SOX-based CRT for Esophageal Cancer.

Study Overview
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Brief Summary
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Patients with esophageal cancer that had locally advanced diseases or with unresectable diseases are being asked to participate in this phase I/II study. This phase I/II study is being conducted to determine the maximum-tolerated dose (MTD), dose-limiting toxicity (DLT), and efficacy of IMRT combined with S-1 and Oxaliplatin (SOX) based chemotherapy for unresectable locally advanced esophageal cancer.

Detailed Description
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Esophageal carcinoma (EC) remains difficult to cure with overall 5-year survival rates for locally advanced stages being poor. Definitive concurrent chemoradiotherapy (dCRT) remains the mainstay of treatment for locally advanced and unresectable EC. Oxaliplatin is a new generation platinum with a more preferable toxicity profile compared to cisplatin. Furthermore, S-1 combines 5-Fu prodrug (tegafur) and two modulators of 5-Fu metabolism, gimeracil (CDHP) and oteracil. Basic studies showed that S-1 has superior anti-cancer effects than 5-Fu and enhances the sensitivity of cancer cells to the effects of radiotherapy. Herein, we designed a prospective phase I/II study, which is combined S-1 and oxaliplatin with IMRT for the patients with locally advanced and unresectable esophageal cancer, and evaluated the tolerability and efficacy of this combination. <Phase I> Primary Objective: To establish the safety of combination chemotherapy comprising oxaliplatin (escalating doses: 110, 120, 130 mg/m2, day 1 and day 29), fixed dose of S-1 (80 mg/m2, day1-14 and day 29-42) and IMRT (5040cGy/28fx/5W+) in unresectable locally advanced esophageal cancer. Secondary Objective: To observe the efficacy of this regimen in these patients. <Phase II> Primary Objective: To assess the response rate of combination chemotherapy comprising oxaliplatin (recommended dose determined in phase I study, day1 and day29), fixed dose of S-1 (80 mg/m2, day1-14 and day 29-42), and IMRT (5040cGy/28fx/5W+) in unresectable locally advanced esophageal cancer. Secondary Objectives: To determine the adverse reactions of this regimen in these patients. To determine PFS(Progression free survival) of patients treated with this regimen. To determine OS (overall survival) of patients treated with this regimen. To explore the Health-related Quality of life using EORTC QLQ-C30 and EORTC QLQ-OES18 in these patients.

Official Title
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A Phase I/II Study of S-1 and Oxaliplatin Based Definitive Concurrent Chemoradiotherapy (SOX-CRT-01) for Unresectable Locally Advanced Esophageal Cancer.

Conditions
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Esophageal Cancer

Intervention / Treatment
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* Drug: Oxaliplatin
* Drug: S-1 capsule
* Radiation: Intensity modulated radiotherapy (IMRT)


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Cytopathological confirmed esophageal cancer with unresectable locally advanced diseases; Age of 18-70; ECOG performance status: 0-1; No treatments prior to enrollment; Patients must have measurable or evaluable disease with at least one tumor mass maximum diameter ≥10mm by multi-slice spiral CT or MR scan. Imaging exam must be performed within 15 days from enrollment. Normal marrow function and the blood tests must be collected within 7 days from enrollment with a hemoglobin of ≥90g/L, an white blood cell (WBC) counts of ≥4.0×109/L，a neutrophil count of ≥2.0×109/L, , a platelet count of ≥100×109/L, a total bilirubin (TBil) of ≤1.0 upper normal limitation (UNL), a creatinine (Cr) of ≤ 1.0 UNL, alanine aminotransferase (ALAT) and aspartate aminotransferase (ASAT) of ≤2.5 UNL, Alkaline phosphatase (AKP) ≤5.0 UNL. Pulmonary function (FEV1 >1L), and no major electrocardiogram abnormalities. Normal electrocardiogram results and no history of congestive heart failure; Patients must be with good compliance and agree to accept follow-up of disease progression and adverse events; Informed consent signed. Exclusion Criteria: Prior treatments of chemotherapy or irradiation; Poor bone marrow, liver and kidney functions, which would make chemotherapy intolerable; Contraindication for irradiation: complete obstruction of esophagus, deep esophageal ulcer, fistula to mediastinum, or haematemesis; Participating in other clinical trials; Pregnancy, breast feeding, or not adopting birth control; Clinically significant and uncontrolled major medical conditions including but not limited to: active uncontrolled infection, symptomatic congestive heart failure, Unstable angina pectoris or cardiac arrhythmia, psychiatric illness/ social situation that would limit compliance with study requirements; any medical condition, which in the opinion of the study investigator places the subject at an unacceptably high risk for toxicities; Weight loss of 20% or more of normal body weight within 3 months. The subject has had another active malignancy within the past five years except for cervical cancer in site, in situ carcinoma of the bladder or non-melanoma carcinoma of the skin;

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 70 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: SOX-based Chemoradiotherapy<br>IMRT is delivered with a daily fraction of 1.8 Gy to a total dose of 50.4 Gy over 5 weeks. Concurrent Oxaliplatin (3 levels for phase I: 110mg/m², 120 mg/m² and 130 mg/m², d1) and fixed dose of S-1 (80mg/ m², d1-14) are administered concurrently with IMRT, every 4 weeks. The recommended dose of Oxaliplatin are then further evaluated in the Phase II setting. | Drug: Oxaliplatin<br>* Oxaliplatin (3 levels for phase I: 110 mg/m², 120 mg/m² and 130 mg/m²) is administered as a 2 h intravenous infusion in 500 mL of 5% glucose on day 1 and day 29 during the treatment course.<br>Drug: S-1 capsule<br>* Patients received a fixed dose of S-1 with a dose of 80 mg/m2/d twice daily for 2 weeks, every 4 weeks.<br>Radiation: Intensity modulated radiotherapy (IMRT)<br>* The total radiation dose was set to 50.4 Gy, which was given in 28 fractions of 1.8 Gy once-daily fractions for over 5 weeks.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Incidence of Treatment-Emergent Adverse Events | Phase I: toxicities will be assessed based on the common toxicity criteria for adverse events version 4.0 (CTCAE v4.0). | 1 month | 
| Response rate | Phase II: Response rate will be done after 4 weeks following the last radiotherapy session as evaluated by RECIST 1.1. | 1 month | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Recommended dose of Oxaliplatin for phase II trial. | To determine the recommended phase II dose (RD) of Oxaliplatin with fixed dose of S-1 in combination with IMRT for esophageal cancer (Phase I). | 1 month | 
| Number of Participants with Adverse Events (Phase II). | Both the number of subjects with adverse events and the degree of the adverse events of each participant according to NCI CTCAE version 4.0 will be recorded. And the outcome of each adverse event will be followed. | 6 months | 
| Overall survival time | Overall survival (OS) is determined as the time (in months) between the first day of therapy and the last follow-up or the date of death. | 0-2 years | 
| Progression-free survival time | Progression-free survival (PFS) is calculated from the date of CRT initiation to the date of documented failure (local recurrence or metastasis occurrence) or the date of the last follow-up for those remaining. | 0-2 years | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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S-1, esophageal cancer, chemoradiotherapy, oxaliplatin