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

Study Overview
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Brief Summary
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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.

Detailed Description
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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.

Official Title
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ANCHOR Study: Anal Cancer/HSIL Outcomes Research Study

Conditions
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Anal Cancer, High-grade Squamous Intraepithelial Lesion, HIV Infection, Human Papilloma Virus Infection

Intervention / Treatment
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* Drug: imiquimod
* Drug: fluorouracil
* Device: infrared photocoagulation therapy
* Device: thermal ablation therapy
* Device: laser therapy
* Other: clinical observation
* Other: laboratory biomarker analysis


Participation Criteria
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Eligibility Criteria
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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

Ages Eligible for Study
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Minimum Age: 35 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Prevention
Allocation: Randomized
Intervention Model: Parallel Assignment
Interventional Model Description: All participants are evaluated with high resolution anoscopy and anal cytology every 6 months during study participation. Participants randomized to treatment undergo biopsy of anal HSIL at each 6-month visit, and receive topical or ablative therapies for incident anal HSIL lesions. Active monitoring participants undergo close observation, with biopsy of anal HSIL at annual visits. Participants undergo biopsy of lesions at any time cancer is suspected.
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Arm I (treatment)<br>Patients are directed to receive either topical or ablative treatment at the discretion of the clinician. Patients receiving topical treatment apply imiquimod intra-anally, peri-anally or both thrice weekly for up to 16 weeks, fluorouracil twice daily for 5 days every 2 weeks for up to 16 weeks, or trichloroacetic acid every 3 weeks up to 12 weeks. Patients receiving ablative treatment using infrared photocoagulation therapy, hyfrecation/electrocautery (thermal ablation therapy), or laser therapy. 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. All participants will have samples collected for laboratory biomarker analysis. | Drug: imiquimod<br>* Applied topically<br>* Other names: R 837;Drug: fluorouracil<br>* Applied topically<br>* Other names: Efudex;Device: infrared photocoagulation therapy<br>* Undergo infrared coagulation<br>* Other names: IRC;Device: thermal ablation therapy<br>* Undergo hyfrecation/electrocautery therapy<br>Device: laser therapy<br>* Undergo laser therapy<br>* Other names: therapy, laser;Other: clinical observation<br>* Undergo active monitoring (High Resolution Anoscopy [HRA]) with biopsies<br>* Other names: observation;Other: laboratory biomarker analysis<br>* Correlative studies<br>|
| Active Comparator: Arm II (active monitoring) (closed since SEP2021)<br>Patients undergo active monitoring with examinations for clinical observation every 6 months. Every 12 months, patients undergo biopsies of visible lesions. Patients have cytology sampling performed at every visit. All participants will have samples collected for laboratory biomarker analysis. | Other: clinical observation<br>* Undergo active monitoring (High Resolution Anoscopy [HRA]) with biopsies<br>* Other names: observation;Other: laboratory biomarker analysis<br>* Correlative studies<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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 Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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 | 
| 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 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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HIV, HIV/AIDS, human papillomavirus, HPV, anal cancer, high-grade squamous intraepithelial lesion, anal HSIL