Topical or Ablative Treatment in Preventing Anal Cancer in Patients With HIV and Anal High-Grade Squamous Intraepithelial Lesions (ANCHOR)

Study Description

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Brief Summary:

This randomized phase III trial compares 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. It is not yet known if treating HSIL is more effective than active monitoring in preventing patients from developing anal cancer.

Condition or disease	Intervention/treatment	Phase
Anal Cancer; High-grade Squamous Intraepithelial Lesion; HIV Infection; Human Papilloma Virus Infection	Drug: imiquimod; Drug: fluorouracil; Device: infrared photocoagulation therapy; Device: thermal ablation therapy; Device: laser therapy; Other: clinical observation; Other: laboratory biomarker analysis	Phase 3

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Study Design

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Study Type :	Interventional (Clinical Trial)
Estimated Enrollment :	5058 participants
Allocation:	Randomized
Intervention Model:	Parallel Assignment
Masking:	None (Open Label)
Primary Purpose:	Prevention
Official Title:	ANCHOR Study: Anal Cancer/HSIL Outcomes Research Study
Study Start Date :	September 24, 2014
Estimated Primary Completion Date :	June 30, 2022
Estimated Study Completion Date :	June 30, 2022

Arms and Interventions

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Arm	Intervention/treatment
Experimental: Arm I (treatment); 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; Applied topically; Other Names: Aldara; IMQ; R 837; Drug: fluorouracil; Applied topically; Other Names: 5-fluorouracil; 5-Fluracil; 5-FU; Device: infrared photocoagulation therapy; Undergo infrared coagulation; Other Names: infrared coagulation; IRC; Device: thermal ablation therapy; Undergo hyfrecation/electrocautery therapy; Device: laser therapy; Undergo laser therapy; Other Name: therapy, laser; Other: laboratory biomarker analysis; Correlative studies
Active Comparator: Arm II (active monitoring); 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; Undergo active monitoring; Other Name: observation; Other: laboratory biomarker analysis; Correlative studies

Outcome Measures

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Primary Outcome Measures :

1. Time to anal cancer [ Time Frame: Time from randomization to diagnosis of anal cancer, assessed up to 5 years ]
   The log-rank test will be used to compare the treatment and control arms with respect to time to detection of anal cancer. For each arm, the hazard rate and its 95% confidence interval will be estimated. The proportional hazards model will be used to assess the association of study site, lesion size, lesion location, nadir CD4 level and gender with time to detection of anal cancer.

Secondary Outcome Measures :

1. Incidence of adverse events for each treatment [ Time Frame: Up to 5 years ]
   Summarized by type of adverse event and severity grade for each of the treatments. For adverse events that occur in more than 5% of any of the treatments, the Poisson rates will be used to estimate the number of adverse events per unit time and the binomial proportion and its 95% confidence interval will be used to estimate the proportion of participants who reported the event.
2. Quality of life assessed using the Functional Assessment of Incontinence Therapy - Fecal (FAIT-F) questionnaire [ Time Frame: Up to 5 years ]
   Descriptive statistics will be used for subscales and scores for each arm and each time point. General estimating equations will be used to compare the two arms with respect to subscales and scores across time points and adjustment for intra-participant variability.

Other Outcome Measures:

1. Viral factors in HSIL progression to cancer [ Time Frame: Up to 5 years ]
   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.
2. Host factors in HSIL progression to cancer [ Time Frame: Up to 5 years ]
   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.
3. Host and viral biomarkers of progression from HSIL to cancer [ Time Frame: Up to 5 years ]
4. Behavioral risk factors for HSIL progression to cancer [ Time Frame: Up to 5 years ]
   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.

Eligibility Criteria

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Ages Eligible for Study:	35 Years and older (Adult, Older Adult)
Sexes Eligible for Study:	All
Accepts Healthy Volunteers:	No

Criteria

Inclusion Criteria:

• HIV-1 infection, as documented by any federally approved, licensed HIV test performed in conjunction with screening (or enzyme-linked immunosorbent assay [ELISA], test kit, and confirmed by western blot or other approved test); alternatively, this documentation may include a record that another physician has documented that the participant has HIV infection based on prior ELISA and western blot, or other approved diagnostic tests; an approved antibody test will be used to confirm diagnosis; if the physician is treating a patient with combination antiretroviral therapy (cART) with a history of HIV positivity based on an approved antibody test then repeat antibody confirmation is not necessary
• No history of treatment or removal of HSIL
• No history of anal cancer or signs of anal cancer at baseline, and no history of penile, vulvar, vaginal or cervical cancer
• 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, cervical cytology (if having a cervix) and gynecologic evaluation including vulvar examination 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), 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 in this study; men who could father a child should use at least two forms of birth control for 3 months after stopping all study 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 within the 4 weeks before randomization enrollment, other than investigational antiretroviral agents for HIV
• History of anal cancer, penile, vulvar, vaginal or cervical cancer
• History of prior treatment or removal of anal HSIL
• 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
• History of HPV vaccination, or intention to receive an HPV vaccine during study participation
• Prior pelvic radiation therapy that would preclude radiation therapy if anal cancer develops
• 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 during study participation

Contacts and Locations

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Contacts

Contact: Abigail Arons, MPH	844-448-2888	abigail.arons@ucsf.edu

Locations

United States, California
UCLA CARE Clinic	Recruiting
Los Angeles, California, United States, 90035
Contact: Faith Landsman 310-557-3743 flandsman@mednet.ucla.edu
Principal Investigator: Ronald Mitsuyasu, MD
UCLA School of Nursing	Suspended
Los Angeles, California, United States, 90095
University of California at San Francisco Anal Dysplasia Clinic	Recruiting
San Francisco, California, United States, 94115
Contact: Rachel Silverstein 415-353-7443 rachel.silverstein@ucsf.edu
Principal Investigator: Joel Palefsky, MD
Sub-Investigator: J. Michael Berry-Lawhorn, MD
Sub-Investigator: Naomi Jay, RN, NP, PhD
United States, Colorado
University of Colorado Hospital	Recruiting
Aurora, Colorado, United States, 80045
Contact: M. Ray, MSN 303-724-0712 graham.ray@ucdenver.edu
Principal Investigator: Hillary Dunlevy, MD
Denver Public Health	Recruiting
Denver, Colorado, United States, 80204
Contact: Jim Scott 303-602-8741 james.scott@dhha.org
Principal Investigator: Edward Gardner, MD
Sub-Investigator: Jeff Logan, PA
United States, District of Columbia
Capital Digestive Care	Recruiting
Washington, District of Columbia, United States, 20006
Contact: Jessica Korman 240-737-0085 anchor@capitaldigestivecare.com
Principal Investigator: Jessica Korman, MD
Dupont Circle Physicians Group	Recruiting
Washington, District of Columbia, United States, 20009
Contact: Benjamin Stearn, MD 202-745-0201 anchor@dupontdocs.com
Principal Investigator: Benjamin Stearn, MD
United States, Florida
ACC Clinic, Jackson Hospital	Recruiting
Miami, Florida, United States, 33136
Contact: Isabella Rosa-Cunha 305-243-4598 irosa-cunha@med.miami.edu
Principal Investigator: Isabella Rosa-Cunha, MD
University of Miami Miller School of Medicine - Sylvester Cancer Center	Recruiting
Miami, Florida, United States, 33136
Contact: Isabella Rosa-Cunha 305-213-4713 isrosa-cunha@med.miami.edu
Principal Investigator: Isabella Rosa-Cunha, MD
United States, Illinois
Anal Dysplasia Clinic MidWest	Recruiting
Chicago, Illinois, United States, 60614
Contact: Gary Bucher, MD 312-623-2625 garybuchermd@comcast.net
Principal Investigator: Gary Bucher, MD
United States, Louisiana
CrescentCare Health	Recruiting
New Orleans, Louisiana, United States, 70119
Contact: Christiane Geisler 504-293-6878 Christiane.geisler@crescentcarehealth.org
Principal Investigator: Toby Fugate, DO
Sub-Investigator: Michael Hagensee, PhD
United States, Massachusetts
Boston Medical Center	Recruiting
Boston, Massachusetts, United States, 02118
Contact: Elizabeth Stier, MD 617-414-5149 elizabeth.stier@bmc.org
Principal Investigator: Elizabeth Stier, MD
Fenway Health	Terminated
Boston, Massachusetts, United States, 02215
United States, New York
Montefiore - Albert Einstein College of Medicine	Recruiting
Bronx, New York, United States, 10461
Contact: Natalie Frey 929-263-3911 nfrey@montefiore.org
Principal Investigator: Rebecca Levine, MD
Cornell Clinical Trials Unit, Chelsea Center	Recruiting
New York, New York, United States, 10010
Contact: Christina Megill 212-746-7163 chm2029@med.cornell.edu
Principal Investigator: Timothy Wilkin, MD, MPH
Laser Surgery Care	Recruiting
New York, New York, United States, 10011
Contact: Stephen Goldstone 212-242-6500 drgoldstone@lasersurgerycare.com
Principal Investigator: Stephen Goldstone, MD
United States, North Carolina
Wake Forest Baptist Health	Recruiting
Winston-Salem, North Carolina, United States, 27157
Contact: Jin Zhang 336-716-4267 jinzhang@wakehealth.edu
Principal Investigator: Luis Barroso, MD
United States, Washington
Virginia Mason Medical Center	Recruiting
Seattle, Washington, United States, 98101
Contact: Angie Woodstock 206-342-6539 angela.woodstock@virginiamason.org
Principal Investigator: David Aboulafia, MD
Harborview Medical Center	Recruiting
Seattle, Washington, United States, 98104
Contact: Lindsay Legg 206-744-8748 lmlegg@u.washington.edu
Principal Investigator: Robert Harrington, MD
The Polyclinic	Recruiting
Seattle, Washington, United States, 98104
Contact: Gary Brown 206-860-4761 gary.brown@polyclinic.com
Principal Investigator: Juan De La Ossa, MD
Puerto Rico
University of Puerto Rico	Recruiting
San Juan, Puerto Rico, 00936
Contact: Maribel Tirado-Gomez 787-772-8300 maribel.tirado1@upr.edu
Principal Investigator: Maribel Tirado-Gomez, MD

Sponsors and Collaborators

AIDS Malignancy Consortium

National Cancer Institute (NCI)

The EMMES Corporation

University of Arkansas

University of California, San Francisco

Investigators

Principal Investigator:	Joel Palefsky, MD	AIDS Malignancy Consortium

More Information

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Responsible Party:	AIDS Malignancy Consortium
ClinicalTrials.gov Identifier:	NCT02135419 History of Changes
Other Study ID Numbers:	AMC-A01; NCI-2014-00636 ( Registry Identifier: CTRP (Clinical Trial Reporting Program) ); AMC-A01 ( Other Identifier: AIDS - Associated Malignancies Clinical Trials Consortium ); AMC-A01 ( Other Identifier: CTEP ); U01CA121947 ( U.S. NIH Grant/Contract )
First Posted:	May 12, 2014
Last Update Posted:	June 1, 2018
Last Verified:	May 2018

Studies a U.S. FDA-regulated Drug Product:		Yes
Studies a U.S. FDA-regulated Device Product:		Yes
Device Product Not Approved or Cleared by U.S. FDA:		No
Pediatric Postmarket Surveillance of a Device Product:		No
Product Manufactured in and Exported from the U.S.:		No

Additional relevant MeSH terms:

Infection; Communicable Diseases; HIV Infections; Virus Diseases; Papilloma; Anus Neoplasms; Squamous Intraepithelial Lesions of the Cervix; Papillomavirus Infections; Lentivirus Infections; Retroviridae Infections; RNA Virus Infections; Sexually Transmitted Diseases, Viral; Sexually Transmitted Diseases; Immunologic Deficiency Syndromes; Immune System Diseases	Neoplasms, Squamous Cell; Neoplasms, Glandular and Epithelial; Neoplasms by Histologic Type; Neoplasms; Rectal Neoplasms; Colorectal Neoplasms; Intestinal Neoplasms; Gastrointestinal Neoplasms; Digestive System Neoplasms; Neoplasms by Site; Digestive System Diseases; Gastrointestinal Diseases; Intestinal Diseases; Anus Diseases; Rectal Diseases