Conditions: Esophageal Cancer
Keywords: non resectable locally advanced Cetuximab radiation
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 74
Healthy volunteers: no

Brief summary:
Esophageal cancer is a highly aggressive tumor. Treatment options are various and range from chemotherapy to radiotherapy and several surgical techniques. Nevertheless, the overall survival rates for this disease remain poor.

During the last years the combination of cetuximab with standard chemotherapy or radiotherapy has mainly be investigated in clinical trials focusing on colorectal and/or head and neck cancer.

The results obtained from theses studies were very encouraging and led to the initiation of active clinical research in esophageal cancer patients with antibody inhibition of the epidermal growth factor receptor (EGFR).

The first data in this indication are encouraging showing that cetuximab can safely be added to chemoradiation for esophageal cancer patients with first hints of efficacy.

Based on the experiences with cetuximab in colorectal cancer and in combination with radiotherapy in head and neck cancer, the aim of the present study is to evaluate the feasibility of a combined treatment of cetuximab with continuous infusional 5-FU, cisplatin and radiotherapy in patients with esophageal cancer and to assess if the overall survival rates can be increased by addition of an EGFR-targeted therapy.

Detailed description:
Esophageal cancer is a highly aggressive neoplasm which is fatal in the great majority of patients. On a global basis, cancer of the esophagus is the sixth leading cause of cancer death worldwide. In fact, gastric and esophageal cancers together accounted for nearly 1.3 million new cases and 980,000 deaths worldwide in 2000 - more than lung, breast, or colorectal cancer. With advances in surgical techniques and treatment, the prognosis of esophageal cancer has slowly improved over the past decades. However, with a 5-year overall survival rate of approximately 14%, at the time of development of the LEOPARD-II protocol, survival was poor, even in comparison with the dismal survival rates (4%) from the 1970s. Underlying reasons for this disappointingly low survival rate are above all the difficulties in cancer detection at an advanced stage, with over 50% of patients with unresectable disease or distant metastasis at presentation and the limited survival achieved with palliative chemotherapy alone for patients with metastatic or unresectable disease.

Clearly, additional strategies are needed to improve the systemic treatment options for esophageal cancer.

The optimal treatment of locally advanced esophageal cancer, a potentially curable disease, is controversial. Through several non-randomized cooperative group trials, concurrent cisplatin-based chemoradiation or surgery alone represent acceptable standards of care for patients with resectable tumors.

Metastatic or unresectable esophageal cancer is found at presentation in more than 50% of patients and is considered incurable. At the time of protocol development, chemotherapy was palliative, improving quality of life and dysphagia in 60%-80% of patients. Typical clinical and radiographic responses lasted for fewer than 4 months, with a median overall survival time of 8-10 months.

Combination chemotherapies have been demonstrated to be superior to best supportive care and chemotherapy given as a single agent, with occasional patients achieving complete responses (0%-11%). However, even with the combination regimens, the median survival time remained less than 10 months.

An improved understanding of the molecular pathogenesis of cancer has facilitated the development of novel agents designed to target critical pathways involved in cancer development and progression. Epidermal growth factor receptor (EGFR) plays a crucial role in tumour growth. EGFR-dependent signaling is involved in cell proliferation, apoptosis, angiogenesis, and metastatic spread.

The overexpression of EGFR has repeatedly been shown to predict poor prognosis in both esophageal squamous cell carcinoma and gastro esophageal junction adenocarcinoma. EGFR blockade through monoclonal antibodies (Cetuximab, Matuzumab and Panitumumab) and tyrosine kinase inhibitors (gefitinib, erlotinib) has translated into promising evidence of clinical benefit in clinical trials.

Cetuximab is a targeted therapeutic agent, a chimeric monoclonal antibody that specifically binds to the EGFR with high affinity, internalising the receptor and preventing ligands from interacting with the receptors and thus effectively blocking ligand-induced EGFR phosphorylation. In addition, cetuximab had been found to potentiate the effects of chemotherapy and radiotherapy in experimental systems. The dose of cetuximab (initial dose 400 mg/m2 and subsequent weekly doses of 250 mg/m2) has been found to be generally safe and effective in several studies in major tumor types expressing the EGFR. These included colorectal cancer and squamous cell carcinoma of the head and neck, with cetuximab given either in combination studies with chemotherapy and radiotherapy or as monotherapy.

In two phase I studies prior to LEOPARD-II, EGFR-directed antibodies had shown activity in patients with esophageal cancer. In the phase I study of the humanized EGFR monoclonal antibody (mAb) EMD72000, one patient with metastatic, pretreated squamous cell carcinoma had had a durable, 6-month partial response.

In addition, a phase I trial with a fully human EGFR mAb, had reported stable disease for 7 months in one esophageal cancer patient. Preclinical and these early clinical studies suggested potential activity and minimal toxicities with EGFR antibodies for esophageal cancer.

Furthermore, a randomised phase II compared cisplatin + 5-FU (CF) to cisplatin + 5-FU + cetuximab (CET-CF) (n=62). Cetuximab did not increase grade 3/4 toxicity, except for rash (6% versus 0%) and diarrhea (16% versus 0%). The overall response rates were 19% and 13% for the CET-CF and CF arms respectively, and the disease control rates were 75% and 57%, respectively. The median progression free survival was 5.9 and 3.6 months and median overall survival 9.5 and 5.5 months for CET-CF and CF, respectively.

With respect to the combination of Cetuximab with radiotherapy, preclinical studies have shown, that Cetuximab enhanced the radiosensitivity of EGFR expressing tumour cells in vitro and in tumour xenografts and the repopulation of epithelial tumour cells after exposure to radiation was related to the activation and expression of EGFR. Cetuximab also enhanced the efficacy of docetaxel chemoradiotherapy in human adenocarcinoma xenografts.

Rationale for the LEOPARD-II study Esophageal cancer is a highly aggressive tumor and one of the most frequent malignant diseases worldwide.

Treatment options are various and range from chemotherapy to radiotherapy and several surgical techniques. Nevertheless, the overall survival rates for this disease remain poor. During the last years before protocol development the combination of cetuximab with standard chemotherapy or radiotherapy had mainly been investigated in clinical trials focusing on colorectal and/or head and neck cancer. The results obtained from these studies had been very encouraging and led to the initiation of active clinical research in esophageal cancer patients with antibody inhibition of the EGFR. The first data in this indication were encouraging showing that cetuximab could safely be added to chemoradiation for esophageal cancer patients with first hints of efficacy. Based on the experiences with cetuximab in colorectal cancer and in combination with radiotherapy in head and neck cancer, the aim of the LEOPARD-II study was to evaluate the feasibility of a combined treatment of cetuximab with continuous infusional 5-FU, cisplatin and radiotherapy in patients with esophageal cancer and to assess if the overall survival rates could be increased by addition of an EGFR-targeted therapy.

Arms:
arm 1: Cetuximab: Initial doses 400mg/m2 (day 1), followed by weekly doses of 250mg/m2 for 14 weeks in total, IV

5-fluorouracil (5-FU): 1000mg/m2 per day as continuous infusion on day 8-11 and 36-39, 750mg/m2/day as continuous infusion on day 71-74 and 99-102

Cisplatin 20mg/m2/day as intravenous bolus over 60 min on day 1-4 of every cycle (day 8-11, 36-39, 71-74 and 99-102)

radiotherapy: 59.4 Gy (33 fractions of 1.8 Gy) over 6.5-7 weeks (5 x 1.8 Gy per week)on primary tumor. 50.4 Gy on locoregional lymphnodes. If resectability is reached after 4-4.5 weeks (36-41.4 Gy) the radiotherapy stops after 45 Gy and the patient undergoes surgery. arm 2: 5-FU: 1000mg/m2 per day as continuous infusion on day 1-4 and 29-32, 750mg/m2/day as continuous infusion on day 64-67 and 92-95

Cisplatin 20mg/m2/day as intravenous bolus over 60 min on day 1-4 of every cycle (day 1-4, 29-32, 64-67 and 92-95)

radiotherapy: 59.4 Gy (33 fractions of 1.8 Gy) over 6.5-7 weeks (5 x 1.8 Gy per week)on primary tumor. 50.4 Gy on locoregional lymphnodes. If resectability is reached after 4-4.5 weeks (36-41.4 Gy) the radiotherapy stops after 45 Gy and the patient undergoes surgery.

Interventions: intervention 1: Cetuximab intervention 2: Cisplatin, 5-FU intervention 3: Radiotherapy
Intervention descriptions: intervention 1: Initial doses 400mg/m2 (day 1), followed by weekly doses of 250mg/m2 for 14 weeks in total intervention 2: 5-FU: 1000mg/m2 per day as continuous infusion on day 1-4 of cycle 1 and 2, 750mg/m2/day as continuous infusion on day 1-4 of cycle 3 and 4

Cisplatin 20mg/m2/day as intravenous bolus over 60 min on day 1-4 of every cycle intervention 3: 59.4 Gy (33 fractions of 1.8 Gy) over 6.5-7 weeks (5 x 1.8 Gy per week)on primary tumor. 50.4 Gy on locoregional lymphnodes. If resectability is reached after 4-4.5 weeks (36-41.4 Gy) the radiotherapy stops after 45 Gy and the patient undergoes surgery.

Protocol document:
Prot_SAP_000.pdf: 
StudyCode: LEOPARD-II 
 
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Clinical Study Protocol 
 
 
Study protocol No.  
LEOPARD-II 
 
EudraCT No.  
 
2010-023427-18 
 
Title 
Definitive radiochemotherapy with 5-FU / cisplatin plus/minus 
cetuximab in unresectable locally advanced esophageal cancer: 
a phase II study 
 
 
Study phase 
II 
 
 
Coordinating Investigator Dirk Rades, MD (LKP according to §40 AMG) 
Department of Radiation Oncology  
 
 
 
Sponsor 
University Hospital Schleswig-Holstein, Campus Luebeck,  
Ratzeburger Allee 160, 23538 Luebeck 
 
 
 
Date/Version  
 
Version final 3.0 2016.10.06 
 


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Abbreviations 
 
 
5-FU  
 
5-fluorouracil 
ADR 
 
 
adverse drug reaction 
ANC 
 
 
absolute neutrophil count 
AE 
 
 
adverse event 
ALT  
 
 
alanine aminotransferase (SGPT) 
AST   
 
aspartate aminotransferase (SGOT) 
ß-HCG 
 
beta human chorionic gonadotrophin 
BSA   
 
body surface area 
CEA 
 
 
carcinoembryonic antigen value 
CIOMS 
 
Council for International Organizations of Medical Sciences 
CR  
 
 
complete response 
CRF   
 
case report form 
CT  
 
 
computed tomography 
DNA 
 
 
desoxyribonucleic acid 
DLT 
 
 
dose limiting toxicity 
EC 
 
 
Ethic’s Committee 
ECG   
 
electrocardiogram 
ECOG  
 
Eastern Cooperative Oncology Group 
EGF   
 
epidermal growth factor 
EGFR   
 
epidermal growth factor receptor 
EORTC  
 
European Organization for Research and Treatment of Cancer 
FPI 
 
 
first patient in 
FAS 
 
 
full analysis Set 
G-CSF  
 
granulocyte colony stimulating factor 
GCP   
 
good clinical practice 
GFR   
 
glomerular filtration rate 
GM-CSF  
 
granulocyte-macrophage colony stimulating factor 
GMP   
 
good manufacturing practice 
Gy 
 
 
Gray 
γ-GT   
 
gamma glutamyl transferase 
HR 
 
 
hazard ratio 
HAHA   
 
human anti-humanized antibody 
ICH 
 
 
International Conference on Harmonisation 
IgG  
 
 
immunglobulin G 
IRB 
 
 
Institutional Review Board 
ITT  
 
 
intention to treat 
i.v.  
 
 
intravenous 
LC 
 
 
locoregional control 
LDH   
 
lactate dehydrogenase 
LKP 
 
 
Leiter der klinischen Prüfung 
LP 
 
 
last patient 
LPI 
 
 
last patient in 
LVEF  
 
left ventricular ejection fraction 
MAb   
 
monoclonal antibody 
MFS 
 
 
metastases-free survival 
MRI  
 
 
magnetic resonance imaging 
MTD  
 
maximum tolerated dose 
NCI CTC 
 
National Cancer Institute Common Toxicity Criteria  
pCR 
 
 
pathological complete response 
PD  
 
 
progressive disease 
PK  
 
 
pharmacokinetics 
PPE   
 
palmar-plantar erythrodysesthesia (hand and foot syndrome) 
pPR 
 
 
pathological partial response 
PR  
 
 
partial response 
Q3, Q4 
 
quartal 3, quartal 4 
QoL   
 
quality of life 


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SAE   
 
serious adverse event 
SD  
 
 
stable disease 
SGOT  
 
aspartate aminotransferase 
SGPT  
 
alanine aminotransferase 
SmPC  
 
summary of product characteristics 
SUSAR 
 
serious unexpected suspected adverse reaction 
TNM   
 
tumor classification index (tumor, nodes, metastasis) 
TME 
 
 
total mesorectal excision 
UICC  
 
International Union against Cancer 
ULN   
 
upper limit of normal 
WHO   
 
World Health Organization 
 
 
 
 
 


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Table of Contents 
 
1 Synopsis ........................................................................................................................... 7 
2 Introduction and study background.............................................................................. 18 
2.1 
Disease background ............................................................................................ 18 
2.2 
Current treatment options for esophageal cancer ................................................. 18 
2.3 
Novel targeted therapies for esophageal cancer .................................................. 19 
2.3.1 
Epidermal growth factor receptor ................................................................. 19 
2.3.2 
Cetuximab....................................................................................................... 20 
2.3.2.1 
Cetuximab in chemotherapy ......................................................................... 20 
2.3.2.2 
Cetuximab in combination with radiotherapy ................................................ 21 
2.3.2.3 
Cetuximab general safety information .......................................................... 22 
2.3.2.4 
Clinically relevant adverse events related to cetuximab ................................ 23 
2.4 
Rationale for the study ......................................................................................... 24 
2.5 
Risk-benefit assessment ...................................................................................... 24 
2.6 
Contributing Scientific Investigations .................................................................... 25 
2.6.1 
Determination of TKR-Receptors and their Soluble Ligands ...................... 25 
2.6.2 
Functional Magnetic Resonance Tomography (DC-MRT) ........................... 25 
3 Study objectives ............................................................................................................. 26 
3.1 
Primary objective ................................................................................................. 26 
3.2 
Secondary objectives ........................................................................................... 26 
4 Study design ................................................................................................................... 26 
4.1 
Overall study design and plan .............................................................................. 26 
4.2 
Selection of the study population ......................................................................... 27 
4.2.1 
Study population and justification of choice of gender .............................. 27 
4.2.2 
Inclusion criteria ............................................................................................ 28 
4.2.3 
Exclusion criteria ........................................................................................... 28 
4.2.4 
Removal of patients from the study or study treatment .............................. 29 
4.2.5 
Study discontinuation.................................................................................... 29 
4.2.6 
Definition of the end of treatment ................................................................. 29 
4.2.7 
Plan for treatment after the end of study ...................................................... 30 
4.2.8 
Definition of the end of study ........................................................................ 30 
5 Treatments ...................................................................................................................... 30 
5.1 
Treatments administered ..................................................................................... 30 
5.1.1 
Cetuximab....................................................................................................... 30 
5.1.1.1 
Recommended materials, compatibility, storage requirements and stability . 30 
5.1.1.2 
Instructions for use and handling .................................................................. 30 
5.1.2 
5-Fluoruracil (5-FU) ........................................................................................ 32 
5.1.3 
Cisplatin .......................................................................................................... 32 
5.2 
Methods of assigning patients to treatment .......................................................... 33 
5.2.1 
Randomization ............................................................................................... 33 
5.2.2 
Blinding .......................................................................................................... 33 
5.2.3 
Procedure for emergency code-breaks ........................................................ 33 
5.3 
Special precautions .............................................................................................. 33 
5.3.1 
Cetuximab administration ............................................................................. 33 
5.3.2 
Chemotherapy administration ....................................................................... 34 
5.4 
Selection, timing and modification of dose for each patient .................................. 35 
5.4.1 
Cetuximab....................................................................................................... 35 
5.4.1.1 
Skin toxicities ............................................................................................... 35 
5.4.1.2 
Allergic/hypersensitivity reactions ................................................................. 36 
5.4.1.3 
Other reasons for cetuximab discontinuation ................................................ 37 
5.4.2 
5-Fluorouracil ................................................................................................. 37 
5.4.2.1 
Dose modifications and treatment alterations for 5-FU ................................. 37 
5.4.3 
Cisplatin .......................................................................................................... 39 
5.4.3.1 
Dose modifications and treatment alterations for cisplatin ............................ 39 
5.5 
Radiotherapy ....................................................................................................... 40 


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5.5.1 
Technique and dosage of radiotherapy ........................................................ 40 
5.5.1 
Adverse reactions and dose modifications of radiotherapy ....................... 40 
5.6 
Prior and concomitant therapy ............................................................................. 41 
5.7 
Other study conditions ......................................................................................... 41 
5.8 
Treatment compliance.......................................................................................... 42 
6 Assessment of safety ..................................................................................................... 42 
6.1 
Adverse events .................................................................................................... 42 
6.1.1 
Definition of adverse event, adverse drug reaction and serious adverse 
event 
42 
6.1.1.1 
Adverse events (or adverse experience) (AE) .............................................. 42 
6.1.1.2 
Adverse drug reaction (ADR): ...................................................................... 42 
6.1.1.3 
Serious adverse event or reaction/experience (SAE): .................................. 43 
6.1.1.4 
Other events to be treated as SAEs ............................................................. 43 
6.1.1.5 
Events not to be treated as SAEs ................................................................. 43 
6.1.2 
Methods of recording and assessing adverse events ................................. 44 
6.1.3 
Procedure for reporting serious adverse events ......................................... 45 
6.1.4 
Monitoring of subjects with adverse events ................................................ 45 
6.1.5 
Overdose and intoxication with the study drug ........................................... 46 
6.2 
Laboratory assessments ...................................................................................... 46 
6.3 
Vital signs and physical examination .................................................................... 46 
7 Schedule of assessments .............................................................................................. 46 
7.1 
Screening examinations ....................................................................................... 47 
7.1.1 
Examinations within 4 weeks prior to treatment start ................................. 47 
7.1.2 
Examinations within 7 days prior to treatment start .................................... 48 
7.2 
Evaluations during radio-immunochemotherapy................................................... 48 
7.2.1 
Weekly examinations ..................................................................................... 48 
7.2.2 
Examinations every 4 weeks ......................................................................... 48 
7.2.3 
Examinations after 4 weeks of treatment ..................................................... 48 
7.3 
End of Treatment Evaluations .............................................................................. 49 
7.4 
Evaluations during the Follow up phase ............................................................... 49 
7.5 
Evaluation of Efficacy ........................................................................................... 49 
7.5.1 
Tumor assessment ........................................................................................ 49 
7.5.2 
Residual tumor classification (R-classification) in patients undergoing 
surgery 51 
8 Statistical Considerations .............................................................................................. 51 
8.1 
Analysis set descriptions ...................................................................................... 51 
8.2 
Target variables ................................................................................................... 52 
8.2.1 
Primary variables ........................................................................................... 52 
8.2.2 
Secondary variables ...................................................................................... 52 
8.3 
Statistical analysis ................................................................................................ 52 
8.3.1 
Present therapeutic situation ........................................................................ 53 
8.3.2 
Rationale for the application of a randomized phase II design ................... 53 
8.3.3 
Design and assumptions ............................................................................... 53 
8.4 
Sample size calculation ........................................................................................ 54 
8.5 
Data Management ............................................................................................... 55 
9 Immuno(histo)chemistry and blood samples (applicable if patient agrees to 
participate in translational study) .................................................................................... 55 
9.1 
DC-MRT .............................................................................................................. 56 
10Data Safety Monitoring Board ...................................................................................... 56 
11Ethical and regulatory aspects ..................................................................................... 57 
11.1 
Responsibilities of the Investigator ....................................................................... 57 
11.2 
Patient information ............................................................................................... 57 
11.3 
Patient consent .................................................................................................... 57 
11.3.1 
Informed Consent procedures ...................................................................... 57 
11.3.2 
Witnessed informed consent ........................................................................ 57 
11.4 
Patient insurance ................................................................................................. 58 


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11.5 
Ethics Committee or Institutional Review Board ................................................... 58 
11.6 
Notification to authorities ...................................................................................... 58 
11.7 
Sponsorship ......................................................................................................... 58 
12Study management ....................................................................................................... 59 
12.1 
Case Report Form handling ................................................................................. 59 
12.2 
Source data and subject files ............................................................................... 59 
12.3 
Investigator Site File and archiving....................................................................... 59 
12.4 
Monitoring, Quality Assurance and inspection by authorities ................................ 60 
12.5 
Changes to the study protocol .............................................................................. 60 
12.6 
Study report and publication policy....................................................................... 61 
13References ..................................................................................................................... 62 
 
 
APPENDICES 
 
Appendix 1 
 
Protocol Signature Pages 
Appendix 2 
 
Patient information sheet and consent form 
Appendix 3 
 
Karnofsky Performance Status Scale 
Appendix 4 
 
RECIST criteria (Version 1.1) 
Appendix 5 
 
Treatment of acneiform skin reactions related to Cetuximab 
Appendix 6 
 
Management options for radiation dermatitis and co-existing acneiform  
skin reactions related to Cetuximab  
Appendix 7 
 
NCI Common Toxicity Criteria Version 4.0 
Appendix 8 
 
Summary of product characteristics Cetuximab 
Appendix 9 
 
Summary of product characteristics 5-FU 
Appendix 10  
Summary of product characteristics Cisplatin 
 
 
 
 


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1 
Synopsis 
 
Study number 
Definitive radiochemotherapy with 5-FU / cisplatin 
plus/minus cetuximab in unresectable locally advanced 
esophageal cancer: a phase II study 
 
EudraCT number 
2010-023427-18  
Acronym 
LEOPARD-II 
Sponsor 
University Hospital Schleswig-Holstein,  
Campus Luebeck, Ratzeburger Allee 160, 23538 Lübeck 
 
Principal investigator 
Dirk Rades, MD, University Hospital Schleswig-Holstein, 
Campus Luebeck, Department of Radiation Oncology, 
Ratzeburger Allee 160, 23538 Lübeck 
Study phase 
Phase II 
Study center(s)/country(ies) 
Approximately 15 German Centers  
Planned study period  
(first enrollment-last subject 
out) 
Start of Enrolment (FPI): Q3 / 2011
 
End of Enrolment  (LPI): Q4 / 2016
 
End of Treatment period  (LP off treatment):
Q1 / 2017
 
End of Follow-up period (LP off study):
Q1 / 2019
 
Study objectives 
Primary objective: 
2-year overall survival (OS) 
Secondary objectives:  
• 
1-year OS 
• 
1-year and 2-year progression-free survival (PFS) 
• 
1-year and 2-year loco-regional control (LC) 
• 
1-year and 2-year metastases-free survival (MFS) 
• 
Toxicity (NCI-CTC 4.0) 
• 
Overall response rate (RECIST Version 1.1) 
• 
Quality of Life (EORTC QLQ-C30 and QLQ 
OES18) 
In addition the following parameters will be assessed 
irrespective of a specific time point:  
• 
OS 
• 
PFS 
•
MFS
Study design and plan 
This is an open-label, randomized Phase II study in 
patients with unresectable esophageal cancer  
Planned number of patients 
Total number of patients:  72-78 patients 
Number of patients per center:   9-15 
Number of patients per treatment arm: 
 33-36 patients 


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Schedule of visits and 
assessments 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Within 4 weeks prior to treatment start 
• 
Written informed consent 
• 
Medical History 
• 
Clinical staging (endoscopy incl. biopsy) 
• 
Endoscopic ultrasound 
• 
Tumor Assessment CT/MRI chest and abdomen 
• 
ECG and LVEF 
• 
FEV1 
• 
Evaluation by a surgeon with respect to 
resectability 
• 
Tissue immunohistochemistry 
Within 7 days prior to treatment start 
• 
Height, weight, vital signs 
• 
Karnofsky-Performance Status 
• 
Hematology (leucocytes, neutrophils, platelets, 
erythrocytes, hemoglobin) 
• 
Clinical Chemistry (sodium, potassium, calcium, 
magnesium, creatinine, bilirubin, SGOT, SGPT, 
LDH, alkaline phosphatase, γ-GT) 
• 
Pregnancy test in women of child-bearing potential 
• 
Serum sample (10 ml) and whole blood sample (10 
ml) for EGFR and ligands determination (if patient 
agrees to participate in translational study) 
Evaluations during radio-immunochemotherapy: 
Weekly: 
• 
Vital signs 
• 
Weight 
• 
Hematology (leucocytes, neutrophils, platelets, 
erythrocytes, hemoglobin) 
• 
Clinical signs and symptoms, toxicity according to 
the NCI-CTC version 4.0  
• DC-MRT: at day 7 (+/-2) or day 14 (+/-2) of the first 
cycle (in selected centers) 
Every 4 weeks: 
• 
Karnofsky-Performance Status 
• 
Biochemistry (sodium, potassium, calcium,  
magnesium, creatinine, bilirubin, SGOT, SGPT, 
LDH, alkaline phosphatase, γ-GT) 
After 4-4.5 weeks (36-41.4 Gy): 
• 
Endoscopy (incl. biopsy, if patient agrees to 
participate in translational study) 
• 
Endoscopic ultrasound (optional) 
• 
Tumor assessment (CT/MRI chest and abdomen) 
• 
serum sample (10 ml) for EGFR and ligands 
determination (if patient agrees to participate in 
translational study) 
 


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• 
Re-evaluation by a surgeon with respect to 
resectability* 
*: If resectability has been achieved, radiochemotherapy +/- 
cetuximab is stopped after 45 Gy, and the patient is referred 
to surgery. If resectability has not been achieved, 
radiochemotherapy +/- cetuximab is continued.  
End of Treatment (planned after 14 weeks): 
At the end of study treatment or at the time of premature 
withdrawal for any reason the following assessments will 
be performed: 
• 
Vital signs 
• 
Karnofsky-performance status 
• 
Hematology (leucocytes, neutrophils, platelets, 
erythrocytes, hemoglobin) 
• 
Clinical Chemistry (sodium, potassium, calcium, 
magnesium, creatinine, bilirubin, SGOT, SGPT, 
LDH, alkaline Phosphatase, γ-GT) 
• 
Clinical signs and symptoms, toxicity according to 
the NCI-CTC version 4.0 
• 
Endoscopy (incl. biopsy, if patient agrees to 
participate in translational study) 
• 
Endoscopic ultrasound (optional) 
• 
Tumor Assessment (CT/MRI chest and abdomen) 
• 
serum sample (10 ml) for EGFR and ligands 
determination (if patient agrees to participate in 
translational study) 
 
Follow up period: 
• 
Evaluation of toxicity  
• 
Treatment outcome 
• 
Endoscopic ultrasound (optional) 
• 
Tumor Assessment (CT/MRI chest and abdomen) 
 
Diagnosis 
Initially unresectable esophageal cancer 


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Criteria for inclusion 
• 
Signed written informed consent 
• 
Male or female between 18 and 75 years; patients 
> 75 years if KPS ≥ 80  
• 
Histologically proven squamous cell carcinoma or 
adenocarcinoma of the esophagus, which is not 
curatively resectable* 
*resectability has to be defined and documented by a surgeon 
prior to randomisation: 
The tumor is considered unresectable due to: 
T-stage, N-stage, performance status/nutritional status, co-
morbidity (pulmonary function, other), tumor location upper third 
of the esophagus, relation to other organs/structures), other 
reasons (please define in CRF). 
 
• 
KPS ≥ 70  
• 
Women of child-bearing potential must have a 
negative pregnancy test 
• 
Adequate cardiac, pulmonary, and ear function 
• 
Adequate bone marrow function: leucocytes > 3.0 x 
109/L, neutrophils > 1.5 x 109/L, platelets > 100 x 
109/L, hemoglobin > 10.0 g/dL 
• 
Adequate liver function: Bilirubin < 2.0 mg/dL, 
SGOT, SGPT, AP, γ-GT < 3 x ULN 
• 
Adequate renal function: serum creatinine < 1.5 
mg/dL, creatinine clearance > 50 ml/min (calculated 
value according to Cockroft-Gault equation) 
• 
No known allergy against chimeric antibodies 
• 
Effective contraception for both male and female 
patients if the risk of conception exists 


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Criteria for exclusion  
• 
Distant metastasis (M1b) 
• 
Previous treatment of esophageal cancer 
• 
Previous exposure to monoclonal antibodies and / 
or EGFR-targeted therapy 
• 
Other previous malignancy with exception of a 
history of a previous curatively treated basal cell 
carcinoma of the skin or pre-invasive carcinoma of 
the cervix 
• 
Serious concomitant disease or medical condition 
• 
FEV1 < 1,1 
• 
Clinically relevant coronary artery disease or a 
history of myocardial infarction within the last 12 
months or left ventricular ejection fraction (LVEF) 
below the institutional range of normal 
• 
Any active dermatological condition > Grade 1 
• 
Contraindications to receive cisplatin, 5-FU or 
cetuximab 
• 
Concurrent treatment with other experimental drugs 
or participation in another clinical trial with any 
investigational drug within 30 days prior to study 
screening 
• 
Pregnancy or lactation 
• 
Known active drug abuse/alcohol abuse 
• 
Social situations limiting the compliance with the 
study requirements 
Investigational therapy: 
dose/mode of administration/ 
dosing schedule 
Product: Cetuximab 
Supplied in single-use, ready-to-use vials, containing 5 
mg/ml cetuximab, with a nominal fill volume of 50 mL (250 
mg/50 mL). 
Dosing schedule:  Initial dose of 400 mg/m2 (day 1), 
followed by weekly doses of 250 mg/m2 for a total of 14 
weeks.  
Mode of administration:  intravenous infusion 


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Concomitant anti-tumor 
therapy:  
dose/mode of administration/ 
dosing schedule 
Treatment arm A (Radiochemotherapy + cetuximab) 
Cetuximab: Initial dose of 400 mg/m2 (day 1), followed by 
weekly doses of 250 mg/m2 for a total of 14 weeks. 
5-FU: 1000 mg/m2/day administered as a continuous 
infusion on days 8-11 and 36-39 
750 mg/m2/day administered as a continuous infusion on 
days 71-74 and 99-102 
Cisplatin: 20 mg/m2/day, administered as an intravenous 
bolus over 60 minutes on days 1-4 of each course (i.e. on 
days 8-11, 36-39, 71-74 and 99-102)  
Radiotherapy: 59.4 Gy (33 fractions of 1.8 Gy) will be 
administered over 6.5-7 weeks (5 x 1.8 Gy per week) to 
the primary tumor and the involved lymph nodes. 50.4 Gy 
will be administered to the loco-regional lymph nodes. If 
resectability has been achieved after 4-4.5 weeks (36-41.4 
Gy), radiotherapy will be stopped at 45 Gy and patient will 
undergo surgery. 
 
Treatment arm B (Radiochemotherapy) 
5-FU: 1000 mg/m2/day administered as a continuous 
infusion on days 1-4 and 29-32 
750 mg/m2/day administered as a continuous infusion on 
days 64-67 and 92-95 
Cisplatin: 20 mg/m2/day, administered as an intravenous 
bolus over 60 minutes on days 1-4 of each course (i.e. on 
days 1-4, 29-32, 64-67 and 92-95) 
Radiotherapy: 59.4 Gy (33 fractions of 1.8 Gy) will be 
administered over 6.5-7 weeks (5 x 1.8 Gy per week) to 
the primary tumor and the involved lymph nodes. 50,4 Gy 
will be administered to the loco-regional lymph nodes. If 
resectability has been achieved after 4-4.5 weeks (36-41.4 
Gy), radiotherapy will be stopped at 45 Gy and patient will 
undergo surgery. 
 
Planned treatment duration 
per subject 
The planned treatment duration per patient is 14 weeks. 
The planned duration of radio-immunochemotherapy is 6.5 
to 7 weeks.  
Patients will be withdrawn at any time during the study if 
they develop unacceptable toxicities or if they withdraw the 
consent to participate in the trial. 
Ongoing adverse events related to study treatment will be 
followed for 6 weeks (skin toxicities until outcome is 
known) after end of treatment. 
Primary target variable 
2-year overall survival (OS) 
Secondary efficacy target 
variables 
• 
1-year OS 
• 
1-year and 2-year PFS 
• 
1-year and 2-year LC 
• 
1-year and 2-year MFS 
• 
Overall response rate (RECIST Version 1.1) 
 


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Tolerability/safety variable(s) 
Toxicity (NCI-CTC 4.0) 
Pharmacokinetics  
Not applicable 
Pharmacodynamics, -
genomics and/or -genetics 
Not applicable 
Quality of life and 
pharmacoeconomics 
Quality of Life (EORTC QLQ-C30 and QLQ OES18) 
Other assessments  
Not applicable 
Data Safety Monitoring Board 
 
A Data Safety Monitoring Board (DSMB) will be 
implemented to formally review safety data when 20 
patients and again when 67 patients (50% of the entire 
cohort) are randomized and have completed 4 weeks of 
treatment. The DSMB will focus on safety and survival 
data only. In addition, the DSMB will be provided with 
regular reports every 6 months summarizing the same 
safety information used for the formal review. 
 
The key safety parameters to be monitored will be  
• 
Overall incidence of patients with any CTCAE-grade 
III/IV adverse event 
• 
Incidence of Serious Adverse Events (SAEs)  
 
In case of significant excess toxicity associated with the 
experimental arm, the DSMB may decide together with the 
Sponsor to stop the trial early due to safety concerns. 


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Statistical methods 
Treatment outcome: 
Loco-regional control is defined as absence of loco-
regional progression based on findings of endoscopy, 
endoscopic ultrasound, and computed tomography.  
OS, PFS, MFS and LC are calculated for both treatment 
groups and for several potential prognostic factors with the 
Kaplan-Meier method and measured from the day of 
randomization .  
Such potential prognostic factors are: age (≤60 vs. >60 
years), Karnofsky performance status (100%-80% vs. 
70%), tumor location (upper third vs. middle third vs. lower 
third), tumor length (<7 cm vs. ≥7 cm, according to 
endoscopy), histology (squamous cell carcinoma vs. 
adenocarcinoma), histologic grade (G1-2 vs. G3), T-stage 
(T2-3 vs. T4, according to endoscopic ultrasound and 
computed tomography), N-Stage (N0 vs. N+), and 
hemoglobin before radiotherapy (<12 vs. 12-14 vs. > 14 
g/dl). 
Differences 
between 
the 
Kaplan-Meier 
curves 
are 
evaluated with the log-rank test. Results are considered 
significant if P < 0.05. Potential prognostic factors found to 
be significant in the univariate analysis, are evaluated in a 
multivariate analysis performed with the Cox proportional 
hazard model.  
 
Stratification at randomization according to : 
Histology (SCC vs. adeno) 
KPS (100%-80% vs. 70%) 
Stage (T1-3 N0-1 vs. T4 and/or N2 and/or M1a)  
 
Toxicity: 
Both treatment groups are compared for toxicity using the 
Chi-square test. 
 


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Sample size calculation and 
explanation 
This is an explorative randomized study with 2 parallel 
groups. Using a standard single-stage phase II design by 
FLEMING (1981), n = 62 patients evaluable for efficacy 
have to be recruited. As a similar number of patients is to 
be recruited to the standard arm, a total number of 124 
patients is required. The standard treatment control group 
serves to reduce some of the result variability which is 
typically encountered in single-arm phase II trials, 
especially caused by patient selection phenomena and 
investigator bias. To cover potentially drop outs 67 patients 
per arm will be recruited. 
 
The OS rate after 2 years is chosen as primary efficacy 
endpoint. The estimation of the efficacy rate of 40% of the 
reference group is based on the findings of several studies 
(Bedenne 2007, Herskovic 1992, Minsky 2002, Stahl 2005, 
Al-Sarraf 1997, Cooper 1999).  Therefore, the respective 
experimental therapy arm would be rated as insufficiently 
active, if the observed OS rate at 2 years is 40 % or lower. 
On the other hand, the experimental therapy would be 
considered to be a very promising candidate for further 
development (e.g. in a phase III trial), if the true OS rate at 
2 years amounted to 45 % or more. 
Probability to accept the experimental therapy as 
promising (> 45% OS rate) with respect to efficacy, in spite 
of a true OS rate of ≤ 40%: 5% (type I error).  
Probability to reject the experimental therapy as not 
sufficiently efficient (≤ 40%), although the true OS rate is 
promising (> 45%): 20% (type II error, corresponding to a 
power of 80%). 
The final conclusion of this trial will depend on the definite 
OS rate (and its confidence interval), the respective 
findings in the 5-FU/cisplatin reference arm, as well as the 
information on type, frequency and severity of toxicities. 
 
 
End of the study 
The end of study is reached when the last patient has 
completed the 2-year Follow-up period. 
 
 


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Schedule of Assessments 
 
Screening
Radio-immunochemotherapy
Evaluation 
Day -
28 to 
0 
Day 
-7 to 0 
weekly 
 
every 
4 
weeks
after 
4-4.5 
weeks
End of 
Treatment 
Follow-Up 
(every 3 
month)8 
Written informed consent 
X 
 
 
 
 
 
 
Medical history 
X 
 
 
 
 
 
 
Clinical staging (endoscopy incl. 
biopsy) 
X 
 
 
 
X 
X 
 
Endoscopic ultrasound 
X 
 
 
 
X 
X 
X 
Tumor assessment (CT chest, CT 
abdomen)  
X 
 
 
 
X 
X 
X 
(Re)-evaluation by a surgeon with 
respect to resectability 
X 
 
 
 
X 
 
 
ECG and LVEF 
X 
 
 
 
 
 
 
FEV1 
X 
 
 
 
 
 
 
Height 
 
X 
 
 
 
 
 
Weight 
 
X 
X 
 
 
 
 
Vital signs (blood pressure, pulse) 1 
 
X 
X 
 
 
X 
 
Karnofsky-Performance Status 
 
X 
 
X 
 
X 
 
Hematology 2 
 
X 
X 
 
 
X 
 
Clinical chemistry 3 
 
X 
 
X 
 
X 
 
Pregnancy test 4 
 
X 
 
 
 
 
 
Serum Sample for EGFR and 
ligands determination5  
 
X 
 
 
X 
X 
 
Tissue Immunohistochemistry5 
X 
 
 
 
X 
 
 
DC-MRT 6 
 
 
X 
 
 
 
 
Quality of Life 7 
 
X 
 
 
X 
X 
 
Clinical signs and symptoms 
 
 
continuing 
X 
Treatment outcome 
 
 
 
 
 
 
X 
 
1: 
vital signs weekly during radio-immunochemotherapy: prior, during and after each 
cetuximab-infusion 
2: 
Hematology includes: leucocytes, neutrophils, platelets, erythrocytes, hemoglobin 
3: 
Clinical chemistry includes: sodium, potassium, calcium, magnesium, creatinine, 
bilirubine, SGOT, SGPT, LDH, alkaline phosphatase, γ-GT 
4: 
serum or urine β-HCG in patients of child-bearing potential 
5: 
Serum Sample (10ml), an additional whole blood sample (10 ml) at screening, Frozen 
tissue or paraffin-embedded tissue for immunohistochemistry from previous 
operations/biopsies or biopsies obtained at screening or after week 4-4.5 and end of 
treatment (optional, if patient agrees to participate in translational study) 
6: 
DC-MRT: at day 7 (+/-2) or day 14 (+/-2) of the first cycle (in selected centers) 
7: 
Quality of Life will be assessed using the EORTC QLQ-30 questionnaire and the 
esophagus-specific EORTC QLQ-OES18 module 
8: 
The first follow-up assessment will be performed 3 months after the end of treatment 
assessment. Follow-up assessments will terminate 2 years after the last patient has 
completed end of treatment (incl.biopsy, if patient agrees to participate in translational 
study). 
 
 
 


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Study Design Flow Chart 
 
Arm A 
 
 
 
 
 
Arm B 
 
 
 
 
day 
Radiotherapy: 
59.4 Gy (33 x 
1.8 Gy) 
8-11 
Immunotherapy: 
Cetuximab 
1      8      15       22        29       36      43      50      57      64     71    78     85      92     99      
36-39 
d1     d8      d15   d22     d29     d36     d43   d50    d57     d64   d71   d78   d85   d92      
day 
Radiotherapy: 
59.4 Gy (33 x 
1.8 Gy) 
1-4 
1      8      15       22        29       36      43      50      57      64     71    78     85      92     99      
29-32 
Chemotherapy: 
Cisplatin 20mg/m2 
5-FU 1000 mg/m2 
5-FU 750 mg/m2 
71-74 
99-102 
92-95 
Chemotherapy: 
Cisplatin 20mg/m2 
5-FU 1000 mg/m2 
5-FU 750 mg/m2 
64-67 


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2 
Introduction and study background 
2.1 
Disease background 
Esophageal cancer is a highly aggressive neoplasm, a disease of which more than 90% of 
patients positively diagnosed die of [1]. On a global basis, cancer of the esophagus is the 
sixth leading cause of cancer death worldwide. In fact, gastric and esophageal cancers 
together accounted for nearly 1.3 million new cases and 980,000 deaths worldwide in 2000 - 
more than lung, breast, or colorectal cancer [2].  
Although esophageal squamous cell carcinoma cases have steadily declined, the incidence 
of gastroesophageal junction adenocarcinoma has increased 4%-10% per year among U.S. 
men since 1976, more rapidly than for any other cancer type, and parallels rises in 
population trends in obesity and reflux disease [3, 4].  
With advances in surgical techniques and treatment, the prognosis of esophageal cancer has 
slowly improved over the past three decades. However, the 5-year overall survival rate (14%) 
remains poor, even in comparison with the dismal survival rates (4%) from the 1970s [5]. 
Underlying reasons for this disappointingly low survival rate are beyond others the difficulties 
in cancer detection at an advanced stage, with over 50% of patients with unresectable 
disease or distant metastasis at presentation and the limited survival achieved with palliative 
chemotherapy alone for patients with metastatic or unresectable disease [6]. 
Clearly, additional strategies are needed to improve our systemic treatment options. Over the 
past decade, the field of drug development has been transformed with the identification of 
and ability to direct treatment at specific molecular targets.  
 
2.2 
Current treatment options for esophageal cancer 
The optimal treatment of locally advanced esophageal cancer, a potentially curable disease, 
is controversial. Through several non-randomized cooperative group trials, concurrent 
cisplatin-based chemoradiation or surgery alone represent acceptable standards of care for 
patients with resectable tumors. 
 
Treatment decisions are often individualized with respect to the patient’s stage and 
underlying co-morbidities. For patients with bulky advanced tumors unlikely to be cured 
surgically, upfront chemoradiation is often preferred. With sufficient tumor downstaging, 
preoperative chemoradiation can be followed by salvage surgery, especially for those 
patients with residual disease [7]. Preoperative chemoradiation has yet to show a significant 
improvement in overall survival compared with surgery alone in a prospective randomized 
trial, although there is a trend of higher survival rates (40%–60%) in those with pathologic 
complete responses (pCRs) at surgery [8, 9]. 
 
Metastatic or unresectable esophageal cancer is found at presentation in more than 50% of 
patients and remains incurable. Chemotherapy is considered palliative, improving quality of 
life and dysphagia in 60%–80% of patients [10–12]. Typical clinical and radiographic 
responses last for fewer than 4 months, with a median overall survival time of 8–10 months. 
Although a survival benefit has yet to be demonstrated with chemotherapy in advanced 
esophageal cancer, clinical trials in metastatic gastric cancer have consistently shown a 
survival benefit with chemotherapy compared with best supportive care alone [13]. 
 
One current research focus has been the development of more active and tolerable 
preoperative 
cisplatin-containing 
chemoradiation 
regimens. 
Standard 
chemotherapy 
regimens with paclitaxel or irinotecan have being studied, as well as those with newer 
targeted agents.  
 
Chemotherapy can be given as a single agent or in combination, usually in a cisplatin-
containing regimen. Active agents include cisplatin, 5-FU, the taxanes, irinotecan, mitomycin 
C, etoposide and vinorelbine. Response rates for single agents range from 15%–30% [13]. 


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Combination regimens, usually containing cisplatin, tend to produce higher response rates 
(30%–57%), with occasional patients achieving complete responses (0%–11%) [10–12, 14–
17]. However, with the combination regimens, the median survival time remains less than 10 
months. Recent randomized trials have indicated that adding a third agent to the combination 
of 5-FU and cisplatin, either epirubicin or docetaxel modestly improve response rates, time to 
progression, and survival with greater therapy-related toxicity [18, 19]. 
 
2.3 
Novel targeted therapies for esophageal cancer 
An improved understanding of the molecular pathogenesis of cancer has facilitated the 
development of novel agents designed to target critical pathways involved in cancer 
development and progression. Epidermal growth factor receptor (EGFR) plays a crucial role 
in tumor growth. EGFR-dependent signaling is involved in cell proliferation, apoptosis, 
angiogenesis, and metastatic spread.  
The overexpression of EGFR has repeatedly been shown to predict poor prognosis in both 
esophageal squamous cell carcinoma and gastro esophageal junction adenocarcinoma [20–
23]. EGFR blockade through monoclonal antibodies (Cetuximab, Matuzumab and 
Panitumumab) and tyrosine kinase inhibitors (gefitinib, erlotinib) has translated into promising 
evidence of clinical benefit in clinical trials [2]. 
EGFR-targeted agents are generally well tolerated and are typically not associated with the 
severe adverse events often seen with cytotoxic chemotherapy. 
Other strategies involve ras-mediated signal transduction using inhibitors of farnesyl 
transferase to block the post-translational modification of the ras oncogene. Inhibitors of 
vascular 
growth 
factor 
(bevacizumab) 
and 
vascular 
growth 
factor 
receptors 
(PTK787/ZK222584) and matrix metalloproteinase target the effects of the host environment 
and are currently also subjects in clinical trials as an adjunct to more traditional cytotoxic 
therapies [3]. Evidence suggests that novel agents can be administered alone or in 
combination with standard therapies such as 5-FU or radiation with little additional toxicity. 
These ongoing and future research efforts will clarify the optimal use and survival benefit of 
targeted therapies for patients with esophageal cancer.  
 
2.3.1 Epidermal growth factor receptor 
The EGFR is a transmembrane glycoprotein, which is commonly expressed, in many normal 
human tissues.  It was one of several growth factors and their receptors, which were found to 
be encoded by proto-oncogenes. It is a member of the tyrosine kinase family of growth factor 
receptors, and is over-expressed in many human tumor types. The EGFR, when situated in 
the transmembrane position, has an extracellular domain, which provides a ligand-binding 
site for epidermal growth factor (EGF) and transforming growth factor alpha (TGFα). The 
intracellular domain of EGFR is activated upon ligand binding, which triggers the EGF-
mediated tyrosine kinase signal transduction pathway and cascades many cellular 
operations concerning cell growth and division. 
Analyses performed in vitro, using cell lines with a high degree of EGFR expression have 
shown a proliferation of cells in culture, probably due to activation via an autocrine pathway. 
In contrast, EGFR antagonists, which block the ligand-binding site, have been developed in 
order to inhibit proliferation of EGFR-expressing cells.  
 
Table 1 indicates the prevalence of EGFR expression in some common tumor types. 
 
 
 


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Table 1: Prevalence of EGFR expression in common tumor types  
 
Tumor Type 
Percentage of EGFR Expression 
Esophagus carcinoma 
92% 
Squamous cell carcinoma of the head and neck (SCCHN) 
90% 
Pancreatic carcinoma  
89% 
Colorectal carcinoma (CRC) 
82% 
Prostate carcinoma 
65% 
Bladder carcinoma 
65% 
Epithelial ovarian carcinoma 
60% 
Cervical carcinoma 
60% 
Renal cell carcinoma  
50% 
Non-small cell lung carcinoma (NSCLC)  
50% 
 
2.3.2 Cetuximab 
A novel targeted therapy, cetuximab (ERBITUX®) has recently been introduced in the United 
States, European Union, Switzerland, Mexico and Argentina, and is in the regulatory 
approval procedure in many other countries. Cetuximab is a targeted therapeutic agent, a 
chimeric IgG1 monoclonal antibody that specifically binds to the EGFR with high affinity, 
internalising the receptor and preventing the ligands EGF and TGF-α from interacting with 
the receptors and thus effectively blocking ligand-induced EGFR phosphorylation. In 
addition, cetuximab has been found to potentiate the effects of chemotherapy and 
radiotherapy in experimental systems. The dose of cetuximab (initial dose 400 mg/m2 and 
subsequent weekly doses of 250 mg/m2) has been found to be generally safe and effective in 
several studies in major tumor types expressing the EGFR. These included colorectal 
cancer, squamous cell carcinoma of the head and neck and non-small cell lung cancer, with 
cetuximab given either in combination studies with chemotherapy and radiotherapy or as 
monotherapy. The main side effects of cetuximab monotherapy are hypersensitivity- and 
acne-like skin reactions. 
 
2.3.2.1 Cetuximab in chemotherapy 
Over the past years, cetuximab has shown promising results in colorectal and head and neck 
cancer trials. For metastatic colon cancer patients who previously failed irinotecan, cetuximab 
plus irinotecan produced a response rate of 23%, and as a single agent, the response rate 
was 9%–11% [25, 26]. The median time to progression was significantly greater in the 
irinotecan/cetuximab group than in the cetuximab monotherapy group (4.1 months versus 1.5 
months, p < .001). However, there was no significant difference in overall survival (8.6 
months versus 6.9 months, p = .45) [25]. These results suggest that the addition of cetuximab 
helps overcome irinotecan resistance. Patients enrolled in these trials were required to have 
immunohistochemical (IHC) evidence of positive EGFR expression. Recent studies illustrate 
that EGFR-negative tumors have the potential to respond to cetuximab and that IHC 
techniques do not have a predictive value [27]. However, acneiform skin rash consistently 
correlates with response and survival [25, 28].  
 
In head and neck cancer, several phase II studies have evaluated the combination of 
cetuximab with platinum-based regimens in pretreated patients with recurrent or metastatic 
head and neck cancer, with a control rate (complete response [CR] + partial response [PR] + 
stable disease [SD]) in the range of 29%–66%. In the randomized Eastern Cooperative 
Oncology Group phase III trial, there was a significant difference in response rate between 
cisplatin plus cetuximab and cisplatin alone (22.6% versus 9.3%, p = .05). While there was a 


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trend favoring the combination arm in terms of progression-free and overall survival, this 
underpowered study did not reach statistical significance [29].  
 
Given these encouraging results from the colorectal and head and neck cancer trials, there is 
active clinical research in esophageal cancer patients with antibody inhibition of the EGFR. 
Overexpression of EGFR via IHC analysis occurs in 30%–90% of esophageal cancer cases 
and correlates with poor prognosis [20, 22, 24, 30, 31]. In a retrospective review of 38 
patients with resected gastroesophageal adenocarcinoma, Wilkinson et al. demonstrated that 
poorly differentiated adenocarcinomas of the esophagus demonstrated higher EGFR 
expression than low-grade tumors based on IHC analysis (57% versus 13%, p = .02). The 
median overall survival times were 35 months for EGFR-negative patients and 16 months for 
EGFR-positive patients [30]. Kitagawa and colleagues showed that the cumulative survival 
rate for patients with EGFR gene amplification in their primary tumors was significantly lower 
than that for patients without amplification (p < .001). A significant correlation was also 
observed between extensive lymph node involvement at the time of surgery and EGFR gene 
amplification (p < .05) [23]. 
In two phase I studies, EGFR-directed antibodies have shown activity in patients with 
esophageal cancer. In the phase I study of the humanized EGFR mAb EMD72000, one 
patient with metastatic, pretreated squamous cell carcinoma had a durable, 6-month PR [32]. 
In addition, a phase I trial with ABX-EGF, a fully human IgG2 EGFR mAb, reported stable 
disease for 7 months in one esophageal cancer patient [33]. Preclinical and these early 
clinical studies suggest potential activity and minimal toxicities with EGFR antibodies for 
esophageal cancer. 
 
Lorenzen et al. [34] reported a randomized phase II of cisplatin + 5-FU (CF) compared to 
cisplatin + 5-FU + cetuximab (CET-CF)(n=62). Cetuximab did not increase grade 3/4 toxicity, 
except for rash (6% versus 0%) and diarrhea (16% versus 0%). The overall response rates 
were 19% and 13% for the CET–CF and CF arms respectively, and the disease control rates 
were 75% and 57%, respectively. The median progression free survival was 5.9 and 3.6 
months and median overall survival 9.5 and 5.5 months for CET–CF and CF, respectively.  
 
2.3.2.2 Cetuximab in combination with radiotherapy 
Preclinical studies have shown, that Cetuximab enhances the radiosensitivity of EGFR-
expressing tumor cells in vitro and in tumor xenografts [35, 36] and the repopulation of 
epithelial tumor cells after exposure to radiation is related to the activation and expression of 
EGFR [37, 38]. Cetuximab also enhanced the efficacy of docetaxel chemoradiotherapy in 
human adenocarcinoma xenografts [39].  
 
So far, cetuximab in combination with radiotherapy has mainly been investigated in head and 
neck cancer. 
 
Radiation or radiochemotherapy are the standard treatment options for locally advanced, 
unresectable head and neck cancer. However, with conventional radiotherapy, the relapse-
free survival is still disappointing and the majority of patients die from locoregional 
recurrence. Several attempts have therefore been made to improve the outcome of these 
patients. In a dose-finding phase I study performed by Robert et al [40], 16 patients with 
advanced head and neck cancer were treated with conventional or hyperfractionated 
radiotherapy together with cetuximab. The monoclonal antibody was delivered at a loading 
dose of 100 to 500 mg/m2, followed by weekly infusions of 100 to 250 mg/m2 for 7 to 8 
weeks. 15 patients were evaluable for response and all achieved an objective response (13 
complete and 2 partial remissions). The median time to progression was 8 months and the 2-
year survival rate was 65%. The treatment was well tolerated with asthenia, fever, nausea 
and skin toxicities being the most common adverse experiences. The recommended dose for 
cetuximab was defined with a loading dose of 400 to 500 mg/m2 and a maintenance dose of 
250 mg/m2. Cetuximab was further evaluated in a randomized phase III study which 


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assessed radiation alone for 6 to 7 weeks compared with radiation plus weekly cetuximab in 
424 patients with locoregionally advanced head and neck cancer [41]. The addition of 
cetuximab to radiotherapy resulted in statistically significant prolongation of overall survival 
(54 months versus 28 months, p=0.02). Again, the immunoradiotherapy was well tolerated 
with most of the side effects related to the high dose radiation. Grade 3 to 4 infusion 
reactions were observed in 3% of the patients treated with cetuximab.  
Su et al. [42] observed in a phase II study very promising overall survival data of a 
combination of Cetuximab with Cisplatin (100 mg/m2 d1 and 22) concurrent to radiotherapy 
with concurrent boost. 76% of the patients were alive after three years with a locoregional 
control rate of 71% and progression free survival after 3 years of 56%. However, frequent 
typical radiochemotherapy-associated toxicities were observed with 2 deaths on therapy 
(pneumonia and unknown cause) and 3 severe adverse events (myocardial infarction, 
bacteremia, arrhythmia). These events led to early study closure after 22 of 25 planned 
patients. 
Based on this study the RTOG started a phase III trial evaluating the addition of cetuximab to 
Cisplatin concurrent to radiotherapy (RTOG 0522). Recruitment of over 900 patients were 
closed as planned without reporting of safety issues. 
 
Several phase I and II studies evaluating cetuximab in combination with chemoradiotherapy 
for patients with esophageal carcinoma have reported first data on congresses. Safran et al. 
[43] observed esophagitis rates (12% grade 3 and 3 % grade 4) in 60 patients treated with 
cetuximab and paclitaxel, carboplatin, and 50.4 Gy radiation comparable to treatment 
schedules without cetuximab. 70% of the patients had a complete clinical response after 
chemoradiation. 28 patients were treated preoperatively with 3 cycles cisplatin, docetaxel, 
and cetuximab followed by 45 Gy radiation combined with weekly cisplatin (25 mg/m2) and 
cetuximab in a Phase IB/II trial [44]. After 7 patients without limiting toxicities, weekly 
docetaxel (20 mg/m2) was added to the chemoimmunoradiation. There were no deaths 30 
days post surgery and no treatment-related death after a follow-up of 1 year. Complete or 
near pathologic regression was found in 68% of the patients. R0 resection was performed in 
25 patients and 1-year overall survival was 86%. 
 
2.3.2.3 Cetuximab general safety information 
Adverse event data are available for 3339 patients treated with cetuximab alone or in 
combination with chemotherapy and/or radiation therapy from investigational trials across all 
indications conducted by ImClone, BMS, Merck KGaA, Investigator sponsored Trials (IST), 
Cooperative Groups and the National Cancer Institute (NCI). As most of the trials were 
conducted under different settings and in combination with various cytostatic therapies, 
adverse reaction rates cannot be validly pooled and quoted as mean rates. Nethertheless, 
they constitute a basis for identifying approximate adverse event rates associated with the 
administration of Cetuximab. 
Skin reactions may develop in more than 80% of patients and mainly present as acne-like 
rash and/or, less frequently, as pruritus, dry skin, desquamation, hypertrichosis, or nail 
disorders (e.g. paronychia). The majority of skin reactions develop within the first three 
weeks of therapy. They generally resolve, without sequelae, over time following cessation of 
treatment if the recommended adjustments in dose regimen are followed [45]. Approximately 
15% of the skin reactions are severe, including single cases of skin necrosis. In the event of 
Grade 3 or 4 skin reactions the patients should be referred for dermatological advice.  
The incidence of radiation dermatitis of any grade was comparable between the treatment 
groups in a phase 3 SCCHN trial in patients receiving either cetuximab in combination with 
RT (86%) or RT alone (90%) [46].  
Other side effects observed in patients receiving cetuximab monotherapy include asthenia, 
dyspnoea, mucositis, nausea, pain, fever and headache.  
Mild or moderate infusion-related reactions may occur (≥ 1/10) comprising symptoms such 
as fever, chills, nausea, vomiting, headache, dizziness, or dyspnoea that occur in a close 
temporal relationship mainly to the first cetuximab infusion [45]. They can be managed by 


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slowing the infusion rate of cetuximab and by the continued use of pre- medications for 
subsequent doses in addition to the mandatory use for the first infusion.  
Severe infusion-related reactions may occur (≥ 1/100, < 1/10), in rare cases with fatal 
outcome. They usually develop during or within 1 hour of the initial cetuximab infusion and 
may include symptoms such as rapid onset of airway obstruction (bronchospasm, stridor, 
hoarseness, difficulty in speaking), urticaria, hypotension, or loss of consciousness; in rare 
cases, angina pectoris, myocardial infarction or cardiac arrest have been observed. Severe 
infusion reactions (grade 3 or 4) require immediate interruption of the cetuximab infusion and 
permanent discontinuation from further treatment [45].  
A large multinational study of cetuximab plus irinotecan in irinotecan-resistant metastatic 
colorectal cancer (MABEL) investigated in a post-hoc analysis whether the type of 
prophylactic pre-medication had an impact on the incidence of infusion-related reactions 
including allergic/hypersensitivity reactions. The incidence of infusion-related reactions was 
lower in patients who received anti-histamines and corticosteroids as prophylactic medication 
(9.6%, n=700) compared to patients who received anti-histamines but not corticosteroids 
(25.6%, n=422). A similar trend was seen in the analysis of the grade 3/4 infusion-related 
reactions (1% vs. 4.7%). These data suggest that the addition of corticosteroids to 
antihistamines as prophylactic pre-medication seems to reduce the incidence of infusion-
related reactions such as allergic/-hypersensitivity reactions [47]. 
Progressively decreasing serum magnesium levels have been observed leading to severe 
hypomagnesaemia 
in 
some 
patients. 
Hypomagnesaemia 
is 
reversible 
following 
discontinuation of cetuximab. Depending on severity, other electrolyte disturbances, mainly 
hypocalcaemia or hypokalaemia, have also been observed. Determination of serum 
electrolyte levels is recommended prior to and periodically during cetuximab treatment. 
Electrolyte repletion is recommended, as appropriate. 
 
For supplementary information see also the EU Summary of Product Characteristics (4.4 
Special warnings and precautions for use and 4.8 Undesirable effects). 
 
2.3.2.4 Clinically relevant adverse events related to cetuximab 
Skin reactions are the most common AEs associated with cetuximab. They usually present 
as an acneform rash, acne-like rash or, less frequently, as nail disorders. Acneform 
rash/Acne-like rash usually occurs in the first 3 weeks of treatment on the face, upper chest 
and back, but occasionally extends to the extremities. It occurs as multiple follicular or 
pustular lesions characterized histologically as lymphocytic perifolliculitis or suppurative 
superficial folliculitis. It tends to resolve without sequelae over time following cessation of 
therapy. In patients who have received cetuximab in doses lower than 100 mg/m2, the acne-
like rash has been reported infrequently and has been restricted to grades 1 and 2. The 
etiology of the acne-like rash is believed to be the result of cetuximab interfering with the role 
of EGFR in the homeostasis of epidermis, hair follicle and sebaceous glands as well as in the 
regulation of cutaneous inflammation. Clinical trials in patients with CRC have shown that the 
occurrence of acne-like skin reactions were correlated with better efficacy outcomes 
(response, and time to progressive disease and survival). 
Nail disorders: Another typical but less frequent reported AE is nail disorder which presents 
as pain, tenderness and fissuring of the distal finger tufts to different degrees. The patients 
developed paronychial inflammation with associated swelling of the lateral nail folds of the 
toes and fingers. The most commonly affected digits are the great toes and thumbs. From 
investigator reports, it is known that nail disorders may persist for up to 3 months after 
discontinuation of cetuximab. Dermatological advice should be sought. 
Allergic/hypersensitivity reactions: Grade 3 or 4 hypersensitivity reactions (including 
allergic and anaphylactic reactions) characterized by the rapid onset of airway obstruction 
(bronchospasm, stridor, hoarseness), urticaria, and/or hypotension, have been observed in 
2.5% patients treated with cetuximab. Approximately 80% of all allergic/hypersensitivity 


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reactions occurred during the first infusion of cetuximab and were observed during or within 1 
hour of the completion of the infusion. 
Prior to the first administration of cetuximab, patients must be premedicated with an 
antihistamine as well as with a glucocorticoid. This premedication is also recommended prior 
to all subsequent infusions of cetuximab as there were patients who experienced their first 
severe allergic/hypersensitivity reaction during later infusions. In studies with cetuximab to 
date, patients who experienced severe reactions received standard treatment, and all with 
the exception of three patients recovered without sequelae and were withdrawn from the 
studies concerned. Three reports exist which are associated with death. 
The occurrence of allergic/hypersensitivity reactions does not appear to be related to single-
drug therapy or combination therapy, underlying disease, or previous exposure to murine 
monoclonal antibodies. Mild to moderate allergic/hypersensitivity reactions can generally be 
managed by slowing the infusion rate of cetuximab 
 
2.4 
Rationale for the study 
Esophageal cancer is a highly aggressive tumor and one of the most frequent malignant 
diseases worldwide.  
Treatment options are various and range from chemotherapy to radiotherapy and several 
surgical techniques. Nevertheless, the overall survival rates for this disease remain poor.  
 
During the last years the combination of cetuximab with standard chemotherapy or 
radiotherapy has mainly be investigated in clinical trials focusing on colorectal and/or head 
and neck cancer. 
The results obtained from theses studies were very encouraging and led to the initiation of 
active clinical research in esophageal cancer patients with antibody inhibition of the EGFR. 
The first data in this indication are encouraging showing that cetuximab can safely be added 
to chemoradiation for esophageal cancer patients with first hints of efficacy. 
 
Based on the experiences with cetuximab in colorectal cancer and in combination with 
radiotherapy in head and neck cancer, the aim of the present study is to evaluate the 
feasibility of a combined treatment of cetuximab with continuous infusional 5-FU, cisplatin 
and radiotherapy in patients with esophageal cancer and to assess if the overall survival 
rates can be increased by addition of an EGFR-targeted therapy. 
 
2.5 
Risk-benefit assessment 
The clinical data available to date suggest that cetuximab in combination with a standard 
radiochemotherapy should be well tolerated and aggravations of 5-FU-related or radiation-
related toxicities are not expected. However, in one study in head and neck cancer with high-
dose radiation and cisplatin combined with cetuximab severe toxicities were observed [29]. 
Nonetheless, a phase III study of the Radiation Therapy Oncology Group (RTOG 0522) 
comparing the same dosing-schedule of cetuximab with cisplatin and concomitant high-dose 
radiation vs. the standard combination without cetuximab has recently closed recruitment 
without reporting of safety issues. As determined in our Phase I study (LEOPARD Phase I) a 
dose of 1000 mg/m2 of continuous infusional 5-FU is safe in combination with cisplatin, 
radiotherapy, and cetuximab. 
 
In head and neck cancer, the combination of cetuximab with radiotherapy alone was safe 
and resulted in only minimal enhancement in the overall toxicity profile associated with 
radiation therapy, especially regarding skin reactions.  
 


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Given the possible benefits of the treatment regarding increased response rate and survival, 
the conduct of the study is regarded as justifiable and there is no indication that patients are 
exposed to an increased risk associated with study participation. 
 
If therapy-related toxicities occur during the study, dose modifications of cetuximab and 5-FU 
will be performed as outlined in section 5.4 of this protocol.  
 
2.6 
Contributing Scientific Investigations 
2.6.1 Determination of TKR-Receptors and their Soluble Ligands 
For esophageal cancer, major steps of carcinogenesis are still unknown. However, as tumor 
cellular blockade of different angiogenic and anti-apoptotic pathways are well known to 
promote carcinogenesis, expression and regulation of the EGF and other kinase dependent 
receptor pathways and their soluble ligands are of major interest in translational research. 
Thus, the targeted blockade of their pathways may be very effective to induce tumor 
regressions and a better clinical outcome than traditional chemotherapeutic regimens. 
Thus, it is the aim of the translational study, to prospectively analyse the expression of EGF 
and other kinase dependent receptor pathways and their soluble ligands during Cetuximab 
therapy in these cancer patients. Their expression profiles will be correlated with clinical 
outcome, responses and survival times. 
For this purpose, the serum samples, paraffin-embedded tissues, and when available fresh 
frozen 
specimens, 
of 
included 
patients 
will 
be 
characterized 
via 
ELISA, 
immunohistochemistry and PCR, respectively (if patient agrees to participate in translational 
study). 
In addition, a prospective follow-up of serum levels of targeted ligands (ELISA) is planned 
before and during Cetuximab therapy to correlate the kinase dependent receptor pathways 
with initial tumor staging and response (according to Hector program, Weinheim).  
 
2.6.2 Functional Magnetic Resonance Tomography (DC-MRT)  
The functional magnetic resonance tomography (DC-MRT) can quantify blood flow, arterial 
permeability and the percentage of extracellular volume in tumor tissue. Clinically, the DC-
MRT is of special interest to analyze the efficacy of new biological substances, which block 
angiogenesis or lymphangiogenesis. 
One important precondition for these techniques is the development of special MRT- 
sequences and a program, with which the data can be processed and tissue specific 
parameters can be quantified. These have been established at the Department of Radiology 
or Dept. of Nuclear Medicine in conjunction with the Department of Physics of the Max 
Planck Institute in Mainz, Germany. Currently Mainz University works with the program 
Medlab. Pharmacokinetics can also be automatically documented. At present, the 
Department of Radiology of Mainz University runs three phase I to II multicenter studies with 
these techniques, looking at new biological substances, such as LBH589 in hematological 
disorders or PTK787 in lung cancer. Responsible for the project in the protocol will be K. 
Oberholzer, MD, Radiology Department. Therefore, the DC-MRT will be performed in an 
explorative manner before and during Cetuximab-therapy to analyze the influence of therapy 
to the tumor microcirculation with its blood flow and arterial permeability 
 


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3 
Study objectives 
3.1 
Primary objective 
Assessment of the 2-year overall survival (OS) 
 
3.2 
Secondary objectives 
The secondary objectives of this study are to assess the following parameters: 
 
• 
1-year OS 
• 
1-year and 2-year progression-free survival (PFS) 
• 
1-year and 2-year loco-regional control (LC) 
• 
1-year and 2-year metastases-free survival (MFS) 
• 
Toxicity (NCI-CTC 4.0) 
• 
Overall response rate (RECIST Version 1.1) 
 
In addition the following parameters will be assessed irrespective of a specific time point:  
• 
OS 
• 
PFS 
• 
MFS 
4 
Study design 
4.1 
Overall study design and plan 
This is an open-label, randomized Phase II-study to evaluate immuno-radiochemotherapy in 
patients with unresectable esophageal cancer.  
 
Up to approximately 15 German centers will participate in the trial (up to 134 patients). 
However, the randomization to one of the two treatment groups will be stopped at December 
31, 2016, at the latest, which is 2.5 years later than originally planned.  
 
Eligible patients will have a diagnosis of histologically confirmed locally advanced initially 
unresectable esophageal cancer. 
Resectability has to be defined and documented by a surgeon prior to randomisation: 
The tumor is considered unresectable due to: 
• 
T-stage 
• 
N-stage 
• 
Performance status/Nutritional status 
• 
Comorbidity: 
 
Pulmonary function 
 
Other 
• 
Tumor location  
Upper third of the esophagus 
Relation to other organs/structures 
• 
Other reasons (please define in CRF) 
 
 
Patients will be randomized into two treatment arms (Arm A and B) and according to this 
treated plus or minus cetuximab. 
 
Patients in Arm A will receive cetuximab with concurrent radiochemotherapy as follows: 


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• 
Cetuximab initial dose of 400 mg/m2 (day 1), followed by weekly doses of 250 mg/m2 
for a total of 14 weeks. 
• 
5-FU:  1000 mg/m2/day* administered as continuous infusion over 4 days at the 
beginning 
of 
course 
1 
and 
2, 
i.e. 
on 
days 
8-11 
and 
36-39. 
750 mg/m2/day administered as continuous infusion over 4 days at the beginning of 
course 3 and 4, i.e. on days 71-74 and 99-102. The time period between course 2 
and 3 is prolonged to 5 weeks. 
• 
Cisplatin (20 mg/m2/day) administered as intravenous bolus over 60 minutes on days 
1-4 at the beginning of each course, i.e. on days 8-11, 36-39, 71-74 and 99-102. 
• 
Radiotherapy: 59.4 Gy (33 fractions of 1.8 Gy) will be administered over 6.5 - 7 
weeks (5 x 1.8 Gy per week) to the primary tumor and the involved lymph nodes. 50,4 
Gy will be administered to the loco-regional lymph nodes (mediastinum). If 
resectability has been achieved after 4-4.5 weeks (36-41.4 Gy), radiotherapy will be 
stopped at 45 Gy and patient will undergo surgery. 
 
*Safe dose level identified in the earlier phase I-study (LEOPARD Phase I) 
 
 
Patients in Arm B will be treated with radiochemotherapy as follows without receiving 
cetuximab: 
: 
• 
5-FU:  1000 mg/m2/day* administered as continuous infusion over 4 days at the 
beginning 
of 
course 
1 
and 
2, 
i.e. 
on 
days 
1-4 
and 
29-32. 
750 mg/m2/day administered as continuous infusion over 4 days at the beginning of 
course 3 and 4, i.e. on days 64-67 and 92-95. The time period between course 2 and 
3 is prolonged to 5 weeks. 
• 
Cisplatin (20 mg/m2/day) administered as intravenous bolus over 60 minutes on days 
1-4 at the beginning of each course, i.e. on days 1-4, 29-32, 64-67 and 92-95. 
• 
Radiotherapy: 59.4 Gy (33 fractions of 1.8 Gy) will be administered over 6.5 - 7 
weeks (5 x 1.8 Gy per week) to the primary tumor and the involved lymph nodes. 50,4 
Gy will be administered to the loco-regional lymph nodes (mediastinum). If 
resectability has been achieved after 4-4.5 weeks (36-41.4 Gy), radiotherapy will be 
stopped at 45 Gy and patient will undergo surgery. 
 
At the end of study treatment or at the time of premature withdrawal for any reason the 
patient will undergo an end of treatment evaluation.  
 
The assessments to be performed in this study are summarized in the study schedule. 
 
4.2 
Selection of the study population 
4.2.1 Study population and justification of choice of gender 
Patients with locally advanced unresectable esophageal cancer are eligible for this study if all 
of the following criteria are fulfilled and the patients have provided written informed consent. 
There is no preferred enrolment of men or women within this study. However, pregnant or 
breast-feeding women are excluded from participation. 


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4.2.2 Inclusion criteria 
For inclusion in the study, all of the following criteria must be met: 
 
• 
Signed written informed consent 
• 
Male or female between 18 and 75 years; patients > 75 years if KPS ≥ 80  
• 
Histologically proven squamous cell carcinoma or adenocarcinoma of the esophagus, 
which is not curatively resectable* 
*resectability has to be defined and by a surgeon prior to randomisation: 
The tumor is considered unresectable due to: 
T-stage, N-stage, performance status/nutritional status, co-morbidity (pulmonary function, 
other), tumor location upper third of the esophagus, relation to other organs/structures), other 
reasons (please define in CRF). 
 
• 
KPS ≥ 70  
• 
Women of child-bearing potential must have a negative pregnancy test 
• 
Adequate cardiac, pulmonary, and ear function 
• 
Adequate bone marrow function: leucocytes > 3.0 x 109/L, neutrophils > 1.5 x 109/L, 
platelets > 100 x 109/L, hemoglobin > 10.0 g/dL 
• 
Adequate liver function: Bilirubin < 2.0 mg/dL, SGOT, SGPT, AP, γ-GT < 3 x ULN 
• 
Adequate renal function: serum creatinine < 1.5 mg/dL, creatinine clearance > 50 
ml/min (calculated value according to Cockroft-Gault equation) 
• 
No known allergy against chimeric antibodies. 
• 
Effective contraception for both male and female patients if the risk of conception 
exists 
 
4.2.3 Exclusion criteria 
Patients are not eligible for this study, if they meet one or more of the following exclusion 
criteria: 
 
• 
Distant metastasis (M1b) 
• 
Previous treatment of esophageal cancer 
• 
Previous exposure to monoclonal antibodies and / or EGFR-targeted therapy 
• 
Other previous malignancy with exception of a history of a previous curatively treated 
basal cell carcinoma of the skin or pre-invasive carcinoma of the cervix 
• 
Serious concomitant disease or medical condition 
• 
FEV1 < 1,1 
• 
Clinically relevant coronary artery disease or a history of myocardial infarction within 
the last 12 months or left ventricular ejection fraction (LVEF) below the institutional 
range of normal 
• 
Any active dermatological condition > Grade 1 
• 
Contraindications to receive cisplatin, 5-FU or cetuximab 
• 
Concurrent treatment with other experimental drugs or participation in another clinical 
trial with any investigational drug within 30 days prior to study screening 
• 
Pregnancy or lactation 


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• 
Known active drug abuse/alcohol abuse 
• 
Social situations limiting the compliance with the study requirements 
 
4.2.4 Removal of patients from the study or study treatment 
Patients are free to discontinue the study at any time without giving their reason(s). 
 
The patient must be withdrawn from study treatment in the event of any of the following: 
 
• 
Withdrawal of the patient’s consent 
• 
Occurrence of an exclusion criterion which is clinically relevant and affects the 
patient’s safety 
• 
Occurrence of AEs, if discontinuation is desired or considered necessary by the 
patient and/or investigator 
• 
Occurrence of pregnancy during treatment 
• 
Lack of subject compliance 
• 
A delay of treatment with cetuximab for more than 2 consecutive weeks 
• 
Occurrence of any grade 4 toxicities related to cetuximab 
• 
Occurrence of > grade 3 allergic/hypersensitivity reaction related to cetuximab 
• 
Occurrence of disease progression 
 
If there is a medical reason for withdrawal, the patient will remain under the supervision of 
the investigator until the AEs have been resolved or declined to baseline values. 
 
If a patient has failed to attend scheduled assessments in the study, the investigator must 
determine the reasons and circumstances as completely and accurately as possible.  
 
In case of premature discontinuation of the study treatment by a patient, the investigations 
scheduled for the last visit should be performed, if possible. In any case, the CRF section 
entitled “End of Treatment” must be completed.  
 
4.2.5 Study discontinuation 
The whole study may be discontinued at the discretion of the coordinating investigator (LKP) 
in the event of any of the following: 
 
• 
Medical or ethical reasons affecting the continued performance of the study 
• 
Difficulties in the recruitment of patients 
• 
Occurrence of AEs unknown to date in respect of their nature, severity, and duration 
or the unexpected incidence of known AEs. 
 
Safety data from the study will be reviewed by the DSMB on a regular and ongoing basis to 
ensure that the continuation of the study is appropriate as described in Section 10. 
 
4.2.6 Definition of the end of treatment 
Treatment of the individual patient continues until the end of treatment evaluation (i.e. 14 
weeks) or until one of the criteria listed under 4.2.4 is fulfilled. 


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4.2.7 Plan for treatment after the end of study 
Following the end of treatment evaluation or end of treatment for any other cause, patients 
will be treated and followed according to the guidelines of the German Cancer Society.  
 
4.2.8 Definition of the end of study 
The study terminates after the last patient has completed the 2-year Follow-up phase. 
 
5 
Treatments 
5.1 
Treatments administered 
5.1.1 Cetuximab 
5.1.1.1 Recommended materials, compatibility, storage requirements and stability 
Infusion sets or syringes made of polyethylene, polyurethane, polyolefine thermoplastic, 
polyamide glass microfibre, polypropylene and polyvinyl chloride have been tested for 
compatibility with cetuximab, and are recommended for use. 
 
Cetuximab must be stored under refrigeration at +2ºC to +8ºC. It may not be exposed to 
direct sunlight or heat. DO NOT FREEZE CETUXIMAB. 
 
Cetuximab is stable, and is compatible with infusion systems made from any combination of 
the recommended infusion system components when administered at room temperature (up 
to 25°C). Preparations of cetuximab in the recommended infusion containers are chemically 
and physically stable for up to 48 hours at controlled room temperatures up to 25 °C. The 
product contains no antimicrobial agent and should be used immediately. If not used 
immediately, in-use storage times and conditions prior to use are the responsibility of the 
user. In-use storage at 2-8 °C should not exceed 24 hours, unless preparation has taken 
place under controlled and validated aseptic conditions. Discard any unused portion of the 
vial. 
 
5.1.1.2 Instructions for use and handling 
Do not mix cetuximab solution with any intravenously administered medicinal product 
other than a sterile 0.9 % NaCl solution. Use a separate infusion line for cetuximab 
infusion. For dose reduction due to adverse events, see the section 5.4.1. If the patient is to 
receive chemotherapy on the same day, wait at least one hour after completing the 
cetuximab infusion. 
 
Preparation and Administration of the Infusion 
 
Cetuximab solution contains no antimicrobial preservative or bacteriostatic agent. This 
means care must be taken to ensure aseptic handling when preparing the infusion.  
There are two options: 
Syringe Pump: 
• 
Calculate the required amount of cetuximab per patient and administration (e.g., 
250 mg/m² for a 2 m² patient = 500 mg cetuximab). Calculate the required amount in 


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volume cetuximab solution at 5 mg/mL (e.g., 500 mg cetuximab = 100 mL cetuximab 
5 mg/mL) 
• 
Draw up the volume calculated above from one or several cetuximab 5 mg/mL vials, 
using one or several appropriate sterile syringes attached to a suitable needle. 
• 
Remove the needle, affix the infusion line to the first filled syringe, and prime it with 
cetuximab. 
• 
Put the first filled syringe into the syringe pump and set the rate. Repeat for remaining 
syringes. 
• 
Monitor the infusion rate. The calculated infusion rate must not exceed the maximum 
infusion rate of 10 mg/min, i.e. 120 mL/h of the ready-to-use solution.  
• 
Use a sterile 0.9% NaCl solution to flush the line at the end of infusion. 
Infusion Pump or Gravity Drip: 
• 
Calculate the required amount of cetuximab per patient and administration (e.g., 250 
mg/m² for a 2 m² patient = 500 mg cetuximab). Calculate the required amount in volume 
cetuximab solution at 5 mg/mL (e.g., 500 mg cetuximab = 100 mL cetuximab 5 mg/mL) 
• 
Take an infusion bag of adequate size (e.g., 250 mL) of 0.9% NaCl solution for infusion 
(isotonic saline for infusion). 
• 
Draw up the volume calculated above from the NaCl bag, using an appropriate sterile 
syringe attached to a suitable needle. Discard the drawn up NaCl solution. 
• 
Draw up the volume calculated above from one or several cetuximab 5 mg/mL vials, 
using one or several appropriate sterile syringes attached to a suitable needle. 
• 
Fill the calculated volume of cetuximab into the NaCl infusion bag. 
• 
Affix the infusion line and prime it with cetuximab before starting the infusion. 
• 
Monitor the infusion rate. The calculated infusion rate must not exceed the maximum 
infusion rate of 10 mg/min.  
• 
Use a sterile 0.9% NaCl solution to flush the line at the end of infusion. 
A one-hour observation period is recommended after the cetuximab infusion. 
For the initial dose, the recommended infusion period is 120 minutes. For subsequent weekly 
doses, the recommended infusion period is 60 minutes. 
The maximum infusion rate must not exceed 10 mg/min (i.e., 2 mL/min of the 5 mg/mL 
solution, or, after dilution of 1 part cetuximab 5 mg/mL in 4 parts 0.9%-NaCl solution (1:5 
dilution) 10 mL/min = 600 mL/h). 
Cetuximab must be administered under the supervision of a physician 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, patients must receive premedication with an antihistamine and 
glucocorticoid. This premedication is recommended prior to all subsequent infusions. Check 
the vital signs pre-, mid-, post- and one hour post-infusion. 
Cetuximab is administered once a week for a total of 14 weeks. The initial dose is 400 mg 
cetuximab per m² body surface area. The subsequent weekly doses are 250 mg/m² each.  
Cetuximab should always be administered prior to cisplatin and 5-FU. There must be at least 
one hour between the end of the cetuximab infusion and the beginning of the chemotherapy 
infusions.  


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5.1.2 5-Fluoruracil (5-FU) 
The mechanism of action of 5-FU is based on its use as a “false” nucleotide in DNA 
synthesis. Like uracil, 5-FU is converted into its deoxymonophosphate within the cell. F-
deoxy-UMP competitively inhibits the enzyme thymidilate synthetase and therefore stops 
DNA synthesis. Therefore, 5-FU shows maximal cytotoxic activity in the S-phase of the cell 
cycle. 
 
5-FU is one of the oldest and most commonly used cytotoxic agents in the treatment of 
cancer. Main adverse reactions observed are myelosuppression, nausea and vomiting, 
mucositis and diarrhea. Following continuous infusion, hand-foot syndrome is commonly 
observed.  
 
Commercially available 5-FU will be used. Investigators should refer to the respective 
Summary of Product Characteristics (SmPC) for complete prescription information such as 
dosage and administration, safety issues (warning, precautions), adverse reactions, dose 
modifications and omissions and storage information. Investigators should also follow 
institutional procedures for the administration of 5-FU. 
 
Cetuximab should always be administered prior to 5-FU. There must be at least one hour 
between the end of the cetuximab infusion and the beginning of the 5-FU infusion.  
 
5-FU will be administered as a continuous intravenous infusion on days 1-4 at the beginning 
of each course.  
 
5.1.3 Cisplatin 
The cytotoxicity of cisplatin might be due to its ability to crosslink different DNA stands. Thus  
DNA replication is inhibited. Nevertheless, the mechanism of how platinum-caused DNA 
defects can lead to cell death is not yet known in detail. 
Cisplatin is one of the most effectiv and most frequently applied substances in the treatment 
of metastasized and advanced gastric cancers. It is the basis of different combination 
regimes like ECF (epirubicin, cisplatin, 5-FU), FUP (5-FU, cisplatin), MCF (mitomycin, 
cisplatin, 5-FU), EAP (Etoposid, Doxorubicin, Cisplatin) FLEP (5-FU, folinic acid, etoposid, 
cisplatin) or FLP (5-FU, folinic acid, cisplatin).  
 
In this trial commercially available cisplatin will be used. Investigators should refer to the 
respective Summary of Product Characteristics (SmPC) for complete prescription information 
such as dosage and administration, safety issues (warning, precautions), adverse reactions, 
dose modifications and omissions and storage information. Investigators should also follow 
institutional procedures for the administration of cisplatin. 
 
Cisplatin will be administered after saline hydration as intravenous bolus infusion on days 1-4 
at the beginning of each course. The saline hyperhydration will be given according to the 
investigational centre’s routine. 
 
All subjects must receive adequate anti-emetic therapy prior to the administration of cisplatin. 
It is recommended that a 5HT3 antagonist (e.g. Granisetron) and dexamethasone 8mg i.v. 
are administered prior to each cycle of treatment.  
 


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5.2 
Methods of assigning patients to treatment 
5.2.1 Randomization 
Randomization (assigning patients to treatment arms A and B) will be performed centrally by 
the 
GSO Gesellschaft für Studienmanagement   
und Onkologie mbH 
Harvestehuder Weg 21 
20148 Hamburg 
Tel.:        040 44 19 54 - 60 
Fax:        040 44 19 54 - 78 
 
The notification will be carried out via Fax with a standardized randomization-form. 
 
To achieve uniform distribution within both treatment arms the patients will be stratified with 
respect to the Karnofsky performance status (100%-80% vs. 70%), the tumor stage (T1-3 
N0-1 vs. T4 and/or N2 and/or M1a) and the type of carcinoma (adenocarcinoma vs. 
squamous cell carcinoma).  
 
All patients will be assigned a unique 6-digit identification number during randomization.. The 
first 2 digits of this number indicate the center number. The last 4 digits are consecutively 
assigned to the patients at each center. For example, patient number 01-0001 corresponds 
to the first patient enrolled at center number 01 and patient number 02-0001 corresponds to 
the first patient enrolled at center number 02.  
 
5.2.2 Blinding 
Not applicable 
 
5.2.3 Procedure for emergency code-breaks 
Not applicable 
 
5.3 
Special precautions 
5.3.1 Cetuximab administration 
Allergic/Hypersensitivity reactions 
Allergic/Hypersensitivity reactions may occur during or following the administration of 
cetuximab. Subjects must therefore be pretreated with an appropriate antihistamine and a 
glucocorticoid before the first infusion. Pretreatment with an antihistamine and a 
glucocorticoid is recommended before subsequent infusions. As a routine precaution, 
subjects enrolled into this study should be observed closely for any potential AEs and a 
physician able to give emergency medical treatment must be present from the start of 
cetuximab infusion until at least 1 hour after the end of the infusion. The subject should be 
observed in an area with resuscitation equipment and other agents available (epinephrine, 
prednisolone equivalents etc). Should an allergic/hypersensitivity or infusion reaction to 
cetuximab occur, then the subject must be treated according to the best available medical 
practices. For adjustment of cetuximab treatment, see section 5.4.1. Grade 3 or 4 
allergic/hypersensitivity reactions require immediate interruption of the cetuximab infusion, 
appropriate medical measures and permanent discontinuation of treatment. Subjects should 
be carefully monitored until the complete resolution of all signs and symptoms.  


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Skin reactions 
The most common AE associated with cetuximab administration are skin reactions, 
particularly acne-like rash. If a subject experiences a grade 3 skin reaction, cetuximab 
therapy must be interrupted for up to 2 consecutive weeks. Treatment may only be resumed, 
if the reaction has resolved to grade 2. For recommended adjustments in dose regimen, see 
section 5.4.1. If grade 3 skin reactions occur a fourth time or do not resolve to grade ≤ 2 
during treatment interruption, permanent discontinuation of cetuximab treatment is required. 
Interstitial pneumonitis 
Severe interstitial pneumonitis has been described in subjects treated with the EGFR-
pathway targeting therapy gefitinib. To date, no increased risk of interstitial pneumonitis has 
been identified with cetuximab. Nevertheless, all subjects must have adequate chest imaging 
prior to commencing cetuximab therapy in the study, as a safety precaution in order to 
document the baseline pulmonary condition. If there are respiratory symptoms at study entry, 
lung function tests and further diagnostic procedures must also be undertaken in order to 
diagnose pre-existing pulmonary fibrosis or interstitial pneumonitis. Furthermore, subjects will 
be regularly questioned about pulmonary symptoms during the study. Should pulmonary 
symptoms appear or worsen during or after cetuximab treatment, a detailed description is 
required and investigators should use their discretion in ordering such diagnostic procedures 
as are necessary to elicit an accurate diagnosis. 
Electrolyte disturbances 
Progressively decreasing serum magnesium levels occur frequently and may lead to severe 
hypomagnesaemia. Hypomagnesaemia is reversible following discontinuation of cetuximab. 
In addition, hypokalaemia may develop as a consequence of diarrhoea. Hypocalcaemia may 
also occur; in particular in combination with platinum-based chemotherapy the frequency of 
severe hypocalcaemia may be increased. Determination of serum electrolyte levels is 
recommended prior to and periodically during cetuximab treatment. Electrolyte repletion is 
recommended, as appropriate. 
Neutropenia and related infectious complications 
Patients who receive cetuximab in combination with platinum-based chemotherapy are at an 
increased risk for the occurrence of severe neutropenia, which may lead to subsequent 
infectious complications such as febrile neutropenia, pneumonia or sepsis. Careful 
monitoring is recommended in such patients, in particular in those who experience skin 
lesions, mucositis or diarrhoea that may facilitate the occurrence of infections. 
Cardiovascular disorders 
An increased frequency of severe and sometimes fatal cardiovascular events and treatment 
emergent deaths has been observed in the treatment of non-small cell lung cancer, 
squamous cell carcinoma of the head and neck and colorectal carcinoma. In some studies 
(non-small cell lung cancer) association with age ≥ 65 years has been observed. When 
prescribing cetuximab, the cardiovascular status of the patients and concomitant 
administration of cardiotoxic compounds such as fluoropyrimidines should be taken into 
account. 
 
5.3.2 Chemotherapy administration 
5-Fluorouracil and cisplatin are commercially available antineoplastic agents. Investigators 
should use the approved package inserts of these drugs for complete prescribing 
information, including any special precautions.  
 


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5.4 
Selection, timing and modification of dose for each patient 
5.4.1 Cetuximab 
Patients will receive 14 weekly infusions with cetuximab. If a patient has to receive 5-FU and 
cisplatin at the same day, they should be administered after a 1-hour observation period post 
cetuximab infusion.  
 
For all patients, the dosage and administration procedure for cetuximab is as follows:  
 
Initial dose: 
The total initial dose (first infusion) is 400 mg/m² (80 mL/m² ready-to-use solution) 
and is administered over a period of 120 minutes (maximum infusion rate of 10 mg/min, 
corresponding to 2 mL/min ready-to-use solution). Patients must be pre-treated with an 
antihistamine as well as a glucocorticoid. Observe the patient during infusion and for 
one hour afterwards. Check the vital signs pre-, mid-, post- and one hour post-infusion. 
Use a sterile 0.9% NaCl solution to flush the line at the end of infusion. 
 
Further infusions:  
The weekly dose (all further infusions) is 250 mg/m² (= 50 mL/m² ready-to-use 
solution) and is administered over a period of 60 minutes (maximum infusion rate of 
10 mg/min, corresponding to 2 mL/min ready-to-use solution). It is recommended that 
the patient is pre-treated with an antihistamine as well as a glucocorticoid prior to each 
infusion. Observe the patient during infusion and for one hour afterwards. Check the 
vital signs pre-, mid-, post- and one hour post-infusion. Use a sterile 0.9% NaCl solution 
to flush the line at the end of infusion. 
5.4.1.1 Skin toxicities 
If a subject experiences a grade 3 skin toxicity (as defined in the US National Cancer 
Institute’s - Common Toxicity Criteria [NCI-CTC], Version 4.0), cetuximab therapy may be 
delayed for up to two consecutive infusions without changing the dose level. For grade 1 or 2 
acne-like rash treatment with topical antibiotics (e.g. benzoylperoxide, erythromycin) or 
systemic antibiotics (e.g. oral tetracyclines such as doxycycline 100 mg od) should be 
considered. Patients with grade ≥ 3 reactions should be referred to the dermatologist for 
advice and management. If pruritus occurs an oral antihistamine is advised. In case of dry 
skin the use of emollient creams is beneficial. Fissures may occur in dry skin and topical 
dressings are helpful. 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, cetuximab therapy may again be delayed for up to two consecutive weeks with 
concomitant dose reductions to 200 mg/m2 and 150 mg/m2, respectively. Cetuximab dose 
reductions are permanent. Subjects should discontinue cetuximab if more than two 
consecutive infusions are withheld or a fourth occurrence of a grade 3 skin toxicity occurs 
despite appropriate dose reduction (see figure 1). 
However, if in the opinion of the investigator the discontinuation of cetuximab is considered 
necessary, the subject should be withdrawn immediately. 
The dose of cetuximab will be adjusted for cetuximab-related grade 3 skin toxicities only. 
Cetuximab therapy will not be withheld for chemotherapy related toxicities. Therefore, in the 
event that the next infusion of chemotherapy is delayed, the subject will receive cetuximab as 
previously planned. 


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Figure 1: 
Treatment adjustment in the event of grade 3 skin toxicity considered to be 
related to cetuximab. 
 
5.4.1.2 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 2 may be applicable. 
Table 2  
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 subject.  
Administer epinephrine, broncho- dilators, antihistamines, 
glucocorticoids, intravenous fluids, vasopressor agents, 
oxygen, etc., as medically indicated.  
Subjects must be withdrawn immediately from the 
Grade 3 
skin toxicity
Delay infusion
for 1 week
Discontinue
treatment
Delay infusion
for 1 week
Dose at 250 mg/m2
Reduce dose to 150 mg/m2
Reduce dose to 200 mg/m2
Discontinue treatment
1st occurrence
2nd occurrence
3rd occurrence
4th occurrence
Which grade 3
occurrence?
Resolved to
grade < 2
yes
2nd consecutive week
3rd consecutive week
no
Grade 3 
skin toxicity
Delay infusion
for 1 week
Discontinue
treatment
Delay infusion
for 1 week
Dose at 250 mg/m2
Reduce dose to 200 mg/m2
Reduce dose to 150 mg/m2
Discontinue treatment
1st occurrence
2nd occurrence
3rd occurrence
4th occurrence
Which grade 3
occurrence?
Resolved to
grade < 2
yes
2nd consecutive week
3rd consecutive week
no


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treatment and must not receive any further cetuximab 
treatment. 
Re-treatment 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. If the subject has a second 
allergic/hypersensitivity reaction with the slower infusion rate, the infusion should be stopped 
and the subject should be removed from the study. If a subject experiences a Grade 3 or 4-
allergic/hypersensitivity reactions at any time, cetuximab should be discontinued. 
 
5.4.1.3 Other reasons for cetuximab discontinuation 
If a subject develops an intercurrent illness (i.e., infection) that, in the opinion of the 
investigator mandates interruption of cetuximab therapy, that intercurrent illness must resolve 
within a time frame such that no more than two consecutive infusions are withheld. After the 
interruption of treatment, the subject will continue with a cetuximab dose of 250 mg/m2 at 
subsequent visits or the last dose before the interruption if there have been previous dose 
reductions. 
If therapy must be withheld for a longer period of time, the subject 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 Investigator-Sponsor). 
 
5.4.2 5-Fluorouracil 
Toxicities solely related to chemotherapy do not lead to a dose modification or interruption of 
cetuximab and vice versa.  
 
5.4.2.1 Dose modifications and treatment alterations for 5-FU 
The dose of 5-FU will be modified, if the following toxicities (Table 3) are observed during the 
radiochemotherapy on the planned day of 5-FU infusion.  
 
Once a 5-FU dose modification has occurred, the dosage may not be re-escalated for this 
patient. If therapy is delayed for longer than 2 weeks, the patient will be withdrawn from the 
study. 
If on the day of planned 5-FU infusion one of the following toxicities occurs, a dose 
modification according to the following scheme will be performed:  
 


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Table 3: Dose modification for 5-FU in case of toxicities on the day of planned 5-FU 
infusion 
 
Toxicity 
CTC - Grade 
Continue with 
Chemotherapy 
Dose modification 
Neutropenia 
ANC > 1.5 x 
109/L 
Yes 
No 
 
ANC < 1.5 x 
109/L 
Delay until ANC > 1.5 x 
109/L 
No 
 
ANC < 0.5 x 
109/L 
Delay until ANC > 1.5 x 
109/L 
Yes 
5-FU 75% of original 
dose 
Thrombocytopenia 
Platelets > 100 x 
109/L 
Yes 
No 
 
Platelets < 100 x 
109/L 
Delay until platelets > 100 x 
109/L 
No 
 
 
Platelets < 25 x 
109/L 
Delay until platelets > 100 x 
109/L 
Yes 
5-FU 75% of original 
dose 
Diarrhea  
Grade 0-1 
Yes 
No 
 
Grade 2 
Delay until resolved to 
grade < 2 
No 
 
Grade 3 
Delay until resolved to 
grade < 2 
1st occurrence: No 
2nd occurrence: Yes
5-FU 75% of original 
dose 
 
Grade 4 
withdrawal 
withdrawal 
Mucositis/Stomatitis Grade > 1 
Delay until resolved 
Yes 
5-FU 75% of original 
dose 
Skin (except 
irradiated region 
and cetuximab-
related skin 
toxicities) 
Grade > 2 
Delay until grade 0-1 
Yes 
5-FU 75% of original 
dose 
Further non-
hematological 
toxicities (except 
nausea/vomiting 
and alopecia) 
Grade 0-1 
Yes 
No 
 
Grade 2-3 
Delay until grade 0-1 
Yes 
5-FU 75% of original 
dose 
 
Grade 4 
withdrawal 
withdrawal 
 
If at any time during the radiochemotherapy one of the following toxicities occurs, a dose 
modification of 5-FU at the next planned infusion will be performed according to the following 
scheme:  
 


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Table 4: Dose modification for 5-FU in case of toxicities during radiochemotherapy 
 
Toxicity 
CTC-Grade 
Dose modification 
Neutropenia 
ANC < 0.5 x 109/L 
5-FU 75% of original dose 
Thrombocytopenia 
Platelets < 50 x109/l 
5-FU 75% of original dose 
Diarrhea 
≥ Grad 3 
(> stools/day or 
incontinence) 
5-FU 75% of original dose 
Nausea/vomiting 
≥ Grad 3 
5-FU 75% of original dose 
 
5.4.3 Cisplatin 
5.4.3.1 Dose modifications and treatment alterations for cisplatin 
Table 5: Dose modification regarding the cisplatin induced renal toxicity prior to every 
new course: 
Creatinine value
Dose modification
< 1.5 mg/dl 
no dose modification 
> 1.5 mg/dl 
Delay until creatinine is < 1.5 mg/dl, 
then restart with 50% of original 
dose 
 
Additionally the following criteria have to be fulfilled prior to every chemotherapy course: 
• 
Neutrophils ≥ 1,5 x 109/L 
• 
Thrombocytes ≥ 100 x 109/L 
• 
Diarrhea NCI-CTC Version 4.0 Grade < 2 
If these parameters are not appropriately at the scheduled time point of the new course, 
cisplatin administration has to be discontinued until the criteria above will be fulfilled.  
If cisplatin cannot be administered for less than two weeks, the therapy will be continued with 
the initial dosing. 
If cisplatin cannot be administered for more than two weeks the administered dose will be 
75% of the original value. 
 
If at any time during the radiochemotherapy one of the following toxicities occurs, a dose 
modification of cisplatin at the next planned infusion will be performed according to the 
following scheme:  
 


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Table 6: Dose modification for cisplatin in case of toxicities during radiochemotherapy 
 
Toxicity 
CTC-Grade 
Dose modification 
Neutropenia 
ANC < 0.5 x 109/L 
Cisplatin 75% of original dose 
Thrombocytopenia 
Platelets < 25 x109/l 
Cisplatin 75% of original dose 
Further non-
hematological 
toxicities (except 
nausea and 
vomiting) 
Grade 3 
 
Grade 4 
Cisplatin 75% of original dose 
 
Discontinuation of chemotherapy 
 
5.5 
Radiotherapy 
The radiotherapy will be administered over 6.5 - 7 weeks, in 33 fractions of 1.8 Gy up to total 
dose of 59.4 Gy. 50,4 Gy will be administered to the loco-regional lymph nodes. If 
resectability has been achieved after 4-4.5 weeks (36-41.4 Gy), radiotherapy will be stopped 
at 45 Gy and patient will undergo surgery. 
 
5.5.1 Technique and dosage of radiotherapy 
Radiotherapy starts on the first day of the chemotherapy following cetuximab infusion and 
prior to the 5-FU and cisplatin infusions. A total of 59.4 Gy (at the reference point according 
to ICRU 62) will be delivered in daily fractions of 1.8 Gy for 6.5 - 7 consecutive weeks (5 
fractions/week). Irradiation will be performed using high energetic photons, preferably a 
linear accelerator with photon energies of at least 6 MV. The 95% isodose should cover the 
target volume.  
 
Isocentric 3- or 4- field techniques with individual absorbers will be used. To adequately 
perform planning a treatment simulator and computerized 3-D-treatment planning must be 
used. The CT-slices should be contiguous and not thicker than 10 mm, preferably 5 mm with 
clip labelling. Optimal patient positioning to reduce normal tissue damage - if necessary 
including the use of a belly board should be performed. 
 
5.5.1 Adverse reactions and dose modifications of radiotherapy 
Expected acute adverse reactions of the radiotherapy are esophagitis and dysphagia. These 
reactions may be aggravated by the concurrent chemotherapy. Treatment will be 
symptomatic. Generally, these acute adverse reactions abate within two to four weeks 
following completion of radiotherapy. In severe cases, the treatment may be interrupted for up 
to one week, if deemed necessary be the responsible radio-oncologist. If radiotherapy has to 
be stopped due to adverse reactions, the LKP has to be informed. Rare severe events are 
e.g.: skin reactions, pneumonitis, arrhythmia. 
 
Interruption or termination of radiotherapy due to adverse reactions should be based on the 
following recommendations:  
 


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Table 7: Interruption of radiotherapy in case of gastrointestinal toxicity 
 
Toxicity grade 
esophagitis/dysphagia 
Radiotherapy 
0
none 
continue 
1
Mild dysphagia, but can eat regular 
diet 
continue 
2
Dysphagia requiring predominantly 
liquid, pureed or soft diet 
Continue  
 
3
Dysphagia, requiring feeding tube, 
IV hydration or hyperalimentation  
Interruption of radiotherapy 
for a maximum of 7 days. If 
the esophagitis/dysphagia 
does not resolve, the 
radiotherapy should be 
stopped. 
 
 
4
Complete obstruction (cannot 
swallow saliva); ulceration 
withbleedingnot induced by minor 
trauma or abrasion or perforation 
 
Stop radiotherapy 
 
5.6 
Prior and concomitant therapy 
All concomitant medication or medication administered within the 4 weeks preceding study 
start and during the study must be recorded in the CRF. The generic name of the medication 
must be specified along with the duration of the treatment.  
 
Additionally, any therapeutic, or surgical procedures performed during this study period 
should be recorded in the CRF, including the date, indication, description of the procedures, 
and any clinical findings.  
 
Any change in the permitted concomitant medication being taken at the beginning of the 
clinical study must be recorded in the CRF, noting the type of medication, duration, and 
indication. 
 
Additional concurrent chemotherapy of radiation therapy may not be administered. 
Sedatives, antibiotics, analgesics, antihistamines, steroids, Granulocyte-Colony-Stimulating 
Factor (G-CSF), erythropoietin or other medications as well as red blood cells, platelets or 
fresh frozen plasma transfusions may be given to assist in the management of pain, 
infection, and other complications of the malignancy. Patients must be premedicated with an 
antihistamine and a glucocortiocoid prior to receiving the initial dose of cetuximab. 
Premedication with an antihistamine and a glucocorticoid is recommended prior to further 
subsequent weekly doses.  
 
5.7 
Other study conditions 
Anything which may interfere with the immune systems of the patient should preferably be 
avoided except the indicated study regimen and necessary supportive treatment. 
 


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5.8 
Treatment compliance 
Since the intravenous infusion is administered in a hospital or in an outpatient setting, 
compliance can easily be supervised. Cetuximab, cisplatin and 5-FU will be administered 
either by the investigator or under his direct supervision.  
 
The date and the exact amount of cetuximab given at each infusion will be documented in 
the CRF.  
As a routine precaution, patients enrolled in this study will be observed from the start of the 
infusion until at least one hour after the end of the infusion in an area with resuscitation 
equipment and emergency agents (epinephrine, prednisolone equivalents etc.) available. In 
the event that the treatment has to be interrupted during infusion, the clinical staff should 
make an estimate of the percentage of dose received by the patient and document it in the 
CRF. Any reason for non-compliance should also be documented. Insufficient compliance is 
defined as a patient missing more than two infusions of cetuximab without medical reason. In 
the event of insufficient compliance, discontinuation of study treatment for this patient will be 
considered in mutual agreement between the investigator and the Investigator-Sponsor.  
 
6 
Assessment of safety 
6.1 
Adverse events 
6.1.1 Definition of adverse event, adverse drug reaction and serious adverse event 
6.1.1.1 Adverse events (or adverse experience) (AE) 
An AE is any untoward medical occurrence in a patient or clinical investigation subject 
administered a pharmaceutical product and which does not necessarily have a causal 
relationship with this treatment. 
An AE can therefore be any unfavorable and unintended sign (including an abnormal 
laboratory finding, for example), symptom, or disease temporally associated with the use of a 
medicinal product, whether or not considered related to the medicinal product. 
Due to regulatory requirements, events occurring during pre- and post-treatment periods 
should also be designated as AEs. Therefore, safety surveillance - reporting of (S)AEs -
commences at the time when the subject is enrolled into the study (date of signature of the 
informed consent) until the End of Study Visit has been performed. Therefore events 
occurring in the period between the signed informed consent and beginning of the study drug 
administration are to be designated as AEs. This procedure complies with requirements by 
some authorities. 
 
6.1.1.2 Adverse drug reaction (ADR): 
All noxious and unintended responses to a medicinal product related to any dose should be 
considered adverse drug reactions (ADRs). 
The phrase “responses to a medicinal product” means that a causal relationship between a 
medicinal product and an AE is at least a reasonable possibility i.e. the relationship cannot 
be ruled out. 
 


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6.1.1.3 Serious adverse event or reaction/experience (SAE): 
A serious AE (experience) or reaction 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 subject 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 in-patient hospitalization or prolongation of existing hospitalization 
• Results in persistent or significant disability/incapacity 
• Is a congenital anomaly/birth defect or 
• Is an important medical event 
Medical and scientific judgment should be exercised in deciding whether expedited reporting 
is appropriate in cases of important medical events that may not be immediately life-
threatening or result in death or hospitalization but may jeopardize the subject or may require 
intervention to prevent one of the other outcomes listed in the definition above. These should 
also usually be considered serious. 
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, or malignant tumors when they are 
histologically different from the primary tumor. 
 
6.1.1.4 Other events to be treated as SAEs 
Exposure to drug during pregnancy/lactation. 
In principle, pregnancy and the lactation period are exclusion criteria. In the event of a 
pregnancy occurring during the course of a study, the subject must be withdrawn from study 
drug immediately. The Investigator-Sponsor must be notified without delay and the subject 
followed during the entire course of the pregnancy and postpartum period. Parental and 
neonatal outcomes must be recorded even if they are completely normal and without AEs. 
The “Serious Adverse Event Form” (SAE report form) should be used, even though 
pregnancy is not considered a SAE. No “serious criterion box” should be checked. The SAE 
report form is solely used to ensure expedited reporting. 
 
6.1.1.5 Events not to be treated as SAEs 
Progression of disease is not to be regarded as a SAE. 
Due to the seriousness of the disease in this study, certain conditions defined as SAEs will 
be excluded from expedited reporting on a SAE report form: 
• Elective hospitalization and surgery for treatment of disease 
• Elective hospitalization to simplify treatment or study procedures 
 


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6.1.2 Methods of recording and assessing adverse events 
All AEs must be documented in the appropriate section of the CRF. For SAEs, a SAE report 
form (initial or follow up) must be completed in addition. 
The following aspects must be recorded for each event in the CRF: 
• A description of the AE in medical terms, not as reported by the subject; 
• The date of onset (start date) 
• The date of recovery (stop date) 
• The grade as assessed by the investigator according to the definitions in NCI-CTC, 
Version 4.0.  
Grade 1 = mild 
Grade 2 = moderate 
Grade 3 = severe 
Grade 4 = life-threatening or disabling 
Grade 5 = death related to AE  
• The causal relationship to cetuximab or chemotherapy as assessed by the investigator; 
the decisive factor in the documentation is the temporal relation between the AE and the 
study drug. The following judgments of the causality to study drug or study procedures are 
to be used: 
Not Related = There is not a temporal relationship to study drug administration (too early, 
too late, or study drug not taken), or there is a reasonable causal relationship between 
another drug, concurrent disease, or circumstance and the AE. 
Not Likely = There is a temporal relationship to study drug administration, but there is not 
a reasonable causal relationship between the study drug and the AE, 
Possible = There is a reasonable causal relationship between the study drug and the AE. 
Dechallenge information (information referring to withdrawal of drug) is lacking or unclear.  
Probable = There is a reasonable causal relationship between the study drug and the AE. 
The event responds to dechallenge (withdrawal of study drug). Rechallenge is not 
required. 
Certain/Definite = There is a reasonable causal relationship between the study drug and 
the AE. The event responds to dechallenge and recurs with rechallenge, when clinically 
feasible. 
• Action taken on cetuximab (none, medication discontinued, dose reduction, medication 
delayed, reduction of infusion rate). 
• Other action (none, concomitant medication given, new or prolonged hospitalization, 
procedural surgery, chemotherapy delayed, chemotherapy discontinued, chemotherapy 
dose reduction). 
• The outcome according to the following definitions:  
 
Recovered with sequelae. 
Recovered without sequelae. 
Ongoing, no therapy. 
Ongoing, therapy. 
Died. 
Change in toxicity grade/severity. 


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• Seriousness: yes or no 
• In case of SAEs it must be indicated whether the SAE is the leading event, i.e. the primary 
medical reason for SAE reporting. 
If in any one subject the same AE occurs on several occasions, then the AE in question must 
be documented and assessed anew each time. 
 
6.1.3 Procedure for reporting serious adverse events 
In the event of the occurrence of any clinical AE or abnormal laboratory test value that is 
serious or medically important during the course of the study or the post-treatment period, 
irrespective of the treatment received by the subject, the investigator is obliged to 
immediately inform the Investigator-Sponsor. 
The immediate report by the investigator to the Investigator-Sponsor shall be followed by 
detailed, written reports using the SAE report form (for an “initial” SAE or for “follow-up” 
information on a previous SAE). The immediate and follow up reports shall identify subjects 
by unique code numbers assigned to the latter. 
For names, addresses, telephone and fax numbers, see SAE report form. 
The Investigator-Sponsor shall ensure that all reporting requirements according to the 
respective national law are followed. “Expectedness” to be assessed with regard to the valid 
IB for cetuximab. “Expectedness” with respect to a comparator or a concomitant anti-cancer 
treatment, if applicable, is to be assessed according to either the respective IB or versus the 
Product Information.  A CIOMS-1 format shall be used for submitting expedited reports to the 
competent authorities, the ethics committee and to all investigators involved in this study 
according to all appropriate national and international laws. Where necessary, the CIOMS-1 
form shall be accompanied by the relevant pages of the case report form. 
Cetuximab SUSARs represent Serious Adverse Events related to cetuximab (=Adverse 
Reactions), considered “unexpected” with regard to the valid IB for cetuximab. 
With respect to cetuximab, the Investigator-Sponsor shall only copy Merck in any cetuximab 
individual case safety report, which has been submitted expeditedly to the competent 
authorities. The report to Merck shall be sent via Fax only at the same time of reporting to the 
competent authorities. 
The Investigator-Sponsor shall ensure that for a reported death of a subject, the investigator 
shall supply the Investigator-Sponsor and the Ethics Committee with any additional 
information as requested. 
 
6.1.4 Monitoring of subjects with adverse events 
Any AE that occurs in the course of a clinical study must be monitored and followed up until 
the End of Study Visit. Ongoing adverse events related to study treatment will be followed for 
6 weeks (skin toxicities until outcome is known) after end of treatment. In addition SAEs must 
be reported via a SAE report form (see section 6.1.1.3 Procedure for reporting serious 
adverse events). 
It is the responsibility of the investigator that any necessary additional therapeutic measures 
and follow-up procedures are performed. 


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6.1.5 Overdose and intoxication with the study drug 
There is no experience with single doses of cetuximab higher than 500 mg/m² body surface 
area in human clinical trials. In the event of a drug overdose occurring in the course of the 
present study, this must be reported as a SAE. 
 
6.2 
Laboratory assessments 
All clinical laboratory evaluations will be performed at the local laboratory of the 
investigational site complying with GCP and local requirements. 
A safety laboratory examination consisting of hematology must be performed at baseline, 
weekly during radio-immunochemotherapy and at the end of treatment evaluation. Clinical 
chemistry must be performed at baseline, on day 1 of every course (every 4 weeks) of the 
radio-immunochemotherapy, and at the end of treatment evaluation.  
Women of childbearing potential must have a negative serum or urine pregnancy test 
(minimum sensitivity according to local regulation) within 7 days prior to the start of the study 
medication. 
Safety laboratory parameters 
• 
Hematology (5 ml) 
Leucocytes, neutrophils, platelets, erythrocytes, hemoglobin 
• 
Clinical chemistry (10 ml) 
Sodium, potassium, calcium, magnesium, creatinine, bilirubin, SGOT, SGPT, LDH, 
alkaline phosphatase, γ-GT 
• 
Pregnancy test (if applicable) 
Male or female patients must be practicing a medically accepted contraception. 
 
6.3 
Vital signs and physical examination 
A physical examination including weight and height will be performed at screening.  
Resting blood pressure (systolic/diastolic, supine, after 5 minutes rest) and heart rate (after 5 
minutes rest) will be measured at screening, weekly during radio-immunochemotherapy and 
at the end of treatment.  
7 
Schedule of assessments 
The table below summarizes the assessments to be made during (pre)-screening and during 
the study. Descriptions of the methodology to be used are given in the following sections. 
Table 8: Overview of assessments during screening and during the study. 
Screening and During Study 
Includes 
Informed Consent 
• 
Written informed consent for participation in the 
study 


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Medical History 
• 
Demographic data 
• 
Tumor diagnosis 
• 
Check of inclusion and exclusion criteria 
• 
Previous relevant diseases other than esophageal 
cancer 
• 
Concomitant medications within 4 weeks preceding 
study start 
Vital signs 
• 
Resting heart rate 
• 
Resting blood pressure (systolic/diastolic) 
• 
Height / weight 
• 
Body surface area 
Performance status 
• 
Karnofsky performance status 
Safety lab 
• 
Hematology 
• 
Clinical chemistry 
• 
Pregnancy test (where applicable) 
Cardiac evaluation 
• 
ECG and measurement of ejection fraction (LVEF) 
Lung function test 
• 
FEV1 
Clinical staging and imaging 
• 
Endoscopy 
• 
Endoscopic ultrasound (optional) 
• 
CT 
• 
DC-MRT (in selected centers) 
7.1 
Screening examinations 
After the patient has signed the informed consent, all eligibility criteria will be checked. 
Patients may only be enrolled, if all inclusion criteria and none of the exclusion criteria are 
met.  
If frozen tissues or immunohistochemical blocks from previous biopsies are available at the 
local study site or the regional Pathology Department, they should be transported to Mainz 
for further analysis. 
 
7.1.1 Examinations within 4 weeks prior to treatment start 
• 
Written informed consent for participation in the study 
• 
Medical History 
• 
Clinical staging (endoscopy incl. biopsy) 
• 
Endoscopic ultrasound 


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• 
Tumor Assessment CT/MRI chest and abdomen 
• 
ECG and LVEF 
• 
FEV1 
• 
Evaluation by a surgeon with respect to resectability 
• 
Tissue immunohistochemistry 
 
7.1.2 Examinations within 7 days prior to treatment start 
• 
Height, weight, vital signs 
• 
Karnofsky-Performance Status 
• 
Hematology (leucocytes, neutrophils, platelets, erythrocytes, hemoglobin) 
• 
Clinical chemistry (sodium, potassium, calcium, magnesium, creatinine, bilirubin, , 
SGOT, SGPT, LDH, alkaline phosphatase, γ-GT) 
• 
Pregnancy test in women of child-bearing potential 
• 
Serum sample (10 ml) and whole blood sample (10 ml) for EGFR and ligands 
determination (if patient agrees to participate in translational study) 
 
7.2 
Evaluations during radio-immunochemotherapy 
7.2.1 Weekly examinations 
• Vital signs  
• Weight 
• Hematology (leucocytes, neutrophils, platelets, erythrocytes, hemoglobin) 
• Clinical signs and symptoms, toxicity according to the NCI-CTC version 4.0  
• DC-MRT: at day 7 (+/-2) or day 14 (+/-2) of the first cycle (in selected centers) 
 
7.2.2 Examinations every 4 weeks 
• 
Karnofsky-Performance Status 
• 
Biochemistry (sodium, potassium, calcium, magnesium, creatinine, bilirubin, SGOT, 
SGPT, LDH, alkaline phosphatase, γ-GT) 
 
7.2.3 Examinations after 4 weeks of treatment 
• 
Endoscopy (incl. biopsy, if patient agrees to participate in translational study) 
• 
Endoscopic ultrasound (optional) 
• 
Tumor assessment (CT/MRI chest and abdomen) 
• 
serum sample (10 ml) for EGFR and ligands determination (if patient agrees to 
participate in translational study) 
• 
Tissue immunochemistry (if patient agrees to participate in translational study; 
immunohistochemical blocks should be transported to Mainz for further analysis) 
• 
Re-evaluation by a surgeon with respect to resectability* 
*If resectability has been achieved, radiochemotherapy +/- cetuximab is stopped after 45 Gy, 
and the patient is referred to surgery. If resectability has not been achieved, 
radiochemotherapy +/- cetuximab is continued as indicated above.  
 
 


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7.3 
End of Treatment Evaluations 
After completion of the radio-immunochemotherapy or at the time of premature withdrawal 
for any reason the following assessments will be performed: 
 
• 
Vital signs 
• 
Karnofsky performance status 
• 
Hematology (leucocytes, neutrophils, platelets, erythrocytes, hemoglobin) 
• 
Clinical chemistry (sodium, potassium, calcium, magnesium, creatinine, bilirubin, , 
SGOT, SGPT, LDH, alkaline Phosphatase, γ-GT) 
• 
Assessment of clinical signs or symptoms, toxicity according to NCI-CTC version 4.0 
• 
Endoscopy (incl. biopsy, if patient agrees to participate in translational study) 
• 
Endoscopic ultrasound (optional) 
• 
Tumor Assessment (CT/MRI chest and abdomen) 
serum sample (10 ml) for EGFR and ligands determination (if patient agrees to 
participate in translational study) 
 
7.4 
Evaluations during the Follow up phase 
Follow-up assessments will terminate 2 years after the last patient has completed end of 
treatment (incl. biopsy, if patient agrees to participate in translational study). 
 
• 
Evaluation of toxicity  
• 
Treatment outcome 
• 
Endoscopic ultrasound (optional) 
Tumor Assessment (CT/MRI chest and abdomen) 
 
7.5 
Evaluation of Efficacy 
7.5.1 Tumor assessment 
Assessment of tumor response will be evaluated using the international criteria proposed by 
the RECIST (Response Evaluation Criteria in Solid Tumors) committee (New response 
evaluation criteria in solid tumours: Revised RECIST guideline (version 1.1), Eisenhauer EA 
et al., Eur J Cancer 2009, see Appendix 4 for further reference).  
 
 
Only subjects with measurable disease may be enrolled into this study. Measurable disease 
requires the presence of at least one measurable lesion. Imaging, CT- or MRI-scan, of chest 
and abdomen must be performed at baseline (within 28 days before start of treatment) for 
eligibility and also to establish a baseline tumor assessment.  
The same method of assessment and the same technique should be used to characterize 
the reported lesion at baseline and during the following tumor assessments. A switch from 
CT- to MRI-scan is considered the only acceptable change in modality and should not 
preclude response assessment if, in the judgment of the radiologist, there is no significant 
difference in the assessment by CT- and MRI-scan. 
CT- and MRI-scan are the best currently available and most reproducible methods of 
measuring index lesions selected for response assessment. CT- or MRI-scans of the chest 
and abdomen anatomies are required at baseline. Thereafter, at each imaging time point, a 
chest CT- or MRI-scan and abdomen CT-or MRI scan are required. CT- or MRI-scans of the 
chest and abdomen are required at the Final Tumor Assessment visit. 
The CT- or MRI-scans should be performed with spiral technique using a 5 mm or less 
contiguous reconstruction algorithm. Non-spiral CT is also allowed with a recommended 
reconstruction algorithm or slice thickness of 10 mm or less. Intravenous and oral contrast 
should be administered if it is not contraindicated. At baseline, tumor lesions will be 


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categorised measurable if the minimum size is 10 mm (if CT scans are performed at 5 mm 
slice thickness or less). If CT scans at slice thickness greater than 5 mm are used, the 
minimum size of measurable lesions at baseline should be twice the slice thickness of the 
baseline scans.  
The lesion will be assessed with imaging with the same method as at baseline and at the end 
of treatment to monitor progression of disease. Furthermore, at the end of treatment visit, the 
investigator will exclude symptomatic deterioration suggestive of progression of disease (e.g. 
a decrease in Karnofsky performance status, metastases). If progression of disease is 
suspected for any reason during the treatment phase, radiological confirmation is necessary 
and a new scan must be performed unless a scan taken no more than 14 days earlier is 
available.  
 
Resectability / Response Criteria per Time Point: 
Resectability of the primary tumor and the lymph nodes will be assessed by a surgeon after 
4-4.5 weeks of treatment (see 7.2.3). 
 
Overall response will be defined according to the RECIST criteria Version 1.1 based on the 
assessments for target lesions, non-target lesions as well as considering the occurrence of 
new lesions, and will be assessed at week 5 and at the end of treatment. 
 
Evaluation of target lesions 
Complete Response 
(CR): 
Disappearance of all target lesions. Any pathological lymph nodes 
(whether target or non-target) must have reduction in short axis to < 10 
mm.  
Partial Response (PR): At least a 30% decrease in the sum of diameters of target lesions, taking 
as reference the baseline sum diameters. 
Progressive Disease 
(PD): 
At least a 20% increase in the sum of diameters of target lesions, taking 
as reference the smallest sum on study (this includes the baseline sum 
if that is the smallest on study). In addition to the relative increase of 
20%, the sum must also demonstrate an absolute increase of at least 5 
mm. (Note: the appearance of one or more new lesions is also 
considered progression). 
Stable Disease (SD): 
Neither sufficient shrinkage to qualify for PR nor sufficient increase to 
qualify for PD, taking as reference the smallest sum diameters while on 
study 
Evaluation of non-target lesions 
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) 
Non-CR/Non-PD:  
Persistence of one or more non-target lesion(s) or/and maintenance of 
tumor marker level above the normal limits 
Progressive Disease 
(PD): 
Unequivocal progression of existing non-target lesions. (Note: the 
appearance of one or more new lesions is also considered 
progression).  
Evaluation of best overall response 
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). In general, the patient's best response assignment will 
depend on the achievement of both measurement and confirmation criteria  
 


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Table 9:  RECISIT 1.1 Evaluation of best overall  response 
Target lesions 
Non-Target lesions 
New Lesions 
Overall response 
CR 
CR 
No 
CR 
CR 
Non-CR/Non-PR 
No 
PR 
CR 
Not evaluated 
No 
PR 
PR 
Non-PD or not all 
evaluated 
No 
PR 
SD 
Non-PD or not all 
evaluated 
No 
SD 
Not all evaluated 
Non-PD 
No 
NE 
PD 
Any 
Yes or No 
PD 
Any 
PD 
Yes or No 
PD 
Any 
Any 
Yes 
PD 
 
7.5.2 Residual tumor classification (R-classification) in patients undergoing surgery 
The R-classification will be performed by the pathologist using the resected tumor. The 
pathologist will determine, if residual tumor is present at the resection lines. The definitive R-
classification considers clinical and pathological information and includes the following 
categories: 
 
R0 
no residual tumor 
R1 
microscopic residual tumor 
R2a 
macroscopic residual tumor, microscopically not confirmed 
R2b 
macroscopic residual tumor, microscopically confirmed 
 
8 
Statistical Considerations 
Having fixed the safe dose in our former phase I study (LEOPARD Phase I), 134 patients 
should  be treated at a dose of 1000 mg/m2 FU and 20 mg/m2 cisplatin to evaluate the 2-year 
overall survival of the immuno-radiochemotherapy. However, the last patient will be 
randomized on December 31, 2016 at the atest, which is 2.5 years later than originally 
planned.    
 
8.1 
Analysis set descriptions 
Safety Analysis Set 
The safety population includes all patients who received at least one dose of trial medication 
and for whom at least one post-baseline safety measurement is available. 
 
Full Analysis Set 
The Full Analysis Set includes all patients who received at least one dose of trial medication 
and for whom at least one post-baseline efficacy measurement is available. 
 
Per Protocol Set 
 
This population includes all patients with at least six weeks of trial medication plus all 
patients who discontinued the study prematurely due to lack of efficacy, death or toxicity. 
Detailed criteria will be defined before analysis. 
 


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All safety analyses will be performed on the Safety Analysis Set. For efficacy analysis of the 
trial, the primary analyses will be based on the per-protocol set. Additional analyses will be 
performed on the Full Analysis Set for sensitivity purposes.  
 
8.2 
Target variables 
8.2.1 Primary variables 
For quantification of efficacy the primary objective is the 2-year overall survival.  
8.2.2 Secondary variables  
• 
The 1-year overall survival 
• 
The 1-year and 2- year progression-free survival 
• 
The 1-year and 2-year loco-regional control 
• 
The 1-year and 2-year metastases-free survival 
• 
The overall response rate3 (RECIST Version 1.1) 
• 
Toxicity (NCI-CTC 4.0) 
• 
Quality of Life (EORTC QLQ-C30 and QLQ-OES18) 
 
In addition the following parameters will be assessed irrespective of a specific time point:  
• 
OS 
• 
PFS 
• 
MFS 
 
8.3 
Statistical analysis 
8.3.1 Statistical Methode 
Treatment outcome: 
Loco-regional control is defined as absence of loco-regional progression based on findings of 
endoscopy, endoscopic ultrasound, and computed tomography.  
OS, PFS, MFS and LC are calculated for both treatment groups and for several potential 
prognostic factors with the Kaplan-Meier method and measured from the day of 
randomization .  
Such potential prognostic factors are: age (≤60 vs. >60 years), Karnofsky performance status 
(100%-80% vs. 70%), tumor location (upper third vs. middle third vs. lower third), tumor 
length (<7 cm vs. ≥7 cm, according to endoscopy), histology (squamous cell carcinoma vs. 
adenocarcinoma), histologic grade (G1-2 vs. G3), T-stage (T2-3 vs. T4, according to 
endoscopic ultrasound and computed tomography), N-Stage (N0 vs. N+), and hemoglobin 
before radiotherapy (<12 vs. 12-14 vs. > 14 g/dl). 
Differences between the Kaplan-Meier curves are evaluated with the log-rank test. Results 
are considered significant if P < 0.05. Potential prognostic factors found to be significant in 
the univariate analysis, are evaluated in a multivariate analysis performed with the Cox 
proportional hazard model.  
 
Stratification at randomization according to : 
Histology (SCC vs. adeno) 
KPS (100%-80% vs. 70%) 
Stage (T1-3 N0-1 vs. T4 and/or N2 and/or M1a)  


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Toxicity: 
Both treatment groups are compared for toxicity using the Chi-square test. 
 
8.3.2 Present therapeutic situation 
The most effective radiochemotherapy regimens, containing 5-FU and cisplatin, achieve a 
overall survival (OS) rate of 36% to 40% after two years [49, 50, 52]. Thus, a 40% OS rate at 2 
years is assumed as the baseline efficacy level for the present trial.  
 
8.3.3 Rationale for the application of a randomized phase II design 
The present trial is designed as a randomized phase II study which aims at estimating the 
therapeutic efficacy of the experimental targeted regimen including the EGFR antibody in 
relation to the standard combination. The OS rate after 2 years is chosen as primary efficacy 
endpoint. 
 
The estimation of the efficacy rate of the experimental cetuximab regimen is to be based on an 
explorative pilot study, since immediate embarking on a large scale comparative efficacy trial 
would not be acceptable from the point of view of resources. Moreover, this would induce 
ethical objections, as it does not seem to be justifiable to expose a large number of patients to 
an experimental approach without any exploratory indications of an improved risk-benefit ratio. 
 
In this situation, a randomized phase II trial with a standard treatment control group proves to 
be an appropriate research design in order to achieve a valid efficacy estimation. This type of 
cancer study design is propagated since the early 1980s, especially by representatives of the 
National Cancer Institute [48]. The key idea of randomizing already in the phase II of the 
treatment development offers the opportunity to reduce some of the result variability which is 
typically encountered in phase II trials, especially caused by patient selection phenomena and 
investigator bias. Thus, with a randomized control group at hand, differences obtained for the 
two treatments will more likely represent real differences in efficacy rather than differences in 
patient selection, clinical evaluation, and other factors, since these factors will be handled in 
similar fashion for both arms of the study. The purpose of randomized phase II designs is not a 
formal, rigorous comparison of two or more treatment arms, but rather a reduction in certain 
sources of variability that afflict conventional phase II trials and their comparison across 
studies. Moreover, this design offers the additional advantage, that the trial may immediately 
be expanded into a phase III trial including the patients already randomized, if the results of 
the experimental group(s) are considered to be promising. 
 
8.3.4 Design and assumptions 
• Explorative randomized phase II study with 2 parallel groups. 
• Primary endpoint: Overall survival rate after 2 years. Survival time will be calculated from 
time of randomization until death for any reason, or until last date known to be alive, 
whichever occurs first. In patients without death, the last date known to be alive will be 
considered as censored survival time.   
• The respective experimental therapy arm would be rated as insufficiently active, if the 
observed OS rate at 2 years is 40 % or lower, as this corresponds to the standard treatment 
efficacy. 
• On the other hand, the experimental therapy would be considered to be a promising 
candidate for further development (e.g. in a phase III trial), if the true OS rate at 2 years 
amounted to 45% or more. 


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• In order to detect potential differences with respect to the investigated study endpoints 
between female and male gender, subgroup analyses will be performed for both female and 
male patients. Furthermore, the potential prognostic impact of gender will be analyzed in a 
univariate and a multivariate manner. Because an adequate statistical power cannot be 
expected in each of the two subgroups, the statistical evaluation analyses with respect to 
gender related differences will be presented in a descriptive manner. 
8.4 
Sample size calculation  
This phase II study is an explorative randomized study with 2 parallel groups. Using a 
standard single-stage phase II design by FLEMING (1981), n = 62 patients evaluable for 
efficacy have to be recruited. As a similar number of patients is to be recruited to the 
standard arm, a total number of 124 patients is required. The standard treatment control 
group serves to reduce some of the result variability which is typically encountered in single-
arm phase II trials, especially caused by patient selection phenomena and investigator bias. 
To cover potentially drop outs 67 patients per arm will be recruited. 
 
The OS rate after 2 years is chosen as primary efficacy endpoint. The estimation of the 
efficacy rate of 40% of the reference group is based on the findings of several studies [49-
54]. Therefore, the respective experimental therapy arm would be rated as insufficiently 
active, if the observed OS rate at 2 years is 40 % or lower. 
On the other hand, the experimental therapy would be considered to be a very promising 
candidate for further development (e.g. in a phase III trial), if the true OS rate at 2 years 
amounted to 45 % or more. 
Probability to accept the experimental therapy as promising (> 45% OS rate) with respect to 
efficacy, in spite of a true OS rate of ≤ 40%: 5% (type I error).  
Probability to reject the experimental therapy as not sufficiently efficient (≤ 40%), although 
the true OS rate is promising (> 45%): 20% (type II error, corresponding to a power of 80%). 
However, the last patient will be randomized on December 31, 2016 at the latest, which is 
2.5 years later than originally planned. Based on number of patients randomized until end of 
July and who received study treatment (n=66) it is expected that the total number of patients 
in the Full Analysis Set (FAS) will be between 72 and 78 patients, while the number of 
patients in the Per Protocol Population is expected to be between 66 and 72 patients. 
The final conclusion of the phase II trial will depend on the definite OS rate (and its 
confidence interval), the respective findings in the 5-FU/cisplatin reference arm, as well as 
the information on type, frequency and severity of toxicities.  
The 2-years overall survival rates will be estimated using Kaplan-Meier methods and the 
difference between treatment groups regarding 2-years overall survival curves will be 
compared using the log-rank test. In addition, univariate Cox proportional hazard methods 
will be used to estimate the corresponding hazard ratio (HR) and 95% confidence intervals 
for HR.  
Based on the expected number of patients randomized until end of 2016, the following 
difference (hazard ratios) can be detected between the two treatment arms with 80% power 
and a two-sided significance level of 0.05, assuming that the 2-years OS probability is 
between 30 and 40%, and number of lost-to-follow-ups is about 5% during the 2 years.  


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Table 10: Hazard ratios and necessary numbers of events 
Sample size 
2-year OS probability 
Necessary 
number of 
events 
Hazard ratio 
CT only 
CT plus 
Cetuximab 
2 x 33 
30% 
63.14 
34 
0.3820 
 
35% 
68.38 
31 
0.3621 
 
40% 
73.19 
28 
0.3407 
2 x 36 
30% 
61.73 
38 
0.4007 
 
35% 
67.02 
35 
0.3812 
 
40% 
71.90 
31 
0.3601 
2 x 39 
30% 
60.48 
42 
0.4177 
 
35% 
65.81 
38 
0.3986 
 
40% 
70.74 
34 
0.3778 
 
8.5 
Data Management 
To ensure that the database accurately reflects the data reported on the CRF, a double data 
entry procedure (data entered by different staff members in two different data files) will be 
used. In addition to an electronic comparison of these two data files, mainly electronic 
validation of the data will take place (e.g. check of ranges, consistency and plausibility). 
Additionally the CRFs will be reviewed by qualified personnel for completeness, consistency 
and plausibility. Unclear data will be clarified using data correction forms. The procedures of 
data entry, comparison and correction will be tracked and appropriately documented. All data 
management procedures and systems will be described in detail in the Data Validation Plan 
which will be approved by the sponsor. 
 
9 
Immuno(histo)chemistry and blood samples (applicable if patient agrees to 
participate in translational study) 
Serum samples, paraffin-embedded tissues, and when available fresh frozen specimens (if 
applicable) of included patients will be characterized via ELISA, immunohistochemistry and 
PCR, respectively. In addition, a prospective follow-up of serum levels of targeted ligands 
(ELISA) is planned before and during Cetuximab therapy to correlate the receptor pathways 
with initial tumor staging and clinical response.  
The tissues were collected during diagnosis and follow up (operations, biopsies) of the 
patient. They are stored frozen in the study centers and will be transported to Mainz. Serum 
samples will be collected at screening, after 4 weeks of treatment and at the end of 
treatment. A full blood sample will be collected at screening for SNP-analysis. All samples 
will be transported to Mainz for further analysis.  
Tissues and serum samples will be analysed by: Klinische Immunologie, Frau Annett Müller, 
Universitätsklinik Mainz, I. Medizinische Klinik und Poliklinik, Gebäude 206, U2, 
Langenbeckstraße 1, 55101 Mainz 


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9.1 
DC-MRT  
The DC-MRT will be performed in an explorative manner before the beginning of the first 
cycle, and 7 (+/-2) days or 14 (+/-2) days after start of the first cycle to analyze the efficacy of 
Cetuximab to influence the tumor microcirculation with its blood flow and arterial 
permeability. 
 
One important precondition for using MRT is the development of special imaging sequences 
and programs, with which the data can be processed and tissue specific parameters can be 
quantified. This has been established at the Department of Radiology and Nuclear Medicine 
in conjunction with the Department of Physics of the Max Planck Institute in Mainz, Germany. 
Currently Mainz University works with the program Medlab. Pharmacokinetics can also be 
automatically documented. Responsible for the project in the protocol will be Dr. K. 
Oberholzer, MD, Radiology Department. Regarding MRT scanning programs, all study 
centers are invited to participate.  
 
10 Data Safety Monitoring Board 
A Data Safety Monitoring Board (DSMB) will be implemented that independently supervises 
the trial with respect to any potential safety issues. The DSMB will function in accordance 
with the principles of the following documents: EMEA guideline on data monitoring 
committees (EMEA/CHMP/EWP/5872/03 Corr); ICH Note for guidance E3 (structure and 
content of clinical study reports), ICH Note for guidance E6 (Good Clinical Practice) and ICH 
Note for Guidance E9 (Statistical Principles for Clinical Trials). 
The DSMB will be an independent board consisting of a group of 2 physicians with 
experience in oncology. A physician is not allowed to participate in this clinical trial while 
serving on the DSMB. The DSMB will be supported by an independent statistician, if 
necessary.  
The DSMB will formally review safety data when 20 patients and again when 67 patients 
(50% of the entire cohort) are randomized have completed 4 weeks of treatment. The DSMB 
will focus on safety and survival data only. An interim analysis with respect to efficacy/futility 
is planned after recruitment stop at December 31, 2016. In addition, the DSMB will be 
provided with regular reports every 3 months summarizing the same safety information used 
for the formal review. 
 
The key safety parameters to be monitored will be  
• 
Overall incidence of patients with any CTCAE-grade III/IV adverse event 
• 
Incidence of Serious Adverse Events (SAEs) 
 
A separate DSMB charter will be set up which defines the roles and responsibilities of the 
DSMB, delineates qualifications of the membership, describes the purpose and timing of 
meetings, provides the procedures for ensuring confidentiality and proper communication, 
and outlines the content of the reports. In addition, the statistical guidance for evaluating 
safety and their associated stopping rules will be presented. These rules are meant as 
guidance rather than as mandatory decision rule. In case of unexpected results, the DSMB 
has the discretion to deviate appropriately form this guidance.  
In case of significant excess toxicity associated with the experimental arm, the DSMB may 
decide together with the sponsor to stop the trial early due to safety concerns. 
 
 


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11 Ethical and regulatory aspects 
11.1 Responsibilities of the Investigator 
The investigator shall be responsible for ensuring that the clinical study is performed in 
accordance with the protocol, the ethical principles that have their origin in the Declaration of 
Helsinki (World Medical Association Declaration of Helsinki) as well as with the International 
Conference on Harmonization of Technical Requirements of Pharmaceuticals for Humans 
Use (ICH) Note for Guidance on Good Clinical Practice (ICH, Topic E6, 1995) approved July 
17, 1996 and applicable regulatory requirements. These documents state that the informed 
consent of the patients is an essential precondition for participation in the clinical study. 
 
11.2 Patient information 
An unconditional prerequisite for a subject participating in the study is his/her written 
informed consent. Adequate information must therefore be given to the subject by the 
investigator before informed consent is obtained. A person designated by the investigator 
may give the information, if permitted by local regulations. A subject information sheet in the 
local language and prepared in accordance with the ICH Note for Guidance on Good Clinical 
Practice (ICH, Topic E6, 1995) will be provided for the purpose of obtaining informed 
consent. In addition to this written information, the investigator or his designate will inform the 
subject verbally. In doing so, the wording used will be chosen so that the information can be 
fully and readily understood by laypersons. 
The subject information sheet will be revised whenever important new information becomes 
available that may be relevant to the consent of subjects. 
 
11.3 Patient consent 
11.3.1 Informed Consent procedures 
The consent of the patient to participate in the clinical study has to be given in writing before 
any study-related activities are carried out. lt must be signed and personally dated by the 
subject and by the investigator/person designated by the investigator to conduct the informed 
consent discussion. 
Provision of consent will be confirmed in the CRF by the investigator. The signed and dated 
declaration of informed consent will remain at the investigator’s site and must be safely 
archived by the investigator so that the forms can be retrieved at any time for monitoring, 
auditing and inspection purposes. A copy of the signed and dated information and consent 
should be provided to the subject prior to participation. 
 
11.3.2 Witnessed informed consent 
If the subject or legally acceptable representative is unable to read, a reliable and 
independent witness should be present during the entire informed consent discussion. The 
choice of the witness must not breach the subject‘s right to confidentiality. A reliable 
independent witness is defined as one not affiliated with the institution or engaged in the 
investigation. A family member or acquaintance is an appropriate independent witnesses. 
After the subject or legally acceptable representative orally consents and has signed, if 
capable, the witness should sign and personally date the consent form attesting that the 
information is accurate and that the subject or legally acceptable representative has fully 
understood the content of the informed consent agreement and is giving true informed 
consent. 


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11.4 Patient insurance  
Insurance coverage shall be provided for at Allianz Versicherungs-AG, 10900 Berlin, 
Germany, policy number AS-9100160845 as stipulated by law, for all patients enrolled in the 
study from the time of patients‘ inclusion into the study ( date of given second consent or 
screening visit).  
This insurance covers any damage to health arising from participation in the study up to 
maximum sum required by law. 
 
In order not to violate the insurance cover, the patient must immediately notify the insurance 
company in case of any damage to health arising from participation in the clinical study. 
 
A copy of the complete insurance terms and conditions will be made available to the patient. 
 
11.5 Ethics Committee or Institutional Review Board 
Prior to commencement of the study, the study protocol will be submitted together with its 
associated documents (patient information, consent form, investigator‘s brochure) to the 
relevant EC for their favorable opinion.  
The study will only commence following provision of a written favorable opinion, documenting 
the date of the meeting, constitution of the committee and voting members present at the 
meeting as well as clearly identifying the trial, protocol version, and consent documents 
reviewed.  
Any amendments to the protocol will be submitted to the EC and they will be informed about 
SAEs in accordance with national and/or local requirements. 
 
11.6 Notification to authorities 
Prior to commencement of the study, the study protocol will be submitted together with its 
associated documents (patient information, consent form, investigator‘s brochure) to the 
regulatory authority for their favorable opinion. According to the German Drug Law, the study 
may only commence after approval by the regulatory authority. This approval is granted, if no 
objections have been issued by the regulatory authority within 30 days after submission of 
the documents.  
To comply with § 67 of the German Drug Law, the study and the investigators will also be 
notified to the local authorities. 
 
11.7 Sponsorship 
This is an investigator sponsored trial. The study will be sponsored by the University Hospital 
Schleswig-Holstein, Campus Luebeck, Germany. 
 


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12 Study management 
12.1 Case Report Form handling 
The main objective is to obtain those data required by the study protocol in a complete, 
accurate, legible and timely fashion. The data in the CRF should be consistent with the 
relevant source documents. 
The data recorded in the course of this study must be documented in the CRF and/or the 
form ARF, and must be forwarded to the data management. They shall then be processed, 
evaluated, and stored anonymously in accordance with the data-protection regulations. 
The investigator must ensure that the CRFs forwarded to the data management and any 
other associated documents contain no mention of any patient names. 
The CRFs must be filled in completely and legibly (with either black or blue ballpoint pen, 
acceptable for use on official documents). Any amendments and corrections necessary must 
be undertaken and countersigned by the investigator, stating the date of the 
amendment/correction. Errors must remain legible and may not be deleted with correction 
aids (e.g. Tipp-Ex®). The investigator must state his/her reasons for the correction of 
important data. 
In the case of missing data/remarks, the entry spaces provided for in the case report form 
should be cancelled out so as to avoid unnecessary follow-up inquiries. 
The CRFs are regulatory documents and must be suitable for submission to authorities. 
 
12.2 Source data and subject files 
The investigator has to keep a written or electronic subject file for every subject participating 
in the clinical study. In this subject file, the available demographic and medical information of 
a subject has to be documented, in particular the following: name, date of birth, sex, height, 
weight, subject history, concomitant diseases and concomitant drug (including changes 
during the study), statement of entry into the study, study identification, subject number, the 
date of informed consents, all study visit dates, predefined performed examinations and 
clinical findings, observed AEs (if applicable), and reason for withdrawal from the study if 
applicable. lt should be possible to verify the inclusion and exclusion criteria for the study 
from the available data in this file. 
lt must be possible to identify each subject by using this patient file. 
Additionally, any other documents with source data, especially original printouts of data that 
were generated by technical equipment have to be filed. All these documents have to bear at 
least subject identification and the printing date printed by the recording device to indicate to 
which subject and to which study procedure the document belongs. The medical evaluation 
of such records should be documented as necessary and signed/dated by the investigator. 
Computerized subject files will be printed whenever source data verification is performed by 
the monitor. Printouts must be signed and dated by the investigator, countersigned by the 
monitor and kept in a safe place. 
Data to be recorded directly on the CRFs (i.e. no prior written or electronic record of data) 
are considered to be source data. 
 
12.3 Investigator Site File and archiving 
The investigator will be provided with an ISF at the start of the study. This file contains all 
relevant documents necessary for the conduct of the study. This file must be safely archived 
after termination of the study. 


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lt is the responsibility of the investigator to ensure that the patient-identification sheets are 
stored for at least 15 years beyond the end of the clinical study. All original patient files must 
be stored for the longest possible time permitted by the regulations at the hospital, research 
institute, or practice in question. If archiving can no longer be maintained at the site, the 
investigator will notify the Investigator-Sponsor. 
 
12.4 Monitoring, Quality Assurance and inspection by authorities 
This study is to be conducted in accordance with the ICH Note for Guidance on Good Clinical 
Practice (ICH, Topic E6, 1995) dated July 17, 1996. The appointed clinical monitor will 
arrange regular visits to the study center(s) on a regular basis to check progress with the 
study and to collect completed CRFs. 
During monitoring visits the monitors will: 
• Help resolve any problems. 
• Examine all CRFs for omission of data, compliance and possible AEs. 
• Discuss inconsistencies in the trial data. 
• Ensure that all trial materials are correctly stored and dispensed. 
• Check adherence to the obligations of the investigator. 
• Review consent forms, in particular the date of consent and signature. 
• Perform Source Data Verification as described below. 
In line with ICH GCP guidelines monitoring will include verification of data entered in the 
CRFs against original patient records. This verification will be performed by direct access to 
the original patient records and the monitoring organization guarantees that patient 
confidentiality will be respected at all times. Participation in this study will be taken as 
agreement to permit direct source data verification. Data generated at the pre-screening visit 
are verified against source data only in case the patient enters the study. 
In addition the representatives of the Clinical Quality Assurance of monitoring organizations, 
and of national regulatory authorities, are permitted to inspect the study documents (study 
protocol, case report forms, study medication, original medical records/files). All patient data 
shall be treated confidentially. 
In the course of the clinical study, the CRFs shall be forwarded to the data management 
organization after completion of the individual sections (e.g. visits) of the study. 
The study protocol, each step of the data-recording procedure, and the handling of the data 
as well as the study report shall be subject to an Clinical Quality Assurance. Audits can be 
conducted to assure the validity of the study data. 
 
12.5 Changes to the study protocol 
Changes to, or formal clarifications of, the study protocol must be documented in writing. 
Major changes to the protocol will be described in a “Protocol Amendment“. lt will be 
submitted to the relevant ECs and to authorities where required. Approval/favorable opinion 
from the relevant ECs will be required prior to implementation of the amendment. 
Any Amendment affecting the subject requires the subject’s informed consent prior to 
implementation. 
Changes of administrative or technical nature will be recorded in a document entitled 
“Administrative Change to Study Protocol“. lt will be sent for information to the relevant ECs 
or to authorities, if so required. 


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Amendment and Administrative Changes will be signed by all signatories of the protocol. All 
investigators will acknowledge the receipt and confirm by their signature on the Amendment 
or 
Administrative 
Change 
Signature 
Sheet 
that 
they 
will 
adhere 
to 
the 
Amendment/Administrative Change. This sheet will be issued in duplicate and after signing 
one will be filed in the Investigator Study File and one in the Study Master File. 
 
12.6 Study report and publication policy 
After the clinical cut-off date of the study, an integrated clinical and statistical study report 
shall be written by the Investigator-Sponsor in consultation with the coordinating investigator. 
The first publication will be a full publication of all data of all sites. Any publications of the 
results, either in part or in total (abstracts in journals or newspapers, oral presentations, etc.) 
by investigators or their representatives will require pre-submission review by the 
Investigator-Sponsor.  
 


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13 References 
 
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17. Ilson DH, Ajani J, Bhalla K et al. Phase II trial of paclitaxel, fluorouracil, and cisplatin 
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18. Ajani JA Van Cutsem E, Moiseyenko V et al. Docetaxel (D), cisplatin, 5-fluorouracil 
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20. Nicholson RI, Gee JM, Harper ME. EGFR and cancer prognosis. Eur J Cancer 
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22. Itakura Y, Sasano H, Shiga C et al. Epidermal growth factor receptor over-expression 
in 
esophageal 
carcinoma. 
An 
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23. Kitagawa Y, Ueda M, Ando N et al. Further evidence for prognostic significance of 
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24. al-Kasspooles M, Moore JH, Orringer MB et al. Amplification and over-expression of 
the EGFR and erbB-2 genes in human esophageal adenocarcinomas. Int J Cancer 
1993;54:213–219. 
 
25. Cunningham D, Humblet Y, Siena S et al. Cetuximab monotherapy and cetuximab 
plus irinotecan in irinotecan-refractory metastatic colorectal cancer. N Engl J Med 
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26. Saltz LB, Meropol NJ, Loehrer PJ Sr et al. Phase II trial of cetuximab in patients with 
refractory colorectal cancer that expresses the epidermal growth factor receptor. J 
Clin Oncol 2004;22:1201–1208. 
 
27. Chung KY, Shia J, Kemeny NE et al. Cetuximab shows activity in colorectal cancer 
patients with tumors that do not express the epidermal growth factor receptor by 
immunohistochemistry. J Clin Oncol 2005;23:1803–1810. 
  
28. Susman E. Rash correlates with tumour response after cetuximab. Lancet Oncol 
2004;5:647.  
 
29. Burtness B Li Y, Flood Wet al. Phase III trial comparing cisplatin + placebo to cisplatin 
+ cetuximab in patients with metastatic/recurrent head & neck cancer. Proc Am Soc 
Clin Oncol 2002;21:901a. 
 
30. Wilkinson NW, Black JD, Roukhadze E et al. Epidermal growth factor receptor 
expression correlates with histologic grade in resected esophageal adenocarcinoma. 
J Gastrointest Surg 2004;8:448–453. 
  


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31. Sunpaweravong P, Sunpaweravong S, Puttawibul P et al. Epidermal growth factor 
receptor and cyclin D1 are independently amplified and overexpressed in esophageal 
squamous cell carcinoma. J Cancer Res Clin Oncol 2005;131:111–119. 
  
32. Vanhoefer U, Tewes M, Rojo F et al. Phase I study of the humanized anti-epidermal 
growth factor receptor monoclonal antibody EMD72000 in patients with advanced 
solid tumors that express the epidermal growth factor receptor. J Clin Oncol 
2004;22:175–184.  
 
33. Figlin RA, Belldegrun AS, Crawford J et al. ABX-EGF, a fully human anti-epidermal 
growth factor receptor (EGFR) monoclonal antibody (mAb) in patients with advanced 
cancer: phase 1 clinical results. Proc Am Soc Clin Oncol 2002;21:10a. 
 
34. Lorenzen S, Schuster T, Porschen R et al. Cetuximab plus cisplatin/5-fluorouracil 
versus cisplatin/5-fluorouracil alone in first-line metastatic squamous cell 
carcinoma of the esophagus: a randomized phase II study of the 
Arbeitsgemeinschaft Internistische Onkologie (AIO). Ann Oncol 2009; 20(10): 
1667-1673 
 
35. Saleh MN, Raisch KP, Stackhouse MA et al. Combined modality therapy of A431 
human epidermoid cancer using anti-EGFR antibody C225 and radiation. Cancer 
Biother Radiopharm 1999 ; 14 :451-63 
 
36. Milas L, Mason K, Hunter N et al. In vivo enhancement of tumor radioresponse by 
C225 antiepidermal growth factor receptor antibody. Clin Cancer Res 2000 ; 6 :701-
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37. Peter RU, Beetz A, Ried C et al. Increased expression of the epidermal growth 
factor receptor in human epidermal keratinocytes after exposure to ionizing 
radiation. Radiat Res 1993 ; 136 :65-70 
 
38. Schmidt-Ullrich RK, Mikkelsen RB, Dent P et al. Radiation-induced proliferation of 
the human A431 squamous carcinoma cells is dependent on EGFR tyrosine 
phosphorylation. Oncogene 1997 ; 15 :1191-97 
 
39. Nakama E, Hunter N, Mason K et al. C225 antiepidermal growth factor receptor 
antibody enhances the efficacy of docetaxel chemoradiotherapy. Int J Radiat Oncol 
Biol Phys 2004 ; 59(4) : 1163-73 
 
40. Robert F, Ezekiel MP, Spencer SA et al. Phase I study of anti-epidermal growth 
factor receptor antibody cetuximab in combination with radiation therapy in patients 
with advanced head and neck cancer. J Clin Oncol 2001 ; 19 :3234-4343 
 
41. Bonner JA, Harari PM, Giralt J et al. Cetuximab prolongs survival in patients with 
locoregionally advanced squamous cell carcinoma of head and neck : a phase III 
study of high dose radiation therapy with or without cetuximab. 
 
42. Su YB, Kraus DH, Zelefsky MJ et al. Concurrent Cetuximab, Cisplatin, and 
radiotherapy (RT) for loc-regionally advanced squamous cell carcinoma of the head 
and neck (SCCHN): Updated results of a novel combined modality paradigm. Proc 
Am Soc Clin Oncol 2005; abstr. 5529 
 
43. Safran H, Suntharalingam M, Dipetrillo T et al. Cetuximab with concurrent 
chemoradiation for esophagogastric cancer: assessment of toxicity. Int J Radiat 
Oncol Biol Phys 2008; 70(2): 391-395 
 


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44. Ruhstaller T, Pless M, Dietrich D et al. Cetuximab in combination with 
chemoradiotherapy before surgery in patients with respectable, locally advanced 
esophageal carcinoma: A prospective, multicenter phase IB/II trial (SAKK 75/06). J 
Clin Oncol 2011; Jan 04, Epub ahead of print 
 
45. Erbitux SmPC (Nov 2010) 
 
46. Bonner JA, Harari PM, Giralt J et al. Radiotherapy plus cetuximab for squamous-cell 
carcinoma of the head and neck. NEJM 2006; 354: 567-578 
 
47. Siena S, Glynne-Jones R, Adenis A et al. Reduced incidence of infusion-related 
reactions in metastatic colorectal cancer during treatment with cetuximab plus 
irinotecan with combined corticosteroid and antihistamine premedication. Cancer 
2010; 116(7): 1827-1837 
 
48. Buyse M. Randomized designs in early trials of new cancer treatments: an overview. 
Drug Inf J 2000; 34: 387-96 
 
49. Bedenne L, Michel P, Bouché O et al. Chemoradiation followed by surgery 
compared with chemoradiation alone in squamous cancer of the esophagus: FFCD 
9102. J Clin Oncol 2007; 25: 1160-1168 
 
50. Herskovic A, Martz K, Al-Sarraf M et al. Combined chemotherapy and radiotherapy 
compared with radiotherapy alone in patients with cancer of the esophagus. N Engl 
J Med 1992; 326: 1593-1598 
 
51. Minsky BD, Pajak TF, Ginsberg RJ et al. INT 0123 (Radiation Therapy Oncology 
Group 94-05) Phase III Trial of combined-modality therapy for esophageal cancer: 
High-dose versus standard radiation therapy. J Clin Oncol 2002; 20: 1167-1174 
 
52. Stahl M, Stuschke M, Lehmann N  et al. Chemoradiation with and without surgery in 
patients with locally advanced squamous cell carcinoma of the esophagus. J Clin 
Oncol 2005; 23: 2310-2317 
 
53. Al-Sarraf M, Martz K, Herskovic A et al. Progress report of combined 
chemoradiotherapy versus radiotherapy alone in patients with esophageal cancer: 
An intergroup study. J Clin Oncol 1997; 15: 277-284 
 
54. Cooper JS, Guo MD, Herskovic A et al. Chemoradiotherapy of locally advanced 
esophageal cancer – Long-term follow-up of a prospective randomized trial (RTOG 
85-01). JAMA 1999; 281: 1623-1627 
 
 
 
 


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Appendix 1 
 
 
Protocol Signature Pages 
 
 


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Approval of the Protocol 
 
 
Study protocol No.  
LEOPARD -II 
 
EudraCT No.  
 
2010-023427-18 
 
 
Title 
Definitive radiochemotherapy with 5-FU / cisplatin plus/minus 
cetuximab in locally advanced unresectable esophageal cancer: 
a phase II study. 
 
Version 
 
 
final 3.0 2016.10.06 
 
 
 
 
I confirm that the protocol and the appendices include all necessary information for the 
proper conduct of the study and are in compliance with Good Clinical Practice and applicable 
regulatory requirements. 
 
 
 
 
 
 
 
 
 
Sponsor/Coordinating 
Investigator 
 
Date 
Prof. Dr. Dirk Rades 
 
 
 
 
 


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Investigator Signature Page 
 
 
Study protocol No.  
LEOPARD -II 
 
EudraCT No.  
 
2010-023427-18 
 
 
Title 
Definitive radiochemotherapy with 5-FU / cisplatin plus/minus 
cetuximab in locally advanced unresectable esophageal cancer: 
a phase II study. 
 
Version 
 
 
final 3.0 2016.10.06 
 
 
 
 
I agree to conduct the study in accordance with the protocol described in this document and 
in compliance with Good Clinical Practice and applicable regulatory requirements.  
 
 
Center Number 
 
 
Investigator’s name  
 
Institution 
 
 
 
Address 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Signature Investigator 
 
Date 
 
 
 
 
 
 


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Appendix 2 
 
 
Patient Information Sheet and Consent Form 
 
 
 


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Appendix 3 
 
 
Karnofsky Performance Status Scale 
 


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KARNOFSKY PERFORMANCE STATUS SCALE DEFINITIONS RATING (%) 
CRITERIA 
 
Able to carry on normal activity and to work; no 
special care needed. 
  100  Normal no complaints; no evidence 
of disease. 
90 
Able to carry on normal activity; 
minor signs or symptoms of disease. 
80 
Normal activity with effort; some 
signs or symptoms of disease.  
Unable to work; able to live at home and care 
for most personal needs; varying amount of 
assistance needed. 
70 
Cares for self; unable to carry on 
normal activity or to do active work. 
60 
Requires occasional assistance, but 
is able to care for most of his 
personal needs. 
50 
Requires considerable assistance 
and frequent medical care.  
Unable to care for self; requires equivalent of 
institutional or hospital care; disease may be 
progressing rapidly. 
40 
Disabled; requires special care and 
assistance. 
30 
Severely disabled; hospital admission 
is indicated although death not 
imminent. 
20 
Very sick; hospital admission 
necessary; active supportive 
treatment necessary. 
10 
Moribund; fatal processes 
progressing rapidly. 
0 
Dead 


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Appendix 4 
 
 
RECIST criteria Version 1.1 
 
C:\Dokumente und 
Einstellungen\pilz\Eige 
 


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Appendix 5 
 
Treatment of acneiform skin reactions related to cetuximab 
 
(English version as requested by clinicaltrials.gov;  
for presentation at clinicaltrials.gov only)  
 
Proposed modifications to the NCI–CTCAE v4.03 grading and grade-specific management 
strategies for patients developing radiation dermatitis during treatment with cetuximab plus 
radiotherapy.  
[Bernier J et al., Ann Oncol. 2011 Oct;22(10):2191-200. doi: 10.1093/annonc/mdr139] 
 
Grade of dermatitis associated with radiation-based therapy 
Grade 1 
Grade 2a 
Grade 3a 
Grade 4a 
Definition: 
NCI–
CTCAE, 
v4.03 
dermatitis 
radiation 
Faint erythema 
or dry 
desquamation 
Moderate to brisk 
erythema; patchy 
moist desquamation, 
mostly confined to 
skin folds and 
creases; moderate 
edema 
Moist desquamation 
in areas other than 
skin folds and 
creases; bleeding 
induced by minor 
trauma or abrasion 
Life-threatening 
consequences; 
skin necrosis or 
ulceration of full-
thickness dermis; 
spontaneous 
bleeding from 
involved site; skin 
graft indicated 
Definition: 
Proposed 
modification 
of NCI–
CTCAE, 
v4.03 
Faint erythema 
or dry 
desquamation 
Moderate to brisk 
erythema and/or dry 
desquamation; patchy 
moist desquamation, 
or non-hemorrhagic 
crusts mostly 
confined to skin folds 
and creases 
Moist desquamation 
or hemorrhagic 
crusts; non-
hemorrhagic crusts 
other than in skin 
folds and mostly 
confined to skin folds 
and creases; bleeding 
induced by minor 
trauma or abrasion; 
superinfection 
requiring oral 
antibiotics 
Life-threatening 
consequences; 
extensive 
confluent 
hemorrhagic 
crusts or 
ulceration (>50% 
of involved field); 
extensive 
spontaneous 
bleeding from 
involved site 
(>40% of the 
involved site); 
skin necrosis or 
ulceration of full-
thickness dermis 
or any size ulcer 
with extensive 
destruction, tissue 
necrosis or 
damage to 
muscle, bone or 


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Grade of dermatitis associated with radiation-based therapy 
Grade 1 
Grade 2a 
Grade 3a 
Grade 4a 
supporting 
structures with or 
without full-
thickness skin 
lossb; skin graft 
indicated; 
ulceration 
associated with 
extensive 
superinfection 
with i.v. 
antibiotics 
indicated 
General 
management 
approaches 
Reinforce 
general 
management 
approachesc 
Reinforce general 
management 
approachesc 
Reinforce general 
management 
approachesc 
Reinforce general 
management 
approachesc 
Grade-
specific 
management 
approaches 
• Weekly 
follow-up is 
adequate, 
unless rapid 
progression is 
noted 
• Consider twice-
weekly assessments 
to monitor for rapid 
change 
A. Dry desquamation 
without crusts: 
• Consider 
glucocorticosteroid 
cream or ointment for 
a limited period (1–2 
weeks) 
• Topical antiseptics 
and antibiotics at any 
sign of superinfection
• Consider the use of 
topical antiseptics and 
antibiotics for the 
prevention of more 
severe reactions 
B. Moist 
desquamation in skin 
folds: 
• Topical antiseptic 
• Consider adding 
daily topical 
glucocorticosteroid 
lotion to reduce 
inflammation for a 
limited period (1–2 
weeks) 
• Topical antibiotics 
• Evaluate the need 
for daily assessment 
• Closely monitor for 
signs of local or 
systemic infection 
• For grade 3 
reactions occurring at 
<50 Gy, consider 
brief interruption in 
treatment 
A. Confluent moist 
desquamation without 
crusts: 
• Topical antiseptic• 
Consider adding daily 
topical 
glucocorticosteroid 
lotion to reduce 
inflammation for a 
limited period (1–2 
weeks) 
• Topical antibiotics 
active against S. 
aureus at any sign of 
superinfection 
• If superinfection 
becomes more severe, 
consider the use of 
i.v. antibiotics if 
unresponsive to oral 
antibiotics 
• Consider 
interrupting 
treatment with 
both radiotherapy 
and cetuximab. 
Cetuximab should 
be interrupted 
until the skin 
reaction has 
resolved to at 
least grade 2 
• In the case of 
severe 
superinfection, 
consider the use 
of i.v. antibiotics 
if unresponsive to 
oral antibiotics 
• Hospitalize the 
patient 


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Grade of dermatitis associated with radiation-based therapy 
Grade 1 
Grade 2a 
Grade 3a 
Grade 4a 
active against 
Staphylococcus 
aureus at any sign of 
superinfection. 
Consider systemic 
antibiotics if 
superinfection 
becomes more severe
• Topical eosin or soft 
zinc preparations in 
the skin folds. A thin 
layer of a soft zinc 
preparation may be 
used in skin folds, but 
should be removed 
before treatment with 
radiotherapy to avoid 
radiation dosimetric 
problems. Topical 
eosin in skin folds or 
on erosive lesions 
may also be a useful 
treatment approach. 
C. Dry desquamation 
with isolated non-
hemorrhagic crusts: 
• Topical antiseptic 
• Consider adding 
daily topical 
glucocorticosteroid 
lotion to reduce 
inflammation for a 
limited period (1–2 
weeks) 
• Topical antibiotics 
active against S. 
aureus at any sign of 
superinfection. 
Consider systemic 
antibiotics if 
superinfection 
becomes more severe
• Topical eosin or soft 
zinc preparations in 
the skin folds. A thin 
layer of a soft zinc 
preparation may be 
used in skin folds but 
should be removed 
• Topical eosin or soft 
zinc preparations in 
the skin folds. A thin 
layer of a soft zinc 
preparation may be 
used in skin folds, but 
should be removed 
before treatment with 
radiotherapy to avoid 
radiation dosimetric 
problems. Topical 
eosin in skin folds or 
on erosive lesions 
may also be a useful 
treatment approach 
B. Confluent moist 
desquamation with 
crusts: 
• Topical antiseptic 
• If superinfection 
becomes more severe, 
consider the use of 
i.v. antibiotics if 
unresponsive to oral 
antibiotics 
• Consider 
debridement using 
hydrogels. Skin 
trauma should be 
avoided to prevent 
superinfection 
• If hydrocolloid 
dressings are used, 
the thickness of the 
dressing should be 
taken into account for 
the radiotherapy 
dosimetry. Hydrofiber 
dressings can be used 
after completion of 
radiotherapy 


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Grade of dermatitis associated with radiation-based therapy 
Grade 1 
Grade 2a 
Grade 3a 
Grade 4a 
before treatment with 
radiotherapy to avoid 
radiation dosimetric 
problems 
• Hydrogels can be 
used to keep crusts 
flexible 
• Consider 
debridement using 
hydrogels. Skin 
trauma should be 
avoided to prevent 
superinfection 
Management 
team 
Radiation 
oncologist, 
medical 
oncologist, 
nurse, 
dermatologistd
Radiation oncologist, 
medical oncologist, 
nurse, dermatologistd 
Radiation oncologist, 
medical oncologist, 
nurse, dermatologistd 
Involve a wound-
healing specialist 
in addition to the 
radiation 
oncologist, 
medical 
oncologist, nurse, 
dermatologistd 
 
 
a Possibility of local superinfection as indicated by the clinical appearance (moist desquamation and crusts, with 
yellowing) and by microbiological assessment (from swabs of the area and blood tests); suspected systemic 
superinfection is indicated by the presence of at least two of the following four variables of systemic 
inflammatory response syndrome; fever with a core temperature >38°C or <36°C, heart rate >90 beats per min, 
respiratory rate >20 breaths per min, leukocytosis (>12 × 109/l) or leukopenia (<4 × 109/l). 
b Skin necrosis of full-thickness dermis is rarely seen with the recommended doses of cetuximab plus 
radiotherapy and this type of diagnosis should be based only on a biopsy of tissue from the involved site. 
c See ‘General Measures’ section in the text. 
d Early involvement of a dermatologist may facilitate effective management. 


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Appendix 6 
 
Management options for radiation dermatitis and co-existing 
acneiform skin reactions related to Cetuximab  
 
 
 
 


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Appendix 7 
 
 
NCI Common Toxicity Criteria Version 4.0 
 


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Appendix 8 
 
 
Summary of Product Characteristics Cetuximab 
 
 
 
 


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Appendix 9 
 
 
Summary of Product Characteristics 5-FU (Example) 
 
 
 


StudyCode: LEOPARD-II 
 
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Appendix 10 
 
 
Summary of Product Characteristics Cisplatin 
 

ICF_001.pdf: 
Study code: LEOPARD-II 
EudraCT-Number: 2010-023427-18 
Version 2, 06-08-2012 
 
 
 
Informed consent form – Cover page   
 
 
 
Study protocol No.  
LEOPARD-II 
 
EudraCT No.  
 
2010-023427-18 
 
Title 
Definitive radiochemotherapy with 5-FU / cisplatin plus/minus 
cetuximab in unresectable locally advanced esophageal cancer: 
a phase II study 
 
 
Study phase 
II 
 
 
Coordinating Investigator Dirk Rades, MD (LKP according to §40 AMG) 
Department of Radiation Oncology  
 
 
 
Sponsor 
University Hospital Schleswig-Holstein, Campus Luebeck,  
Ratzeburger Allee 160, 23538 Luebeck 
 
 
 
Date/Version  
 
Version 2, 2012-08-06 
 
 
 


Study code: LEOPARD-II 
EudraCT-Number: 2010-023427-18 
Version 2, 06-08-2012 
 
Informed consent form  
English version as requested by clinicaltrials.gov, for presentation at clinicaltrials.gov only 
 
Center:  
University Hospital Schleswig-Holstein, Campus Lübeck 
 
 
Department of Radiation Oncology, Ratzeburger Allee 160, 23538 Lübeck 
Coordinating Investigator:  Prof. Dr. med. Dirk Rades 
EudraCT-number:   
2010-023427-18 
Study title:    Definitive radiochemotherapy with 5-FU/cisplatin plus/minus cetuximab for 
unresectable locally advanced esophageal cancer: A phase II-study 
 
Protocol code:  
 
LEOPARD-II 
 
 
Patient: 
Full Name (block letters): 
________________________________________ 
 
 
 
Date of birth:  _________________            Patient number:  ________________ 
 
 
Physician: 
Full Name: 
___________________________________________ 
 
 
I have been informed by the above mentioned physician in detail about the investigational 
drug and the comparative therapy, as well as about the nature, extent and significance of this 
study, including the study aim and duration, requirements and possible side effects, my rights 
and obligations, insurance coverage and voluntariness of participation.  
 
I was assured that the informing was complete. I have read and understood the text of the 
patient information and the data protection declaration printed below. The questions I had 
with respect to these have been answered adequately and completely.  
The following topics were discussed in addition to the written information: 
 
___________________________________________________________________________ 
___________________________________________________________________________ 
___________________________________________________________________________ 
I was given sufficient time to decide whether I would like to take part in this study or not.  
 
I have been informed that I may withdraw my consent to participate in this clinical study at 
any time without giving any reasons (orally or in writing), without any negative consequences 
for me regarding my medical treatment.  
 
 
 


Study code: LEOPARD-II 
EudraCT-Number: 2010-023427-18 
Version 2, 06-08-2012 
 
Consent with respect to data protection: 
 
I am aware that personal data collected during this clinical study, in particular medical 
findings, will be recorded, stored and evaluated. The use of my medical data will be in 
accordance with legal stipulations and requires my voluntary consent prior to my 
participation in the study. This means that without the following consent, I cannot take 
part in the clinical study.  
 
1. I agree that personal data collected within this clinical study, in particular medical 
data, will be collected and stored both in paper form and on electronic data storage 
devices. If necessary, the data collected may be communicated in pseudonymous form 
(encoded): 
 
a) to the GSO mbH, the sponsor and a representative of the sponsor responsible for 
scientific evaluation (study management), 
 
b)  in case of application for approval, to the applicant and the responsible regulatory 
authority, the Paul-Ehrlich Institute,   
 
c)  in case of adverse events, to the GSO mbH, the sponsor, the responsible ethics 
committee and the responsible higher federal authority, the Paul-Ehrlich Institute, 
and from this authority to the European database, and 
 
d)  to the manufacturer of the investigational drug (Merck Serono GmbH) 
 
2. In addition, I agree that persons authorized by the sponsor and subject to 
confidentiality, as well as the regulatory authorities, may access the personal data 
stored by the investigator, in particular medical data, if this is necessary to verify that 
the study is being conducted according to protocol. In this respect, I release the 
investigator from the confidentiality agreement.  
 
3. The consent to the storing and processing of my personal data, in particular my 
medical data, is irrevocable. I have already been informed that I may terminate my 
participation in the clinical study at any time. In the case that I withdraw my consent 
to participate in the clinical study, I agree that all data saved until that point may 
continue to be used if necessary in order to:  
 
a) evaluate the effects of the drug investigated.  
 
b) ensure that my legitimate interests are not affected.  
 
c) comply with the obligation to provide complete documents for approval. 
 
4. I agree to the condition that my data will be stored for at least 10 years after the end of 
the study or the termination of my participation therein, as stipulated by guidelines for 
the conduct of clinical studies. After this period, my personal data will be deleted, 
except if longer storage periods are required according due to other reasons. 
 
5. I have been informed about the following legal requirements: In case that I withdraw 
my consent to take part in the clinical study, all locations storing my personal data, in 
particular my medical data, must check whether the data stored for purposes given 
under 3 a) to c) are still required.  
 
Any data that is no longer required must be deleted without delay.  
 
 


Study code: LEOPARD-II 
EudraCT-Number: 2010-023427-18 
Version 2, 06-08-2012 
 
 
6. I agree that my general practitioner (GP)  
 
 
................................................................................................................................... 
 
(Name, address) 
 
 
 
will be informed of my participation in the clinical study and may transfer information 
about my health status to the investigator of this study (if not desired, please cross 
out).  
 
 
 
I agree to participate on a voluntary basis in the clinical study mentioned 
above. 
 
I have received one copy of the patient information plus the informed consent form and the 
conditions of the insurance. One copy remains at the study site.  
 
 
 
___________________________________________________________________________ 
Name of the patient (in block letters) 
 
 
___________________________________________________________________________
Date 
 
 
 
 
 
Signature of the Patient 
 
 
 
I hereby confirm that I have conducted the informed consent discussion and obtained the 
consent from the patient. 
 
 
___________________________________________________________________________
Name of the investigator (on block letters) 
 
 
___________________________________________________________________________
Date 
 
 
 
 
Signature of the Investigator who obtained consent