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

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.

• imiquimod (Drug), also known as Aldara, IMQ, R 837: Applied topically
• fluorouracil (Drug), also known as 5-fluorouracil, 5-Fluracil, 5-FU, Efudex: Applied topically
• infrared photocoagulation therapy (Device), also known as infrared coagulation, IRC: Undergo infrared coagulation
• thermal ablation therapy (Device): Undergo hyfrecation/electrocautery therapy
• laser therapy (Device), also known as therapy, laser: Undergo laser therapy
• clinical observation (Other), also known as observation: Undergo active monitoring (High Resolution Anoscopy \[HRA\]) with biopsies
• laboratory biomarker analysis (Other): Correlative studies

Primary outcomes

• Anal Cancer Incidence [Time from randomization to diagnosis of anal cancer, assessed up to 5 years post randomization]: Anal cancer incidence is calculated as the number of anal cancer cases detected per 100,000 person years

Secondary outcomes

• Incidence of Adverse Events for Each Treatment [Up to 5 years after randomization]: Participants who had at least one adverse event (serious or non-serious)
• Change in Physical Symptom Score From Baseline (2-7 Days Post Randomization) Until 4 Weeks Post Randomization [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.

Other outcomes

• Viral Factors in HSIL Progression to Cancer [Up to 5 years after randomization]: 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.
• Host Factors in HSIL Progression to Cancer [Up to 5 years after randomization]: 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.
• Host and Viral Biomarkers of Progression From HSIL to Cancer [Up to 5 years after randomization]: Biomarkers that are correlated with progression from anal HSIL to anal cancer
• Behavioral Risk Factors for HSIL Progression to Cancer [Up to 5 years after randomization]: 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.
• ANCHOR Study Health-Related Symptom Index (A-HRSI) Scale Responsiveness (Sensitivity to Change) [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).]: 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).
• Quality of Life Assessment Measured by the A-HRSI (Validated Tool) [A-HRSI completion occurred at 3 time points: Pre-randomization (T1), within 2-7 days (T2) and at 4 weeks of treatment/randomization (T3).]: 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.

Sex: All, ages: 35 Years to any

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

Participant flow

Outcome results

• Anal Cancer Incidence (Primary), Number, cases per 100,000 person years: Arm I (Treatment) 173 (90 to 332); Arm II (Active Monitoring) (Closed Since SEP2021) 402 (262 to 616)
• Incidence of Adverse Events for Each Treatment (Secondary), Count of participants, Participants: Arm I (Treatment) 416; Arm II (Active Monitoring) (Closed Since SEP2021) 429
• Change in Physical Symptom Score From Baseline (2-7 Days Post Randomization) Until 4 Weeks Post Randomization (Secondary), Mean, score on a scale: Arm I (Treatment) -2.22 +/- 4.69; Arm II (Active Monitoring) (Closed Since SEP2021) -0.08 +/- 3.31
• Viral Factors in HSIL Progression to Cancer (Other pre specified)
• Host Factors in HSIL Progression to Cancer (Other pre specified)
• Host and Viral Biomarkers of Progression From HSIL to Cancer (Other pre specified)
• Behavioral Risk Factors for HSIL Progression to Cancer (Other pre specified)
• ANCHOR Study Health-Related Symptom Index (A-HRSI) Scale Responsiveness (Sensitivity to Change) (Other pre specified)
• Quality of Life Assessment Measured by the A-HRSI (Validated Tool) (Other pre specified)

Adverse events

Time frame: Adverse events were collected from randomization until up to 5 years after randomization

Serious adverse events by term

16 more terms not shown.

Other adverse events by term

• 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. PMID 35017115
• Results publication: 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, de la Ossa J, Levine R, Korman JD, Hagensee M, Atkinson TM, Einstein MH, Cracchiolo BM, Wiley D, Ellsworth GB, Brickman C, Berry-Lawhorn JM; ANCHOR Investigators Group. Treatment of Anal High-Grade Squamous Intraepithelial Lesions to Prevent Anal Cancer. N Engl J Med. 2022 Jun 16;386(24):2273-2282. doi: 10.1056/NEJMoa2201048. PMID 35704479
• Results publication: Barroso LF, Stier EA, Hillman R, Palefsky J. Anal Cancer Screening and Prevention: Summary of Evidence Reviewed for the 2021 Centers for Disease Control and Prevention Sexually Transmitted Infection Guidelines. Clin Infect Dis. 2022 Apr 13;74(Suppl_2):S179-S192. doi: 10.1093/cid/ciac044. PMID 35416975
• Results publication: Higashi RT, Rodriguez SA, Betts AC, Tiro JA, Luque AE, Rivera R, Barnes A. Anal cancer screening among women with HIV: provider experiences and system-level challenges. AIDS Care. 2022 Feb;34(2):220-226. doi: 10.1080/09540121.2021.1883512. Epub 2021 Feb 17. PMID 33594934

• Study Protocol and Statistical Analysis Plan (PDF, 2021-01-22)
• Informed Consent Form (PDF, 2021-01-22)

• Joel Palefsky, MD, Principal investigator, AIDS Malignancy Consortium

NIH grants: U01CA121947, UM1CA121947