E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
Locally advanced esophageal carcinoma. |
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E.1.1.1 | Medical condition in easily understood language |
Advanced esophagus cancer. |
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E.1.1.2 | Therapeutic area | Diseases [C] - Cancer [C04] |
MedDRA Classification |
E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 20.0 |
E.1.2 | Level | LLT |
E.1.2 | Classification code | 10041824 |
E.1.2 | Term | Squamous cell carcinoma of esophagus |
E.1.2 | System Organ Class | 100000004864 |
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E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 20.0 |
E.1.2 | Level | LLT |
E.1.2 | Classification code | 10056092 |
E.1.2 | Term | Adenocarcinoma of oesophagus |
E.1.2 | System Organ Class | 100000004864 |
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E.1.3 | Condition being studied is a rare disease | No |
E.2 Objective of the trial |
E.2.1 | Main objective of the trial |
Determine the efficacy of neoadjuvant radiochemotherapy (RCT) combined with immunotherapy followed by adjuvant immunotherapy compared with the same schedule without immunotherapy (neoadjuvant and adjuvant). |
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E.2.2 | Secondary objectives of the trial |
Compare the toxicity of the two therapy arms and determine patterns of failure overall and with regard to histology; further to evaluate economic aspects in a subproject and to perform a radiotherapy quality assurance program. |
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E.2.3 | Trial contains a sub-study | Yes |
E.2.3.1 | Full title, date and version of each sub-study and their related objectives |
Translational research: Biobanking of tissue samples from initial biopsy and from surgical specimen (applicable for patients who gave consent for biobanking only). |
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E.3 | Principal inclusion criteria |
Histologically confirmed squamous cell carcinoma (including basaloid-squamous cell and adenosquamous carcinoma) or adenocarcinoma of the thoracic esophagus or the esophagogastric junction (from 5 cm below the entrance of the esophagus into the thorax to the gastric cardia (=esophagogastric junction), types I and II according to the Siewert staging system). Resectable, locally advanced disease (the stage is determined by the combination of CT scan, EUS and PET and by a multidisciplinary team discussion) Age: 18-75 years Health status: WHO performance status (PS) ≤ 1 Patient is considered operable (appropriate organ functions) Adequate renal function: creatinine clearance > 60 mL/min, calculated according to the formula of Cockroft-Gault Adequate pulmonary function: FEV1 > 1.5L or, if < 1.5L at least 75% of the reference value Adequate hepatic function: bilirubin ≤ 1.0 x ULN, AP ≤ 2.5 x ULN, AST ≤ 1.5 x ULN Adequate hematologic values: neutrophils ≥ 1.5 x 109/L, platelets ≥ 100 x 109/L Adequate coagulation profile: normal INR, PTT ≤ 1.0 x ULN Patient compliance and geographic proximity allow proper staging and follow-up. Women are not breastfeeding, are using effective contraception if sexually active, are not pregnant and agree not to become pregnant during participation in the trial and during the 12 months thereafter. Men agree not to father a child during participation in the trial and during the twelve months thereafter. |
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E.4 | Principal exclusion criteria |
Stage T1 Nany M0 Stage T2 N0 M0 Stage T4a due to infiltration of the tracheo-bronchial tree or organ involvement which cannot be operated on with curative intent (R0) as decided by a multidisciplinary team discussion Stage T4b Distant metastasis (M1) Cervical esophageal carcinoma and tumors involving the first 5 cm of the thoracic esophagus Airway infiltration in case of tumors at or above the tracheal bifurcation Peritoneal carcinomatosis in case of adenocarcinomas infiltrating the gastric cardia (i.e. esophagogastric junction carcinoma Siewert type I or II) Previous malignancies within five years or concomitant malignancies, except: nonmelanomatous skin cancer or adequately treated in situ cervical cancer Prior chemotherapy or prior RT to the chest Severe or uncontrolled cardiovascular disease (congestive heart failure NYHA III or IV, unstable angina pectoris, history of myocardial infarction within the last twelve months, significant arrhythmias) Psychiatric disorder precluding understanding of information on trial related topics, giving informed consent and answering the questions of the EQ-5D questionnaire and HEA forms (EQ-5D questionnaire and HEA forms applicable for Swiss centers and for patients who gave consent for the HEA only) Active uncontrolled infection Serious underlying medical condition (judged by the investigator) which could impair the ability of the patient to participate in the trial (e.g. uncontrolled diabetes mellitus, active autoimmune disease) Preexisting peripheral neuropathy (> grade 1) Concurrent treatment with other experimental drugs or other anti-cancer therapy; treatment in a clinical trial within 30 days prior to trial entry Definite contraindications for the use of corticosteroids and antihistamines as premedication Known hypersensitivity to trial drugs or hypersensitivity to any other component of the trial drugs Any concomitant drugs contraindicated for use with the trial drugs according to the product information of the pharmaceutical companies |
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E.5 End points |
E.5.1 | Primary end point(s) |
Progression-free survival (PFS) |
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E.5.1.1 | Timepoint(s) of evaluation of this end point |
Time from randomization to one of the following events, whichever comes first: · Tumor progression at any time · Recurrence at local, regional or distant site after surgery · Death from any cause |
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E.5.2 | Secondary end point(s) |
· Progression-free survival after surgery (PFS-OP) · Adverse events according to CTCAE version 4.0 and major postoperative complications · Pathological remission (=TRG 1+2) · R0-resection · Overall survival · Time to loco-regional failure after R0-resection · Time to systemic failure after R0-resection · Feasibility of the therapy: Completion of therapy · In-hospital mortality · Compliance with radiotherapy standards |
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E.5.2.1 | Timepoint(s) of evaluation of this end point |
Please refer to protocol section 13. |
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E.6 and E.7 Scope of the trial |
E.6 | Scope of the trial |
E.6.1 | Diagnosis | No |
E.6.2 | Prophylaxis | No |
E.6.3 | Therapy | Yes |
E.6.4 | Safety | Yes |
E.6.5 | Efficacy | Yes |
E.6.6 | Pharmacokinetic | No |
E.6.7 | Pharmacodynamic | No |
E.6.8 | Bioequivalence | No |
E.6.9 | Dose response | No |
E.6.10 | Pharmacogenetic | No |
E.6.11 | Pharmacogenomic | No |
E.6.12 | Pharmacoeconomic | No |
E.6.13 | Others | No |
E.7 | Trial type and phase |
E.7.1 | Human pharmacology (Phase I) | No |
E.7.1.1 | First administration to humans | No |
E.7.1.2 | Bioequivalence study | No |
E.7.1.3 | Other | No |
E.7.1.3.1 | Other trial type description | |
E.7.2 | Therapeutic exploratory (Phase II) | No |
E.7.3 | Therapeutic confirmatory (Phase III) | Yes |
E.7.4 | Therapeutic use (Phase IV) | No |
E.8 Design of the trial |
E.8.1 | Controlled | Yes |
E.8.1.1 | Randomised | Yes |
E.8.1.2 | Open | Yes |
E.8.1.3 | Single blind | No |
E.8.1.4 | Double blind | No |
E.8.1.5 | Parallel group | Yes |
E.8.1.6 | Cross over | No |
E.8.1.7 | Other | No |
E.8.2 | Comparator of controlled trial |
E.8.2.1 | Other medicinal product(s) | No |
E.8.2.2 | Placebo | No |
E.8.2.3 | Other | Yes |
E.8.2.3.1 | Comparator description |
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E.8.2.4 | Number of treatment arms in the trial | 2 |
E.8.3 |
The trial involves single site in the Member State concerned
| No |
E.8.4 | The trial involves multiple sites in the Member State concerned | Yes |
E.8.4.1 | Number of sites anticipated in Member State concerned | 10 |
E.8.5 | The trial involves multiple Member States | Yes |
E.8.5.1 | Number of sites anticipated in the EEA | 16 |
E.8.6 Trial involving sites outside the EEA |
E.8.6.1 | Trial being conducted both within and outside the EEA | Yes |
E.8.6.2 | Trial being conducted completely outside of the EEA | No |
E.8.6.3 | If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned |
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E.8.7 | Trial has a data monitoring committee | Yes |
E.8.8 |
Definition of the end of the trial and justification where it is not the last
visit of the last subject undergoing the trial
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The inclusion of patients is planned to start in Q2 2010 and will stop after the inclusion of 300 patients, which is expected in Q3 2013. End of trial treatment (last patient, last visit) is expected for Q2 2014. All patients will be followed up for five years after the inclusion of the last patient, or less than five years if the trial team decides to stop collecting further follow-up data. |
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E.8.9 Initial estimate of the duration of the trial |
E.8.9.1 | In the Member State concerned years | 4 |
E.8.9.1 | In the Member State concerned months | 0 |
E.8.9.1 | In the Member State concerned days | 0 |
E.8.9.2 | In all countries concerned by the trial years | 4 |
E.8.9.2 | In all countries concerned by the trial months | 0 |
E.8.9.2 | In all countries concerned by the trial days | 0 |