Clinical trial NCT00081263: Celecoxib in Treating Patients With Cervical Intraepithelial Neoplasia
Official title: 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)
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE2
Conditions: Cervical Carcinoma
Cervical Intraepithelial Neoplasia Grade 2/3
Stage 0 Cervical Cancer
Lead sponsor: GOG Foundation
Sponsor class: NETWORK
Collaborators: name: National Cancer Institute (NCI)
First posted: 2004-04-08
Enrollment: 130
Sex: FEMALE
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: PREVENTION

Brief summary: 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.

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.

Eligibility criteria: 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

Primary outcomes:
measure: Histologic Regression
timeFrame: Post treatment evaluation was done 14 to 18 weeks after treatment randomization
measure: Incidence of Adverse Effects (Grade 3 or Higher) as Assessed by Common Terminology Criteria for Adverse Events Version 3.0
timeFrame: Assessed every cycle while on treatment, 30 days after the last cycle of treatment
Secondary outcomes:
Other outcomes:
measure: To Examine the Association of Histologic Response in COX-2 in Tissue
timeFrame: Up to 18 weeks
measure: To Examine the Association of Histologic Response in HPV Viral Load in Serum Before and After Treatment
timeFrame: Up to 18 weeks
measure: HPV Viral Load Before and After Treatment
timeFrame: Up to 18 weeks
measure: To Examine the Association of Histologic Response in the Levels of Celecoxib in Serum During Treatment.
timeFrame: Up to 18 weeks
measure: Levels of Serum bFGF
timeFrame: Up to 18 weeks
measure: Levels of Serum VEGF
timeFrame: Up to 18 weeks
measure: To Determine the Feasibility of Digital Imaging Using Pathologist's Diagnosis and Diagnostic Technique (Web-based or Standard Method).
timeFrame: Baseline
measure: To Examine the Association of Histologic Response in Proliferation Index (Ki67).
timeFrame: Up to 18 weeks
measure: Proportion of Patients Whose Eligibility Can be Successfully Determined Using the Web-based Review
timeFrame: Baseline
measure: The Number of Quadrants Involving CIN
timeFrame: Up to 18 weeks
measure: To Examine the Association of Histologic Response in Apoptosis Index (TUNEL Assay)
timeFrame: Up to 18 weeks
measure: To Examine the Association of Histologic Response in Angiogenisis (VEGF)
timeFrame: Up to 18 weeks
Locations:
city: Tucson
country: United States
facility: University of Arizona Cancer Center-North Campus
state: Arizona
city: Little Rock
country: United States
facility: University of Arkansas for Medical Sciences
state: Arkansas
city: Lewes
country: United States
facility: Beebe Medical Center
state: Delaware
city: Newark
country: United States
facility: Christiana Care Health System-Christiana Hospital
state: Delaware
city: Urbana
country: United States
facility: Carle Clinic-Urbana Main
state: Illinois
city: Elkhart
country: United States
facility: Elkhart Clinic
state: Indiana
city: Elkhart
country: United States
facility: Michiana Hematology Oncology PC-Elkhart
state: Indiana
city: Elkhart
country: United States
facility: Elkhart General Hospital
state: Indiana
city: Kokomo
country: United States
facility: Community Howard Regional Health
state: Indiana
city: La Porte
country: United States
facility: IU Health La Porte Hospital
state: Indiana
city: Mishawaka
country: United States
facility: Michiana Hematology Oncology PC-Mishawaka
state: Indiana
city: Mishawaka
country: United States
facility: Saint Joseph Regional Medical Center-Mishawaka
state: Indiana
city: Plymouth
country: United States
facility: Michiana Hematology Oncology PC-Plymouth
state: Indiana
city: South Bend
country: United States
facility: Memorial Hospital of South Bend
state: Indiana
city: South Bend
country: United States
facility: Michiana Hematology Oncology PC-South Bend
state: Indiana
city: South Bend
country: United States
facility: Northern Indiana Cancer Research Consortium
state: Indiana
city: Westville
country: United States
facility: Michiana Hematology Oncology PC-Westville
state: Indiana
city: Elkton
country: United States
facility: Union Hospital of Cecil County
state: Maryland
city: Kalamazoo
country: United States
facility: Borgess Medical Center
state: Michigan
city: Kalamazoo
country: United States
facility: Bronson Methodist Hospital
state: Michigan
city: Kalamazoo
country: United States
facility: West Michigan Cancer Center
state: Michigan
city: Saint Joseph
country: United States
facility: Lakeland Hospital
state: Michigan
city: Saint Joseph
country: United States
facility: Marie Yeager Cancer Center
state: Michigan
city: Columbia
country: United States
facility: University of Missouri - Ellis Fischel
state: Missouri
city: Saint Louis
country: United States
facility: Saint Louis University Hospital
state: Missouri
city: Las Vegas
country: United States
facility: Women's Cancer Center of Nevada
state: Nevada
city: Newark
country: United States
facility: Rutgers New Jersey Medical School
state: New Jersey
city: The Bronx
country: United States
facility: Montefiore Medical Center - Moses Campus
state: New York
city: Chapel Hill
country: United States
facility: UNC Lineberger Comprehensive Cancer Center
state: North Carolina
city: Greenville
country: United States
facility: Gynecologic Oncology Network
state: North Carolina
city: Pinehurst
country: United States
facility: FirstHealth of the Carolinas-Moore Regional Hosiptal
state: North Carolina
city: Winston-Salem
country: United States
facility: Wake Forest University Health Sciences
state: North Carolina
city: Cincinnati
country: United States
facility: University of Cincinnati
state: Ohio
city: Cleveland
country: United States
facility: Case Western Reserve University
state: Ohio
city: Mayfield Heights
country: United States
facility: Hillcrest Hospital Cancer Center
state: Ohio
city: Mentor
country: United States
facility: Lake University Ireland Cancer Center
state: Ohio
city: Oklahoma City
country: United States
facility: University of Oklahoma Health Sciences Center
state: Oklahoma
city: Tulsa
country: United States
facility: Oklahoma Cancer Specialists and Research Institute-Tulsa
state: Oklahoma
city: Sioux Falls
country: United States
facility: Sanford USD Medical Center - Sioux Falls
state: South Dakota
city: Nashville
country: United States
facility: Vanderbilt University/Ingram Cancer Center
state: Tennessee
city: Fort Sam Houston
country: United States
facility: Brooke Army Medical Center
state: Texas
city: Roanoke
country: United States
facility: Carilion Clinic Gynecological Oncology
state: Virginia
city: Milwaukee
country: United States
facility: Froedtert and the Medical College of Wisconsin
state: Wisconsin
Study officials:
affiliation: NRG Oncology
name: Janet Rader
role: PRINCIPAL_INVESTIGATOR
References:
citation: 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.