Irinotecan, Cisplatin, and Radiation Therapy With or Without Celecoxib in Treating Patients With Stage II, Stage III, or Stage IV Esophageal Cancer

This study has been completed.
Sponsor:
Collaborator:
Information provided by (Responsible Party):
UNC Lineberger Comprehensive Cancer Center
ClinicalTrials.gov Identifier:
NCT00520091
First received: August 21, 2007
Last updated: May 16, 2012
Last verified: May 2012
  Purpose

RATIONALE: Drugs used in chemotherapy, such as irinotecan and cisplatin, work in different ways to stop the growth of tumor cells, either by killing the cells or by stopping them from dividing. Radiation therapy uses high-energy x-rays to kill tumor cells. Celecoxib may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth. Giving chemotherapy and radiation therapy together with celecoxib may kill more tumor cells.

PURPOSE: This phase II trial is studying how well giving irinotecan and cisplatin together with radiation therapy with or without celecoxib works in treating patients with stage II, stage III, or stage IV esophageal cancer.


Condition Intervention Phase
Esophageal Cancer
Drug: CPT- 11
Drug: Cisplatin
Drug: Celecoxib
Radiation: Radiation
Procedure: Surgery
Phase 2

Study Type: Interventional
Study Design: Allocation: Non-Randomized
Endpoint Classification: Safety/Efficacy Study
Intervention Model: Parallel Assignment
Masking: Open Label
Primary Purpose: Treatment
Official Title: A Pilot Study of the Biologic Efficacy and Safety of the Addition of Celecoxib to a Program of Induction Chemotherapy and Neo-Adjuvant Chemo-Radiotherapy for the Treatment of Esophageal Cancer

Resource links provided by NLM:


Further study details as provided by UNC Lineberger Comprehensive Cancer Center:

Primary Outcome Measures:
  • Rates of cellular apoptosis and proliferation [ Time Frame: 5 weeks ] [ Designated as safety issue: Yes ]
    Measure the rates of cellular apoptotis and proliferation in esophageal cancers from biopsy samples pre-study and during chemoradiation with and without celecoxib therapy

  • Rate of pathologic complete remission in patients with resectable disease [ Time Frame: 4 years ] [ Designated as safety issue: No ]
    To determine if an acceptable rate of pathologic complete remissions can be achieved in a cohort of patients with potentially resectable esophageal carcinoma


Secondary Outcome Measures:
  • Number of subjects experiencing adverse events [ Time Frame: 30 days post radiation ] [ Designated as safety issue: Yes ]
    Adverse events/toxicity will graded per the CTCAE criteria

  • Median overall survival of patients with resectable disease [ Time Frame: 4 years ] [ Designated as safety issue: No ]
    Follow up for survival will occur at 3 month intervals during the first two years, then every 6 months during years 3 and 4.

  • Formation of prostaglandin E2 (PGE2) in tumor tissue [ Time Frame: 12 weeks ] [ Designated as safety issue: No ]
    The ability of celecoxib to decrease formation of prostaglandin E2 (PGE2) in tumor tissue will be analyzed using a Wilcoxon signed rank test on the difference (log scale) of the pre- and post-treatment tumor concentrations of PGE2

  • Downstream effects of inhibition of cyclooxygenase 2 function [ Time Frame: 12 weeks ] [ Designated as safety issue: No ]
    A difference in location of the mRNA expression of the two cohorts will be tested for using the Wilcoxon rank sum test. A difference in the immunohistochemistry staining of the two cohorts will be tested for using polytomous logistic regression

  • Response Rate [ Time Frame: 4 years ] [ Designated as safety issue: No ]
    Radiographic repsonse will be measured using RECIST critera in patients with unresectable esophageal cancer.


Enrollment: 14
Study Start Date: March 2005
Study Completion Date: September 2010
Primary Completion Date: November 2006 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Active Comparator: Cohort 1
Induction chemotherapy and chemoradiation without celecoxib
Drug: CPT- 11
65mg/m2 given on days 1, 8 ,22 and 29 prior to surgery
Other Name: Irinotecan
Drug: Cisplatin
Cisplatin 30mg/m2 will be administered on days 1, 8, 22 and 29 prior to surgery
Other Name: Cis-diammine-dichloro-platinum
Radiation: Radiation
4,500 cGy in 180 cGy fractions 5 days per week, over a period of 5 weeks
Procedure: Surgery
Surgery will occur prior to chemoradiation therapy for those patients with resectable disease
Experimental: Cohort 2
Induction chemotherapy and chemoradiation with celecoxib
Drug: CPT- 11
65mg/m2 given on days 1, 8 ,22 and 29 prior to surgery
Other Name: Irinotecan
Drug: Cisplatin
Cisplatin 30mg/m2 will be administered on days 1, 8, 22 and 29 prior to surgery
Other Name: Cis-diammine-dichloro-platinum
Drug: Celecoxib
400 mg, orally, twice per day beginning on day minus 3 and continue until the end of chemoradiation with CPT-11 and Cisplatin
Radiation: Radiation
4,500 cGy in 180 cGy fractions 5 days per week, over a period of 5 weeks
Procedure: Surgery
Surgery will occur prior to chemoradiation therapy for those patients with resectable disease

Detailed Description:

OBJECTIVES:

Primary

  • To measure the rates of cellular apoptosis and proliferation at baseline and during chemoradiotherapy with and without celecoxib using biopsy samples from patients with stage II, III, or IV esophageal cancer.
  • To determine if an acceptable rate of pathologic complete remission can be achieved in a subset of patients with potentially resectable esophageal cancer.

Secondary

  • To assess the safety of the addition of daily celecoxib to chemoradiotherapy.
  • To estimate the median overall survival in a subset of patients with resectable disease.
  • To quantitate expression of cyclooxygenase (COX)-2 and formation of prostaglandin E2 (PGE2) in patients with esophageal cancer.
  • To assess the ability of celecoxib to decrease formation of PGE2 in tumor tissue by measuring pre- and post-treatment tumor concentrations of PGE2.
  • To quantitate downstream effects of inhibition of COX-2 function in the setting of treatment with chemotherapy.
  • To measure the radiographic response rate in patients with unresectable esophageal cancer.

OUTLINE: This is a multicenter study. Patients are sequentially enrolled into 1 of 2 treatment groups.

  • Group 1: Patients receive cisplatin IV over 1 hour and irinotecan hydrochloride IV over 90 minutes on days 1, 8, 22, 29, 43, 50, 64, and 71. Patients also undergo radiotherapy once daily 5 days a week for 5 weeks beginning on day 43.
  • Group 2: Patients receive chemoradiotherapy as in group 1. Patients also receive oral celecoxib twice daily beginning 3 days before the initiation of chemotherapy and continuing until the completion of chemoradiotherapy.

In both groups, patients with potentially resectable disease undergo surgery no more than 12 weeks after completion of chemoradiotherapy.

Endoscopic tumor biopsy specimens are collected at baseline and on day 3 of radiotherapy. Samples are analyzed for cyclooxygenase (COX)-2 gene and protein expression; PGE2 secretion; apoptotic activity; caspase-3 activation; cytochrome c translocation; VEGF mRNA quantitation; and cellular proliferation. Laboratory techniques used include RT-PCR, IHC, enzyme immunoassay, TUNEL assay, colorimetric assay, and northern blotting.

After completion of study treatment, patients are followed every 3 months for 2 years, every 6 months for 2 years, and then annually thereafter.

PROJECTED ACCRUAL: A total of 34 patients (8-10 in group 1 and 24 in group 2) will be accrued for this study.

  Eligibility

Ages Eligible for Study:   18 Years and older
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No
Criteria

DISEASE CHARACTERISTICS:

  • Biopsy proven squamous cell carcinoma or adenocarcinoma of the esophagus

    • Lesions including the gastroesophageal junction allowed provided the tumor involves less than 2 cm of gastric cardia
  • Meets 1 of the following criteria:

    • Clinical stage II, III, or IV disease AND planning to receive chemoradiotherapy either for preoperative or palliative indications (group 1)

      • Suitable candidate for bimodality (palliative intent) or trimodality (curative intent) therapy
    • Clinical stage II or III disease AND candidate to receive chemoradiotherapy for preoperative indication followed by planned esophagectomy or esophagogastrectomy (group 2)

      • Suitable candidate for trimodality (curative intent) therapy
  • No tracheoesophageal fistula on bronchoscopy

PATIENT CHARACTERISTICS:

  • ECOG performance status 0-2
  • Life expectancy > 3 months (group 1)
  • Not pregnant
  • Adequate nutrition
  • WBC ≥ 4,000/μL
  • ANC ≥ 1,500/μL
  • Platelet count ≥ 100,000/μL
  • Serum creatinine ≤ 1.5 mg/dL
  • Bilirubin ≤ 1.5 mg/dL
  • No other prior or concurrent malignancy other than curatively treated carcinoma in situ of the cervix; localized prostate cancer that was previously treated with local therapy more than 2 years ago with a PSA of less than 4 ng/mL; basal cell carcinoma of the skin; or superficial transitional cell carcinoma of the bladder

    • Patients who have had a prior malignancy are eligible if they have been free of disease for ≥ 5 years
  • No serious medical or psychiatric illnesses that would preclude giving informed consent or otherwise limit survival to less than 2 years
  • No history of known NSAID-induced gastrointestinal bleeding
  • No current peptic ulcer disease
  • No active coronary artery disease
  • No myocardial infarction or cerebrovascular accident within the past 3 months
  • No history of refractory congestive heart failure or cardiomyopathy

PRIOR CONCURRENT THERAPY:

  • More than 1 week since prior major surgery (group 1)
  • More than 2 weeks since prior major surgery (group 2)
  • No prior chemotherapy or radiotherapy
  • More than 30 days since prior cyclooxygenase-2 inhibitors (selective or non-selective), including, but not limited to, any of the following:

    • Acetylsalicylic acid (aspirin)
    • Piroxicam
    • Diclofenac
    • Meloxicam
    • Indomethacin
    • Fenoprofen
    • Sulindac
    • Flurbiprofen
    • Tolmetin
    • Ibuprofen
    • Celecoxib
    • Ketoprofen
    • Rofecoxib
    • Ketoprofen ER
    • Valdecoxib
    • Naproxen
    • Meclofenamate
    • Oxaprozin
    • Mefenamic acid
    • Etodolac
    • Nabumetone
    • Ketorolac
  • No concurrent seizure medications
  • No concurrent amifostine or other such agents
  Contacts and Locations
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT00520091

Sponsors and Collaborators
UNC Lineberger Comprehensive Cancer Center
Investigators
Principal Investigator: Bert H. O'Neil, MD UNC Lineberger Comprehensive Cancer Center
  More Information

Additional Information:
No publications provided

Responsible Party: UNC Lineberger Comprehensive Cancer Center
ClinicalTrials.gov Identifier: NCT00520091     History of Changes
Obsolete Identifiers: NCT00280124
Other Study ID Numbers: LCCC 0203, CDR0000561610
Study First Received: August 21, 2007
Last Updated: May 16, 2012
Health Authority: United States: Federal Government
United States: Institutional Review Board

Keywords provided by UNC Lineberger Comprehensive Cancer Center:
adenocarcinoma of the esophagus
squamous cell carcinoma of the esophagus
stage II esophageal cancer
stage III esophageal cancer
stage IV esophageal cancer

Additional relevant MeSH terms:
Esophageal Neoplasms
Digestive System Diseases
Digestive System Neoplasms
Esophageal Diseases
Gastrointestinal Diseases
Gastrointestinal Neoplasms
Head and Neck Neoplasms
Neoplasms
Neoplasms by Site
Celecoxib
Cisplatin
Irinotecan
Analgesics
Analgesics, Non-Narcotic
Anti-Inflammatory Agents
Anti-Inflammatory Agents, Non-Steroidal
Antineoplastic Agents
Antineoplastic Agents, Phytogenic
Antirheumatic Agents
Central Nervous System Agents
Cyclooxygenase 2 Inhibitors
Cyclooxygenase Inhibitors
Enzyme Inhibitors
Molecular Mechanisms of Pharmacological Action
Peripheral Nervous System Agents
Pharmacologic Actions
Physiological Effects of Drugs
Radiation-Sensitizing Agents
Sensory System Agents
Therapeutic Uses

ClinicalTrials.gov processed this record on October 21, 2014