Chemotherapy & Erlotinib in Treating Patients w/ Esophageal or Gastroesophageal Cancer That Cannot Be Removed by Surgery

Study Overview
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Brief Summary
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The purpose of this study is to test the safety and effectiveness of erlotinib and FOLFOX in patients with esophageal or gastro-esophageal cancer that cannot be removed by surgery.

Detailed Description
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More than 50% of patients with advanced esophageal cancer present with disease that cannot be removed by surgery or has spread to other parts of the body. Improved therapies for patients with advanced esophageal cancer are therefore urgently needed. The epidermal growth factor receptor (EGFR) inhibitor erlotinib (in combination with chemotherapy) has lead to improved survival in patients with pancreatic and lung cancer. EGFR is a target in esophageal cancer therapy since its overexpression is associated with more aggressive disease and poor survival. Early studies have shown some clinical activity of EGFR inhibitors in this disease alone or in combination with chemotherapy. This study aims to explore how safe and effective treatment with erlotinib and FOLFOX is in patients with advanced esophageal or gastro-esophageal cancer.

Official Title
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A Single-Arm, Phase II Study of Tarceva Plus FOLFOX6 in Patients With Unresectable or Metastatic Cancer of Esophagus or Gastroesophageal Junction

Conditions
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Esophageal Cancer

Intervention / Treatment
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* Drug: Erlotinib
* Drug: 5-fluorouracil
* Drug: Leucovorin
* Drug: Oxaliplatin


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Histologically confirmed esophageal carcinoma (squamous or adenocarcinoma) Surgically unresectable disease and/or metastatic disease; endoscopic accessibility of the primary tumor is preferred but not a prerequisite No prior chemotherapy therapy except for neoadjuvant treatment (radiation and/or chemotherapy); prior treatment with EGFR-inhibiting agents is not allowed Life expectancy > 12 weeks Patients must have the ability to take and retain oral medications or have an appropriate percutaneous feeding tube in place Patients must have Eastern Cooperative Oncology Group (ECOG) performance status of 0, 1, or 2 (Karnofsky Performance Status (KPS) >= 50%) Patients must have measurable disease by Response Evaluation Criteria in Solid Tumors (RECIST) criteria and radiographic imaging performed within 28 days prior to registration Absolute neutrophil count (ANC) >= 1500/mL Platelet count >= 100,000/mL Hemoglobin level >= 10.0 gm/dL Serum creatinine =< 1.5 x IULN (institutional upper limits of normal); OR measured creatinine clearance >= 60 mL/min Aspartate aminotransferase (AST) (serum glutamic oxaloacetic transaminase (SGOT)) or alanine aminotransferase (ALT) (serum glutamic pyruvate transaminase (SGPT)) =< 2.5 x IULN (unless the liver is involved by tumor, in which case it must be =< 5.0 x IULN) Total bilirubin =< 1.5 x IULN Provision of written informed consent Women of childbearing potential (WOCBP) must be willing to practice acceptable methods of birth control to prevent pregnancy; WOCBP are any females who have experienced menarche and who have not undergone surgical sterilization (hysterectomy, bilateral tubal ligation, or bilateral oophorectomy), who are not postmenopausal (defined as amenorrhea >= 12 consecutive months), or are on hormone replacement therapy; acceptable methods of birth control include oral or hormonal contraceptives and barrier methods (e.g., condom, diaphragm) used in combination with other methods (e.g., spermicide) Male patients who are capable of fathering a child must avoid doing so while participating in this study through the use of acceptable methods of birth control; this is a precautionary measure because this study involves chemotherapy agents Exclusion Criteria: Presence of a Kras mutation Lack of expression of EGFR (tumors that do not have detectable EGFR staining in at least 10% of tumor cells will not be considered EGFR-positive) Prior treatment with EGFR-inhibiting agents, chemotherapy, or radiotherapy for esophagogastric carcinomas (other than neoadjuvant treatment as noted in inclusion criteria) Patients must not be receiving any other investigational agents; use of erythropoietin is allowable; secondary prophylaxis with granulocyte colony stimulating factor (G-CSF) (Filgrastim) is allowable The patient concomitantly uses phenytoin, carbamazepine, barbiturates, rifampicin, phenobarbital, or St. John's wort Uncontrolled brain metastases Patients must not have uncontrolled intercurrent illness at the time of registration including, but not limited to, ongoing or active infection, symptomatic congestive heart failure, unstable angina, pectoris, cardiac arrhythmia, or psychiatric illness/social situations that would limit compliance with study requirements Patients must not have current New York Heart Association Class III or IV heart disease Known human immunodeficiency virus (HIV) infection Pregnant or breast-feeding women Patients who have had prior malignancies, except non-melanoma skin cancer (basal or squamous cell carcinoma) are not eligible for this study; unless greater than 5 years has passed since the event Known severe hypersensitivity to Tarceva Treatment with a non-approved or investigational drug within 30 days before day 1 of trial treatment Incomplete healing from previous oncologic or other major surgery Serum creatinine level greater than Common Toxicity Criteria (CTC) grade 2

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: Tarceva and FOLFOX<br>COMBINATION THERAPY PHASE: Patients receive erlotinib hydrochloride orally (PO) once daily (QD) on days 1-56. Patients also receive FOLFOX6 therapy comprising oxaliplatin intravenously (IV) over 2 hours, leucovorin calcium IV over 2 hours, and fluorouracil IV over 46-48 hours on days 1, 15, 29, and 43. Courses repeat every 8 weeks in the absence of disease progression or unacceptable toxicity. Patients with stable disease or no evidence of disease after course 2 or subsequent courses continue on to maintenance phase. MAINTENANCE PHASE: Patients receive erlotinib hydrochloride PO QD on days 1-42. Treatment repeats every 6 weeks in the absence of disease progression or unacceptable toxicity. | Drug: Erlotinib<br>* Tarceva single agent therapy: 150 mg/day PO<br>* Other names: Tarceva;Drug: 5-fluorouracil<br>* 5-FU bolus: 400 mg/m2 IV once every 2 weeks for 16 weeks 5-FU infusion: 2400 mg/m2 IV over 46-48 hours, once every 2 weeks for 16 weeks<br>* Other names: Adrucil;Drug: Leucovorin<br>* 400 mg/m2 IV once every 2 weeks for 16 weeks<br>* Other names: Folinic acid;Drug: Oxaliplatin<br>* 85 mg/m2 IV once every 2 weeks for 16 weeks<br>* Other names: Eloxatin;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Progression Free Survival (PFS) | PFS is defined as the duration of time from enrollment into the run-in period of the study to objective tumor progression as determined by Response Evaluation Criteria in Solid Tumors (RECIST) criteria. The proportion of patients with PFS will be reported and evaluated using Kaplan-Meier survival curves with median survival and 95% confidence interval. | Up to 2 years | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Objective Response Rate (RR) | The best overall response is the best response recorded from the start of the treatment until disease progression/recurrence (taking as reference for Progressive Disease (PD) the smallest measurements recorded since the treatment started). Best response assignment will depend on the achievement of both measurement and confirmation criteria using RECIST for both target and non-target lesions. For target lesions, response is defined as follows: Complete Response (CR): Disappearance of all target lesions; Partial Response (PR): >= 30% decrease in sum of the LD, taking as reference the baseline sum LD; PD: >=20% increase in sum of the LD of target lesions, taking as reference smallest sum LD recorded since treatment started or appearance of one or more new lesions , Stable Disease (SD): Neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for PD, taking as reference the smallest sum LD since the treatment started. | Up to 2 years | 
| Time to Progression (TTP) | Patient with objective tumor response or stable disease will be treated with single agent Tarceva until tumor progression. For this study, time to progression will be determined as the number of days following the first day of single agent treatment with Tarceva following the last and completed cycle of Tarcerva/FOLFOX combination therapy. TTP will be calculated for the entire patient population as well as for patients that objectively responded to the combination therapy versus those that did not. | Up to 2 years | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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metastatic esophageal cancer, erlotinib, folfox, advanced esophageal cancer, unresectable esophageal cancer