Background
Methods and design
Study objectives
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➢ Arm A = experimental arm: durvalumab in combination with FOLFOX and definitive IMRT.Chemoradiotherapy (CRT): IMRT 50 Gy in 25 daily fractions in combination with FOLFOX regimen administrated during and after radiotherapy every two weeks for a total of 6 cycles. Durvalumab: 1500 mg one infusion q4w starting with CRT for a total of 12 cycles.
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➢ Arm B = standard arm: CRT: FOLFOX and definitive IMRT.Chemoradiotherapy IMRT 50 Gy in 25 daily fractions in combination with FOLFOX regimen administrated during and after radiotherapy every two weeks for a total of 6 cycles.
Sample size and main statistical analysis
Patient selection
Main inclusion criteria | Main exclusion criteria |
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• Histologically proven squamous cell carcinoma or adenocarcinoma of the esophagus, • Unresectable disease due to anatomical consideration or medical condition (patient unfit for surgical procedure) according to local multidisciplinary team meeting, • Presence of at least one measurable lesion > 10 mm with spiral CT-scan, • No prior therapy for the esophageal cancer including chemotherapy or radiotherapy prior to the study, except anterior out of field radiotherapy, received for treatment of another primary tumor considered in remission, in the past 5 years, • Age ≥ 18 years old, • WHO performance status < 2, • Body weight > 35 kg, • Patients must have provided consent for the study by signing and dating a written informed consent form prior to any study specific procedures, sampling, or analyses, • Patient must be affiliated to a social security regimen | • Previous treatment with an PD-1, PD-L1 or CTLA-4 inhibitor • Metastatic disease, • Patients should not receive live vaccine 30 days prior to study treatment • Female patients who are pregnant or breastfeeding • Uncontrolled intercurrent illness including, but not limited to diabetes, hypertension, pulmonary failure, chronic renal or hepatic diseases, active peptic ulcer disease or gastritis, active bleeding, diatheses (non-exhaustive list), • Clinically significant cardiac disease or impaired cardiac function, • Current or prior use of immunosuppressive medication within 28 days before the first administration of durvalumab (exception: systemic corticosteroids at physiologic doses not exceeding 10 mg/day of prednisone or equivalent are allowed as well as steroids as premedication for hypersensitivity reactions (e.g., CT scan premedication)—Topical, inhaled, nasal, and ophthalmic steroids are allowed, • Active or prior documented autoimmune or inflammatory disorders • Known primary immunodeficiency or active HIV, • Patient with a dihydropyrimidine dehydrogenase (DPD) deficiency (the test must be done for all patients before 5-FU administration), • Known active or chronic viral hepatitis or history of any type of hepatitis within the last 6 months indicated by positive HBs antibody test for hepatitis B or hepatitis C virus ribonucleic acid (HCV antibody), • Current pneumonitis or interstitial lung disease, • Other invasive malignancy within 2 years prior to entry into the study, except for those treated with curative surgical therapy alone, • History of severe allergic reactions or hypersensitivity to any unknown allergens or any components of the study drug, • Any prior corticosteroid-refractory immune-related adverse event (irAE), • Oeso-tracheal or oeso-bronchial fistulae, • Major surgery within 28 days prior to the first dose of study treatment |
Clinical study endpoints
Secondary endpoints are:
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Progression-Free Survival (local PFS) is defined as the time from randomization until progression or deaths; patients alive and without progression at last follow-up news are censored at this date.
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OS defined by the delay between randomization and the occurrence of death due to any cause. Patients still alive at the time of analysis (including lost of follow-up) will be censored at the last known alive date.
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Safety will be assessed by the toxicity grading of the National Cancer Institute Common Terminology Criteria for Adverse Events (NCI-CTCAE v 5.0). To be considered evaluable for safety, patients must have received at least one treatment dose.
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Quality of life (QL) will be assessed by the European Organization for Research and Treatment of Cancer (EORTC) core QL questionnaires, the EORTC QLQ-C30 and QLQ-OES18 (Oesophageal Cancer Module).
Medical procedures
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FOLFOX 4 simplified protocol, 1 infusion every 2 weeks during 3 months starting with radiotherapy (± 1 day): IV oxaliplatin 85 mg/m2 in 2 h on day 1 (D1), IV Leucovorin 200 mg/m2 in 2 h on day 1 (D1), followed by IV 5-FU 400 mg/m2 in 10 min on day 1 (D1) followed by IV continuous infusion 5-FU 2400 mg/m2 during 46 h.
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Durvalumab is delivered to patients included in the experimental arm with a cumulative dose over the whole trial of 18,000 mg (12 cycles):◦Every 4 weeks during concurrent RT and FOLFOX (dose: 1500 mg): 3 infusions (IV administration before the FOLFOX regimen).◦Every 4 weeks (dose: 1500 mg) after FOLFOX completion: 9 infusions (IV administration).
Treatment planning
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50 Gray (Gy) in 25 fractions of 2 Gy delivered to the macroscopic disease (tumour and involved lymph nodes)
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45 Gy in 25 fractions of 1.8 Gy to the adjacent peri-tumoural mucosis and prophylactic lymph nodes.
Quality assurance in radiotherapy
Data management
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The management and the monitoring of the study according to UNICANCER procedures;
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The quality control data of the investigational centers by the monitor involves:
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verifying that the protocol, as well as the current guidelines ICH-GCP, the national regulatory requirements, are accurately followed,
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verifying the informed consent and the eligibility of each patient participating in another research,
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verifying that the CRF data is consistent and in agreement with the source documents,
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verifying the notification of each SAE,
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verifying the drug traceability (dispatching, storage and accountability),
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verifying that patients are not already participating in another research trial which may exclude their inclusion in this protocol. The monitor also verifies that patients have not participate in another trial following which an exclusion period if applicable before they can participate in another protocol,
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The audit of the participating investigational centers when deemed necessary;
Treatment tolerance
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Starts at the date of the signature on the informed consent form,
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Covers the entire period during which the patient is receiving the investigational treatment or is subject to specific procedures related to the trial,
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Covers a period of 150 days after the last administration of durvalumab for Arm A and 30 days after FOLFOX for Arm B.