Paclitaxel, Cisplatin, Gefitinib, and Radiation Therapy Followed by Surgery and Gefitinib in Treating Patients With Locally Advanced Cancer of the Esophagus or Gastroesophageal Junction That Can Be Removed By Surgery

Study Overview
=================
Brief Summary
-----------------
RATIONALE: Drugs used in chemotherapy, such as paclitaxel and cisplatin, work in different ways to stop the growth of tumor cells, either by killing the cells or by stopping them from dividing. Gefitinib may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth. Radiation therapy uses high-energy x-rays to kill tumor cells. Giving these treatments before surgery may make the tumor smaller and reduce the amount of normal tissue that needs to be removed. Giving gefitinib after surgery may kill any tumor cells that remain after surgery. PURPOSE: This phase II trial is studying how well giving paclitaxel, cisplatin, gefitinib, and radiation therapy followed by surgery and gefitinib works in treating patients with locally advanced cancer of the esophagus or gastroesophageal junction that can be removed by surgery.

Detailed Description
-----------------
OBJECTIVES: Primary Determine the pathologic complete response rate in patients with resectable, locally advanced adenocarcinoma of the esophagus or gastroesophageal junction treated with neoadjuvant paclitaxel, cisplatin, gefitinib, and radiotherapy followed by surgery and adjuvant gefitinib. Secondary Determine the survival of patients treated with this regimen. Determine the safety and tolerability of this regimen in these patients. Determine time to disease progression in patients treated with this regimen. Determine the plasma pharmacokinetics of unbound gefitinib in these patients. Conduct exploratory studies to determine if EGFR pathway component expression and activation correlates with response to therapy and survival of these patients. Determine if treatment with gefitinib alters the EGFR pathway in these patients. OUTLINE: This is a prospective study. Neoadjuvant therapy: Patients receive oral gefitinib beginning 14 days prior to the start of chemoradiotherapy and continuing until 7 days prior to surgery (10-12 weeks). Patients also receive paclitaxel IV over 1 hour and cisplatin IV over 2-3 hours on days 1, 8, 15, 22, and 29. Patients also undergo radiotherapy 5 days a week for 5 weeks. Surgery: Patients undergo surgical resection 4-6 weeks after the completion of neoadjuvant therapy. Adjuvant therapy: Patients receive gefitinib once a day beginning 2-8 weeks after surgery and continuing for up to 1 year in the absence of disease progression or unacceptable toxicity. Blood samples are obtained at baseline and periodically during study for pharmacokinetic studies. Tumor tissue samples are obtained by core biopsy at baseline for biomarker correlative studies. Samples are analyzed by IHC to measure expression and activation of EGFR-signaling pathway biomarkers in pretreatment esophageal tumor tissue, including EGFR and phosphorylated (p)-EGFR, ERK and p-ERK, Akt and p-Akt, p70s6k and p-p70s6k, and p27. After completion of study therapy, patients are followed periodically for at least 5 years.

Official Title
-----------------
Phase II Study in Operable Adenocarcinoma of the Esophagus to Measure Response Rate and Toxicity of Preoperative Combined Modality Paclitaxel (Taxol®, Bristol-Myers Squibb), Cisplatin (Platinol®, Abbott Laboratories), ZD1839 (IRESSA®) and Radiotherapy Followed by Postoperative ZD1839

Conditions
-----------------
Esophageal Cancer

Intervention / Treatment
-----------------
* Drug: cisplatin
* Drug: gefitinib
* Drug: paclitaxel
* Procedure: adjuvant therapy
* Radiation: radiation therapy


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: Histologically confirmed adenocarcinoma of the esophagus or gastroesophageal junction meeting the following criteria: Newly diagnosed disease Surgically resectable tumor Primary esophageal tumor < 20 cm below the incisors Tumor extending ≤ 2 cm into the cardia Stage T2-3, N0-1, M0-1a tumor, as determined by imaging studies and biopsy Documentation by endoscopic ultrasound, endoscopy, and CT scan of the chest and abdomen required Any lesion suspicious for metastasis must be biopsied M1a disease (i.e., celiac nodal metastasis) is allowed if other eligibility criteria are met T4 disease (i.e., involvement of the pleura, pericardium, or diaphragm) allowed provided it is considered resectable No CNS metastasis ECOG performance status 0-1 Granulocyte count > 1,000/mm³ Platelet count > 75,000/mm³ Creatinine clearance > 60 mL/min Total bilirubin < 1.5 mg/dL No concurrent illness likely to preclude protocol therapy or surgical resection Not pregnant or nursing Negative pregnancy test Fertile patients must use effective contraception during and for 3 months after completion of study therapy Exclusion Criteria Known severe hypersensitivity to gefitinib or any of its excipients Evidence of severe or uncontrolled systemic disease (e.g., unstable or uncompensated respiratory, cardiac, hepatic, or renal disease) Evidence of other significant clinical disorder or laboratory finding that would preclude study participation Evidence of clinically active interstitial lung disease Chronic, stable radiographic changes that are asymptomatic are eligible Prior or concurrent malignancy except basal cell or squamous cell skin cancer, cervical cancer, or any other curatively treated malignancy from which the patient has been disease-free and has a survival prognosis of > 5 years Preexisting peripheral neuropathy > grade 1 Incomplete healing from prior oncologic or other major surgery Prior chemotherapy, radiotherapy, or surgery for this cancer More than 30 days since prior nonapproved or investigational drugs Concurrent phenytoin, carbamazepine, barbiturates, rifampin, phenobarbital, or Hypericum perforatum (St. John's wort) Concurrent oral retinoids

Ages Eligible for Study
-----------------
Minimum Age: 18 Years
Maximum Age: 80 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Paclitaxel, Cisplatin, ZD1839 and Radiotherapy<br>Paclitaxel, Cisplatin, ZD1839 and Radiotherapy Followed by Postoperative ZD1839 | Drug: cisplatin<br>* Cisplatin IV<br>Drug: gefitinib<br>* Gefitinib IV<br>* Other names: Combined Modality Paclitaxel, Cisplatin, ZD1839 and Radiotherapy Followed by Postoperative ZD1839;Drug: paclitaxel<br>* Paclitaxel IV<br>* Other names: Combined Modality Paclitaxel, Cisplatin, ZD1839 and Radiotherapy Followed by Postoperative ZD1839;Procedure: adjuvant therapy<br>* Postoperative ZD1839<br>* Other names: Combined Modality Paclitaxel, Cisplatin, ZD1839 and Radiotherapy Followed by Postoperative ZD1839;Radiation: radiation therapy<br>* Radiotherapy<br>* Other names: Combined Modality Paclitaxel, Cisplatin, ZD1839 and Radiotherapy Followed by Postoperative ZD1839;|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Pathologic Complete Response Rate to the Neoadjuvant Regimen | Study closed due to early stopping rule. Patient data was not analyzed. No additional information is available to report | 5 years | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Toxicity as Assessed by NCI CTC v2.0 |  | 5 years | 
| Safety and Tolerability of This Regimen |  | 5 years | 
| Time to Progression |  | 5 years | 
| Survival |  | 5 years | 
| Correlation Between EGFR Pathway Component Expression and Activation With Pathologic Complete Response and Survival |  | 5 years | 

 Terms related to the study
=================
Keywords Provided by Centre Hospitalier Valida
-----------------
adenocarcinoma of the esophagus, stage II esophageal cancer, stage III esophageal cancer, stage IV esophageal cancer