Erbitux Combined With Chemo-radiotherapy in Esophageal Squamous Cell Carcinoma

Study Overview
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Brief Summary
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The purpose of this study is to determine whether the treatment of locally advanced esophageal squamous cell carcinoma (ESCC)with cetuximab in combination with paclitaxel, cisplatin and radiation improve clinical outcomes.

Detailed Description
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Esophageal cancer is the sixth leading cause of cancer death worldwide. Over the past 2 decades, well-designed clinical trials have documented the clinical benefits of combination of chemotherapy and radiation for localized esophageal cancer, either as primary therapy or in neoadjuvant setting. Paclitaxel, a radiation sensitizer, has important single-agent activity in esophageal cancer. Paclitaxel-based chemoradiation has been the framework for the recent Radiation Therapy Oncology Group (RTOG) trials of nonoperative management of esophageal cancer. Accumulating clinical evidence suggests that epidermal growth factor receptor (EGFR) represents a viable target in the treatment of esophageal cancer. EGFR expression is associated with poor prognosis. Cetuximab, a monoclonal antibody, binds specifically to EGFR on both normal and tumor cells and competitively inhibits the binding of EGF and other ligands, such as transforming growth factor (TGF)-α. Preclinical models have suggested synergy between cetuximab, paclitaxel, cisplatin and radiation. For patients with locally advanced head and neck cancer, the combination of cetuximab and radiation has demonstrated both response and survival benefit. With all these, the investigators hypothesize that treatment of locally advanced esophageal squamous cell carcinoma (ESCC)with cetuximab in combination with paclitaxel, cisplatin and radiation may further improve clinical outcomes. This trial results will be important as it may support further studies for setting the new treatment standard for ESCC.

Official Title
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An Open-labeled Study to Evaluate Efficacy of Combining Erbitux Plus Concurrent Chemo-radiotherapy in Locally Advanced Esophageal Squamous Cell Carcinoma (ESCC)

Conditions
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Esophageal Cancer

Intervention / Treatment
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* Drug: cetuximab (Erbitux)
* Drug: Paclitaxel
* Drug: Cisplatin
* Radiation: Radiation


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Inpatients or outpatients, ≥ 18 years of age Histologically confirmed primary (non-recurrent) ESCC fulfilling one of the following criteria (AJCC Staging System) cervical esophageal carcinoma, stage Ⅱ-Ⅲ upper thoracic esophageal carcinoma, stage Ⅱ-Ⅲ, or mid-thoracic esophageal carcinoma, stage Ⅱ-Ⅲ,which is medically unfit for surgery, surgery been refused and patient medically able to tolerate chemo-radiation. Evidence of unidimensional measurable disease as per Response Evaluation Criteria in Solid Tumours (RECIST). ECOG Performance status of 0-1 Effective contraception for both male and female patients if the risk of conception exists Adequate bone marrow reserves: neutrophil (ANC) count ≥ 1500 /mm^3, platelet count ≥ 100,000 /mm^3, hemoglobin ≥ 9 g/dl Adequate renal function: serum creatinine ≤ 1.5 mg/dl and/or calculated creatinine clearance ≥ 60 ml/min Adequate hepatic function: bilirubin level ≤ 1.5 x ULN, ASAT & ALST ≤ 1.5 x ULN Tumor tissue available for KRAS biomarker test Signed written informed consent prior to study entry Exclusion Criteria: Previous chest radiotherapy, systemic chemotherapy, and major esophageal surgery Concurrent chronic systemic immune therapy, targeted therapy not indicated in this study protocol Multiple primary carcinomas of the esophagus Pregnancy (confirmed by serum or urine β-HCG) or lactation period; Uncontrolled diabetes, hypertension, and severe cardiac or pulmonary disease Unable to comprehend the study requirements or who are not likely to comply with the study parameters; Distant metastasis Second malignancy, except for curable non-melanoma skin cancer, cervical cancer in situ, or malignant disease, free for ≥ 5 years Known grade 3 or 4 allergic reaction to any of the study treatment

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: cetuximab, concurrent chemo-radiotherapy<br>Cetuximab, injection, loading dose400 mg/m^2,(Day1 in Week1) followed by 250 mg/m^2(Day1, every week for Weeks 2-8) Paclitaxel, injection,45 mg/m^2 (Day 1, every week for Weeks 2-8) Cisplatin, injection,20 mg/m^2 (Day 1, every week for Weeks 2-8) radiation therapy, 59.4 Gy, 1.8 Gy/33 fractions,1 fraction daily, Days 1-5 every week for Weeks 2-7, and Days 1-3 for Week 8 | Drug: cetuximab (Erbitux)<br>* Cetuximab,injection,loading dose400 mg/m^2,(Day1 in Week1) followed by 250 mg/m^2(Day1, every week for Weeks 2-8)<br>* Other names: erbitux;Drug: Paclitaxel<br>* Paclitaxel,injection,loading dose 45 mg/m^2,(Day1 in every week for Weeks 2-8)<br>Drug: Cisplatin<br>* Cisplatin,injection,loading dose 20 mg/m^2,(Day1 in every week for Weeks 2-8)<br>Radiation: Radiation<br>* Radiation, External beam therapy, total 59.4 Gy , 33 fractions, 1.8 Gy per fraction.(Day 1-Day 5 in every week 2-week 8).<br>* Other names: Intensity Modulated Radiotherapy;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Participants With Overall Response Rate (RR) | The overall response rate was defined as the numbers of patients with a complete response (CR) or partial response (PR). CR was defined as no target lesion at follow-up computed tomography scan and barium swallow examination 3-6 weeks after completion of chemo-radiation. PR was defined at least a 30% decrease in the sum of diameters of target lesions, taking as reference the baseline sum diameters. | 1 to 3 month after therapy | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Participants With Toxicity | All patients were regularly monitored for possible adverse events, which were graded according to National Cancer Institute Common Toxicity Criteria version 3.0. | Every week during treatment and 1 month after therapy | 
| Participants With Overall Survival (OS) at 1 Year |  | 1 year from the date of diagnosis | 
| Participants With Overall Survival (OS) at 3 Year |  | 3 year from the date of diagnosis | 
| Participants With Progression Free Survival (PFS) |  | Recurrence or metastasis from the date of diagnosis | 
| Number of Participants With K-ras Gene Mutation | DNA was extracted from tumor specimens.Screened for the presence of KRAS codon 12 and 13 mutations using a PCR clamping and melting curve technique. PCR amplification of the wild-type KRAS sequence was suppressed in this process by the incorporation in the reaction mix of a locked nucleic-acid oligomer16 spanning codons 12 and 13 of the KRAS gene. Post-PCR hybridization and melting curve analysis using fluorescently tagged oligonucleotides incorporated in the original PCR reaction permitted the identification and discrimination of distinct KRAS codon 12 and 13 missense mutations. | 07/29/2010-09/30/2010 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Therapeutic, Drug Therapy, combination, Radiotherapy