CA-IX, p16, Proliferative Markers, and HPV in Diagnosing Cervical Lesions in Patients With Abnormal Cervical Cells

• ClinicalTrials.gov Identifier: NCT00892866
• Recruitment Status: Active, not recruiting
• First Posted: May 5, 2009
• Last Update Posted: October 28, 2022
• Sponsor: Gynecologic Oncology Group
• Collaborator: National Cancer Institute (NCI)
• Information provided by (Responsible Party): GOG Foundation ( Gynecologic Oncology Group )

Tracking Information

• First Submitted Date: May 2, 2009
• First Posted Date: May 5, 2009
• Last Update Posted Date: October 28, 2022
• Actual Study Start Date: February 9, 2009
• Estimated Primary Completion Date: May 31, 2025 (Final data collection date for primary outcome measure)

Current Primary Outcome Measures (submitted: May 4, 2018)

• Biomarker expression in patients from North America [ Time Frame: Baseline ]
  CA-IX, p16, Ki-67, and MCM2 expression in LBC specimens is measured via IHC. A logistic regression and receiver operating characteristic (ROC)-type analysis will be performed.
• Biomarker expression in patients from Japan [ Time Frame: Baseline ]
  CA-IX, p16, Ki-67, and MCM2 expression in LBC specimens is measured via IHC. A logistic regression and ROC-type analysis will be performed.
• Biomarker expression in patients from Korea [ Time Frame: Baseline ]
  CA-IX, p16, Ki-67, and MCM2 expression in LBC specimens is measured via IHC. A logistic regression and ROC-type analysis will be performed.

Original Primary Outcome Measures (submitted: May 2, 2009)

• CA-IX , high-risk HPV, p16, Ki-67, and MCM2 expression as an optimal diagnosis of cervical lesions in patients in North America
• CA-IX , high-risk HPV, p16, Ki-67, and MCM2 expression as an optimal diagnosis of cervical lesions in patients in Japan

Current Secondary Outcome Measures (submitted: May 4, 2018)

• Effect of patient age on the accuracy of diagnosis based on CA-IX, HPV, p16, Ki-67, and/or MCM2 expression in the North American population [ Time Frame: Baseline ]
  Logistic regression analyses will be performed to assess the effect of age and country on sensitivity, specificity, false positive rate (FPR), and complement negative predictive value (NPVC.). For each country and at each age, an upper 95% confidence limit will be calculated for the NPVC.
• Effect of patient age on the accuracy of diagnosis based on CA-IX, HPV, p16, Ki-67, and/or MCM2 expression in the Korean and Japanese populations [ Time Frame: Baseline ]
  Logistic regression analyses will be performed to assess the effect of age and country on sensitivity, specificity, FPR, and NPVC. For each country and at each age, an upper 95% confidence limit will be calculated for the NPVC.

Original Secondary Outcome Measures (submitted: May 2, 2009)

• Effect of patient age and country (North America or Japan) on the accuracy of diagnosis based on CA-IX, HPV, p16, Ki-67, and/or MCM2 expression
• Inter- and intra-reviewer reproducibility of scoring CA-IX, p16, Ki-67 and MCM2 biomarkers

Current Other Pre-specified Outcome Measures (submitted: January 26, 2015)

• Biomarker expression, loss of heterozygosity (LOH), chromosome gains, and chromosome losses in tissue from the highest grade or most abnormal lesions in women with AGC [ Time Frame: Baseline ]
  Exploratory analyses of genomic alterations, including LOH as well as chromosome gains and chromosome losses will be performed to identify genomic alterations associated with cervical dysplasia/neoplasia.
• CA-IX expression, combined p16 and Ki67 expression, and MCM2 expression in LBC specimens [ Time Frame: Baseline ]
  Will be used to see which subset of markers will provide the higher and sensitivity in the diagnosis of cervical AIS.

• Original Other Pre-specified Outcome Measures: Not Provided

Descriptive Information

• Brief Title: CA-IX, p16, Proliferative Markers, and HPV in Diagnosing Cervical Lesions in Patients With Abnormal Cervical Cells
• Official Title: Comparative Analysis of CA-IX, p16, Proliferative Markers, and Human Papilloma Virus (HPV) in the Diagnosis of Significant Cervical Lesions in Patients With a Cytologic Diagnosis of Atypical Glandular Cells (AGC)
• Brief Summary: This research trial studies carbonic anhydrase 9 (CA-IX), p16, proliferative markers, and human papilloma virus (HPV) in diagnosing cervical lesions in patients with abnormal cervical cells. Studying biomarkers in abnormal cervical cells may improve the ability to find cervical lesions and plan effective treatment.

Detailed Description

PRIMARY OBJECTIVES:

I. To examine CA-IX, p16, Ki-67, and mini-chromosome maintenance complex component 2 (MCM2) expression in liquid-based cytology (LBC) specimens to see which subset of markers can provide the optimal diagnosis of significant cervical lesions in women in North America with a cytologic diagnosis of atypical glandular cells (AGC) and a positive test for high risk human papillomavirus (HPV).

II. To examine high risk HPV, CA-IX, p16, Ki-67, and MCM2 expression in LBC specimens to see which subset of markers can provide the optimal diagnosis of significant cervical lesions in women in Japan and Korea (with each country's cohort analyzed separately) with a cytologic diagnosis of AGC.

SECONDARY OBJECTIVES:

I. To determine whether the accuracy of diagnosis based on high risk HPV and expression of CA-IX, p16, Ki-67, and/or MCM2 varies with patient age at enrollment and country of enrollment.

TERTIARY OBJECTIVES:

I. To assess biomarker expression, loss of heterozygosity, and chromosome gains/losses in formalin-fixed, paraffin-embedded tissue from the highest grade or most abnormal lesion in women from North America, Japan, or Korea presenting with a cytologic diagnosis of AGC or with a cytologic/histologic diagnosis of adenocarcinoma in situ (AIS).

II. To determine CA-IX, p16, Ki67, and MCM2 expression in LBC specimens to see which subset (or combination) of markers will provide higher sensitivity in the diagnosis of cervical adenocarcinoma in situ (AIS).

OUTLINE:

Patients undergo liquid-based cytology specimen sample collection for analysis of CA-IX, p16, Ki-67, and MCM2 expression via immunohistochemistry (IHC) and for the presence of high risk HPV deoxyribonucleic acid (DNA) and HPV genotyping.

• Study Type: Interventional
• Study Phase: Phase 1
• Study Design: Allocation: Non-Randomized; Intervention Model: Single Group Assignment; Masking: None (Open Label); Primary Purpose: Treatment

Condition

• Atypical Endometrial Hyperplasia
• Human Papillomavirus Infection
• Stage 0 Cervical Cancer AJCC v7

Intervention

• Other: Cytology Specimen Collection Procedure
  Correlative studies
  Other Name: Cytologic Sampling
• Other: Laboratory Biomarker Analysis
  Correlative studies

Study Arms

Ancillary-Correlative (biomarkers in cervical cancer)

Patients undergo liquid-based cytology specimen sample collection for analysis of CA-IX, p16, Ki-67, and MCM2 expression via IHC and for the presence of high risk HPV DNA and HPV genotyping.

Interventions:

• Other: Cytology Specimen Collection Procedure
• Other: Laboratory Biomarker Analysis

• Publications *: Not Provided

Recruitment Information

• Recruitment Status: Active, not recruiting
• Estimated Enrollment (submitted: August 12, 2022): 877
• Original Estimated Enrollment (submitted: May 2, 2009): 754
• Estimated Study Completion Date: May 31, 2025
• Estimated Primary Completion Date: May 31, 2025 (Final data collection date for primary outcome measure)

Eligibility Criteria

Inclusion Criteria:

• Patients with a cytologic diagnosis of AGC (AGC, atypical endocervical cells [AEC], atypical endometrial cells [AEmC]) or a cytologic/histologic diagnosis of AIS documented within the last 6 months who can wait at least one week after the AGC or AIS diagnosis to have an LBC specimen (i.e., ThinPrep) collected and then receive any other intervention; acceptable time frame range is 4 days prior to registration to 7 days after registration
• Patients with positive HPV results who are willing to undergo a complete histologic examination of the uterus and cervix, including the cervical transformation zone, within 6 months of the AGC or AIS diagnosis (histologic examination includes a loop electrosurgical excision procedure [LEEP], loop excision of the transformation zone [LETZ], excisional cone biopsy, or hysterectomy)
• Patients must have signed an approved informed consent and authorization permitting release of personal health information

Exclusion Criteria:

• Patients who have had a hysterectomy
• History of endometrial hyperplasia or cancer of the endometrium, vagina, or cervix
• Patients who have previously been treated, or are currently being treated with radiation therapy or chemotherapy for vaginal or cervical cancer
• Patients who are known to be human immunodeficiency virus (HIV)-positive
• Patients who are pregnant and thought to be at risk for excessive bleeding or preterm labor if a cone biopsy is performed

Sex/Gender

• Sexes Eligible for Study: Female

• Ages: 18 Years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Contacts: Contact information is only displayed when the study is recruiting subjects
• Listed Location Countries: Japan, Korea, Republic of, United States

Administrative Information

• NCT Number: NCT00892866
• Other Study ID Numbers: GOG-0237; NCI-2009-01103 ( Registry Identifier: CTRP (Clinical Trial Reporting Program) ); CDR0000632236; GOG-0237 ( Other Identifier: Gynecologic Oncology Group ); GOG-0237 ( Other Identifier: DCP ); GOG-0237 ( Other Identifier: CTEP ); N01CM62201 ( U.S. NIH Grant/Contract ); U10CA101165 ( U.S. NIH Grant/Contract ); UG1CA189867 ( U.S. NIH Grant/Contract )
• Has Data Monitoring Committee: Yes
• U.S. FDA-regulated Product: Not Provided
• IPD Sharing Statement: Not Provided
• Current Responsible Party: GOG Foundation ( Gynecologic Oncology Group )
• Original Responsible Party: Not Provided
• Current Study Sponsor: Gynecologic Oncology Group
• Original Study Sponsor: Same as current
• Collaborators: National Cancer Institute (NCI)

Investigators

• Principal Investigator: Shu-Yuan liao; Gynecologic Oncology Group

• PRS Account: GOG Foundation
• Verification Date: October 2022