Cervical Carcinoma, Cervical Intraepithelial Neoplasia Grade 2/3, Stage 0 Cervical Cancer
Conditions
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.
Interventions
DRUGCelecoxib
Given orally
OTHERLaboratory Biomarker Analysis
Correlative studies
OTHERPlacebo
Given orally
Sponsors
National Cancer Institute (NCI)
Gynecologic Oncology Group
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
PREVENTION
Masking
DOUBLE (Subject, Investigator)
Eligibility
Sex/Gender
FEMALE
Age
18 Years to No maximum
Healthy volunteers
No
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
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Histologic Regression | Post treatment evaluation was done 14 to 18 weeks after treatment randomization | 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. |
| Incidence of Adverse Effects (Grade 3 or Higher) as Assessed by Common Terminology Criteria for Adverse Events Version 3.0 | Assessed every cycle while on treatment, 30 days after the last cycle of treatment | Number of participants with a grade of 3 or higher during the treatment period. |
Other
| Measure | Time frame |
|---|---|
| Levels of Serum VEGF | Up to 18 weeks |
| Proportion of Patients Whose Eligibility Can be Successfully Determined Using the Web-based Review | Baseline |
| 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 |
| To Examine the Association of Histologic Response in COX-2 in Tissue | Up to 18 weeks |
| To Examine the Association of Histologic Response in the Levels of Celecoxib in Serum During Treatment. | Up to 18 weeks |
| HPV Viral Load Before and After Treatment | Up to 18 weeks |
| 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 |
| To Examine the Association of Histologic Response in HPV Viral Load in Serum Before and After Treatment | Up to 18 weeks |
| Levels of Serum bFGF | Up to 18 weeks |
Countries
United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Arm I (Celecoxib) Patients receive oral celecoxib once daily for 14-18 weeks.
Celecoxib: Given orally
Laboratory Biomarker Analysis: Correlative studies | 50 |
| Arm II (Placebo) Patients receive oral placebo once daily for 14-18 weeks.
Laboratory Biomarker Analysis: Correlative studies
Placebo: Given orally | 41 |
| Total | 91 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | clerical error | 1 | 0 |
| Overall Study | improper pre-protocol therapy | 0 | 1 |
| Overall Study | Inadequate data | 5 | 10 |
| Overall Study | Inadequate pathology | 0 | 1 |
| Overall Study | Never treated | 4 | 5 |
| Overall Study | wrong cell type | 7 | 5 |
Baseline characteristics
| Characteristic | Arm I (Celecoxib) | Arm II (Placebo) | Total |
|---|---|---|---|
| Age, Customized 18-19 years | 1 Participants | 5 Participants | 6 Participants |
| Age, Customized 20-29 years | 30 Participants | 23 Participants | 53 Participants |
| Age, Customized 30-39 years | 13 Participants | 10 Participants | 23 Participants |
| Age, Customized 40-49 years | 6 Participants | 3 Participants | 9 Participants |
| Cell Type Cervical Intraepithelial Neoplasia 2/3 | 14 Participants | 11 Participants | 25 Participants |
| Cell Type Cervical Intraepithelial Neoplasia 3 | 36 Participants | 30 Participants | 66 Participants |
| Sex: Female, Male Female | 50 Participants | 41 Participants | 91 Participants |
| Sex: Female, Male Male | 0 Participants | 0 Participants | 0 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — |
| other Total, other adverse events | 25 / 67 | 25 / 63 |
| serious Total, serious adverse events | 0 / 67 | 1 / 63 |
Outcome results
Primary
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.
Time frame: Post treatment evaluation was done 14 to 18 weeks after treatment randomization
Population: Eligible, Treated, and Evaluable patients
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Arm I (Celecoxib) | Histologic Regression | 40 percentage of participants |
| Arm II (Placebo) | Histologic Regression | 34.1 percentage of participants |
Primary
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.
Time frame: Assessed every cycle while on treatment, 30 days after the last cycle of treatment
Population: Eligible and treated patients.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Arm I (Celecoxib) | Incidence of Adverse Effects (Grade 3 or Higher) as Assessed by Common Terminology Criteria for Adverse Events Version 3.0 | Gastrointestinal | 1 participants |
| Arm I (Celecoxib) | Incidence of Adverse Effects (Grade 3 or Higher) as Assessed by Common Terminology Criteria for Adverse Events Version 3.0 | Pain | 0 participants |
| Arm II (Placebo) | Incidence of Adverse Effects (Grade 3 or Higher) as Assessed by Common Terminology Criteria for Adverse Events Version 3.0 | Gastrointestinal | 0 participants |
| Arm II (Placebo) | Incidence of Adverse Effects (Grade 3 or Higher) as Assessed by Common Terminology Criteria for Adverse Events Version 3.0 | Pain | 1 participants |
Other Pre-specified
HPV Viral Load Before and After Treatment
Time frame: Up to 18 weeks
Other Pre-specified
Levels of Serum bFGF
Time frame: Up to 18 weeks
Other Pre-specified
Levels of Serum VEGF
Time frame: Up to 18 weeks
Other Pre-specified
Proportion of Patients Whose Eligibility Can be Successfully Determined Using the Web-based Review
Time frame: Baseline
Other Pre-specified
The Number of Quadrants Involving CIN
Time frame: Up to 18 weeks
Other Pre-specified
To Determine the Feasibility of Digital Imaging Using Pathologist's Diagnosis and Diagnostic Technique (Web-based or Standard Method).
Time frame: Baseline
Other Pre-specified
To Examine the Association of Histologic Response in Angiogenisis (VEGF)
Time frame: Up to 18 weeks
Other Pre-specified
To Examine the Association of Histologic Response in Apoptosis Index (TUNEL Assay)
Time frame: Up to 18 weeks
Other Pre-specified
To Examine the Association of Histologic Response in COX-2 in Tissue
Time frame: Up to 18 weeks
Other Pre-specified
To Examine the Association of Histologic Response in HPV Viral Load in Serum Before and After Treatment
Time frame: Up to 18 weeks
Other Pre-specified
To Examine the Association of Histologic Response in Proliferation Index (Ki67).
Time frame: Up to 18 weeks
Other Pre-specified
To Examine the Association of Histologic Response in the Levels of Celecoxib in Serum During Treatment.
Time frame: Up to 18 weeks