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

Johns Hopkins Medicine

Status and phase

Terminated

Phase 2

Conditions

Esophageal Cancer

Treatments

Radiation: radiation therapy

Drug: cisplatin

Drug: paclitaxel

Drug: gefitinib

Procedure: adjuvant therapy

Study type

Interventional

Funder types

Other

NIH

Identifiers

NCT00493025

J0386

P30CA006973 (U.S. NIH Grant/Contract)

ZENECA-IRUSIRES0304

JHOC-J0386

CDR0000549896 (Other Identifier)

04-02-20-03 (Other Identifier)

Details and patient eligibility

About

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.

Full 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.

Enrollment

19 patients

Sex

All

Ages

18 to 80 years old

Volunteers

No Healthy Volunteers

Inclusion and exclusion 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