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

• Sponsor: Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins (Other)
• Overall Status: Terminated
• CT.gov ID: NCT00493025
• Collaborator: National Cancer Institute (NCI) (NIH)
• Enrollment: 19
• Location: 1
• Arm: 1
• Duration (Months): 95
• Patients Per Site Per Month: 0.2

Study Details

Study Description

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.

Condition or Disease	Intervention/Treatment	Phase
Esophageal Cancer	Drug: cisplatin; Drug: gefitinib; Drug: paclitaxel; Procedure: adjuvant therapy; Radiation: radiation therapy	Phase 2

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.

Study Design

• Study Type: Interventional
• Actual Enrollment: 19 participants
• Allocation: N/A
• Intervention Model: Single Group Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• 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 Start Date: Apr 1, 2005
• Actual Primary Completion Date: Mar 1, 2013
• Actual Study Completion Date: Mar 1, 2013

Arms and Interventions

Arm

Intervention/Treatment

Experimental: Paclitaxel, Cisplatin, ZD1839 and Radiotherapy Paclitaxel, Cisplatin, ZD1839 and Radiotherapy Followed by Postoperative ZD1839

Drug: cisplatin; Cisplatin IV; Drug: gefitinib; Gefitinib IV; Other Names: Combined Modality Paclitaxel, Cisplatin, ZD1839 and Radiotherapy Followed by Postoperative ZD1839 ; Drug: paclitaxel; Paclitaxel IV; Other Names: Combined Modality Paclitaxel, Cisplatin, ZD1839 and Radiotherapy Followed by Postoperative ZD1839 ; Procedure: adjuvant therapy; Postoperative ZD1839; Other Names: Combined Modality Paclitaxel, Cisplatin, ZD1839 and Radiotherapy Followed by Postoperative ZD1839 ; Radiation: radiation therapy; Radiotherapy; Other Names: Combined Modality Paclitaxel, Cisplatin, ZD1839 and Radiotherapy Followed by Postoperative ZD1839

Outcome Measures

Primary Outcome Measures

1. Pathologic Complete Response Rate to the Neoadjuvant Regimen [5 years]

   Study closed due to early stopping rule. Patient data was not analyzed. No additional information is available to report

Secondary Outcome Measures

1. Toxicity as Assessed by NCI CTC v2.0 [5 years]

2. Safety and Tolerability of This Regimen [5 years]

3. Time to Progression [5 years]

4. Survival [5 years]

5. Correlation Between EGFR Pathway Component Expression and Activation With Pathologic Complete Response and Survival [5 years]

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years to 80 Years
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

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

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins	Baltimore	Maryland	United States	21231-2410

Sponsors and Collaborators

• Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins
• National Cancer Institute (NCI)

Investigators

• Principal Investigator: Arlene A. Forastiere, MD, Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins

Study Documents (Full-Text)

None provided.

More Information

Additional Information:

• Clinical trial summary from the National Cancer Institute's PDQ® database

Publications

None provided.

• Responsible Party: Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins
• ClinicalTrials.gov Identifier: NCT00493025
• Other Study ID Numbers: J0386; P30CA006973; JHOC-J0386; 04-02-20-03; ZENECA-IRUSIRES0304; CDR0000549896
• First Posted: Jun 27, 2007
• Last Update Posted: Dec 6, 2018
• Last Verified: Nov 1, 2018

• Keywords provided by Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins: adenocarcinoma of the esophagus; stage II esophageal cancer; stage III esophageal cancer; stage IV esophageal cancer
• Additional relevant MeSH terms: Esophageal Neoplasms; Paclitaxel; Albumin-Bound Paclitaxel; Cisplatin; Gefitinib

Study Results

Participant Flow

Arm/Group Title	Paclitaxel, Cisplatin, ZD1839 and Radiotherapy
Arm/Group Description	Paclitaxel, Cisplatin, ZD1839 and Radiotherapy Followed by Postoperative ZD1839 cisplatin: Combined Modality Paclitaxel, Cisplatin, ZD1839 and Radiotherapy Followed by Postoperative ZD1839 gefitinib: Combined Modality Paclitaxel, Cisplatin, ZD1839 and Radiotherapy Followed by Posto ZD1839 paclitaxel: Combined Modality Paclitaxel, Cisplatin, ZD1839 and Radiotherapy Followed by Postoperative ZD1839 gene expression analysis: Combined Modality Paclitaxel, Cisplatin, ZD1839 and Radiotherapy Followed by Postoperative ZD1839 immunohistochemistry staining method: Combined Modality Paclitaxel, Cisplatin, ZD1839 and Radiotherapy Followed by Postoperative ZD1839 laboratory biomarker analysis: Combined Modality Paclitaxel, Cisplatin, ZD1839 and Radiotherapy Followed by Postoperative ZD1839 pharmacological study: Combined Modality Paclitaxel, Cisplatin, ZD1839 and Radiotherapy Followed by Postoperative ZD1839 adjuvant therapy: Combined Modality Paclitaxel, Cisplatin,
Period Title: Overall Study
STARTED	19
COMPLETED	0
NOT COMPLETED	19

Baseline Characteristics

Arm/Group Title	Paclitaxel, Cisplatin, ZD1839 and Radiotherapy
Arm/Group Description	Paclitaxel, Cisplatin, ZD1839 and Radiotherapy Followed by Postoperative ZD1839 cisplatin: Combined Modality Paclitaxel, Cisplatin, ZD1839 and Radiotherapy Followed by Postoperative ZD1839 gefitinib: Combined Modality Paclitaxel, Cisplatin, ZD1839 and Radiotherapy Followed by Postoperative ZD1839 paclitaxel: Combined Modality Paclitaxel, Cisplatin, ZD1839 and Radiotherapy Followed by Postoperative ZD1839 gene expression analysis: Combined Modality Paclitaxel, Cisplatin, ZD1839 Radiotherapy Followed by Postoperative ZD1839 immunohistochemistry staining method: Combined Modality Paclitaxel, Cisplatin, ZD1839 and Radiotherapy Followed by Postoperative ZD1839 laboratory biomarker analysis: Combined Modality Paclitaxel, Cisplatin, ZD1839 and Radiotherapy Followed by Postoperative ZD1839 pharmacological study: Combined Modality Paclitaxel, Cisplatin, ZD1839 and Radiotherapy Followed by Postoperative ZD1839 adjuvant therapy: Combined Modality Paclitaxel, Cisplatin,
Overall Participants	19
Age (Count of Participants)
<=18 years	0 0%
Between 18 and 65 years	1 5.3%
>=65 years	18 94.7%
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	67 (7.37)
Sex: Female, Male (Count of Participants)
Female	2 10.5%
Male	17 89.5%
Region of Enrollment (participants) [Number]
United States	19 100%

Outcome Measures

1. Primary Outcome

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

Outcome Measure Data

Analysis Population Description

Study terminated due to early stopping rule. Therefore, data was not collected to assess this outcome measure

Arm/Group Title	Paclitaxel, Cisplatin, ZD1839 and Radiotherapy
Arm/Group Description	Paclitaxel, Cisplatin, ZD1839 and Radiotherapy Followed by Postoperative ZD1839 cisplatin: Combined Modality Paclitaxel, Cisplatin, ZD1839 and Radiotherapy Followed by Postoperative ZD1839 gefitinib: Combined Modality Paclitaxel, Cisplatin, ZD1839 and Radiotherapy Followed by Postoperative ZD1839 paclitaxel: Combined Modality Paclitaxel, Cisplatin, ZD1839 and Radiotherapy Followed by Postoperative ZD1839 gene expression analysis: Combined Modality Paclitaxel, Cisplatin, ZD1839 and Radiotherapy Followed by Postoperative ZD1839 immunohistochemistry staining method: Combined Modality Paclitaxel, Cisplatin, ZD1839 and Radiotherapy Followed by Postoperative ZD1839 laboratory biomarker analysis: Combined Modality Paclitaxel, Cisplatin, ZD1839 and Radiotherapy Followed by Postoperative ZD1839 pharmacological study: Combined Modality Paclitaxel, Cisplatin, ZD1839 and Radiotherapy Followed by Postoperative ZD1839 adj therapy: Combined Modality Paclitaxel, Cisplatin,
Measure Participants	0

2. Secondary Outcome

Title	Toxicity as Assessed by NCI CTC v2.0
Time Frame	5 years

Outcome Measure Data

Analysis Population Description

Study terminated due to early stopping rule. Therefore, data was not collected to assess this outcome measure

Arm/Group Title	Paclitaxel, Cisplatin, ZD1839 and Radiotherapy
Arm/Group Description	Paclitaxel, Cisplatin, ZD1839 and Radiotherapy Followed by Postoperative ZD1839 cisplatin: Combined Modality Paclitaxel, Cisplatin, ZD1839 and Radiotherapy Followed by Postoperative ZD1839 gefitinib: Combined Modality Paclitaxel, Cisplatin, ZD1839 and Radiotherapy Followed by Posto ZD1839 paclitaxel: Combined Modality Paclitaxel, Cisplatin, ZD1839 and Radiotherapy Followed by Postoperative ZD1839 gene expression analysis: Combined Modality Paclitaxel, Cisplatin, ZD1839 and Radiotherapy Followed by Postoperative ZD1839 immunohistochemistry staining method: Combined Modality Paclitaxel, Cisplatin, ZD1839 and Radiotherapy Followed by Postoperative ZD1839 laboratory biomarker analysis: Combined Modality Paclitaxel, Cisplatin, ZD1839 and Radiotherapy Followed by Postoperative ZD1839 pharmacological study: Combined Modality Paclitaxel, Cisplatin, ZD1839 and Radiotherapy Followed by Postoperative ZD1839 adjuvant therapy: Combined Modality Paclitaxel, Cisplatin,
Measure Participants	0

3. Secondary Outcome

Title	Safety and Tolerability of This Regimen
Time Frame	5 years

Outcome Measure Data

Analysis Population Description

Study terminated due to early stopping rule. Therefore, data was not collected to assess this outcome measure

Arm/Group Title	Paclitaxel, Cisplatin, ZD1839 and Radiotherapy
Arm/Group Description	Paclitaxel, Cisplatin, ZD1839 and Radiotherapy Followed by Postoperative ZD1839 cisplatin: Combined Modality Paclitaxel, Cisplatin, ZD1839 and Radiotherapy Followed by Postoperative ZD1839 gefitinib: Combined Modality Paclitaxel, Cisplatin, ZD1839 and Radiotherapy Followed by Posto ZD1839 paclitaxel: Combined Modality Paclitaxel, Cisplatin, ZD1839 and Radiotherapy Followed by Postoperative ZD1839 gene expression analysis: Combined Modality Paclitaxel, Cisplatin, ZD1839 and Radiotherapy Followed by Postoperative ZD1839 immunohistochemistry staining method: Combined Modality Paclitaxel, Cisplatin, ZD1839 and Radiotherapy Followed by Postoperative ZD1839 laboratory biomarker analysis: Combined Modality Paclitaxel, Cisplatin, ZD1839 and Radiotherapy Followed by Postoperative ZD1839 pharmacological study: Combined Modality Paclitaxel, Cisplatin, ZD1839 and Radiotherapy Followed by Postoperative ZD1839 adjuvant therapy: Combined Modality Paclitaxel, Cisplatin,
Measure Participants	0

4. Secondary Outcome

Title	Time to Progression
Time Frame	5 years

Outcome Measure Data

Analysis Population Description

Study terminated due to early stopping rule. Therefore, data was not collected to assess this outcome measure

Arm/Group Title	Paclitaxel, Cisplatin, ZD1839 and Radiotherapy
Arm/Group Description	Paclitaxel, Cisplatin, ZD1839 and Radiotherapy Followed by Postoperative ZD1839 cisplatin: Combined Modality Paclitaxel, Cisplatin, ZD1839 and Radiotherapy Followed by Postoperative ZD1839 gefitinib: Combined Modality Paclitaxel, Cisplatin, ZD1839 and Radiotherapy Followed by Posto ZD1839 paclitaxel: Combined Modality Paclitaxel, Cisplatin, ZD1839 and Radiotherapy Followed by Postoperative ZD1839 gene expression analysis: Combined Modality Paclitaxel, Cisplatin, ZD1839 and Radiotherapy Followed by Postoperative ZD1839 immunohistochemistry staining method: Combined Modality Paclitaxel, Cisplatin, ZD1839 and Radiotherapy Followed by Postoperative ZD1839 laboratory biomarker analysis: Combined Modality Paclitaxel, Cisplatin, ZD1839 and Radiotherapy Followed by Postoperative ZD1839 pharmacological study: Combined Modality Paclitaxel, Cisplatin, ZD1839 and Radiotherapy Followed by Postoperative ZD1839 adjuvant therapy: Combined Modality Paclitaxel, Cisplatin,
Measure Participants	0

5. Secondary Outcome

Title	Survival
Time Frame	5 years

Outcome Measure Data

Analysis Population Description

Study terminated due to early stopping rule. Therefore, data was not collected to assess this outcome measure

Arm/Group Title	Paclitaxel, Cisplatin, ZD1839 and Radiotherapy
Arm/Group Description	Paclitaxel, Cisplatin, ZD1839 and Radiotherapy Followed by Postoperative ZD1839 cisplatin: Combined Modality Paclitaxel, Cisplatin, ZD1839 and Radiotherapy Followed by Postoperative ZD1839 gefitinib: Combined Modality Paclitaxel, Cisplatin, ZD1839 and Radiotherapy Followed by Posto ZD1839 paclitaxel: Combined Modality Paclitaxel, Cisplatin, ZD1839 and Radiotherapy Followed by Postoperative ZD1839 gene expression analysis: Combined Modality Paclitaxel, Cisplatin, ZD1839 and Radiotherapy Followed by Postoperative ZD1839 immunohistochemistry staining method: Combined Modality Paclitaxel, Cisplatin, ZD1839 and Radiotherapy Followed by Postoperative ZD1839 laboratory biomarker analysis: Combined Modality Paclitaxel, Cisplatin, ZD1839 and Radiotherapy Followed by Postoperative ZD1839 pharmacological study: Combined Modality Paclitaxel, Cisplatin, ZD1839 and Radiotherapy Followed by Postoperative ZD1839 adjuvant therapy: Combined Modality Paclitaxel, Cisplatin,
Measure Participants	0

6. Secondary Outcome

Title	Correlation Between EGFR Pathway Component Expression and Activation With Pathologic Complete Response and Survival
Time Frame	5 years

Outcome Measure Data

Analysis Population Description

Study terminated due to early stopping rule. Therefore, data was not collected to assess this outcome measure

Arm/Group Title	Paclitaxel, Cisplatin, ZD1839 and Radiotherapy
Arm/Group Description	Paclitaxel, Cisplatin, ZD1839 and Radiotherapy Followed by Postoperative ZD1839 cisplatin: Combined Modality Paclitaxel, Cisplatin, ZD1839 and Radiotherapy Followed by Postoperative ZD1839 gefitinib: Combined Modality Paclitaxel, Cisplatin, ZD1839 and Radiotherapy Followed by Posto ZD1839 paclitaxel: Combined Modality Paclitaxel, Cisplatin, ZD1839 and Radiotherapy Followed by Postoperative ZD1839 gene expression analysis: Combined Modality Paclitaxel, Cisplatin, ZD1839 and Radiotherapy Followed by Postoperative ZD1839 immunohistochemistry staining method: Combined Modality Paclitaxel, Cisplatin, ZD1839 and Radiotherapy Followed by Postoperative ZD1839 laboratory biomarker analysis: Combined Modality Paclitaxel, Cisplatin, ZD1839 and Radiotherapy Followed by Postoperative ZD1839 pharmacological study: Combined Modality Paclitaxel, Cisplatin, ZD1839 and Radiotherapy Followed by Postoperative ZD1839 adjuvant therapy: Combined Modality Paclitaxel, Cisplatin,
Measure Participants	0

Adverse Events

Arm/Group Title	Paclitaxel, Cisplatin, ZD1839 and Radiotherapy
Arm/Group Description	Paclitaxel, Cisplatin, ZD1839 and Radiotherapy Followed by Postoperative ZD1839 cisplatin: Combined Modality Paclitaxel, Cisplatin, ZD1839 and Radiotherapy Followed by Postoperative ZD1839 gefitinib: Combined Modality Paclitaxel, Cisplatin, ZD1839 and Radiotherapy Followed by Postoperative ZD1839 paclitaxel: Combined Modality Paclitaxel, Cisplatin, ZD1839 and Radiotherapy Followed by Postoperative ZD1839 gene expression analysis: Combined Modality Paclitaxel, Cisplatin, ZD1839 and Radiotherapy Followed by Postoperative ZD1839 immunohistochemistry staining method: Combined Modality Paclitaxel, Cisplatin, ZD1839 and Radiotherapy Followed by Postoperative ZD1839 laboratory biomarker analysis: Combined Modality Paclitaxel, Cisplatin, ZD1839 and Radiotherapy Followed by Postoperative ZD1839 pharmacological study: Combined Modality Paclitaxel, Cisplatin, ZD1839 and Radiotherapy Followed by Postoperative ZD1839 adj therapy: Combined Modality Paclitaxel, Cisplatin,
All Cause Mortality
	Paclitaxel, Cisplatin, ZD1839 and Radiotherapy
	Affected / at Risk (%)	# Events
Total	/ (NaN)
Serious Adverse Events
	Paclitaxel, Cisplatin, ZD1839 and Radiotherapy
	Affected / at Risk (%)	# Events
Total	0/19 (0%)
Other (Not Including Serious) Adverse Events
	Paclitaxel, Cisplatin, ZD1839 and Radiotherapy
	Affected / at Risk (%)	# Events
Total	0/19 (0%)

Limitations/Caveats

Study was closed due to early stopping rule.

More Information

Certain Agreements

All Principal Investigators ARE employed by the organization sponsoring the study.

There is NOT an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.