Clinical trial NCT00493025: 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
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
Study type: INTERVENTIONAL
Overall status: TERMINATED
Phase: PHASE2
Conditions: Esophageal Cancer
Keywords: adenocarcinoma of the esophagus
stage II esophageal cancer
stage III esophageal cancer
stage IV esophageal cancer
Lead sponsor: Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins
Sponsor class: OTHER
Collaborators: name: National Cancer Institute (NCI)
First posted: 2007-06-27
Enrollment: 19
Sex: ALL
Minimum age (years): 18
Maximum age (years): 80
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NA
Intervention model: SINGLE_GROUP
Primary purpose: TREATMENT

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.

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

Primary outcomes:
measure: Pathologic Complete Response Rate to the Neoadjuvant Regimen
timeFrame: 5 years
Secondary outcomes:
measure: Toxicity as Assessed by NCI CTC v2.0
timeFrame: 5 years
measure: Safety and Tolerability of This Regimen
timeFrame: 5 years
measure: Time to Progression
timeFrame: 5 years
measure: Survival
timeFrame: 5 years
measure: Correlation Between EGFR Pathway Component Expression and Activation With Pathologic Complete Response and Survival
timeFrame: 5 years
Other outcomes:
Locations:
city: Baltimore
country: United States
facility: Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins
state: Maryland
Study officials:
affiliation: Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins
name: Arlene A. Forastiere, MD
role: PRINCIPAL_INVESTIGATOR
References: