Plattenepithelkarzinom des Ösophagus, 1 st -line

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1 Plattenepithelkarzinom des Ösophagus, 1 st -line AIO-STO-0309 An open-label, randomized phase III trial of cisplatin and 5-fluorouracil with or without panitumumab for patients with nonresectable, advanced or metastatic esophageal squamous cell cancer (ESCC) POWER - Studie Protocol No. AIO-STO-0309 Protocol Version (Date) Version Title Detailed Title POWER An open-label, randomized phase III trial of cisplatin and 5-fluorouracil with or without panitumumab for patients with nonresectable, advanced or metastatic esophageal squamous cell cancer (ESCC) EudraCT No Inernational Coordinating Investigator PD Dr. Markus Moehler I. Medizinische Klinik und Poliklinik Johannes-Gutenberg-Universität Langenbeckstr Mainz moehler@mail.uni-mainz.de Sponsor Study design AIO-Studien-gGmbH Kuno-Fischer-Straße Berlin Phone: Fax: Open-label, randomized, parallel group, multicenter, multinational Phase III study Patients will receive chemotherapy or chemotherapy plus panitumumab every 3 weeks Start date February 2012 Duration of study Total number of centers Study population 3 years (including recruitment and follow-up phase) Approximately 50 study sites, including approximately 25 sites in Germany and centers in other European countries (BEL, UK, IRL, ESP. ). The study is open for participation of further centers, please contact the AIO- Studien-gGmbH. Patients with nonresectable, advanced or metastatic esophageal squamous cell cancer (ESCC) Objectives Primary objective Secondary objectives To demonstrate superiority of 5-fluorouracil, cisplatin and panitumumab over 5-fluorouracil and cisplatin alone in terms of overall survival in esophageal cancer To compare treatment arms with respect to:

2 Progression-free survival 1-year survival Response rate Safety and tolerability Quality of Life Exploratory objectives To assess: The potential correlation between the regimen and EGFR expression Functional EGFR gene polymorphisms EGFR gene amplification (FISH) KRAS and BRAF mutations EGFR downstream proteins and gene expression parameters, proteomics and epigenetics Planned sample size A total of 300 patients will be randomized in a 1:1 ratio Inclusion criteria Exclusion criteria 1. Signed written informed consent 2. Male or female 18 years of age 3. Histologically proven squamous cell carcinoma of the esophagus, which is not curatively resectable* or locally recurrent disease and both not eligible** for definitive radiochemotherapy, or clearly metastatic disease (Tx, Nx, M1, locally unresectable T4, Nx, M0 or TX, N3, M0)* or macroscopically residual (post-resection) disease not eligible** for definitive radiochemotherapy *resectability has to be defined prior to randomization according to local standards: 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), patient refusal, other reasons. **eligibility to definitive radiochemotherapy will be determined according to local standards based on the extent of disease, performance status/nutritional status, co-morbidity (pulmonary function, other), volume of neighboring organs within the radiation field, patient refusal, other reasons. 4. Measurable or non-measurable disease according to RECIST ECOG Women of child-bearing potential must have a negative pregnancy test 7. Laboratory requirements Hematology: o Absolute neutrophil count 1.5x10 9 /L o Platelet count 100x10 9 /L o Leukocyte count > 3.0x10 9 /L o Hemoglobin 9 g/dl or 5.59 mmol/l Hepatic Function: o Total bilirubin 1.5 time the upper normal limit (UNL) o AST 2.5xUNL in absence of liver metastases, or 5xUNL in presence of liver metastases o ALT 2.5xUNL in absence of liver metastases, or 5xUNL in presence of liver metastases Renal Function: o Creatinine clearance 50 ml/min according to Cockroft-Gault formula Metabolic Function o Magnesium lower limit of normal o Calcium lower limit of normal. Patients with any of the following will not be eligible for participation:

3 1. Previous chemotherapy of esophageal cancer except for neoadjuvant treatment without recurrence within 6 months after the end of treatment. 2. Concurrent radiotherapy involving target lesions used for this study. Concurrent palliative radiation for non-target lesions is allowed if other lesions are available outside the involved field. Previous pre-operative or post-operative radiotherapy is allowed. 3. Previous exposure to EGFR-targeted therapy 4. 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 or other curatively treated malignant disease without recurrence after at least 5 years of follow-up 5. Known brain metastases unless adequately treated (surgery or radiotherapy) with no evidence of progression and neurologically stable off anticonvulsants and steroids 6. Serious concomitant disease or medical condition that in the judgment of the investigator renders the subject at high risk of treatment complication or reduces the probability of assessing clinical effect. 7. Clinically significant cardiovascular disease (including myocardial infarction, unstable angina, symptomatic congestive heart failure, serious uncontrolled cardiac arrhythmia) 1 year before enrolment 8. Inadequate pulmonary function according to the Investigator s judgment, history of interstitial lung disease e.g. pneumonitis or pulmonary fibrosis or evidence of interstitial lung disease on baseline chest CT scan. 9. Hearing loss > NCI-CTC V.3.0 Grade Subject pregnant or breast feeding, or planning to become pregnant within 6 months after the end of treatment. 11. Subject (male or female) is not willing to use highly effective methods of contraception (per institutional standard) during treatment and for 6 months (male or female) after the end of treatment. 12. Contraindications to receive any platin, 5-FU or panitumumab 13. Concurrent treatment with other experimental drugs or participation in another clinical trial with any investigational drug within 30 days prior to treatment start 14. Known drug abuse/alcohol abuse 15. peripheral polyneuropathy > NCI-CTC V 3.0 Grade chronic inflammatory bowels diseases 17. Social situations limiting the compliance with the study requirements. Treatment scheme Arm A (Active Comparator) CF: Cisplatin 100 mg/m² IV infusion over 2 hours d1 5-FU 1000 mg/m² daily IV infusion over 24 hours d1-4 Each treatment cycle is defined as 21 days. Arm B (Experimental) CF plus panitumumab: Cisplatin 100 mg/m² IV infusion over 2 hours d1 5-FU 1000 mg/m² daily IV infusion over 24 hours d1-4 Each treatment cycle is defined as 21 days. Panitumumab will be administered on Day 1 of each treatment cycle at a dose of 9 mg/kg prior to administration of chemotherapy. Panitumumab will be administered as a 90 minutes ± 15 minutes IV infusion. If the first infusion is well tolerated (without any serious infusion related reactions) all subsequent infusions may be administered over 60 minutes ± 15 minutes. In the event a subject s actual weight requires greater than 150mL volume infusion, panitumumab will be administered over 60 to 90 minutes ± 15 minutes, as

4 tolerated. Patients are treated until progression of disease occurs or any other reason for treatment withdrawal is fulfilled. Data Safety Monitoring Board A Data Safety Monitoring Board (DSMB) will be implemented to formally review safety data when 40, 100 and 200 patients are randomized and treated for at least one cycle. The DSMB will focus on safety and survival data only. 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) In addition, these early toxicity data will also be judged in comparison with other studies combining cisplatin and panitumumab. 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. Primary parameter Overall survival (OS) Secondary parameters Progression-free survival (PFS) 1-year survival Response rate Safety and tolerability Quality of Life Exploratory parameters Translational research analysis in tumor tissue and serum samples Study procedures After the initial screening procedure, eligible patients will be randomized in a ratio of 1:1 to receive either chemotherapy consisting of cisplatin and 5-FU every 3 weeks or chemotherapy consisting of cisplatin and 5-FU plus panitumumab every 3 weeks until disease progression occurs. Tumor assessments will be performed every 9 weeks (beginning from treatment start, i.e. Cycle 1 Day 1). All patients will have an end of treatment visit 3 weeks (+ 7 days) after the last dose of the study agent. Thereafter, all patients will be followed up for survival every 3 months. Randomization procedure Permuted block randomization will be applied to guarantee balanced group numbers.. To increase homogeneity between the two treatment arms, randomization will be stratified by Locally advanced (yes vs. no) Prior neoadjuvant treatment (yes vs. no) Sample size calculation With a total number of events required of 256 deaths, a test of superiority of the survival curves with a 5% two-sided significance level will have 90% power to reject the null-hypothesis when the median survival times in the reference and experiment group are 6 and 9 months, respectively. A total of 300 eligible patients will be enrolled to obtain the 256 deaths across both arms. Planned Interim Analysis No confirmatory interim analyses for efficacy with the aim to stop the trial

5 prematurely due to superiority or futility are foreseen within this study protocol.