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

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.

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