Celecoxib in Treating Patients With Cervical Intraepithelial Neoplasia

A Randomized Double-Blind Phase II Trial of Celecoxib, A COX-2 Inhibitor, in the Treatment of Patients With Cervical Intraepithelial Neoplasia 2/3 or 3 (CIN 2/3 or 3)

This randomized phase II trial studies how well celecoxib works in treating patients with cervical intraepithelial neoplasia, a precancerous lesion of the cervix which can develop into cervical cancer. Celecoxib may be effective in preventing the development of cervical cancer in patients who have cervical intraepithelial neoplasia.

Study Overview

• Status: Completed
• Conditions: Cervical Carcinoma; Cervical Intraepithelial Neoplasia Grade 2/3; Stage 0 Cervical Cancer
• Intervention / Treatment: Other: Laboratory Biomarker Analysis; Drug: Celecoxib; Other: Placebo

Detailed Description

PRIMARY OBJECTIVES:

I. To determine the efficacy of celecoxib to induce complete remission (or partial regression to cervical intraepithelial neoplasia (CIN) 1) of CIN 2/3 or CIN 3 as evaluated in the post-treatment excisional biopsy.

II. To determine the toxicity of celecoxib (400 mg once daily) as assessed by Common Terminology Criteria for Adverse Events in this patient population of women with CIN 2/3 or CIN 3.

SECONDARY OBJECTIVES:

I. To assess whether treatment with celecoxib changes the number of quadrants containing acetowhite lesions as determined through colposcopic examination.

II. To determine the efficacy of celecoxib treatment in changing human papillomavirus (HPV) viral load in cervical cells.

III. To examine the association of histologic response; HPV viral load; lesion size; proliferation index (marker of proliferation Ki-67 [Ki67]), apoptosis index (terminal deoxynucleotidyl transferase (TdT)-mediated dUTP nick end labelin [TUNEL] assay), angiogenesis (vascular endothelial growth factor [VEGF]), and cyclooxygenase-2 (COX-2) in tissue; the amount of VEGF and basic fibroblast growth factor (bFGF) in serum before and after treatment; and the amount of celecoxib present in serum during treatment. Cervical cytology karyometry will be assessed as a potential marker for regression IV. To determine the feasibility of digital imaging, web-based review of histopathology in a Gynecologic Oncology Group (GOG) study.

V. To compare the diagnoses of the web-based review of histopathology with the diagnoses of GOG's standard procedure.

OUTLINE: Patients are randomized to 1 of 2 treatment arms.

ARM I: Patients receive oral celecoxib once daily for 14-18 weeks.

ARM II: Patients receive oral placebo once daily for 14-18 weeks.

• Study Type: Interventional
• Enrollment (Actual): 130
• Phase: Phase 2

Contacts and Locations

Study Locations

• United States
  • Arizona
    • Tucson, Arizona, United States, 85719
      • University of Arizona Cancer Center-North Campus
  • Arkansas
    • Little Rock, Arkansas, United States, 72205
      • University of Arkansas for Medical Sciences
  • Delaware
    • Lewes, Delaware, United States, 19958
      • Beebe Medical Center
    • Newark, Delaware, United States, 19718
      • Christiana Care Health System-Christiana Hospital
  • Illinois
    • Urbana, Illinois, United States, 61801
      • Carle Clinic-Urbana Main
  • Indiana
    • Elkhart, Indiana, United States, 46515
      • Elkhart General Hospital
    • Elkhart, Indiana, United States, 46514
      • Michiana Hematology Oncology PC-Elkhart
    • Elkhart, Indiana, United States, 46514-2098
      • Elkhart Clinic
    • Kokomo, Indiana, United States, 46904
      • Community Howard Regional Health
    • La Porte, Indiana, United States, 46350
      • IU Health La Porte Hospital
    • Mishawaka, Indiana, United States, 46545
      • Michiana Hematology Oncology PC-Mishawaka
    • Mishawaka, Indiana, United States, 46545
      • Saint Joseph Regional Medical Center-Mishawaka
    • Plymouth, Indiana, United States, 46563
      • Michiana Hematology Oncology PC-Plymouth
    • South Bend, Indiana, United States, 46601
      • Memorial Hospital of South Bend
    • South Bend, Indiana, United States, 46601
      • Michiana Hematology Oncology PC-South Bend
    • South Bend, Indiana, United States, 46628
      • Northern Indiana Cancer Research Consortium
    • Westville, Indiana, United States, 46391
      • Michiana Hematology Oncology PC-Westville
  • Maryland
    • Elkton, Maryland, United States, 21921
      • Union Hospital of Cecil County
  • Michigan
    • Kalamazoo, Michigan, United States, 49007
      • West Michigan Cancer Center
    • Kalamazoo, Michigan, United States, 49007
      • Bronson Methodist Hospital
    • Kalamazoo, Michigan, United States, 49001
      • Borgess Medical Center
    • Saint Joseph, Michigan, United States, 49085
      • Marie Yeager Cancer Center
    • Saint Joseph, Michigan, United States, 49085
      • Lakeland Hospital
  • Missouri
    • Columbia, Missouri, United States, 65212
      • University of Missouri - Ellis Fischel
    • Saint Louis, Missouri, United States, 63110
      • Saint Louis University Hospital
  • Nevada
    • Las Vegas, Nevada, United States, 89169
      • Women's Cancer Center of Nevada
  • New Jersey
    • Newark, New Jersey, United States, 07101
      • Rutgers New Jersey Medical School
  • New York
    • The Bronx, New York, United States, 10467-2490
      • Montefiore Medical Center - Moses Campus
  • North Carolina
    • Chapel Hill, North Carolina, United States, 27599
      • UNC Lineberger Comprehensive Cancer Center
    • Greenville, North Carolina, United States, 27834
      • Gynecologic Oncology Network
    • Pinehurst, North Carolina, United States, 28374
      • FirstHealth of the Carolinas-Moore Regional Hosiptal
    • Winston-Salem, North Carolina, United States, 27157
      • Wake Forest University Health Sciences
  • Ohio
    • Cincinnati, Ohio, United States, 45267
      • University of Cincinnati
    • Cleveland, Ohio, United States, 44106
      • Case Western Reserve University
    • Mayfield Heights, Ohio, United States, 44124
      • Hillcrest Hospital Cancer Center
    • Mentor, Ohio, United States, 44060
      • Lake University Ireland Cancer Center
  • Oklahoma
    • Oklahoma City, Oklahoma, United States, 73104
      • University of Oklahoma Health Sciences Center
    • Tulsa, Oklahoma, United States, 74146
      • Oklahoma Cancer Specialists and Research Institute-Tulsa
  • South Dakota
    • Sioux Falls, South Dakota, United States, 57117-5134
      • Sanford USD Medical Center - Sioux Falls
  • Tennessee
    • Nashville, Tennessee, United States, 37232
      • Vanderbilt University/Ingram Cancer Center
  • Texas
    • Fort Sam Houston, Texas, United States, 78234
      • Brooke Army Medical Center
  • Virginia
    • Roanoke, Virginia, United States, 24016
      • Carilion Clinic Gynecological Oncology
  • Wisconsin
    • Milwaukee, Wisconsin, United States, 53226
      • Froedtert and The Medical College of Wisconsin

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: Female

Description

Inclusion Criteria:

• Patients must have histologically proven CIN 2/3 or CIN 3 diagnosed by cervical biopsy between 2 and 8 weeks prior to enrollment

  • For a patient to be eligible, the pathology report must clearly state "CIN 2/3" or "CIN 3" or must state "moderate-severe dysplasia", "moderate-severe dyskaryosis," "severe dysplasia," or "severe dyskaryosis;" patients with a diagnosis of CIN 2 alone or moderate dysplasia or dyskaryosis alone are not eligible for this study (3/26/2007)
• Patients must have a satisfactory (readable, good quality) colposcopic evaluation at least 14 days after diagnostic biopsy
• Patients must have signed an approved informed consent and authorization permitting release of personal health information
• Patients must have colposcopically visible cervical lesion at entry consistent with biopsy
• Patients must have a negative urine pregnancy test; women of childbearing potential must practice an acceptable form of contraception (e.g. intrauterine device, contraceptive pills, diaphragm, condoms)
• Patients must have a GOG Performance Status of 0, 1, or 2
• Patients must agree to refrain from using non-steroidal anti-inflammatory drugs (NSAIDS) and aspirin during the time they are taking the study medication
• Patients must be good candidates for delayed treatment of their CIN, i.e. they must be reliable to return for follow-up and provide a combination of at least three phone numbers or addresses for contact
• Hemoglobin (HgB) greater than 11.0g/dl
• White blood cell (WBC) count greater than 3000/mcl
• Platelet count greater than 125,000/mcl (3/26/2007)
• Creatinine less than or equal to 1.5 x upper limit normal (ULN)
• Total bilirubin less than or equal to 1.5 x ULN excluding Gilbert's disease
• Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) < 2.0 x ULN

Exclusion Criteria:

• Patients who are pregnant or lactating
• Patients with cytologic or biopsy evidence of endocervical dysplasia or invasive cancer
• Patients with undiagnosed abnormal vaginal bleeding
• Patients who have previously taken celecoxib or any other COX-2 inhibitor at a frequency of greater than 3 times per week within 2 months (60 days) prior to randomization; patients can use Naproxen without restriction (6/23/2008)
• Patients with a known immunocompromised condition
• Patients who have had a known allergic reaction to any NSAIDS or aspirin (asthma, urticaria, allergic-type reaction)
• Patients with a prior history of cervical cancer
• Patients with hypersensitivity to Celecoxib
• Patients with a known allergic reaction to sulfonamides
• Patients with a history of peptic ulcer disease
• Patients currently using fluconazole or lithium
• Patients with a chronic or acute renal, or hepatic disorder, a significant bleeding disorder, or any other condition which in the investigator's opinion might preclude study participation for the duration of the trial
• Patients with a history of transient ischemic attack (TIA), stroke, cardiovascular disease or uncontrolled hypertension

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Prevention
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Double

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Arm I (celecoxib); Patients receive oral celecoxib once daily for 14-18 weeks.	Other: Laboratory Biomarker Analysis; Correlative studies; Drug: Celecoxib; Given orally; Other Names: Celebrex; SC-58635; Benzenesulfonamide, 4-[5-(4-methylphenyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl]-; YM 177
Placebo Comparator: Arm II (placebo); Patients receive oral placebo once daily for 14-18 weeks.	Other: Laboratory Biomarker Analysis; Correlative studies; Other: Placebo; Given orally; Other Names: placebo therapy; PLCB; sham therapy

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Histologic Regression	Whether or not patients with CIN 2/3 or CIN 3 upon entry experience a complete remission (or partial regression to CIN 1) in the post-treatment excisional biopsy.	Post treatment evaluation was done 14 to 18 weeks after treatment randomization
Incidence of Adverse Effects (Grade 3 or Higher) as Assessed by Common Terminology Criteria for Adverse Events Version 3.0	Number of participants with a grade of 3 or higher during the treatment period.	Assessed every cycle while on treatment, 30 days after the last cycle of treatment

Other Outcome Measures

Outcome Measure	Time Frame
To Examine the Association of Histologic Response in COX-2 in Tissue	Up to 18 weeks
To Examine the Association of Histologic Response in HPV Viral Load in Serum Before and After Treatment	Up to 18 weeks
HPV Viral Load Before and After Treatment	Up to 18 weeks
To Examine the Association of Histologic Response in the Levels of Celecoxib in Serum During Treatment.	Up to 18 weeks
Levels of Serum bFGF	Up to 18 weeks
Levels of Serum VEGF	Up to 18 weeks
To Determine the Feasibility of Digital Imaging Using Pathologist's Diagnosis and Diagnostic Technique (Web-based or Standard Method).	Baseline
To Examine the Association of Histologic Response in Proliferation Index (Ki67).	Up to 18 weeks
Proportion of Patients Whose Eligibility Can be Successfully Determined Using the Web-based Review	Baseline
The Number of Quadrants Involving CIN	Up to 18 weeks
To Examine the Association of Histologic Response in Apoptosis Index (TUNEL Assay)	Up to 18 weeks
To Examine the Association of Histologic Response in Angiogenisis (VEGF)	Up to 18 weeks

Collaborators and Investigators

• Sponsor: Gynecologic Oncology Group
• Collaborators: National Cancer Institute (NCI)
• Investigators: Principal Investigator: Janet Rader, NRG Oncology

Publications and helpful links

General Publications

• Rader JS, Sill MW, Beumer JH, Lankes HA, Benbrook DM, Garcia F, Trimble C, Tate Thigpen J, Lieberman R, Zuna RE, Leath CA 3rd, Spirtos NM, Byron J, Thaker PH, Lele S, Alberts D. A stratified randomized double-blind phase II trial of celecoxib for treating patients with cervical intraepithelial neoplasia: The potential predictive value of VEGF serum levels: An NRG Oncology/Gynecologic Oncology Group study. Gynecol Oncol. 2017 May;145(2):291-297. doi: 10.1016/j.ygyno.2017.02.040. Epub 2017 Mar 10.

Study record dates

Study Major Dates

• Study Start: June 1, 2005
• Primary Completion (Actual): September 1, 2012

Study Registration Dates

• First Submitted: April 7, 2004
• First Submitted That Met QC Criteria: April 7, 2004
• First Posted (Estimate): April 8, 2004

Study Record Updates

• Last Update Posted (Actual): September 15, 2017
• Last Update Submitted That Met QC Criteria: September 13, 2017
• Last Verified: August 1, 2017

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Neoplasms by Histologic Type; Carcinoma; Neoplasms, Glandular and Epithelial; Neoplasms; Carcinoma in Situ; Cervical Intraepithelial Neoplasia; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Peripheral Nervous System Agents; Enzyme Inhibitors; Analgesics; Sensory System Agents; Anti-Inflammatory Agents, Non-Steroidal; Analgesics, Non-Narcotic; Anti-Inflammatory Agents; Antirheumatic Agents; Cyclooxygenase Inhibitors; Carbonic Anhydrase Inhibitors; Cyclooxygenase 2 Inhibitors; Celecoxib; Benzenesulfonamide
• Other Study ID Numbers: GOG-0207 (Other Identifier: CTEP); U10CA101165 (U.S. NIH Grant/Contract); NCI-2009-00583 (Registry Identifier: CTRP (Clinical Trial Reporting Program)); CDR0000360805