clinical study protocol
resectability / response criteria per

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.  
| Complete Response                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                    | Disappearance of all target lesions. Any pathological lymph nodes                                                                                                                                                                                                                                                 |
|----------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|-------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|
| (CR):                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                | (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                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                  | At least a 20% increase in the sum of diameters of target lesions, taking                                                                                                                                                                                                                                         |
| (PD):                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                | 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  Disappearance of all non-target lesions and normalization of tumor  (CR):  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  Unequivocal progression of existing non-target lesions. (Note: the  (PD):  appearance of one or more new lesions is also considered  progression).  Evaluation of best overall response |                                                                                                                                                                                                                                                                                                                   |
clinical study protocol
evaluation of target lesions

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 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    | No            | PR                 |
| evaluated         |                      |               |                    |
| SD                | Non-PD or not all    | No            | SD                 |
| evaluated         |                      |               |                    |
| Not all evaluated | Non-PD               | No            | NE                 |
| PD                | Any                  | Yes or No     | PD                 |
| Any               | PD                   | Yes or No     | PD                 |
| Any               | Any                  | Yes           | PD                 |
clinical study protocol
7.5.2 residual tumor classification (r-classification)

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 Rclassification 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
clinical study protocol
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.
clinical study protocol
8.1 analysis set descriptions safety

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.
clinical study protocol
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.
clinical study protocol
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. 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.
clinical study protocol
8.2 target variables 8.2.1 primary

For quantification of efficacy the primary objective is the 2-year overall survival.
clinical study protocol
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
clinical study protocol
8.3 statistical analysis 8.3.1 statistical

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)
clinical study protocol
toxicity

Both treatment groups are compared for toxicity using the Chi-square test.
clinical study protocol
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.
clinical study protocol
8.3.3 rationale for the application

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.
clinical study protocol
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.  
- 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.
clinical study protocol
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 singlearm 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 [4954]. 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.  
| 2-year OS probability   | Necessary  number of   |              |    |        |
|-------------------------|------------------------|--------------|----|--------|
| Sample size             | events                 |              |    |        |
| CT only                 | CT plus                | Hazard ratio |    |        |
| 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 |
clinical study protocol
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.
clinical study protocol
9 immuno(histo)chemistry and blood samples

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
clinical study protocol
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.
clinical study protocol
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.
clinical study protocol
11 ethical and regulatory aspects

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.
clinical study protocol
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.
clinical study protocol
11.3 patient consent 11.3.1 informed

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.
clinical study protocol
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.
clinical study protocol
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.
clinical study protocol
11.5 ethics committee or institutional

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.
clinical study protocol
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.
clinical study protocol
11.7 sponsorship

This is an investigator sponsored trial. The study will be sponsored by the University Hospital Schleswig-Holstein, Campus Luebeck, Germany.
clinical study protocol
12 study management 12.1 case

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.
clinical study protocol
12.2 source data and subject

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.
clinical study protocol
12.3 investigator site file and

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.  
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.
clinical study protocol
12.4 monitoring quality assurance and

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.
clinical study protocol
12.5 changes to the study

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.  
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.
clinical study protocol
12.6 study report and publication

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.
clinical study protocol
13 references

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18. Ajani JA Van Cutsem E, Moiseyenko V et al. Docetaxel (D), cisplatin, 5-fluorouracil compared to cisplatin (C) and 5-fluorouracil (F) for chemotherapy-naïve patients with metastatic or locally recurrent, unresectable gastric carcinoma (MGC): Interim results of a randomized phase III trial (V325). Proc Am Soc Clin Oncol 2003;22:249.  
19. Thuss-Patience PC, Kretzschmar A, Repp M et al. Docetaxel and continuous-infusion fluorouracil versus epirubicin, cisplatin, and fluorouracil for advanced gastric adenocarcinoma: a randomized phase II study. J Clin Oncol 2005;23:494–501.  
20. Nicholson RI, Gee JM, Harper ME. EGFR and cancer prognosis. Eur J Cancer 2001;37(suppl 4):S9–S15.  
21. Hirai T, Kuwahara M, Yoshida K et al. Clinical results of transhiatal esophagectomy for carcinoma of the lower thoracic esophagus according to biological markers. Dis Esophagus 1998;11:221–225.  
22. Itakura Y, Sasano H, Shiga C et al. Epidermal growth factor receptor over-expression in esophageal carcinoma. An immunohistochemical study correlated with clinicopathologic findings and DNA amplification. Cancer 1994;74:795–804.  
23. Kitagawa Y, Ueda M, Ando N et al. Further evidence for prognostic significance of epidermal growth factor receptor gene amplification in patients with esophageal squamous cell carcinoma. Clin Cancer Res 1996;2:909–914.  
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 2004;351:337–345.  
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.  
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 :701708 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 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
appendix 1 protocol signature pages
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
appendix 1 protocol signature pages
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  
Patient Information Sheet and Consent Form  
Karnofsky Performance Status Scale
appendix 1 protocol signature pages
karnofsky performance status scale definitions

| 100                                                                                                                   | Normal no complaints; no evidence  of disease.                                          |                                                                        |
|-----------------------------------------------------------------------------------------------------------------------|-----------------------------------------------------------------------------------------|------------------------------------------------------------------------|
| Able to carry on normal activity and to work; no  special care needed.                                                | 90                                                                                      | Able to carry on normal activity;  minor signs or symptoms of disease. |
| 80                                                                                                                    | Normal activity with effort; some  signs or symptoms of disease.                        |                                                                        |
| 70                                                                                                                    | Cares for self; unable to carry on  normal activity or to do active work.               |                                                                        |
| Unable to work; able to live at home and care  for most personal needs; varying amount of  assistance needed.         | Requires occasional assistance, but                                                     |                                                                        |
| 60                                                                                                                    | is able to care for most of his  personal needs.                                        |                                                                        |
| 50                                                                                                                    | Requires considerable assistance  and frequent medical care.                            |                                                                        |
| 40                                                                                                                    | Disabled; requires special care and  assistance.  Severely disabled; hospital admission |                                                                        |
| 30                                                                                                                    | is indicated although death not  imminent.                                              |                                                                        |
| Unable to care for self; requires equivalent of  institutional or hospital care; disease may be  progressing rapidly. | Very sick; hospital admission                                                           |                                                                        |
| 20                                                                                                                    | necessary; active supportive  treatment necessary.                                      |                                                                        |
| 10                                                                                                                    | Moribund; fatal processes  progressing rapidly.                                         |                                                                        |
| 0                                                                                                                     | Dead                                                                                    |                                                                        |  
RECIST criteria Version 1.1 C:\Dokumente und  
  
Einstellungen\pilz\Eigene Dateien\Sonstiges\RECISTGuidelines 1.1.pdf
appendix 5 treatment of acneiform
(english version as requested by

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]  
| Life-threatening  consequences;  skin necrosis or  ulceration of fullthickness dermis;  spontaneous  bleeding from  involved site; skin  graft indicated                                                                                                                                   |                                                                                                                  |    |
|-----------------------------------------------------------------------------------------------------------------------------------|------------------------------------------------------------------------------------------------------------------|----|
| Moderate to brisk  erythema; patchy                                                                                               |                                                                                                                  |    |
| Faint erythema  moist desquamation,  or dry  mostly confined to  desquamation  skin folds and  creases; moderate  edema           |                                                                                                                  |    |
| Definition:  NCI– CTCAE,  v4.03  dermatitis  radiation                                                                            | Moist desquamation  in areas other than  skin folds and  creases; bleeding  induced by minor  trauma or abrasion | 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 fullthickness dermis  or any size ulcer  with extensive  destruction, tissue  necrosis or  damage to  muscle, bone or    |
| Moist desquamation  or hemorrhagic  crusts; nonhemorrhagic 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                                                                                                                                   |                                                                                                                  |    |
| Moderate to brisk  erythema and/or dry  desquamation; patchy                                                                      |                                                                                                                  |    |
| Faint erythema  moist desquamation,  or dry  or non-hemorrhagic  desquamation  crusts mostly  confined to skin folds  and creases |                                                                                                                  |    |
| Definition:  Proposed  modification  of NCI– CTCAE,  v4.03                                                                        |                                                                                                                  |    |
appendix 5 treatment of acneiform
grade of dermatitis associated with

| Grade of dermatitis associated with radiation-based therapy            |                                            |                                            |                                            |
|------------------------------------------------------------------------|--------------------------------------------|--------------------------------------------|--------------------------------------------|
| Grade 1                                                                | Grade 2a                                   | Grade 3a                                   | Grade 4a                                   |
| supporting  structures with or  without fullthickness skin  lossb ; skin graft  indicated;  ulceration  associated with  extensive  superinfection  with i.v.  antibiotics  indicated                                                                        |                                            |                                            |                                            |
| Reinforce  general  management  approachesc                            |                                            |                                            |                                            |
| General  management  approaches                                        | Reinforce general  management  approachesc | Reinforce general  management  approachesc | Reinforce general  management  approachesc |
| - Consider twiceweekly 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                                                                        |                                            |                                            |                                            |
| - Weekly  follow-up is  adequate,  unless rapid  progression is  noted |                                            |                                            |                                            |
| Gradespecific  management  approaches  Version final 3.0 2016.10.06                                                                        | CONFIDENTIAL                               | 74/81                                      |                                            |  
| 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 nonhemorrhagic 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           |            |            |            |  
| 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 | Involve a woundhealing specialist  in addition to the  radiation  oncologist,  medical  oncologist, nurse,  dermatologistd                                                                   |          |          |
| Radiation  oncologist,                                                                                                                                                                                                                | Radiation oncologist,                                             |          |          |
| medical                                                                                                                                                                                                                               | medical oncologist,                                               |          |          |
| oncologist,                                                                                                                                                                                                                           | nurse, dermatologistd                                             |          |          |
| nurse,  dermatologistd                                                                                                                                                                                                                | Radiation oncologist,  medical oncologist,  nurse, dermatologistd |          |          |
| Management  team                                                                                                                                                                                                                      |                                                                   |          |          |  
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.  
Management options for radiation dermatitis and co-existing acneiform skin reactions related to Cetuximab  
NCI Common Toxicity Criteria Version 4.0  
Summary of Product Characteristics Cetuximab  
Summary of Product Characteristics 5-FU (Example)  
Summary of Product Characteristics Cisplatin