEs if the start day is before day of 
first treatment or the start day is after end day of the treatment-emergent period. 
 If the start time and day are missing but the start month is complete, an AE will 
only be excluded from treatment emergent AEs if the start month is before month 
of first treatment or the start month is after end month of treatment-emergent 
period or if the stop date/time information is sufficient to show the event ended 
before the start of treatment. 
 If the start day and months are missing but the start year is complete, an AE will 
only be excluded from treatment-emergent AEs if the start year is before year of 
first treatment or if the start year is after end year of treatment-emergent period or 
if the stop date/time information is sufficient to show the event ended before the 
start of treatment. 
 If start date is completely missing, an AE will not be excluded from treatment-
emergent AEs unless the stop date/time information is sufficient to show the event 
ended before the start of treatment. 
Time from first treatment to onset of AEs [days] and duration of AEs [days] will be 
calculated for complete dates only and will be included in listings. 
In the following infusion related reactions (IRRs) are defined as AE marked as infusion 
related reactions (IRRs) by the investigator and/or specific AEs which occurred at or the 
day after an infusion. The relevant AEs will be identified as a list of Preferred Terms  
which will be compiled before data base lock. 
An AE summary table will be presented including rows with the number of patients with 
 AEs 
 TEAEs 
 SAEs 
 Any Deaths (NCI CTCAE V4.0 Grade 5 TEAEs and/or with an outcome of death) 
 NCI CTCAE Grade 4, 3, 2, 1 TEAEs 
 Adverse drug reactions (ADRs) (related or possibly related TEAEs) 
 TEAEs leading to withdrawal of study treatment 


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 TEAEs leading to drug interruption or infusion rate reduction 
 TEAEs requiring additional medication 
 TEAEs constituting IRRs 
 TEAEs marked as disease related symptoms 
Incidences of TEAEs will be presented for all TEAEs and separately for the combination 
treatment (TEAE which occurred before first maintenance treatment) and maintenance 
treatment (TEAE which occurred at or after first maintenance treatment). 
Incidences of TEAEs will be calculated on Preferred Term level, on System Organ Class 
level (SOC) and globally by treatment group. On each analysis level, a patient will be 
counted only once. Summaries of incidence rates (frequencies and percentages) of 
individual TEAEs by MedDRA SOC and Preferred Term will be prepared. Such 
summaries will be displayed for all TEAEs, TEAEs by maximum severity graded 
according to NCI-CTCAE (Version 4.03), TEAEs by strongest relationship to study 
treatment, and TEAEs by strongest relationship to chemotherapy. In the SOC/PT tables, 
events with missing grade or relationship information will be classified into the worst 
category. No statistical tests will be performed. In addition, separate summaries of 
incidence rates of IRRs and all TEAEs without IRRs by SOC and PT will be given.  
IRRs will be linked to the last infusion administered before the occurrence of the IRR. 
Incidence rates will be calculated by SOC and PT on a per infusion basis. Moreover the 
first infusion per patient with a least one IRR will be identified and summarized in 
frequency tables. 
Also, a summary of incidence rates of TEAEs by SOC and PT and of incidence rates of 
IRRs by FcγRIIIa-allotype subgroups (FF, FV and VV), by FcγRIIa allotypes (HH, HR, 
RR) the occurrence of ADAs (no/yes) and the CetuGEX™ concentration (Cmax) after the 
3rd infusion (≤ median/>median) will be prepared. 
In the AE listings all recorded AEs will be included, TEAEs will be identified by a flag 
variable. 
10.1.1 
Adverse Events Leading to Withdrawal of Study Drug, Drug Interruption or 
Dose Adjustments 
A summary of incidence rates (frequencies and percentages) of TEAEs leading to 
withdrawal of study drug, by SOC, and Preferred Term, will be prepared for the SAF 
population.  
A data listing of AEs leading to withdrawal of study drug will also be provided, 
displaying details of the events captured on the eCRF. 
Similar table and listings will be presented for TEAEs leading to drug 
interruptions/infusion rate reductions or dose reductions. 
10.1.2 
Serious Adverse Events 
SAE Reconciliation will be performed by the Data Manager prior to database lock 
according to the SAE Reconciliation Plan. 


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A summary of incidence rates (frequencies and percentages) of SAEs by SOC, and 
Preferred Term will be prepared for the SAF Population.  
A data listing of SAEs will also be provided, displaying details of the event(s) captured 
on the eCRF. 
10.1.3 
Adverse Events of Special Interest 
The times to the first occurrence of neutropenia (CTC-grade ≥ 3), liver enzymes increases 
(CTC-grade ≥ 3), (hypomagnesemia (CTC-grade ≥ 3), skin reactions (SOC=”Skin and 
subcutaneous tissue disorders”),  gastrointestinal symptoms (SOC=’Gastrointestinal 
disorders), mucositis (PT=’Mucositis’) and conjunctivitis (PT=’Conjunctivitis’) will be 
investigated by Kaplan-Meier methods. Patients who did not experience this AE will be 
censored at the Safety Follow-up visit.  
Logistic regression models including the CetuGex plasma concentration after the 3rd 
infusion as continuous covariable will be fitted to the incidences of AEs of special 
interest. Separate analyses will be performed for each of the AEs. Odds ratios, the 
corresponding 95%-confidence intervals and the p-values of the Wald test will be 
presented. Moreover, sample statistics of the CetuGex plasma concentration after the 3rd 
infusion grouped by the occurrence of these AEs (yes/no) will be presented including p-
values of the Wilcoxon rank test.  
AEs of special interest will be omitted from these analyses if their overall incidence is < 
5%. 
10.2 
Clinical Laboratory Evaluations 
Safety laboratory data (hematology including coagulation panel, biochemistry, urinalysis) 
will be collected from the respective local laboratories of each involved site. 
The analysis of laboratory parameters will be presented for the SAF population, separated 
into blood parameters (hematology, biochemistry) and urine parameters (urinalysis). All 
data will be listed. 
For hematology and biochemistry the laboratory values will be transformed to SI values 
based on SI units to make laboratory parameters comparable between different local 
laboratories. The relevant reference ranges supplied by each laboratory will also be 
transformed to SI reference ranges for each laboratory. 
For hematology and biochemistry variables, descriptive summaries of absolute values 
and changes from baseline will be presented by visit and treatment arm. Visits with less 
than 10 values will be omitted. The description will include two derived visits: “Last 
Value under Combination Therapy” and “Last Value”. 
Each abnormal value will be flagged to show whether it is a value below or above the 
reference range. For the assessment of laboratory variables, five categories will be used 
taking into account the investigator’s assessment of clinical relevance: ‘abnormal high – 
clinically relevant’, ‘abnormal high – not clinically relevant’, ‘within normal limits’, 
‘abnormal low – not clinically relevant’, ‘abnormal low – clinically relevant’. 


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The assessment of laboratory variables will be tabulated by study visit for each clinical 
laboratory parameter by treatment arm (frequency tables). Additionally, for each 
laboratory parameter, shifts in assessments from Baseline to last combination therapy 
visit and overall last visit will be presented by treatment arm (shift tables). 
If NCI-CTCAE grades are available for a clinical laboratory analyte, these will be 
derived according to Common Terminology Criteria for Adverse Events version 4.03 
(CTCAE) and used to present additional frequency and shift tables based on NCI-
CTCAE grades. 
The assessment of categorical urinalysis variables (within normal limits, abnormal – not 
clinically significant, abnormal – clinically significant) will be tabulated by visit for each 
urine parameter by treatment arm (frequency tables). Additionally, for each of these urine 
parameters, shifts in assessments from Baseline to EOS visit will be presented by 
treatment arm (shift tables). 
Laboratory values that are outside the reference range will also be flagged in the data 
listings, along with corresponding reference ranges. 
10.3 
Vital Signs 
Descriptive summaries of observed values and changes from baseline will be calculated 
for weight, temperature, systolic blood pressure, diastolic blood pressure, and pulse rate. 
These summaries will be presented by visit and treatment arm. 
10.4 
Electrocardiogram  
The summary ECG assessment (categories: normal, abnormal – not clinically significant, 
abnormal – clinically significant) will be tabulated by visit (frequency tables). 
Additionally, shifts in assessments from baseline to EOS visit will be presented by 
treatment arm (shift tables). 
Descriptive summaries of actual values and changes from baseline will be presented for 
ECG measures of PR interval, QRS interval, QT interval, QTc interval (Bazett), and HR 
(heart rate) by visit and treatment arm. 
If not available in the clinical database, Bazett’s Correction (QTcb) will be derived as 
follows: 
Bazett’s Correction (QTcb) 
RR
QT
QTc
m
b
sec

 
where: Relative Rate: RR = 60 / HR  
  
HR = heart rate obtained from ECG. 
 
Also, the number and percentage of patients in each treatment group with QTc values 451 
- 480 ms, 481 - 500 ms or >500 ms and the number and percentage of patients in each 
treatment group who experienced a change >30 ms or a change >60 ms will be presented 
by visit. 


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10.5 
ECOG Performance Status 
ECOG assessments will be tabulated by visit and treatment arm (frequency tables). 
Additionally, shifts in assessments from Baseline to EOS visit will be presented by 
treatment arm (shift tables). These analyses will be performed for the SAF population. 
11. OTHER PLANNED ANALYSES 
11.1 
Comparison of Investigator and Centralized Tumor Response Assessments 
Cross-tables comparing case-by-case the best overall investigator and centralized tumor 
response assessments (irRC) based on the entire treatment phase will be presented. 
11.2 
Anti-drug Antibodies 
The incidence of ADAs will be summarized by sampling time point in frequency tables 
for the SAF population. 
11.3 
Hospitalization 
Descriptive summaries of the percentage of days of hospitalization, based on the period 
between randomization and EOS, will be presented by treatment arm for the SAF 
population for all hospitalizations as well as broken down by reason. 
11.4 
Cytokines Release and Immune Cell Status 
Cytokine release and immune cell counts (CD4+ T cells, CD8+ T cells, B cells, NK cells 
from FACS results and eosinophils, neutrophils and monocytes from blood count) 
analyses will include descriptive summaries of measured values and changes from 
baseline (absolute and percent changes, fold change for cytokines). All analyses will be 
performed by sampling time point and treatment arm for the respective subset of the ITT 
population. The time courses of cytokines and immune cell count will be displayed 
graphically (scatter plot overlaid by corresponding medians and interquartile ranges) . 
The change of cytokines/serum factor from pre-first infusion to end of first infusion will 
be summarized by grades of timely related IRRs. 
11.5 
Pharmacokinetic Analysis 
Derivation of pharmacokinetic parameters and statistical analyses will be performed by 
the xxxxxxxxxxxxxxxx Clinical Pharmacokinetics Department. Summaries of serum 
concentration data by sampling time point and derived PK parameters will be presented.  
Serum Concentrations 
For all patients treated with CetuGEX™ its concentration will be analyzed in serum 
samples. 
For serum concentration data, all values below the limit of quantification (BLQ) will be 
set to BLQ/2 for summary statistics and graphs. Individual serum CetuGEX™ 
concentrations will be summarized at each time point using descriptive statistics. 
Individual concentration plots and mean data graphs will be produced. All graphs will be 
presented using both linear and semilogarithmic scales. All CetuGEX™ concentrations 


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will be presented in a by-subject listing.  
Pharmacokinetic Parameters 
Serum PK samples at pre-dose and at the end of each infusion will be collected from all 
patients. In addition, serum PK samples will be collected at 5 hours ± 5 min, 7 hours ± 15 
min, 24 hours ± 1 hour, 48 hours ± 2 hours, 72 hours ± 2 hours and 168 hours ± 2 hours 
after the start of the 1st infusion on Day 1 from a subgroup of approximately 30 patients 
dosed with CetuGEX™. The same sampling regimen will also be taken after the 10th 
infusion. The resulting pharmacokinetic profiles obtained from this subgroup will be 
subjected to noncompartmental analysis, as data permit.  
Pharmacokinetic parameter estimation will be performed using Phoenix WinNonlin® 
(Version 6.4 or later; Pharsight, Cary, NC) on individual serum concentration-time data. 
For the PK parameter calculation, BLQ serum concentrations occurring before Tmax will 
be set to BLQ/2 (50 ng/mL) with the exception of a BLQ value occurring between two 
measurable concentrations, in which case it will be set to missing. BLQ serum 
concentrations occurring after Tmax will be set to missing. Pharmacokinetic parameter 
estimates and summaries will be completed for subjects in the PK Population having 
sufficient measurable concentrations to define the profile. The calculation of terminal 
half-life will only be performed if at least three data points are available.  
Pharmacokinetic parameter estimates, including Cmax, Cmin, Cavg, Tmax, MRT, AUC0-t, 
AUC0-∞, AUC%extrap, AUC0-tau, λz, t1/2, Vz, Vss, and CL, will be summarized using 
descriptive statistics, including arithmetic and geometric means, SD, %CV, median, 
minimum, and maximum. For Tmax, only the median and the range will be reported, as it 
is a categorical variable.  
Values of AUC0-∞ for which the extrapolated part exceeded 20% will be flagged for 
possible exclusion from descriptive statistics.  
The steady state will be assessed by visual observation of the mean trough (pre-dose) 
concentrations over time. Only trough concentrations for which the actual sampling time 
did not deviate by more than 2 hours from the nominal (planned) sampling time will be 
included in the steady state assessment. If the steady state is reached, mean accumulation 
ratio and fluctuation (%fluctuation) will also be calculated. 
All pharmacokinetic calculations will be performed per WinNonlin standard 
noncompartmental algorithms, using actual sampling times elapsed from the start of the 
first infusion. Actual sampling times elapsed from the start of the 10th infusion will also 
be included in the PK input file 
The correlation between PK parameters (AUC0-t, Cmax, Cmin, CL and t1/2) with body 
weight, body surface area and BMI will be explored in scatter plots and by calculating 
correlations coefficients. 
11.6 
Quality of Life Analysis 
To assess the QoL of each patient, patient-reported disease-related symptoms and health 
related QoL will be measured using the EORTC-QLQ-C30 questionnaire and the head 
and neck module (H&N35; according to the availability of the validated translations). 


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The QoL questionnaires EORTC QLQ-C30 version 3.0 and QLQ-H&N35 are collected 
at Baseline and several post-baseline visits. The following scores will be derived: 
 Global health status/QoL (revised): items 29 to 30 
Functional scales (QLQ-C30) 
 Physical functioning (revised): items 1 to 5 
 Role functioning (revised): items 6 to 7 
 Emotional functioning: items 21 to 24 
 Cognitive functioning: items 20 and 25 
 Social functioning: items 26 to 27 
Symptom scales / items (QLQ-C30) 
 Fatigue: items 10, 12, 18 
 Nausea and vomiting: items 14, 15 
 Pain: items 9, 19 
 Dyspnea: item 8 
 Insomnia: item 11 
 Appetite loss: item 13 
 Constipation: item 16 
 Diarrhea: item 17 
 Financial difficulties: item 28 
Symptom scales / items (QLQ-H&N35) 
 Pain: items 1 to 4 
 Swallowing: items 5 to 8 
 Senses problems: items 13 and 14 
 Speech problems: items 16, 23 and 24 
 Trouble with social eating: items 19 to 22 
 Trouble with social contact: items 18 and 25 to 28 
 Less sexuality: items 29 and 30 
 Teeth: item 9 
 Opening mouth: item 10 
 Dry mouth: item 11 
 Sticky saliva: item 12 


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 Coughing: item 15 
 Felt ill: item 17 
 Pain killers: item 31 
 Nutritional supplements: item 32 
 Feeding tube: item 33 
 Weight loss: item 34 
 Weight gain: item 35 
Each of the scores will be derived individually if at least half of the required items are 
available. In general, the mean score will be derived first and then be linearly transformed 
in a way that 0 is the lowest and 100 is the highest possible value. Functional scores for 
QLQ-C30 will be reversed so that a value of 100 represents the highest level of 
functioning. Global and symptom scores will not be reversed so that 100 represents the 
highest possible QoL and the highest level of problems, respectively. 
Summary statistics of all scores and their changes from baseline will be tabulated by 
cycle including p-values of a Wilcoxon rank test for the changes. The time courses of 
means scores will be presented as boxplots. 
In addition, for the QLQ-C30 scales, the difference with respect to baseline will be 
classified as ≤ -10, -10 – 10, ≥ 10. The rates of patients within these ranges will be 
presented by treatment group and visit. The time from randomization to the first 
occurrence of a deterioration of at least 10 points (≤  -10 for global and functional scales, 
≥ 10 for symptom scales) will be analyzed by Kaplan-Meier methods. Patients without 
occurrence of deterioration will be censored at the last assessment. The estimate of the 
quartiles of the time to deterioration as well as the associated 95%-confidence intervals 
will be tabulated by treatment arm together with the p-value of a log rank test. 
 
12. CHANGES COMPARED TO THE CLINICAL TRIAL PROTOCOL 
All planned statistical analyses are in agreement with the clinical trial protocol. 
 
13. REPORTING CONVENTIONS 
The following reporting conventions will be adopted for the presentation of study data. 
These conventions will enhance the review process and help to standardize presentation 
with common notations. 
13.1 
General Reporting Conventions 
 All tables and data listings will be developed in Landscape Orientation, unless 
presented as part of the text in a CSR. 
 Figures will be presented in landscape orientation, unless presented as part of the 
text in a CSR. 
 Legends will be used for all figures with more than one variable or item 


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displayed. 
 Figures will be in black and white, unless color figures have been identified as 
useful for discriminating presentation in the figure. Lines in figures should be 
wide enough to view the line after being photocopied. 
 Specialized text styles, such as bolding, italics, borders, shading, superscripted 
and subscripted text will not be used in tables, figures, and data listings unless 
they add significant value to the table, figure, or data listing.  
 Only standard keyboard characters should be used in tables and data listings. 
Special characters, such as non-printable control characters, printer specific, or 
font specific characters, will not be used on a table, figure, or data listing. 
Hexadecimal character representations are allowed (e.g. , , ). 
 All titles will be centered on a page. The ICH numbering convention is to be used 
for all tables, listings, and graphs. 
 All footnotes will be left justified and at the bottom of a page. Footnotes must be 
present on the page where they are first referenced. Footnotes should be used 
sparingly and must add value to the table, figure, or data listing. If more than four 
footnote lines are planned, then a cover page may be used to display footnotes. 
 Missing values for both numeric and character variables will be presented as 
blanks in a table or data listing. A zero (0) may be used if appropriate to identify 
when the frequency of a variable is not observed. 
 All date values will be presented as DDMMMYYYY (e.g., 29AUG2001) format. 
A four-digit year is preferred for all dates. 
 All observed time values will be presented using a 24-hour clock HH:MM:SS 
format (e.g., 01:35:45 or 11:26). Seconds should only be reported if they were 
measured as part of the study. 
 Time durations will be reported in HH:MM:SS notation. The use of decimal 
notation to present (display) time durations should be avoided (e.g. 0.083h = 5m) 
unless it is necessary to show the computation of time differences in a table, 
figure, or data listing, in which case both notations may be used to display the 
time duration. 
 All tables, figure, and data listings will have the name of the program and a date 
stamp on the bottom of each output. 
13.2 
Population Summary Conventions 
 Population(s) represented on the tables or data listings will be clearly identified in 
the last title of the Table as “Population: <name of population>” and will be 
identical in name to that identified in the protocol or SAP. 
 Consistent terminology will be used to define and identify a population. Common 
nomenclature may include (a) Full Analysis or ITT, (b) All Patients, (c) PP or 
Per-Protocol, (d) Efficacy, (e) Safety, or (f) Pharmacokinetic. 


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 Sub-population(s) or special population(s) descriptions will provide sufficient 
detail to ensure comprehension of the population (e.g., ITT Females, Per-Protocol 
Males >60 years of age) used for analysis in a table or figure. 
 Population sizes may be presented for each treatment or dosing category as totals 
in the column header as (N=xxxx), where appropriate.  
 Population sizes shown with summary statistics are the samples sizes (n) of 
patients with non-missing values.  
 All population summaries for continuous variables will include: N, mean, 
standard deviation, minimum, and maximum. Other summaries (e.g. number 
missing, median, quartiles, 5%, 95% intervals, CV or %CV) may be used as 
appropriate. 
 All percentages are rounded and reported to a single decimal point (xx.x%).  
 Population summaries that include p-values will report the p-value to 
three decimal places with a leading zero (0.001). All p-values reported on default 
output from statistical software (i.e., SAS® Software) may be reported at the 
default level of precision. P-values <0.001 should be reported as <0.001 not 
0.000. 
 


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14. REFERENCES 
1. US Federal Register. (1998) International Conference on Harmonization; 
Guidance on Statistical Principles for Clinical Trials. Department of Health and 
Human Services: Food and Drug Administration [Docket No. 97D-0174]. Federal 
Register Volume 63, Number 179, pages 49583-49598. September 16, 1998. 
2. ASA. (1999) Ethical Guidelines for Statistical Practice. Prepared by the 
Committee on Professional Ethics, August 7, 1999.  
3. RSS. (1993) The Royal Statistical Society: Code of Conduct, August 1993.  
4. Eisenhauer EA., Therasse P, Bogaerts LH, et al: New response evaluation criteria 
in solid tumours: Revised RECIST guideline (version 1.1). Eur J Cancer 45: 228 -
247 (2009) 
5. Metastatic Squamous Cell Carcinoma of the Head and Neck Independent Review 
Charter and User Requirements, Version 1.0  
 


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15. TABLES, LISTINGS, AND FIGURES 
15.1 
Planned Table Descriptions 
The following are planned summary tables for protocol GEXMab52201. Tables will be 
numbered according to the nomenclature used to support the clinical study report. 
Tables will be repeated according to population adding an additional table extension 
digit. 
Table 
Number 
Population 
Table Title / Summary 
Supporting 
Listing 
14.1 DEMOGRAPHIC DATA 
14.1.1.1 
All Patients 
Disposition of Patients  
16.2.1.1 
14.1.1.2 
All Patients 
Analysis Populations 
16.2.1.2 
14.1.1.3 
ITT 
Major Protocol Violations by Type of 
Violations
16.2.2.2 
14.1.1.4 
ITT, PP 
Stratification  
16.2.1.3 
14.1.2.1 
ITT, PP 
Demographics and Baseline Data 
Age, Height, Weight, MI and BSA
16.2.4.1 
14.1.2.2 
ITT, PP 
Demographics and Baseline Data  
Sex, Race, Smoking Status Alcohol 
Consumption and ECOG Status
16.2.4.1 
14.1.3 
ITT, PP 
Tumor Specific Baseline 
Characteristics 
16.2.1.3 
14.1.4.1 
ITT, PP 
SCCHN Diagnosis and History 
Time Since Initial Diagnosis and Time 
Since Most Recent 
Recurrent/Metastatic Diagnosis
16.2.4.6 
14.1.4.2 
ITT, PP 
SCCHN Diagnosis and History  
AJCC/UICC Staging at Initial 
Diagnosis, Location of Primary 
Tumor, Location of Metastases and 
TNM classification
16.2.4.6 
14.1.5 
ITT, PP 
Prior Anti-Cancer Treatments 
16.2.4.10 – 
16.2.4.12 
14.1.6 
ITT, PP 
ECHO/MUGA assessment 
16.2.4.3 


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Table 
Number 
Population 
Table Title / Summary 
Supporting 
Listing 
14.1.7 
 
ITT, PP 
Baseline Physical Examination 
Results by Body System
16.2.4.4 
14.1.8 
 
ITT, PP 
Medical History  
Incidences of Findings by SOC and 
Preferred Term
16.2.4.5 
14.1.9 
ITT, PP 
Baseline Signs and Symptoms 
16.2.4.9 
14.1.10 
 
ITT, PP 
Prior Medications 
Incidences by ATC level 2 and 4 
16.2.9.1 
14.1.11 
 
ITT, PP 
Concomitant Medication  
Incidences by ATC level 2 and 4 
16.2.9.1 
14.1.12 
 
ITT, PP 
Concomitant Pre-Medication  
Incidences by ATC level 2 and 4 
16.2.9.2 
14.1.13 
ITT, PP 
Number of Corticosteroids 
Applications 
16.2.9.2 
 
Table 
Number 
Population 
Table Title / Summary 
Supporting 
Listing 
14.2 EFFICACY DATA  
14.2.1.1 
ITT, PP 
Progression Free Survival 
(Investigator Assessment) – Primary 
Definition 
Log-Rank Test and Kaplan-Meier 
Analysis 
16.2.6.3 
14.2.1.2 
ITT, PP 
Progression Free Survival 
(Investigator Assessment) – Primary 
Definition 
Log-Rank Test and Kaplan-Meier 
Analysis Stratified for Strict 
Adherence to Modified irRC 
16.2.6.3 
14.2.1.3 
ITT, PP 
Progression Free Survival 
(Investigator Assessment ) – Primary 
Definition 
Cox Proportional Hazards Model With 
Stratification Factor 
16.2.6.3 


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Table 
Number 
Population 
Table Title / Summary 
Supporting 
Listing 
14.2.1.4 
ITT, PP 
Progression Free Survival 
(Investigator Assessment) in FcγRIIIa-
allotype Subgroups - Primary 
Definition 
Kaplan-Meier Analysis 
16.2.6.3 
14.2.1.5 
ITT, PP 
Progression Free Survival 
(Investigator Assessment) in Tumor 
Location Subgroups - Primary 
Definition 
Kaplan-Meier Analysis 
16.2.6.3 
14.2.1.6 
ITT, PP 
Progression Free Survival 
(Investigator Assessment) in 
Recurrence Subgroups - Primary 
Definition 
Kaplan-Meier Analysis 
16.2.6.3 
14.2.1.7 
ITT, PP 
Progression Free Survival 
(Investigator Assessment) in EGFR 
treatment subgroups - Primary 
Definition 
Kaplan-Meier Analysis 
16.2.6.3 
14.2.1.8 
ITT, PP 
Progression Free Survival 
(Investigator Assessment) – 
Sensitivity Definition 
Log Rank Test and Kaplan-Meier 
Analysis 
16.2.6.3 
14.2.1.9 
ITT, PP 
Progression Free Survival 
(Investigator Assessment) – 
Sensitivity Definition 
Cox Proportional Hazards Model With 
Stratification Factor 
16.2.6.3 
14.2.2.1 
ITT, PP 
Progression Free Survival 
(Independent Centralized Reading 
Based on irRC) – Primary Definition 
Log-Rank Test and Kaplan-Meier 
Analysis 
16.2.6.3 


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Table 
Number 
Population 
Table Title / Summary 
Supporting 
Listing 
14.2.2.2 
ITT, PP 
Progression Free Survival 
(Independent Centralized Reading 
Based on irRC) – Primary Definition 
Cox Proportional Hazards Model With 
Stratification Factor 
16.2.6.3 
14.2.2.3 
ITT, PP 
Progression Free Survival 
(Independent Centralized Reading 
Based on irRC) in FcγRIIIa-allotype 
Subgroups - Primary Definition 
Kaplan-Meier Analysis 
16.2.6.3 
14.2.2.4 
ITT, PP 
Progression Free Survival 
(Independent Centralized Reading 
Based on irRC) in Tumor Location 
Subgroups - Primary Definition 
Kaplan-Meier Analysis 
16.2.6.3 
14.2.2.5 
ITT, PP 
Progression Free Survival 
(Independent Centralized Reading 
Based on irRC) in Recurrence 
Subgroups - Primary Definition 
Kaplan-Meier Analysis 
16.2.6.3 
14.2.2.6 
ITT, PP 
Progression Free Survival 
(Independent Centralized Reading 
Based on irRC) in EGFR treatment 
subgroups - Primary Definition 
Kaplan-Meier Analysis 
16.2.6.3 
14.2.2.7 
ITT, PP 
Progression Free Survival 
(Independent Centralized Reading 
Based on irRC) – Sensitivity 
Definition 
Log-Rank Test and Kaplan-Meier 
Analysis 
16.2.6.3 
14.2.2.8 
ITT, PP 
Progression Free Survival 
(Independent Centralized Reading 
Based on irRC) – Sensitivity 
Definition 
Cox Proportional Hazards Model With 
Stratification Factor 
16.2.6.3 


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Table 
Number 
Population 
Table Title / Summary 
Supporting 
Listing 
14.2.3.1 
ITT, PP 
Progression Free Survival 
(Independent Centralized Reading 
Based on RECIST 1.1) – Primary 
Definition 
Log-Rank Test and Kaplan-Meier 
Analysis 
16.2.6.3 
14.2.3.2 
ITT, PP 
Progression Free Survival 
(Independent Centralized  Reading 
Based on RECIST 1.1) – Primary 
Definition 
Cox Proportional Hazards Model With 
Stratification Factor 
16.2.6.3 
14.2.3.3 
ITT, PP 
Progression Free Survival 
(Independent Centralized Reading 
Based on RECIST 1.1) in FcγRIIIa-
allotype Subgroups - Primary 
Definition 
Kaplan-Meier Analysis 
16.2.6.3 
14.2.3.4 
ITT, PP 
Progression Free Survival 
(Independent Centralized Reading 
Based on RECIST 1.1) in Tumor 
Location Subgroups - Primary 
Definition 
Kaplan-Meier Analysis 
16.2.6.3 
14.2.3.5 
ITT, PP 
Progression Free Survival 
(Independent Centralized Reading 
Based on RECIST 1.1) in Recurrence 
Subgroups - Primary Definition 
Kaplan-Meier Analysis 
16.2.6.3 
14.2.3.6 
ITT, PP 
Progression Free Survival 
(Independent Centralized Reading 
Based on RECIST 1.1) in EGFR 
treatment subgroups - Primary 
Definition 
Kaplan-Meier Analysis 
16.2.6.3 


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Table 
Number 
Population 
Table Title / Summary 
Supporting 
Listing 
14.2.3.7 
ITT, PP 
Progression Free Survival 
(Independent Centralized  Reading 
Based on RECIST 1.1) – Sensitivity 
Definition 
Log-Rank Test and Kaplan-Meier 
Analysis 
16.2.6.3 
14.2.3.8 
ITT, PP 
Progression Free Survival 
(Independent Centralized  Reading 
Based on RECIST 1.1) – Sensitivity 
Definition 
Cox Proportional Hazards Model With 
Stratification Factor 
16.2.6.3 
14.2.4.1 
ITT, PP 
Best Overall Response Rates by 
Response Category (Investigator 
Assessment) 
16.2.6.1 
14.2.4.2 
ITT, PP 
Best Overall Response Rates by 
Response Category (Independent 
Centralized Reading Based on irRC) 
16.2.6.1 
14.2.4.3 
ITT, PP 
Best Overall Response Rates by 
Response Category (Independent 
Centralized Reading Based on 
RECIST 1.1) 
16.2.6.1 
14.2.5.1 
ITT, PP 
Objective Response Rate (Investigator 
Assessment) 
Frequencies, Chi-Squared Test and 
Confidence Intervals 
16.2.6.1 
14.2.5.2 
ITT, PP 
Objective Response (Investigator 
Assessment) 
Logistic Regression Model 
16.2.6.1 
14.2.5.3 
ITT, PP 
Objective Response (Investigator 
Assessment) in FcγRIIIa-allotype 
Subgroups - Primary Definition 
Frequencies and Confidence Intervals 
16.2.6.3 
14.2.5.4 
ITT, PP 
Objective Response (Investigator 
Assessment) in Tumor Location 
Subgroups - Primary Definition 
Frequencies and Confidence Intervals 
16.2.6.3 


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Table 
Number 
Population 
Table Title / Summary 
Supporting 
Listing 
14.2.5.5 
ITT, PP 
Objective Response (Investigator 
Assessment) in Recurrence Subgroups 
- Primary Definition 
Frequencies and Confidence Intervals 
16.2.6.3 
14.2.5.6 
ITT, PP 
Objective Response (Investigator 
Assessment) in EGFR treatment 
subgroups - Primary Definition 
Frequencies and Confidence Intervals 
16.2.6.3 
14.2.6.1 
ITT, PP 
Objective Response Rate (Independent 
Centralized Reading Based on irRC) 
Frequencies and Confidence Intervals 
16.2.6.2 
14.2.6.2 
ITT, PP 
Objective Response (Independent 
Centralized Reading Based on irRC) 
Logistic Regression Model 
16.2.6.2 
14.2.6.3 
ITT, PP 
Objective Response (Investigator 
Assessment Based on irRC) in 
FcγRIIIa-allotype Subgroups - 
Primary Definition 
Frequencies, Chi-Squared Test and 
Confidence Intervals 
16.2.6.3 
14.2.6.4 
ITT, PP 
Objective Response (Investigator 
Assessment Based on irRC) in Tumor 
Location Subgroups - Primary 
Definition 
Frequencies and Confidence Intervals 
16.2.6.3 
14.2.6.5 
ITT, PP 
Objective Response (Investigator 
Assessment Based on irRC) in 
Recurrence Subgroups - Primary 
Definition 
Frequencies and Confidence Intervals 
16.2.6.3 
14.2.6.6 
ITT, PP 
Objective Response (Investigator 
Assessment Based on irRC) in EGFR 
treatment subgroups - Primary 
Definition 
Frequencies and Confidence Intervals 
16.2.6.3 
14.2.7.1 
ITT, PP 
Objective Response Rate (Independent 
Centralized Reading Based on 
RECIST 1.1) 
Frequencies and Confidence Intervals 
16.2.6.2 


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Table 
Number 
Population 
Table Title / Summary 
Supporting 
Listing 
14.2.7.2 
ITT, PP 
Objective Response (Independent 
Centralized Reading Based on 
RECIST 1.1) 
Logistic Regression Model 
16.2.6.2 
14.2.7.3 
ITT, PP 
Objective Response (Investigator 
Assessment Based on irRC) in 
FcγRIIIa-allotype Subgroups - 
Primary Definition 
Frequencies and Confidence Intervals 
16.2.6.3 
14.2.7.4 
ITT, PP 
Objective Response (Investigator 
Assessment Based on RECIST 1.1) in 
Tumor Location Subgroups - Primary 
Definition 
Frequencies and Confidence Intervals 
16.2.6.3 
14.2.7.5 
ITT, PP 
Objective Response (Investigator 
Assessment Based on RECIST 1.1) in 
Recurrence Subgroups - Primary 
Definition 
Frequencies and Confidence Intervals 
16.2.6.3 
14.2.7.6 
ITT, PP 
Objective Response (Investigator 
Assessment Based on RECIST 1.1) in 
EGFR treatment subgroups - Primary 
Definition 
Frequencies and Confidence Intervals 
16.2.6.3 
14.2.8.1 
ITT, PP 
Clinical Benefit Rate (Investigator 
Assessment) 
Frequencies, Chi-Squared Test and 
Confidence Intervals 
16.2.6.1 
14.2.8.2 
ITT, PP 
Clinical Benefit Rate (Investigator 
Assessment) 
Logistic Regression Model 
16.2.6.1 
14.2.8.3 
ITT, PP 
Clinical Benefit Rate (Investigator 
Assessment) in FcγRIIIa-allotype 
Subgroups - Primary Definition 
Frequencies and Confidence Intervals 
16.2.6.3 
14.2.8.4 
ITT, PP 
Clinical Benefit Rate (Investigator 
Assessment) in Tumor Location 
Subgroups - Primary Definition 
Frequencies and Confidence Intervals 
16.2.6.3 


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Table 
Number 
Population 
Table Title / Summary 
Supporting 
Listing 
14.2.8.5 
ITT, PP 
Clinical Benefit Rate (Investigator 
Assessment) in Recurrence Subgroups 
- Primary Definition 
Frequencies and Confidence Intervals 
16.2.6.3 
14.2.8.6 
ITT, PP 
Clinical Benefit Rate (Investigator 
Assessment) in EGFR treatment 
subgroups - Primary Definition 
Frequencies and Confidence Intervals 
16.2.6.3 
14.2.9.1 
ITT, PP 
Clinical Benefit Rate (Independent 
Centralized Reading Based on irRC) 
Frequencies and Confidence Intervals 
16.2.6.2 
14.2.9.2 
ITT, PP 
Clinical Benefit Rate (Independent 
Centralized Reading Based on irRC) 
Logistic Regression Model 
16.2.6.2 
14.2.9.3 
ITT, PP 
Clinical Benefit Rate (Investigator 
Assessment Based on irRC) in 
FcγRIIIa-allotype Subgroups - 
Primary Definition 
Frequencies, Chi-Squared Test and 
Confidence Intervals 
16.2.6.3 
14.2.9.4 
ITT, PP 
Clinical Benefit Rate (Investigator 
Assessment Based on irRC) in Tumor 
Location Subgroups - Primary 
Definition 
Frequencies and Confidence Intervals 
16.2.6.3 
14.2.9.5 
ITT, PP 
Clinical Benefit Rate (Investigator 
Assessment Based on irRC) in 
Recurrence Subgroups - Primary 
Definition 
Frequencies and Confidence Intervals 
16.2.6.3 
14.2.9.6 
ITT, PP 
Clinical Benefit Rate (Investigator 
Assessment Based on irRC) in EGFR 
treatment subgroups - Primary 
Definition 
Frequencies and Confidence Intervals 
16.2.6.3 


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Table 
Number 
Population 
Table Title / Summary 
Supporting 
Listing 
14.2.10.1 
ITT, PP 
Clinical Benefit Rate (Independent 
Centralized Reading Based on 
RECIST 1.1) 
Frequencies, Chi-Squared Test and 
Confidence Intervals 
16.2.6.2 
14.2.10.2 
ITT, PP 
Clinical Benefit Rate (Independent 
Centralized Reading Based on 
RECIST 1.1) 
Logistic Regression Model 
16.2.6.2 
14.2.10.3 
ITT, PP 
Clinical Benefit Rate (Investigator 
Assessment Based on irRC) in 
FcγRIIIa-allotype Subgroups - 
Primary Definition 
Frequencies and Confidence Intervals 
16.2.6.3 
14.2.10.4 
ITT, PP 
Clinical Benefit Rate (Investigator 
Assessment Based on RECIST 1.1) in 
Tumor Location Subgroups - Primary 
Definition 
Frequencies and Confidence Intervals 
16.2.6.3 
14.2.10.5 
ITT, PP 
Clinical Benefit Rate (Investigator 
Assessment Based on RECIST 1.1) in 
Recurrence Subgroups - Primary 
Definition 
Frequencies and Confidence Intervals 
16.2.6.3 
14.2.10.6 
ITT, PP 
Clinical Benefit Rate (Investigator 
Assessment Based on RECIST 1.1) in 
EGFR treatment subgroups - Primary 
Definition 
Frequencies and Confidence Intervals 
16.2.6.3 
14.2.11.1 
ITT, PP 
Duration of Response (Investigator 
Assessment) 
Log-Rank Test and Kaplan-Meier 
Analysis 
16.2.6.3 
14.2.11.2 
ITT, PP 
Duration of Response (Independent 
Centralized Reading based on irRC) 
Log-Rank Test and Kaplan-Meier 
Analysis 
16.2.6.3 


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Table 
Number 
Population 
Table Title / Summary 
Supporting 
Listing 
14.2.11.3 
ITT, PP 
Duration of Response (Independent 
Centralized Reading based on 
RECIST 1.1) 
Log-Rank Test and Kaplan-Meier 
Analysis 
16.2.6.3 
14.2.12.1 
ITT, PP 
Time to Treatment Failure 
Log-Rank Test and Kaplan-Meier 
Analysis 
16.2.6.3 
14.2.12.2 
ITT, PP 
Time to Treatment Failure 
Cox Proportional Hazards Model 
16.2.6.3 
14.2.13.1 
ITT, PP 
Overall Survival 
Log-Rank Test and Kaplan-Meier 
Analysis 
16.2.6.3 
14.2.13.2 
ITT, PP 
Overall Survival  
Cox Proportional Hazards Model With 
Stratification Factors 
16.2.6.3 
14.2.13.3 
ITT, PP 
Overall Survival in FcγRIIIa-allotype 
Subgroups 
Kaplan-Meier Analysis 
16.2.6.3 
14.2.13.4 
ITT, PP 
Overall Survival in Tumor Location 
Subgroups 
Kaplan-Meier Analysis 
16.2.6.3 
14.2.13.5 
ITT, PP 
Overall Survival in Recurrence 
Subgroups 
Kaplan-Meier Analysis 
16.2.6.3 
14.2.13.6 
ITT, PP 
Overall Survival in EGFR treatment 
subgroups  
Kaplan-Meier Analysis 
16.2.6.3 
14.2.13.7 
ITT, PP 
Overall Survival – Stratification 
Factors and Second Line Treatment 
Cox Proportional Hazards Model 
16.2.6.3 
14.2.14.1 
ITT, PP 
Progression Free Survival 
(Investigator Assessment) – Landmark 
Analysis 
Log Rank Test and Kaplan-Meier 
Analysis 
16.2.6.3 


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Table 
Number 
Population 
Table Title / Summary 
Supporting 
Listing 
14.2.14.2 
ITT, PP 
Progression Free Survival 
(Investigator Assessment ) – 
Landmark Analysis 
Cox Proportional Hazards Model With 
Stratification Factor 
16.2.6.3 
14.2.15.1 
ITT, PP 
Overall Survival – Landmark Analysis 
Log Rank Test and Kaplan-Meier 
Analysis 
16.2.6.3 
14.2.15.2 
ITT, PP 
Overall Survival  – Landmark 
Analysis 
Cox Proportional Hazards Model With 
Stratification Factors 
16.2.6.3 
14.2.16.1 
ITT, PP 
Progression Free Survival 
(Investigator Assessment ) and 
FcγRIIa-allotype  
Cox Proportional Hazards Model  
16.2.6.3 
14.2.16.2 
ITT, PP 
Progression Free Survival 
(Investigator Assessment) in FcγRIIa-
allotype Subgroups 
Kaplan-Meier Analysis 
16.2.6.3 
14.2.16.3 
ITT, PP 
Progression Free Survival 
(Investigator Assessment ) and p16 
Status  
Cox Proportional Hazards Model  
16.2.6.3 
14.2.16.4 
ITT, PP 
Progression Free Survival 
(Investigator Assessment) in p16 
Status Subgroups 
Kaplan-Meier Analysis 
16.2.6.3 
14.2.16.5 
ITT, PP 
Progression Free Survival 
(Investigator Assessment ) EGFR 
Intensity 
Cox Proportional Hazards Model  
16.2.6.3 


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Table 
Number 
Population 
Table Title / Summary 
Supporting 
Listing 
14.2.16.6 
ITT, PP 
Progression Free Survival 
(Investigator Assessment) in EGFR 
Intensity Subgroups 
Kaplan-Meier Analysis 
16.2.6.3 
14.2.16.7 
ITT, PP 
Progression Free Survival 
(Investigator Assessment ) and EGFR 
Stained Cancer Cells 
Cox Proportional Hazards Model  
16.2.6.3 
14.2.16.1 
ITT, PP 
Overall Survival and FcγRIIa-allotype 
Cox Proportional Hazards Model  
16.2.6.3 
14.2.16.2 
ITT, PP 
Overall Survival in FcγRIIa-allotype 
Subgroups 
Kaplan-Meier Analysis 
16.2.6.3 
14.2.16.3 
ITT, PP 
Overall Survival and p16 Status  
Cox Proportional Hazards Model  
16.2.6.3 
14.2.16.4 
ITT, PP 
Overall Survival in p16 Status 
Subgroups 
Kaplan-Meier Analysis 
16.2.6.3 
14.2.16.5 
ITT, PP 
Overall Survival EGFR intensity 
Cox Proportional Hazards Model  
16.2.6.3 
14.2.16.6 
ITT, PP 
Overall Survival in EGFR intensity 
Subgroups 
Kaplan-Meier Analysis 
16.2.6.3 
14.2.16.7 
ITT, PP 
Overall Survival and EGFR Stained 
Cancer Cells 
Cox Proportional Hazards Model  
16.2.6.3 
14.2.17.1 
ITT, PP 
Clinical Benefit Rate (Investigator 
Assessment) and FcγRIIa-allotype 
Logistic Regression Model 
16.2.6.1 


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Table 
Number 
Population 
Table Title / Summary 
Supporting 
Listing 
14.2.17.2 
ITT, PP 
Clinical Benefit Rate (Investigator 
Assessment) in FcγRIIa-allotype 
Subgroups 
Frequencies and Confidence Intervals 
16.2.6.3 
14.2.17.3 
ITT, PP 
Clinical Benefit Rate (Investigator 
Assessment) and p16 Status 
Logistic Regression Model 
16.2.6.1 
14.2.17.4 
ITT, PP 
Clinical Benefit Rate (Investigator 
Assessment) in p16 Status Subgroups 
Frequencies and Confidence Intervals 
16.2.6.3 
14.2.17.5 
ITT, PP 
Clinical Benefit Rate (Investigator 
Assessment) and EGFR Intensity 
Logistic Regression Model 
16.2.6.1 
14.2.17.6 
ITT, PP 
Clinical Benefit Rate (Investigator 
Assessment) in EGRF Intensity 
Subgroups 
Frequencies and Confidence Intervals 
16.2.6.3 
14.2.17.7 
ITT, PP 
Clinical Benefit Rate (Investigator 
Assessment) and EGFR Stained 
Cancer cells 
Logistic Regression Model 
16.2.6.1 
 
 
 
Table 
Number 
Population 
Table Title / Summary 
Supporting 
Listing 
14.3 SAFETY DATA 
14.3.1.1.1 
Safety 
Adverse Events 
Summary Table 
16.2.7 


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Table 
Number 
Population 
Table Title / Summary 
Supporting 
Listing 
14.3.1.2.1 
Safety 
Treatment Emergent Adverse Events – 
All TEAE 
Incidences by SOC and Preferred 
Term 
16.2.7 
14.3.1.2.2 
Safety 
Treatment Emergent Adverse Events – 
During Combination Treatment 
Incidences by SOC and Preferred 
Term 
16.2.7 
14.3.1.2.3 
Safety 
Treatment Emergent Adverse Events – 
During Maintenance Treatment 
Incidences by SOC and Preferred 
Term 
16.2.7 
14.3.1.3.1 
Safety  
Treatment Emergent Adverse Events 
by Maximum CTC Grade – All TEAE 
Incidences by SOC and Preferred 
Term 
16.2.7 
14.3.1.3.2 
Safety  
Treatment Emergent Adverse Events 
by Maximum CTC Grade – During 
Combination Treatment 
Incidences by SOC and Preferred 
Term 
16.2.7 
14.3.1.3.3 
Safety  
Treatment Emergent Adverse Events 
by Maximum CTC Grade – During 
Maintenance Treatment 
Incidences by SOC and Preferred 
Term 
16.2.7 
14.3.1.4.1 
Safety 
Treatment Emergent Adverse Events 
by Strongest Relationship to Study 
Drug – All TEAE 
Incidences by SOC and Preferred 
Term 
16.2.7 
14.3.1.4.2 
Safety 
Treatment Emergent Adverse Events 
by Strongest Relationship to Study 
Drug – During Combination 
Treatment 
Incidences by SOC and Preferred 
Term 
16.2.7 


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Table 
Number 
Population 
Table Title / Summary 
Supporting 
Listing 
14.3.1.4.3 
Safety 
Treatment Emergent Adverse Events 
by Strongest Relationship to Study 
Drug – During Maintenance 
Treatment 
Incidences by SOC and Preferred 
Term 
16.2.7 
14.3.1.5.1 
Safety 
Infusion-Related Reactions 
Incidences by SOC and Preferred 
Term 
16.2.7 
14.3.1.5.3 
Safety 
Infusion-Related Reactions  
Incidences by SOC and Preferred 
Term on a Per Infusion Basis 
16.2.7 
14.3.1.5.3 
Safety 
Infusion-Related Reactions  
Infusion of First Occurrence 
16.2.7 
14.3.1.5.4 
Safety 
TEAE without Infusion-Related 
Reactions 
Incidences by SOC and Preferred 
Term 
16.2.7 
14.3.1.6.1 
Safety 
Treatment Emergent Adverse Events 
Incidences by SOC and Preferred 
Term  by FcγRIIIa-allotype Subgroup 
16.2.7 
14.3.1.6.2 
Safety 
Treatment Emergent Adverse Events 
Incidences by SOC and Preferred 
Term by FcγRIIa-allotype Subgroup 
16.2.7 
14.3.1.6.3 
Safety 
Treatment Emergent Adverse Events 
Incidences by SOC and Preferred 
Term by Occurrence of ADAs 
16.2.7 
14.3.1.6.4 
Safety 
Treatment Emergent Adverse Events 
Incidences by SOC and Preferred 
Term by CetuGEX™ concentration 
after the 3rd infusion 
16.2.7 
14.3.2.1 
Safety 
Treatment Emergent Adverse Events 
Leading to Discontinuation of Study 
Drug 
Incidences by SOC and Preferred 
Term 
16.2.7 


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Table 
Number 
Population 
Table Title / Summary 
Supporting 
Listing 
14.3.2.2 
Safety 
Treatment Emergent Adverse Events 
Leading to Interruptions/Infusion Rate 
Reductions of Study Drug 
Incidences by SOC and Preferred 
Term 
16.2.7 
14.3.2.3 
Safety 
Treatment Emergent Adverse Events 
Leading to Dose Adjustments of Study 
Drug 
Incidences by SOC and Preferred 
Term 
16.2.7 
14.3.2.4 
Safety 
Serious Adverse Events 
Incidences by SOC and Preferred 
Term. 
16.2.7 
14.3.3.1 
Safety 
Treatment Emergent Adverse Events 
Leading to Dose Adjustments of Study 
Drug  
Listing of Cases 
16.2.7 
14.3.3.2 
Safety 
Treatment Emergent Adverse Events 
Leading to Interruptions/Infusion Rate 
Reductions of Study Drug  
Listing of Cases 
16.2.7 
14.3.3.3 
Safety 
Treatment Emergent Adverse Events 
Leading to Discontinuation of Study 
Drug  
Listing of Cases 
16.2.7 
14.3.3.4 
Safety 
Serious Adverse Events 
Listing of Cases  
16.2.7 
14.3.3.5.1 
Safety 
Time to Occurrence of AE of Special 
Interest – Kaplan-Meier Analysis 
16.2.7 
14.3.3.5.2 
Safety 
Effect of CetuGex Plasma 
Concentration After the 3rd Infusion 
on the Occurrence of AE of Special 
Interest – Logistic Regression 
16.2.7 
14.3.3.5.3 
Safety 
CetuGex Plasma Concentration After 
the 3rd Infusion by the Occurrence of 
AE of Special Interest – Sample 
Statistics and Wilcoxon Rank Test 
16.2.7 


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Table 
Number 
Population 
Table Title / Summary 
Supporting 
Listing 
14.3.4.1.1 
Safety 
Laboratory Data – Hematology and 
Biochemistry 
Absolute Values by Visit  
16.2.8.1 – 
16.2.8.2 
14.3.4.1.2 
Safety 
Laboratory Data – Hematology and 
Biochemistry 
Changes from Baseline by Visit  
16.2.8.1 – 
16.2.8.2 
14.3.4.1.3 
Safety 
Laboratory Data – Hematology and 
Biochemistry 
Assessment of Abnormalities by Visit  
16.2.8.1 – 
16.2.8.2 
14.3.4.1.4 
Safety 
Laboratory Data – Hematology and 
Biochemistry 
Shift in Assessment of Abnormalities 
from Baseline to Last Combination 
Therapy Visit 
16.2.8.1 – 
16.2.8.2 
14.3.4.1.5 
Safety 
Laboratory Data – Hematology and 
Biochemistry 
Shift in Assessment of Abnormalities 
from Baseline to Last Visit 
16.2.8.1 – 
16.2.8.2 
14.3.4.1.6 
Safety 
Laboratory Data – Hematology and 
Biochemistry 
CTC Grade by Visit  
16.2.8.1 – 
16.2.8.2 
14.3.4.1.7 
Safety 
Laboratory Data – Hematology and 
Biochemistry 
Shift in CTC Grade at Baseline to 
Maximum Post-Baseline CTC Grade 
16.2.8.1 – 
16.2.8.2 
14.3.4.2.1 
Safety 
Laboratory Data – Urinalysis 
Assessments by Visit 
16.2.8.3 
14.3.4.2.2 
Safety 
Laboratory Data – Urinalysis 
Shift in Assessments from Baseline to 
End of Study 
16.2.8.3 
14.3.5.1.1 
Safety 
Vital Signs Data 
Absolute Values by Visit 
16.2.9.4 
14.3.5.1.2 
Safety 
Vital Signs Data 
Changes from Baseline by Visit 
16.2.9.4 
14.3.5.2.1 
Safety 
Electrocardiogram (ECG) Data 
Summary Assessment by Visit 
16.2.9.5 


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Table 
Number 
Population 
Table Title / Summary 
Supporting 
Listing 
14.3.5.2.2 
Safety 
Electrocardiogram (ECG) Data 
Shift in Summary Assessment from 
Baseline to End of Study 
16.2.9.5 
14.3.5.2.3 
Safety 
Electrocardiogram (ECG) Data 
Absolute Values by Visit 
16.2.9.5 
14.3.5.2.4 
Safety 
Electrocardiogram (ECG) Data 
Changes from Baseline by Visit 
16.2.9.5 
14.3.5.2.5 
Safety 
Electrocardiogram (ECG) Data 
Classification of QTc Intervals by 
Visit 
16.2.9.5 
14.3.5.2.6 
Safety 
Electrocardiogram (ECG) Data 
Classification of QTc Interval 
Changes from Baseline by Visit 
16.2.9.5 
14.3.5.3.1 
Safety 
ECOG Performance Status 
Assessments by Visit 
16.2.9.6 
14.3.5.3.2 
Safety 
ECOG Performance Status 
Shift in Assessments from Baseline to 
End of Study 
16.2.9.6 
14.3.5.4.1 
Safety 
Exposure (CetuGEX™/cetuximab) 
Number of Cycles, Number of 
Infusions, Treatment Duration and 
Total Dose 
16.2.5.1 
14.3.5.4.2 
Safety 
Exposure (CetuGEX™/cetuximab) 
Dose Changes, Dosing Delays, Dosing 
Interruptions and Infusion Rate 
Changes (Per Patient) 
16.2.5.1 
14.3.5.4.3 
Safety 
Exposure (CetuGEX™/cetuximab) 
Dose Reductions, Dosing Delays, 
Dosing Interruptions and Infusion 
Rate Changes (Per Administration) 
16.2.5.1 
14.3.5.5.1 
Safety 
Exposure (5-Fluorouracil) 
Number of Cycles and Total Dose 
16.2.5.3 
14.3.5.5.2 
Safety 
Exposure (5-Fluorouracil) 
Dose Reductions, Dosing Delays, 
Dosing Interruptions (Per Patient) 
16.2.5.3 


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Table 
Number 
Population 
Table Title / Summary 
Supporting 
Listing 
14.3.5.5.3 
Safety 
Exposure (5-Fluorouracil) 
Dose Reductions, Dosing Delays, 
Dosing Interruptions (Per 
Administration) 
16.2.5.3 
14.3.5.6.1 
Safety 
Exposure (Cisplatin/Carboplatin) 
Number of Cycles and Total Dose 
16.2.5.4 
14.35.6.2 
Safety 
Exposure (Cisplatin/Carboplatin) 
Dose Reductions, Dosing Delays, 
Dosing Interruptions (Per Patient) 
16.2.5.4 
14.3.5.6.3 
Safety 
Exposure (Cisplatin/Carboplatin) 
Dose Reductions, Dosing Delays, 
Dosing Interruptions (Per 
Administration) 
16.2.5.4 
14.3.5.7.1 
Safety 
Switch to Carboplatin 
Reason 
16.2.5.4 
14.3.5.7.2 
Safety 
Switch to Carboplatin 
First Cycle of Switch 
16.2.5.4 
 
 
Table 
Number 
Population 
Table Title / Summary 
Supporting 
Listing 
14.4 PHARMACOKINETIC DATA 
14.4.1.1 
PK 
Pharmacokinetic – Summary of 
CetuGEX Serum Concentrations 
Before and After Infusions 
Sample Statistics 
16.2.5.3 
14.4.1.2 
PK 
Pharmacokinetic - Summary of 
CetuGEX Serum Concentrations from 
Extended PK Evaluation 
Sample Statistics
16.2.5.3 
14.4.1.3 
PK 
Pharmacokinetic - Summary of 
Parameters of CetuGEX Serum 
Concentrations 
Sample Statistics
16.2.5.4 
14.4.1.4 
PK 
Pharmacokinetic - Correlation of 
Parameters with Body Weight, BSA 
and BMI 
Correlation Coefficients
16.2.5.4 


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14.4.2.1 
PK 
Effect of  CetuGEX Trough Levels 
After 1st, 2nd and 3rd Infusion on PFS 
Cox Regression Model 
16.2.5.3 and 
16.2.6.3 
14.4.2.2 
PK 
Effect of CetuGEX Post-infusion 
Concentrations After 1st, 2nd and 3rd 
Infusion on PFS 
Cox Regression Model 
16.2.5.3 and 
16.2.6.3 
14.4.2.3 
PK 
Effect of  CetuGEX Trough Levels 
After 1st, 2nd and 3rd Infusion on 
CBR 
Logistic Regression Model 
16.2.5.3 and 
16.2.6.3 
14.4.2.4 
PK 
Effect of CetuGEX Post-infusion 
Concentrations After 1st, 2nd and 3rd 
Infusion on CBR 
Logistic Regression Model 
16.2.5.3 and 
16.2.6.3 
14.4.2.5 
PK 
Pharmacokinetic Parameter by 
Clinical Benefit   
Sample Statistics 
16.2.5.3 and 
16.2.6.3 
 
 
Table 
Number 
Population 
Table Title / Summary 
Supporting 
Listing 
14.5 OTHER DATA ANALYSES 
14.5.1 
ITT 
Investigator and Centralized Tumor 
Assessment – Comparison of Best 
Overall Response Results 
16.2.6.1.4 
and 
16.2.6.2.4 
14.5.2 
Safety 
Anti-drug Antibodies 
16.2.9.7 
14.5.3 
Safety 
Hospitalization (Percentage of 
Individual Study Duration) 
16.2.10..1 
14.5.4.1 
ITT 
Cytokine Release  
Absolute Values 
16.2.9.8 – 
16.2.9.9 
14.5.4.2 
ITT 
Cytokine Release  
Absolute Changes from Baseline 
16.2.9.8 – 
16.2.9.9 


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14.5.4.3 
ITT 
Cytokine Release 
Fold Changes from Baseline 
16.2.9.8 – 
16.2.9.9 
14.5.4.4 
ITT 
Change of Cytokine Release from Cycle 
0 Pre-Infusion to Cycle 0 Post-Infusion 
by Grades of Timely Related IRRs 
Sample Statistics 
16.2.7 and 
16.2.9.8 
14.5.5.1 
ITT 
Immune Cell Counts 
Absolute Values 
16.2.9.8 – 
16.2.9.9 
14.5.5.2 
ITT 
Immune Cell Counts 
Absolute Changes from Baseline 
16.2.9.8 – 
16.2.9.9 
14.5.5.3 
ITT 
Immune Cell Counts 
Percentage Changes from Baseline 
16.2.9.8 – 
16.2.9.9 
14.5.6.1 
ITT 
Quality of Life 
EORTC QLQ-C30 Global Health Status 
– Absolute Values 
16.2.10.1 
14.5.6.2 
ITT 
Quality of Life 
EORTC QLQ-C30 Global Health Status 
– Changes from Baseline 
16.2.10.1 
14.5.6.3 
ITT 
Quality of Life 
EORTC QLQ-C30 Global Health Status 
– Classified Changes from Baseline 
16.2.10.1 
14.5.6.4 
ITT 
Quality of Life 
EORTC QLQ-C30 Functional Scales – 
Absolute Values 
16.2.10.1 
14.5.6.5 
ITT 
Quality of Life 
EORTC QLQ-C30 Functional Scales – 
Changes from Baseline 
16.2.10.1 
14.5.6.6 
ITT 
Quality of Life 
EORTC QLQ-C30 Functional Scales – 
Classified Changes from Baseline 
16.2.10.1 


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14.5.6.7 
ITT 
Quality of Life 
EORTC QLQ-C30 Symptom Scales – 
Absolute Values 
16.2.10.1 
14.5.6.8 
ITT 
Quality of Life 
EORTC QLQ-C30 Symptom Scales – 
Changes from Baseline 
16.2.10.1 
14.5.6.9 
ITT 
Quality of Life 
EORTC QLQ-C30 Symptom Scales – 
Classified Changes from Baseline 
16.2.10.1 
14.5.6.10 
ITT 
Quality of Life 
EORTC QLQ-C30 – Time (Months) to 
First Deterioration of at Least 10 Points 
- Log-Rank Test and Kaplan-Meier 
Analysis 
16.2.10.1 
14.5.7.1 
ITT 
Quality of Life 
EORTC QLQ-H&N35 Symptom Scales 
– Absolute Values 
16.2.10.3 
14.5.7.2 
ITT 
Quality of Life 
EORTC QLQ- H&N35 Symptom 
Scales – Changes from Baseline 
16.2.10.3 
15.2 
Planned Listing Descriptions 
The following are planned data and patient listings for protocol GEXMab52201. Listings 
will be numbered according to the nomenclature used to support the clinical study report. 
Listings will be ordered by patient. In addition the unique patient identification number 
will be displayed on all listings. 
Listings may be split if more space is required using an additional last digit. 
Listing 
Number 
Listing Title / Summary 
16.2.1.1 
Study Completion and Discontinuation Status 
16.2.1.2 
Analysis Populations 
16.2.1.3 
Stratification Factors 
16.2.2.1 
Inclusion and Exclusion Criteria 


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Listing 
Number 
Listing Title / Summary 
16.2.2.2 
Major Protocol Deviations 
16.2.3 
Patients Excluded From Analysis Populations 
16.2.4.1 
Demographic Data 
16.2.4.2 
Tumor Tissue 
16.2.4.3 
ECHO/MUGA Assessment, EGFR Expression, p16 Status, FcγRIIa and 
IIIa Allotypes 
16.2.4.4 
Physical Examination (Screening) 
16.2.4.5 
Medical History 
16.2.4.6 
SCCHN Diagnosis and History 
16.2.4.9 
Baseline Signs and Symptoms 
16.2.4.10 
Prior Anti-Cancer Drug Therapies 
16.2.4.11 
Prior Anti-Cancer Surgeries 
16.2.4.12 
Prior Anti-Cancer Radiotherapy 
16.2.4.13 
Visit Dates 
16.2.5.1 
Study Treatment Administration 
16.2.5.2 
Study Treatment Termination 
16.2.5.3 
5-Fluorouracil Administration 
16.2.5.4 
Cisplatin/Carboplatin Administration 
16.2.5.5 
Chemotherapy Termination 
16.2.5.6.1 
Pharmacokinetics - CetuGEX™ Serum Concentration 
16.2.5.6.2 
Pharmacokinetics - CetuGEX™ Serum Derived Parameters 
16.2.6.1.1 
Tumor Assessment (Investigator) – Target Lesions 
16.2.6.1.2 
Tumor Assessment (Investigator) – Non-Target Lesions 


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Listing 
Number 
Listing Title / Summary 
16.2.6.1.3 
Tumor Assessment (Investigator) –New Lesions 
16.2.6.1.4 
Tumor Response Evaluation (Investigator) 
16.2.6.2.1 
Tumor Assessment (Independent Centralized Reading) – Target Lesions 
16.2.6.2.2 
Tumor Assessment (Independent Centralized Reading) – Non-Target 
Lesions 
16.2.6.2.3 
Tumor Assessment (Independent Centralized Reading) – New Lesions 
16.2.6.2.4 
Tumor Response Evaluation (Independent Centralized Reading) 
16.2.6.3 
Derived Efficacy Variables (BOR, Duration of Response, PFS, TTP, OS) 
16.2.7 
Adverse Events 
16.2.8.1 
Laboratory Data - Hematology 
16.2.8.2 
Laboratory  Data - Biochemistry 
16.2.8.3 
Laboratory  Data - Urinalysis 
16.2.8.4 
Pregnancy Test 
16.2.9.1 
Prior and Concomitant Medication 
16.2.9.2 
Pre-Medication 
16.2.9.3 
Post-Study Anti-Tumor Therapies 
16.2.9.4 
Vital Signs 
16.2.9.5 
ECG 
16.2.9.6 
ECOG Performance Status 
16.2.9.7 
ADAs 
16.2.9.8 
Cytokines  
16.2.9.9 
Immune Cell Status 
16.2.10.1 
Hospitalization 


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Listing 
Number 
Listing Title / Summary 
16.2.10.2 
Quality of Life Questionnaire EORTC-QLQ-C30 
16.2.10.3 
Quality of Life Questionnaire EORTC-QLQ-H&N35 
15.3 
Planned Figure Descriptions 
The following are planned summary figures for protocol GEXMab52201. Figures will 
number according to the nomenclature used to support the clinical study report. 
Figure 
Number 
Population 
Figure Title / Summary 
Supporting 
Table 
Number 
14.5.1.1 
ITT/PP 
Kaplan-Meier Plot of Progression Free 
Survival (Investigator Assessment)  
14.2.1.1 
14.5.1.2 
ITT/PP 
Kaplan-Meier Plot of Progression Free 
Survival (Independent Centralized 
Reading based on irRC)  
14.2.2.1 
14.5.1.3 
ITT/PP 
Kaplan-Meier Plot of Progression Free 
Survival (Independent Centralized 
Reading based on RECIST 1.1)  
14.2.2.1 
14.5.2.1 
ITT/PP 
Kaplan-Meier Plot of Progression Free 
Survival (Investigator Assessment) by 
FcRIIIa Receptor Status Subgroup 
14.2.10.1 
14.5.2.2 
ITT/PP 
Kaplan-Meier Plot of Progression Free 
Survival Independent Centralized 
Reading based on irRC) by FcRIIIa 
Receptor Status Subgroup 
14.2.10.2 
14.5.2.3 
ITT/PP 
Kaplan-Meier Plot of Progression Free 
Survival Independent Centralized 
Reading based on RECIST 1.1) by 
FcRIIIa Receptor Status Subgroup 
14.2.10.2 
14.5.3.1 
ITT/PP 
Kaplan-Meier Plot of Progression Free 
Survival (Investigator Assessment) by 
FcRIIa Receptor Status Subgroup 
14.2.11.1 


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Figure 
Number 
Population 
Figure Title / Summary 
Supporting 
Table 
Number 
14.5.3.2 
ITT/PP 
Kaplan-Meier Plot of Progression Free 
Survival (Independent Centralized 
Reading based on irRC) by FcRIIa 
Receptor Status Subgroup 
14.2.11.2 
14.5.3.3 
ITT/PP 
Kaplan-Meier Plot of Progression Free 
Survival (Independent Centralized 
Reading based on RECIST 1.1) by 
FcRIIa Receptor Status Subgroup 
14.2.11.2 
14.5.4.1 
ITT/PP 
Kaplan-Meier Plot of Progression Free 
Survival (Investigator Assessment) by 
p16 Status Subgroup 
14.2.12.1 
14.5.4.2 
ITT/PP 
Kaplan-Meier Plot of Progression Free 
Survival (Independent Centralized 
Reading based on irRC) by p16 Status 
Subgroup 
14.2.12.2 
14.5.4.3 
ITT/PP 
Kaplan-Meier Plot of Progression Free 
Survival (Independent Centralized 
Reading based on RECIST 1.1) by p16 
Status Subgroup 
14.2.12.2 
14.5.5.1 
ITT/PP 
Kaplan-Meier Plot of Progression Free 
Survival (Investigator Assessment) by 
EGFR Intensity Subgroup 
14.2.13.1 
14.5.5.2 
ITT/PP 
Kaplan-Meier Plot of Progression Free 
Survival (Independent Centralized 
Reading based on irRC) by EGFR 
Intensity Subgroup 
14.2.13.2 
14.5.5.3 
ITT/PP 
Kaplan-Meier Plot of Progression Free 
Survival (Independent Centralized 
Reading based on RECIST) by EGFR 
Expression Subgroup 
14.2.13.2 
14.5.5.4 
ITT 
Kaplan-Meier Plot of Progression Free 
Survival  
Landmark Analysis 
14.2.13.2 


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CONFIDENTIAL 
 
21-DEC-2016 
  
Figure 
Number 
Population 
Figure Title / Summary 
Supporting 
Table 
Number 
14.5.6.1 
ITT/PP 
Kaplan-Meier Plot of Duration of 
Response (Investigator Assessment) 
14.2.6.1 
14.5.7 
ITT/PP 
Kaplan-Meier Plot of Overall Survival  
14.2.8.1 
14.5.8.1 
ITT/PP 
Kaplan-Meier Plot of Overall Survival 
by FcRIIIa Allotypes Subgroup 
14.2.14 
14.5.8.2 
ITT/PP 
Kaplan-Meier Plot of Overall Survival 
by FcRIIa Allotypes Subgroup 
14.2.15 
14.5.8.3 
ITT/PP 
Kaplan-Meier Plot of Overall Survival 
by p16 Status Subgroup 
14.2.16 
14.5.8.3 
ITT/PP 
Kaplan-Meier Plot of Overall Survival 
by EGFR Intensity Subgroup 
14.2.17 
14.5.8.4 
ITT 
Kaplan-Meier Plot of Overall Survival 
Landmark Analysis 
14.2.17 
14.5.9 
ITT/PP 
Kaplan-Meier Plot of Time to 
Treatment Failure 
14.2.9.1 
14.5.10 
ITT 
Maximum Percentage Change of Target 
Lesion Sizes From Baseline 
Waterfall Plots 
14.2.6.1 
14.5.11.1 
PK 
Correlation of Pharmacokinetic 
Parameters with Progression-free 
Survival 
Forest plot 
 
14.5.11.2 
PK 
Correlation of Pharmacokinetic 
Parameters with Clinical Benefit 
Forest plot 
 
14.5.12.1 
ITT/PP 
Cytokine Release – Absolute Values 
Scatterplot with Median and 
Interquartile Range 
14.5.4.1 


Protocol: GEXMab 52201 
 
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Statistical Analysis Plan Final Version 1.0 
 
CONFIDENTIAL 
 
21-DEC-2016 
  
Figure 
Number 
Population 
Figure Title / Summary 
Supporting 
Table 
Number 
14.5.12.2 
ITT/PP 
Cytokine Release – Absolute Changes 
From Baseline 
Scatterplot with Median and 
Interquartile Range 
14.5.4.1 
14.5.12.3 
ITT/PP 
Cytokine Release – Fold Changes From 
Baseline 
Scatterplot with Median and 
Interquartile Range 
14.5.4.1 
14.5.13.1 
ITT/PP 
Immune cell counts –Absolute Values 
Scatterplot with Median and 
Interquartile Range 
14.5.4.1 
14.5.13.2 
ITT/PP 
Immune cell counts – Absolute Changes 
From Baseline 
Scatterplot with Median and 
Interquartile Range 
14.5.4.1 
14.5.13.3 
ITT/PP 
Immune cell counts – Percent Changes 
From Baseline 
Scatterplot with Median and 
Interquartile Range 
14.5.4.1 
14.5.14.1 
PK 
Extended Pharmacokinetic - Individual 
Time Courses of CetuGEX™ 
Concentrations 
14.4.1 
14.5.14.2 
PK 
Extended Pharmacokinetic - Individual 
Time Courses of CetuGEX™ 
Concentrations (log scale) 
14.4.1 
14.5.14.3 
PK 
Extended Pharmacokinetic - Individual 
Time Courses of CetuGEX™ 
Concentrations (log scale) 
14.4.1 
14.5.15.1 
PK 
Extended Pharmacokinetic – Parameters 
and Body Weight 
Scatterplots 
14.4.1 


Protocol: GEXMab 52201 
 
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Statistical Analysis Plan Final Version 1.0 
 
CONFIDENTIAL 
 
21-DEC-2016 
  
Figure 
Number 
Population 
Figure Title / Summary 
Supporting 
Table 
Number 
14.5.15.2 
PK 
Extended Pharmacokinetic – Parameters 
and BMI 
Scatterplots 
14.4.1 
14.5.15.3 
PK 
Extended Pharmacokinetic – Parameters 
and BSA 
Scatterplots 
14.4.1 
14.5.16.1 
PK 
Pharmacokinetic CetuGEX™ -  
Concentrations in All Patients 
Boxplots 
14.4.1 
14.5.16.1 
PK 
Pharmacokinetic CetuGEX™ -  
Concentrations in All Patients (log 
scale) 
Boxplots 
14.4.1