Cetuximab and Radiation Therapy for Surgically Resectable Esophageal and Gastroesophageal (GE) Junction Carcinomas

Study Overview
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Brief Summary
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The interaction of epidermal growth factor receptor (EGFR) inhibitory agents such as cetuximab combined with radiation shows promising results. EGFR inhibitory agents also enhance radiation-induced apoptosis and inhibit radiation induced damage repair. These interactions may represent the principle effects that contribute to the synergy between EGFR and radiation. This trial will investigate the feasibility and activity of this combination in patients with surgically resectable disease.

Detailed Description
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OUTLINE: This is a multi-center study. Cetuximab 400 mg/m2 IV over 120 minutes Day -14 (Loading Dose) Cetuximab 250 mg/m2 IV over 60 minutes, day -7. Cetuximab 250 mg/m2 IV over 60 minutes, days 1, 8, 15, 22, 29 and 36. External beam radiation therapy, beginning on day 1, 4500 cGy to esophagus with boost of 540 cGy at 180 cGy per fraction for 6 weeks. Surgical resection of primary tumor and adjacent mediastinal and/or celiac lymph nodes by a transthoracic approach after satisfactory hematologic and functional recovery within 8 weeks of completion of radiation therapy. For patients who give their consent, fresh frozen tissue will be obtained per EUS at baseline, per EUS 2 weeks after the initiation of cetuximab, and at the time of surgery for pathology submission.

Official Title
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A Pilot Study With Cetuximab and Radiation Therapy for Patients With Surgically Resectable Esophageal and GE Junction Carcinomas: Hoosier Oncology Group Study (GI05-92)

Conditions
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Esophageal Cancer

Intervention / Treatment
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* Procedure: Radiation Therapy
* Procedure: Surgery
* Procedure: Tissue Sample


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Pathological diagnosis of either squamous cell carcinoma or adenocarcinoma of the esophagus or gastroesophageal junction. Clinical stage IIA, IIB or III without metastatic disease Patients must have documented EGFR status or have tumor tissue available for assessment of EGFR status by IHC Patients must be surgical candidates as determined by surgical consult. Patients must agree to surgery. ECOG performance status 0 or 2 Absolute neutrophil count (ANC) > 1,000 mm3 Platelet count > 75,000 mm3· Hemoglobin > 10g/dL Bilirubin < 2.5 X upper limit of normal AST (SGOT) or ALT (SGPT) < 5.0 ´ upper limit of normal Creatinine < 2.0 X upper limit of normal Exclusion Criteria: No history of or current brain metastasis. No significant history of uncontrolled cardiac disease; i.e. uncontrolled hypertension, unstable angina, recent myocardial infarction (within prior 6 months), uncontrolled congestive heart failure, and cardiomyopathy with decreased ejection fraction. No history of interstitial pneumonitis or pulmonary fibrosis, or suspicion of interstitial pneumonitis or pulmonary fibrosis on imaging. No concurrent chemotherapy not indicated in the study protocol or any other investigational agent(s). No prior use of radiation or chemotherapy for cancer of the esophagus or GE junction No prior therapy that specifically and directly targets the EGFR pathway (such as kinase inhibitors and antibodies directed against the HER family receptors). No prior severe infusion reaction to a monoclonal antibody. No major surgery within 28 days prior to being registered for protocol therapy. No clinically significant infections as judged by the treating investigator. No acute hepatitis or known HIV. No other active malignancies. Negative pregnancy test. No female patients currently breastfeeding.

Ages Eligible for Study
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Minimum Age: 18 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: Investigational Treatment<br>Cetuximab 400 mg/m2 IV over 120 minutes Day -14 (Loading Dose) Cetuximab 250 mg/m2 IV over 60 minutes Day -7 Cetuximab 250 mg/m2 IV over 60 minutes Days 1, 8, 15, 22, 29 and 36 Combined with radiation therapy for six weeks. Surgery for esophageal resection after 6 to 8 week rest period. Subjects who consent will provide tissue samples. | Procedure: Radiation Therapy<br>* External beam radiation therapy, beginning on day 1, 4500 cGy to esophagus with boost of 540 cGy at 180 cGy per fraction for 6 weeks<br>Procedure: Surgery<br>* Surgical resection of primary tumor and adjacent mediastinal and/or celiac lymph nodes by a transthoracic approach after satisfactory hematologic and functional recovery within 8 weeks of completion of radiation therapy<br>Procedure: Tissue Sample<br>* For patients who give their consent, fresh frozen tissue will be obtained per EUS at baseline, per EUS 2 weeks after the initiation of chemotherapy, and at the time of surgery for pathology submission<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Complete Pathologic Response (pCR) | To evaluate complete pathologic response rate in patients with esophageal and GE junction carcinomas. Complete pathologic response (pCR) is defined as the absence of tumor cells on the resected specimen in the esophagus and/or GE junction. | 36 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Complete Pathological Response Rate for Patients Who Underwent Esophagectomy. | To evaluate complete pathologic response rate in patients with esophageal and GE junction carcinomas that underwent esophagectomy. Complete pathologic response (pCR) is defined as the absence of tumor cells on the resected specimen in the esophagus and/or GE junction. | Up to 36 months | 
| Time to Relief of Dysphagia | To evaluate time to relief of dysphagia in patients with esophageal and GE junction carcinomas receiving preoperative radiation and cetuximab | 36 months | 
| Evaluate Toxicity | To evaluate the overall toxicities of preoperative radiation and cetuximab in patients with esophageal and GE junction carcinomas | 36 months | 
| Perform Exploratory Molecular Correlates. | To perform exploratory molecular correlates to determine the mechanisms of response and resistance to cetuximab and radiation therapy. | 36 months | 
| Complete and Partial Response Rate for Patients by Disease Stage: IIA | To evaluate complete and partial response rate of preoperative radiation and cetuximab in patients with esophageal and GE junction carcinomas | 36 months | 
| Complete and Partial Response Rate for Patients by Disease Stage: IIB | To evaluate complete and partial response rate of preoperative radiation and cetuximab in patients with esophageal and GE junction carcinomas | 36 months | 
| Complete and Partial Response Rate for Patients by Disease Stage: III | To evaluate complete and partial response rate of preoperative radiation and cetuximab in patients with esophageal and GE junction carcinomas | 36 months | 
| Complete and Partial Response Rate for Patients by Histology: Adenocarcinoma | To evaluate complete and partial response rate of preoperative radiation and cetuximab in patients with esophageal and GE junction carcinomas | 36 months | 
| Complete and Partial Response Rate for Patients by Histology: Squamous Cell | To evaluate complete and partial response rate of preoperative radiation and cetuximab in patients with esophageal and GE junction carcinomas | 36 months |