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

Primary Purpose

Esophageal Cancer

Status
Completed
Phase
Phase 2
Locations
Study Type
Interventional
Intervention
CPT- 11
Cisplatin
Celecoxib
Radiation
Surgery
Sponsored by
UNC Lineberger Comprehensive Cancer Center
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional treatment trial for Esophageal Cancer focused on measuring adenocarcinoma of the esophagus, squamous cell carcinoma of the esophagus, stage II esophageal cancer, stage III esophageal cancer, stage IV esophageal cancer

Eligibility Criteria

18 Years - undefined (Adult, Older Adult)All SexesDoes not accept healthy volunteers

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

Sites / Locations

    Arms of the Study

    Arm 1

    Arm 2

    Arm Type

    Active Comparator

    Experimental

    Arm Label

    Cohort 1

    Cohort 2

    Arm Description

    Induction chemotherapy and chemoradiation without celecoxib

    Induction chemotherapy and chemoradiation with celecoxib

    Outcomes

    Primary Outcome Measures

    Rates of cellular apoptosis and proliferation
    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
    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
    Adverse events/toxicity will graded per the CTCAE criteria
    Median overall survival of patients with resectable disease
    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
    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
    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
    Radiographic repsonse will be measured using RECIST critera in patients with unresectable esophageal cancer.

    Full Information

    First Posted
    August 21, 2007
    Last Updated
    May 16, 2012
    Sponsor
    UNC Lineberger Comprehensive Cancer Center
    Collaborators
    National Cancer Institute (NCI)
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    1. Study Identification

    Unique Protocol Identification Number
    NCT00520091
    Brief Title
    Irinotecan, Cisplatin, and Radiation Therapy With or Without Celecoxib in Treating Patients With Stage II, Stage III, or Stage IV Esophageal Cancer
    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
    Study Type
    Interventional

    2. Study Status

    Record Verification Date
    May 2012
    Overall Recruitment Status
    Completed
    Study Start Date
    March 2005 (undefined)
    Primary Completion Date
    November 2006 (Actual)
    Study Completion Date
    September 2010 (Actual)

    3. Sponsor/Collaborators

    Responsible Party, by Official Title
    Sponsor
    Name of the Sponsor
    UNC Lineberger Comprehensive Cancer Center
    Collaborators
    National Cancer Institute (NCI)

    4. Oversight

    Data Monitoring Committee
    Yes

    5. Study Description

    Brief Summary
    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.
    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.

    6. Conditions and Keywords

    Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
    Esophageal Cancer
    Keywords
    adenocarcinoma of the esophagus, squamous cell carcinoma of the esophagus, stage II esophageal cancer, stage III esophageal cancer, stage IV esophageal cancer

    7. Study Design

    Primary Purpose
    Treatment
    Study Phase
    Phase 2
    Interventional Study Model
    Parallel Assignment
    Masking
    None (Open Label)
    Allocation
    Non-Randomized
    Enrollment
    14 (Actual)

    8. Arms, Groups, and Interventions

    Arm Title
    Cohort 1
    Arm Type
    Active Comparator
    Arm Description
    Induction chemotherapy and chemoradiation without celecoxib
    Arm Title
    Cohort 2
    Arm Type
    Experimental
    Arm Description
    Induction chemotherapy and chemoradiation with celecoxib
    Intervention Type
    Drug
    Intervention Name(s)
    CPT- 11
    Other Intervention Name(s)
    Irinotecan
    Intervention Description
    65mg/m2 given on days 1, 8 ,22 and 29 prior to surgery
    Intervention Type
    Drug
    Intervention Name(s)
    Cisplatin
    Other Intervention Name(s)
    Cis-diammine-dichloro-platinum
    Intervention Description
    Cisplatin 30mg/m2 will be administered on days 1, 8, 22 and 29 prior to surgery
    Intervention Type
    Drug
    Intervention Name(s)
    Celecoxib
    Intervention Description
    400 mg, orally, twice per day beginning on day minus 3 and continue until the end of chemoradiation with CPT-11 and Cisplatin
    Intervention Type
    Radiation
    Intervention Name(s)
    Radiation
    Intervention Description
    4,500 cGy in 180 cGy fractions 5 days per week, over a period of 5 weeks
    Intervention Type
    Procedure
    Intervention Name(s)
    Surgery
    Intervention Description
    Surgery will occur prior to chemoradiation therapy for those patients with resectable disease
    Primary Outcome Measure Information:
    Title
    Rates of cellular apoptosis and proliferation
    Description
    Measure the rates of cellular apoptotis and proliferation in esophageal cancers from biopsy samples pre-study and during chemoradiation with and without celecoxib therapy
    Time Frame
    5 weeks
    Title
    Rate of pathologic complete remission in patients with resectable disease
    Description
    To determine if an acceptable rate of pathologic complete remissions can be achieved in a cohort of patients with potentially resectable esophageal carcinoma
    Time Frame
    4 years
    Secondary Outcome Measure Information:
    Title
    Number of subjects experiencing adverse events
    Description
    Adverse events/toxicity will graded per the CTCAE criteria
    Time Frame
    30 days post radiation
    Title
    Median overall survival of patients with resectable disease
    Description
    Follow up for survival will occur at 3 month intervals during the first two years, then every 6 months during years 3 and 4.
    Time Frame
    4 years
    Title
    Formation of prostaglandin E2 (PGE2) in tumor tissue
    Description
    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
    Time Frame
    12 weeks
    Title
    Downstream effects of inhibition of cyclooxygenase 2 function
    Description
    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
    Time Frame
    12 weeks
    Title
    Response Rate
    Description
    Radiographic repsonse will be measured using RECIST critera in patients with unresectable esophageal cancer.
    Time Frame
    4 years

    10. Eligibility

    Sex
    All
    Minimum Age & Unit of Time
    18 Years
    Accepts Healthy Volunteers
    No
    Eligibility 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
    Overall Study Officials:
    First Name & Middle Initial & Last Name & Degree
    Bert H. O'Neil, MD
    Organizational Affiliation
    UNC Lineberger Comprehensive Cancer Center
    Official's Role
    Principal Investigator

    12. IPD Sharing Statement

    Learn more about this trial

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

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