RATIONALE: Drugs used in chemotherapy, such as oxaliplatin, work in different ways to stop tumor cells from dividing so they stop growing or die. Radiation therapy uses high-energy x-rays to damage tumor cells. Gefitinib may stop the growth of tumor cells by blocking the enzymes necessary for their growth. Combining oxaliplatin and gefitinib with radiation therapy may kill more tumor cells.

PURPOSE: Phase I/II trial to study the effectiveness of combining oxaliplatin and gefitinib with radiation therapy in treating patients who have locally advanced or metastatic esophageal cancer.

Condition	Treatment or Intervention	Phase
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	Drug: gefitinib  Drug: oxaliplatin  Procedure: anti-cytokine therapy  Procedure: antiangiogenesis therapy  Procedure: biological response modifier therapy  Procedure: chemosensitization/potentiation  Procedure: chemotherapy  Procedure: conventional surgery  Procedure: enzyme inhibitor therapy  Procedure: growth factor antagonist therapy  Procedure: neoadjuvant therapy  Procedure: protein tyrosine kinase inhibitor therapy  Procedure: radiation therapy  Procedure: radiosensitization  Procedure: surgery	Phase I Phase II

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.

• 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.

• 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 3-45 patients (3-12 for phase I and 12-33 for phase II) will be accrued for this study within 2 years.

Ages Eligible for Study:  18 Years and above,  Genders Eligible for Study:  Both

Criteria

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 esophagastroduodenoscopy 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

New York
      Roswell Park Cancer Institute, Buffalo,  New York,  14263-0001,  United States; Recruiting

Study chairs or principal investigators

Milind Javle, MD,  Principal Investigator,  Roswell Park Cancer Institute   

Study ID Numbers:  CDR0000389253; RPCI-PH-04603; ZENECA-IRUSIRES0303
Record last reviewed:  September 2004
Record first received:  October 6, 2004
ClinicalTrials.gov Identifier:  NCT00093652
Health Authority: Unspecified
ClinicalTrials.gov processed this record on 2004-11-08