Treatment in Preventing Anal Cancer in Patients With HIV and Anal High-Grade Lesions

HIV Infection Clinical Trial

— ANCHOR  

Official title:

ANCHOR Study: Anal Cancer/HSIL Outcomes Research Study

Clinical Trial Details — Status: Active, not recruiting

Administrative data

• NCT number: NCT02135419
• Other study ID #: AMC-A01
• Secondary ID: NCI-2014-00636AM
• Status: Active, not recruiting
• Phase: Phase 3
• Start date: September 24, 2014
• Est. completion date: March 31, 2024

Study information

• Verified date: January 2024
• Source: AIDS Malignancy Consortium
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

The randomized phase of the trial compared topical or ablative treatment with active monitoring in preventing anal cancer in patients with human immunodeficiency virus (HIV) and high-grade squamous intraepithelial lesions (HSIL). Anal HSIL is tissue in the anal canal that has been damaged by infection with human papillomavirus (HPV) and is at risk for turning into anal cancer.

The ANCHOR Data Safety Monitoring Board (DSMB) determined that the primary study endpoint was completed, based on the data and statistical analysis presented to them on 07SEP2021.

In the post-randomization phase of this trial, all enrolled participants are offered treatment for HSIL and/or follow-up, at the participant's choice.

Description:

PRIMARY OBJECTIVES: The primary objective of this study has been completed for efficacy.

I. To determine the effectiveness of treating anal HSIL to reduce the incidence of anal cancer in human immunodeficiency virus (HIV)-infected men and women.

SECONDARY OBJECTIVES:

I. To determine the safety of infrared coagulation (IRC), electrocautery, imiquimod, laser and 5- fluorouracil treatments for anal HSIL.

II. To assess the responsiveness (sensitivity to change) and clinical significance of the ANCHOR Health-Related Symptom Index (A-HRSI) subscales by comparing change scores within groups of participants as defined by participant responses to the participant global impression of change (PGIC) item. (completed FEB2020)

TERTIARY OBJECTIVES:

Collect clinical specimens and data to create a bank of well-annotated specimens that will enable correlative science:

I. Identification of viral factors in HSIL progression to cancer; II. Identification of host factors in HSIL progression to cancer; III. Identify host and viral biomarkers of progression from HSIL to cancer; IV. Identify medical history and behavioral risk factors for HSIL progression to cancer.

QUALITY OF LIFE OBJECTIVES (completed FEB2022) I. Primary QOL Objective: To compare arms in terms of changes in physical symptoms and impacts from T2 to T3, adjusting for T1.

ANCILLARY (COVID SUPPLEMENT) SUBSTUDY OBJECTIVES:

I. Determine the prevalence of SARS-CoV-2 detection in anal and oropharyngeal swabs among people living with HIV (PLWH) being screened for and enrolled in the ANCHOR study.

II. Determine the relationship between prevalent anal SARS-CoV-2 positivity, anal HPV infection, and anal high-grade squamous intraepithelial lesions (HSIL).

III. Determine the 6-month incidence of SARS-CoV-2 detection in anal and oropharyngeal swabs among participants in the active monitoring arm being assessed for the first time for treatment and individuals already enrolled in the COVID substudy under protocol version 15.0.

IV. Determine the relationship between prevalent or incident SARS-CoV-2 detection and regression of anal HPV infection or HSIL among active monitoring arm participants already enrolled in the COVID substudy under protocol version 15.0, and those who continue the protocol and who choose not to be treated at visit 101.

OUTLINE: The randomized strategy to study the efficacy of HSIL treatment to reduce the risk of progression to anal cancer, as compared to active monitoring, was discontinued for all participants.

Patients are randomized to 1 of 2 treatment arms. (accrual closed SEP2021)

ARM I: Patients are directed to receive either topical or ablative treatment at the discretion of the clinician. Patients receiving topical treatment apply topical imiquimod intra-anally, peri-anally or both thrice weekly for up to 16 weeks, or topical 5-fluorouracil twice daily for 5 days every 2 weeks for up to 16 weeks. Patients receiving ablative treatment using infrared coagulation, hyfrecation/electrocautery, or laser. Patients may undergo excision under anesthesia if the clinician believes none of the other treatment approaches will be effective. The number and timing of such treatments will be at the discretion of the investigator. Patients with persistent HSIL should continue a protocol-approved treatment or a new protocol treatment should be considered.

ARM II: Patients undergo active monitoring with HRA examinations and anal cytology every 6 months. Every 12 months, patients undergo biopsies of visible lesions.

Participants on both arms are to be followed for up to 5 years after randomization of the last participant.

Post-randomization phase: Individuals in the treatment arm may continue treatment, and participants in the active monitoring arm are offered treatment. If upon assessment participants continue to have HSIL but do not intend to get treatment, they will be monitored for the potential for disease progression to anal cancer.

Recruitment information / eligibility

• Status: Active, not recruiting
• Enrollment: 4446
• Est. completion date: March 31, 2024
• Est. primary completion date: August 6, 2021
• Accepts healthy volunteers: No
• Gender: All
• Age group: 35 Years and older

Eligibility

Inclusion Criteria:

• HIV positive. Documentation of HIV-1 infection by means of any one of the following:

1) Documentation of HIV diagnosis in the medical record by a licensed health care provider; 2) Documentation of receipt of ART by a licensed health care provider (receipt of at least two agents is required); 3) HIV-1 RNA detection by a licensed HIV-1 RNA assay demonstrating >1000 RNA copies/mL; or, 4) Any licensed HIV screening antibody and/or HIV antibody/antigen combination assay confirmed by a second licensed HIV assay such as a HIV-1 Western blot confirmation or HIV rapid multispot antibody differentiation assay.

• Biopsy-proven HSIL at baseline

• At least one focus of HSIL must be identified that is not within a condyloma that may be treated after enrollment into the study

• For females, documentation that the participant is being followed for cervical cytology (if having a cervix) and/or HPV testing per current ASCCP guidelines, and visual examination of the vulva, vagina, and cervix to rule out cancer/suspicion for cancer within 12 months prior to enrollment

• Eastern Cooperative Oncology Group (ECOG) performance status <= 1 (Karnofsky >= 70%)

• Life expectancy of greater than 5 years

• Absolute neutrophil count: >= 750/mm^3

• Platelets: >= 75,000/mm^3

• Hemoglobin >= 9.0 g/dL

• Women of childbearing potential must have a negative urine pregnancy test within 7 days of initiating study treatment if they have been randomized to the treatment arm; all women of childbearing potential must agree to use a reliable birth control method (oral contraceptive pills, intrauterine device, Nexplanon, DepoProvera, or permanent sterilization, etc., or another acceptable method as determined by the investigator) during the entire period of the trial (5 years or more), and must not intend to become pregnant during study participation and for 3 months after treatment is discontinued; all participants must be willing to comply with an acceptable birth control regimen as determined by the Investigator

• Men randomized to the treatment arm should not father a baby while receiving topical treatment during this study. Men who could father a child must agree to use at least one form of birth control during or continued abstinence from heterosexual intercourse if receiving topical treatment during the study, and for 2 weeks after stopping topical treatment.

• Ability to understand and the willingness to sign a written informed consent document

• Participant is willing to be randomized and able to comply with the protocol

• Clinician is comfortable with either following patient for up to 5 years without therapy or treating patient for up to 5 years

Exclusion Criteria:

• Inability to provide informed consent

• Patients who are receiving any other immunomodulatory investigational agents (replacement doses of steroids for adrenal insufficiency or treatment with prednisone =5 mg/day is permitted) within the 4 weeks before randomization enrollment, other than investigational antiretroviral agents for HIV, or investigational or approved agents for Hepatitis C.

• History of anal cancer, penile, vulvar, vaginal or cervical cancer, or signs of these cancers at baseline.

• Treatment or removal of HSIL less than 6 months prior to randomization.

• Participant has symptoms related to HSIL and would benefit more from immediate treatment than from entry into the study and potential for randomization to active monitoring arm

• Current systemic chemotherapy or radiation therapy that potentially causes bone marrow suppression that would preclude safe treatment of HSIL

• Participants who only have a single HSIL lesion that is likely to be removed entirely with the initial screening biopsy

• Warts so extensive that they preclude the clinician from determining the extent and location of HSIL

• Participant plans to relocate away from the study site to a location without an ANCHOR study site during study participation

Related Conditions & MeSH terms

• Anal Cancer
• Anus Neoplasms
• Carcinoma in Situ
• Carcinoma, Squamous Cell
• Communicable Diseases
• High-grade Squamous Intraepithelial Lesion
• HIV Infection
• Human Papilloma Virus Infection
• Infections
• Papilloma
• Papillomavirus Infections
• Squamous Intraepithelial Lesions of the Cervix

Intervention

Drug:
• imiquimod
Applied topically
• fluorouracil
Applied topically

Device:
• infrared photocoagulation therapy
Undergo infrared coagulation
• thermal ablation therapy
Undergo hyfrecation/electrocautery therapy
• laser therapy
Undergo laser therapy

Other:
• clinical observation
Undergo active monitoring (High Resolution Anoscopy [HRA]) with biopsies
• laboratory biomarker analysis
Correlative studies

Locations

Country	Name	City	State
Puerto Rico	University of Puerto Rico	San Juan
United States	Grady Health System	Atlanta	Georgia
United States	University of Colorado Hospital	Aurora	Colorado
United States	Boston Medical Center	Boston	Massachusetts
United States	Fenway Health	Boston	Massachusetts
United States	Montefiore - Albert Einstein College of Medicine	Bronx	New York
United States	Anal Dysplasia Clinic MidWest	Chicago	Illinois
United States	Denver Public Health	Denver	Colorado
United States	UCLA CARE Clinic	Los Angeles	California
United States	UCLA School of Nursing	Los Angeles	California
United States	ACC Clinic, Jackson Hospital	Miami	Florida
United States	University of Miami Miller School of Medicine - Sylvester Cancer Center	Miami	Florida
United States	CrescentCare Health	New Orleans	Louisiana
United States	University Medical Center New Orleans	New Orleans	Louisiana
United States	Cornell Clinical Trials Unit, Chelsea Center	New York	New York
United States	Laser Surgery Care	New York	New York
United States	Rutgers University New Jersey Medical School	Newark	New Jersey
United States	DAP Health	Palm Springs	California
United States	University of California at San Francisco Anal Dysplasia Clinic	San Francisco	California
United States	Harborview Medical Center	Seattle	Washington
United States	The Polyclinic	Seattle	Washington
United States	Virginia Mason Medical Center	Seattle	Washington
United States	Capital Digestive Care	Washington	District of Columbia
United States	Dupont Circle Physicians Group	Washington	District of Columbia
United States	Wake Forest Baptist Health	Winston-Salem	North Carolina

Sponsors (6)

Lead Sponsor	Collaborator
AIDS Malignancy Consortium	National Cancer Institute (NCI), The Emmes Company, LLC, University of Arizona, University of Arkansas, University of California, San Francisco

Countries where clinical trial is conducted

United States,  Puerto Rico, 

References & Publications (2)

Lee JY, Lensing SY, Berry-Lawhorn JM, Jay N, Darragh TM, Goldstone SE, Wilkin TJ, Stier EA, Einstein M, Pugliese JC, Palefsky JM; ANCHOR Investigators. Design of the ANal Cancer/HSIL Outcomes Research study (ANCHOR study): A randomized study to prevent anal cancer among persons living with HIV. Contemp Clin Trials. 2022 Feb;113:106679. doi: 10.1016/j.cct.2022.106679. Epub 2022 Jan 10. — View Citation

Palefsky JM, Lee JY, Jay N, Goldstone SE, Darragh TM, Dunlevy HA, Rosa-Cunha I, Arons A, Pugliese JC, Vena D, Sparano JA, Wilkin TJ, Bucher G, Stier EA, Tirado Gomez M, Flowers L, Barroso LF, Mitsuyasu RT, Lensing SY, Logan J, Aboulafia DM, Schouten JT, d — View Citation

Outcome

Type	Measure	Description	Time frame	Safety issue
Other	Viral Factors in HSIL Progression to Cancer	Descriptive statistics will be used to describe the integration locus of HPV In the invasive cancers and whether they differ from those of the overlying HSIL. Descriptive statistics will also be used to determine if the loci differ in HSIL that have progressed and concurrent HSIL biopsies that did not progress. In each case only tissues that contain HPV 16 will be analyzed.	Up to 5 years after randomization
Other	Host Factors in HSIL Progression to Cancer	Linear models will be fitted for each gene. Moderated t-statistics, fold-change and the associated p values will be calculated for each gene. Since thousands of genes will be tested, false discovery rate (FDR)-adjusted values will be calculated using the Benjamini-Hochberg method. FDR values indicate the expected fraction of falsely declared differentially expressed (DE) genes among the total set of declared DE genes, i.e. FDR = 0.15 would indicate that 15% of the declared DE genes were expected to be false due to experimental noise instead of actual differential expression.	Up to 5 years after randomization
Other	Host and Viral Biomarkers of Progression From HSIL to Cancer	Biomarkers that are correlated with progression from anal HSIL to anal cancer	Up to 5 years after randomization
Other	Behavioral Risk Factors for HSIL Progression to Cancer	For each risk factor of interest, Fisher's exact test or Pearson's chi-square test will be used to determine if there is an association. Factors associated with invasive anal cancer at the 0.10 significance level will be incorporated into a logistic regression model to determine if they are independently associated with invasive anal cancer. Cox regression analyses will also be used to evaluate the association between risk factors and time to diagnosis of invasive anal cancer.	Up to 5 years after randomization
Other	ANCHOR Study Health-Related Symptom Index (A-HRSI) Scale Responsiveness (Sensitivity to Change)	Participants at follow-up timepoints were categorized into two sets of three groups based on PGIC and ECOG PS responses ("worse," "no change," "better"), with the primary responsiveness analysis using these three groups in a one-way analysis of variance (ANOVA).	A-HRSI and self-reported Patient Global Impression of Change (PGIC) scale and ECOG Performance Status (ECOG PS) item were administered at time of enrollment (T1) up until time of trial randomization (T2), and 71-112 days post-randomization (T3).
Other	Quality of Life Assessment Measured by the A-HRSI (Validated Tool)	A-HRSI physical symptoms and physical impacts subscale change scores (T3 minus T2) using an analysis of covariance adjusting for the covariate baseline (T1) subscale to test for differences between arms at a one-sided 0.025 significance level with approximately 90% power.	A-HRSI completion occurred at 3 time points: Pre-randomization (T1), within 2-7 days (T2) and at 4 weeks of treatment/randomization (T3).
Primary	Anal Cancer Incidence	Anal cancer incidence is calculated as the number of anal cancer cases detected per 100,000 person years	Time from randomization to diagnosis of anal cancer, assessed up to 5 years post randomization
Secondary	Incidence of Adverse Events for Each Treatment	Participants who had at least one adverse event (serious or non-serious)	Up to 5 years after randomization
Secondary	Change in Physical Symptom Score From Baseline (2-7 Days Post Randomization) Until 4 Weeks Post Randomization	The physical symptom score is made up of the sum of responses to whether or not the participant had any of the 9 physical symptoms: anal pain, pain other than anal pain, pain during bowel movements, constipation, bleeding from anus, itching in/around the anus, discharge (wetness) in anal area, burning sensations in the anal area, and urgency for bowel movements. Responses are 0- not at all, 1-a little bit, 2-somewhat, 3-quite a bit, 4-very much. Thus physical symptom score ranges from 0 to 36.	4 weeks post randomization