E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
Unresectable, locally advanced recurrent or metastatic esophageal
squamous cell carcinoma (ESCC)
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Carcinome épidermoïde de l’œsophage récurrent ou métastatique, non résécable et localement avancé
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E.1.1.1 | Medical condition in easily understood language |
Unresectable, locally advanced recurrent or metastatic esophageal
squamous cell carcinoma (ESCC)
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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 | 10055476 |
E.1.2 | Term | Esophageal squamous cell carcinoma |
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 |
- To evaluate and compare the PFS assessed per RECIST version (v) 1.1 following treatment with tislelizumab in combination with chemotherapy compared to placebo in combination with chemotherapy when given as first-line treatment in patients with unresectable, locally advanced recurrent or metastatic ESCC
- To evaluate and compare the overall survival (OS) following treatment with tislelizumab in combination with chemotherapy compared to placebo in combination with chemotherapy when given as first-line treatment in patients with unresectable, locally advanced recurrent or metastatic ESCC |
- Évaluer et comparer la survie sans progression (SSP) d’après l’évaluation d’un comité d’examen indépendant en aveugle (CEIA) selon les critères d’évaluation de la réponse dans les tumeurs solides (RECIST, Response Evaluation Criteria in Solid Tumors) version (v) 1.1 après un traitement par tislelizumab en association à une chimiothérapie par rapport à un placebo en association à une chimiothérapie en traitement de première ligne chez des patients atteints de carcinome épidermoïde de l’œsophage (CEO), récurrent ou métastatique, non résécable et localement avancé.
- Évaluer et comparer la survie globale (SG) après un traitement par tislelizumab en association à une chimiothérapie par rapport à un placebo en association à une chimiothérapie en traitement de première ligne chez des patients atteints de CEO récurrent ou métastatique, non résécable et localement avancé.
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E.2.2 | Secondary objectives of the trial |
- To evaluate and compare the efficacy of tislelizumab in combination with chemotherapy compared to placebo in combination with chemotherapy as a first-line treatment in unresectable, locally advanced recurrent or metastatic ESCC as measured by ORR and DOR assessed per RECIST v1.1
- To evaluate and compare Patient Reported Outcomes (PROs) of health-related quality of life (HRQoL) between tislelizumab in combination with chemotherapy compared to placebo in combination with chemotherapy
- To compare the safety between tislelizumab in combination with chemotherapy and placebo in combination with chemotherapy |
-Évaluer et comparer l’efficacité du tislelizumab en association à une chimiothérapie par rapport à un placebo en association à une chimiothérapie en traitement de première ligne chez des patients atteints de CEO récurrent ou métastatique, non résécable et localement avancé, d’après la mesure du taux de réponse objective (TRO) et de la durée de la réponse (DdR) évalués par le CEIA selon les critères RECIST v1.1.
-Évaluer et comparer les résultats rapportés par le patient (PRO, patient-reported outcomes) concernant la qualité de vie liée à la santé (HRQoL, health-related quality of life) dans le groupe sous tislelizumab en association à une chimiothérapie par rapport au groupe sous placebo en association à une chimiothérapie.
- Comparer la tolérance du tislelizumab en association à une chimiothérapie par rapport à un placebo en association à une chimiothérapie.
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E.2.3 | Trial contains a sub-study | No |
E.3 | Principal inclusion criteria |
• Pathologically (histologically) confirmed diagnosis of ESCC
• Stage IV unresectable ESCC at first diagnosis OR unresectable, locally advanced recurrent or metastatic disease with a treatment free interval of at least 6 months after definitive treatment - Staging by AJCC 7th Edition
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-Diagnostic de CEO confirmé par examen anatomo-pathologique (confirmation histologique).
-CEO non résécable de Stade IV, selon les critères AJCC 7eÉdition, lors du premier diagnostic OU CEO récurrent ou métastatique, non résécable et localement avancé avec un intervalle sans traitement d’au moins 6 mois après un traitement radical.
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E.4 | Principal exclusion criteria |
• Palliative radiation treatment for ESCC within 4 weeks of study treatment initiation
• Prior systemic therapy for unresectable, locally advanced recurrent or metastatic ESCC
• Received prior therapies targeting PD-1, PD-L1 or PD-L2
• Patients with evidence of fistula (either esophageal/bronchial or esophageal/aorta)
• Uncontrollable pleural effusion, pericardial effusion, or ascites requiring frequent drainage or medical intervention (clinically significant recurrence requiring an additional intervention within 2 weeks of intervention)
• Evidence of complete esophageal obstruction not amenable to treatment
• Unintentional weight loss ≥ 5% within one month prior to randomization or other indicators of severe malnutrition - Severe malnutrition may be determined using the Nutritional Risk Index (Shirasu, et al. 2018)
• Patients receiving chemotherapy doublet C (platinum and paclitaxel) must not have peripheral neuropathy ≥ Grade 2 at baseline
• Patients who recur after definitive surgery and are eligible for non-palliative radiation therapy and/or chemoradiotherapy.
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•Radiothérapie palliative pour le CEO dans les 4 semaines précédant l’instauration du traitement à l’étude.
•Antécédents de traitement systémique pour CEO récurrent ou métastatique, non résécable et localement avancé.
•Antécédents de traitement ciblant PD-1, PD-L1 ou PD-L2
•Présence d’une ou plusieurs fistule(s) (œsophagienne s)/bronchiques ou œsophagiennes/aortiques).
•Épanchement pleural, épanchement péricardique ou ascite incontrôlable nécessitant des ponctions ou des interventions médicales fréquentes (récidive cliniquement significative nécessitant une intervention supplémentaire dans les 2 semaines suivant l’intervention).
•Présence d’une obstruction oesophagienne complète ne pouvant pas bénéficier de traitement.
• Perte de poids non intentionnelle ≥ 5% dans le mois précédant la randomisation ou tout autre indicateur de malnutrition sévère.
La malnutrition sévère sera déterminée à l’aide de l’indice de risque nutritionnel (Shirasu et al 2018).
•Les patients recevant le doublet chimiothérapeutique C (platine et paclitaxel) ne doivent pas avoir de neuropathie périphérique ≥ Grade 2 à l’inclusion.
•Absence de récidive après une chirurgie radicale et éligibilité pour une radiothérapie et/ou chimioradiothérapie non palliative. |
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E.5 End points |
E.5.1 | Primary end point(s) |
PFS - defined as the time from the date of randomization to the date of first documentation of disease progression assessed per RECIST v1.1 or death, whichever occurs first
OS - defined as the time from the date of randomization until the date of death due to any cause |
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E.5.1.1 | Timepoint(s) of evaluation of this end point |
PFS and OS – analysis will be carried out at approximately 31 months |
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E.5.2 | Secondary end point(s) |
- ORR - defined as the proportion of patients whose best overall response (BOR) is complete response (CR) or partial response (PR)
- DOR - defined as the time from the first determination of an objective response until the first documentation of progression
- HRQoL assessment of the patient’s overall health status
- PFS, ORR, and DOR
- The incidence and severity of adverse events |
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E.5.2.1 | Timepoint(s) of evaluation of this end point |
ORR - As assessed per RECIST v1.1
DOR - As assessed per RECIST v1.1 or death, whichever comes first
HRQoL - European EORTC QLQ-C30 index, the European esophageal cancer specific module EORTC QLQ-OES18, and the generic health state instrument EuroQol 5D (EQ-5D-5L)
PFS, ORR, and DOR- As assessed by the investigator per RECIST v1.1
- The incidence and severity of adverse events according to NCI-CTCAE v4.03 |
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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 | Yes |
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 | Yes |
E.6.13.1 | Other scope of the trial description |
Immunogenicity, Tolerability |
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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 | No |
E.8.1.3 | Single blind | No |
E.8.1.4 | Double blind | Yes |
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 | Yes |
E.8.2.3 | Other | No |
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 | 11 |
E.8.5 | The trial involves multiple Member States | Yes |
E.8.5.1 | Number of sites anticipated in the EEA | 57 |
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 |
Australia |
Belgium |
China |
Czech Republic |
France |
Germany |
Italy |
Japan |
Korea, Republic of |
Poland |
Romania |
Russian Federation |
Spain |
Taiwan |
United Kingdom |
United States |
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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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E.8.9 Initial estimate of the duration of the trial |
E.8.9.1 | In the Member State concerned years | 2 |
E.8.9.1 | In the Member State concerned months | 4 |
E.8.9.1 | In the Member State concerned days | 0 |
E.8.9.2 | In all countries concerned by the trial years | 2 |
E.8.9.2 | In all countries concerned by the trial months | 6 |
E.8.9.2 | In all countries concerned by the trial days | 0 |