Oxaliplatin, Gefitinib, and Radiation Therapy in Treating Patients With Locally Advanced or Metastatic Esophageal Cancer

Study Overview
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Brief Summary
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RATIONALE: Drugs used in chemotherapy, such as oxaliplatin, work in different ways to stop tumor cells from dividing so they stop growing or die. Gefitinib may stop the growth of tumor cells by blocking the enzymes necessary for their growth. Radiation therapy uses high-energy x-rays to damage tumor cells. Combining oxaliplatin and gefitinib with radiation therapy may kill more tumor cells. PURPOSE: This phase I/II trial is studying the side effects and best dose of oxaliplatin when given together with gefitinib and radiation therapy and to see how well they work in treating patients with locally advanced or metastatic esophageal cancer.

Detailed Description
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OBJECTIVES: Primary Determine the maximum tolerated dose of oxaliplatin when administered with gefitinib and radiotherapy in patients with locally advanced or metastatic adenocarcinoma or squamous cell carcinoma of the esophagus or gastroesophageal junction. (Phase I) Determine the response rate in patients treated with this regimen. (Phase II) Secondary Determine time to tumor progression and median survival in patients treated with this regimen. Determine quality of life in patients treated with this regimen. Determine the safety of this regimen in these patients. OUTLINE: This is a phase I, open-label, dose-escalation study of oxaliplatin followed by a phase II study. Phase I: Patients receive oxaliplatin IV over 2 hours on days 1, 15, and 29. Beginning on day 1, patients undergo radiotherapy once daily, 5 days a week, for 5.5 weeks. Patients also receive oral gefitinib once daily on days 1-365. Treatment continues in the absence of disease progression or unacceptable toxicity Approximately 3-6 weeks after the completion of chemoradiotherapy, patients are evaluated. Some patients undergo surgical resection* and possibly receive a second course of oxaliplatin (IV over 2 hours on days 1, 15, and 29) 4-8 weeks after surgery. If surgery is not indicated, some patients may receive an additional course of oxaliplatin. Cohorts of 3-6 patients receive escalating doses of oxaliplatin until the maximum tolerated dose is determined. The MTD is defined as the dose preceding that at which 2 of 3 or 2 of 6 patients experience dose-limiting toxicity. Phase II: Patients receive oxaliplatin, gefitinib, and radiotherapy as in phase I at the MTD. Some patients then either undergo surgical resection* and/or begin a second course of oxaliplatin as in phase I. NOTE: *Oral gefitinib is discontinued ≥ 7 days before surgery and is restarted when the patient has recovered. Quality of life is assessed at baseline, 5-6 weeks, and then every 2-3 months for 1 year. Patients are followed every 2-3 months for 1 year. PROJECTED ACCRUAL: Approximately 15-45 patients (3-12 for phase I and 12-33 for phase II) will be accrued for this study within 2 years.

Official Title
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ZD1839 (IRESSA®) With Oxaliplatin and Radiotherapy for Esophageal Carcinoma. A Phase I/II Study With Biologic Correlates

Conditions
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Esophageal Cancer

Intervention / Treatment
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* Drug: gefitinib
* Drug: oxaliplatin
* Procedure: conventional surgery
* Procedure: neoadjuvant therapy
* Radiation: radiation therapy


Participation Criteria
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Eligibility Criteria
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DISEASE CHARACTERISTICS: Histologically confirmed adenocarcinoma or squamous cell carcinoma of the esophagus or gastroesophageal (GE) junction Locally advanced or metastatic disease by clinical staging, including esophagogastroduodenoscopy and esophageal ultrasound Stage T2, N0 disease and beyond Bulk of tumor must be in the esophagus of patients with GE junction tumor Bronchoscopy is required if primary esophageal tumor is < 26 cm from the incisors No brain metastases PATIENT CHARACTERISTICS: Age Over 18 Performance status ECOG 0-1 Life expectancy At least 4 months Hematopoietic WBC ≥ 3,000/mm^3 Granulocyte count ≥ 1,500/mm^3 Platelet count > 100,000/mm^3 Hepatic Bilirubin normal ALT and AST ≤ 2.5 times upper limit of normal (ULN) Alkaline phosphatase ≤ 2.5 times ULN Renal Not specified Cardiovascular No symptomatic congestive heart failure No unstable angina pectoris No cardiac arrhythmia Pulmonary No clinically active interstitial lung disease Patients with chronic stable asymptomatic radiographic changes are eligible Other Not pregnant or nursing Negative pregnancy test Fertile patients must use effective double-method (including barrier) contraception during and for 3 months after study participation No peripheral neuropathy ≥ grade II No severe hypersensitivity to gefitinib or any of its excipients No history of allergy to platinum-based compounds or antiemetics administered with protocol-directed chemotherapy No active or ongoing infection No other uncontrolled illness No other significant clinical disorder or laboratory finding that would preclude study participation PRIOR CONCURRENT THERAPY: Biologic therapy No concurrent colony-stimulating factors during course 1 of study therapy Chemotherapy More than 4 weeks since prior chemotherapy Endocrine therapy Concurrent steroid therapy allowed Radiotherapy More than 4 weeks since prior radiotherapy Surgery Not specified Other More than 30 days since prior non-approved or investigational drugs No concurrent administration of any of the following: Phenytoin Carbamazepine Rifampin Barbiturates Highly-active antiretroviral therapy (HAART) Hypericum perforatum (St. John's wort) No other concurrent investigational agents or therapy

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 120 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
Masking: None (Open Label)


Arms and Interventions

| Intervention/Treatment |
| --- |
|Drug: gefitinib|nan|
|Drug: oxaliplatin|nan|
|Procedure: conventional surgery|nan|
|Procedure: neoadjuvant therapy|nan|
|Radiation: radiation therapy|nan|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Maximum tolerated dose (phase I) |  |  | 
| Response (phase II) |  |  | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Survival |  |  | 
| Quality of life |  |  | 
| Safety and toxicity |  |  | 
| Immunohistochemistry |  |  | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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adenocarcinoma of the esophagus, recurrent esophageal cancer, stage II esophageal cancer, stage III esophageal cancer, stage IV esophageal cancer, squamous cell carcinoma of the esophagus