Therapy Adapted for High Risk and Low Risk HIV-Associated Anal Cancer

PRIMARY OBJECTIVES: I. To determine the safety of reduced intensity chemo-radiation therapy (CRT) in low-risk disease. II. To determine the safety of nivolumab after standard CRT in high-risk disease. SECONDARY OBJECTIVES: I. To estimate the efficacy (2-year disease-control rate \[DCR\]) of reduced intensity CRT in low risk disease. II. To estimate the efficacy (2-year disease-free survival \[DFS\] rate) of nivolumab after standard CRT in high risk disease. III. To evaluate the effect of low-dose CRT on immune function (CD4+ cell count) and human immunodeficiency virus (HIV) viral load. IV. To evaluate the effect of nivolumab on immune function (CD4+ cell count) and HIV viral load. V. To assess combination antiretroviral therapy (cART) adherence before, during, and after treatment with CRT and nivolumab to identify potential barriers to cART adherence when receiving concurrent oncological care. EXPLORATORY OBJECTIVES: I. To determine the human papillomavirus (HPV) genotype in primary tumor and explore the relationship between specific HPV subtypes and clinical response to reduced intensity CRT or nivolumab. II. To explore the relationship between expression of PD-1 in immune cells and PD-L1 in immune cells or cancer epithelial cells in the primary diagnostic tumor and clinical response to nivolumab or reduced intensity CRT. III. To describe the effects of reduced intensity CRT and nivolumab on viral HIV reservoirs. IV. To identify the presence of cell-free plasma HPV deoxyribonucleic acid (DNA) before and after reduced intensity CRT and nivolumab and explore the relationship with clinical response. V. To describe the effect of reduced intensity CRT on quality of life (QOL). OUTLINE: Patients are assigned to 1 of 2 stratum. HIGH-RISK STRATUM: Patients receive nivolumab intravenously (IV) over 30 minutes on day 1. Treatment repeats every 4 weeks for up to 6 cycles in the absence of disease progression or unacceptable toxicity. Patients also undergo echocardiography (ECHO) during screening as clinically indicated, sigmoidoscopy/colonoscopy, anoscopy/proctoscopy or digital rectal exam and computed tomography (CT) throughout the study as well as blood sample collection during screening and end of treatment (EOT). LOW-RISK STRATUM: Patients receive mitomycin IV on day 1 and either fluorouracil IV on day 1 or capecitabine orally (PO) twice daily (BID) on Monday-Friday until the completion of radiation therapy at the discretion of the treating physician. Patients also undergo intensity modulated radiation therapy (IMRT) once daily (QD) for 20-23 treatment sessions over 6 weeks. Patients also undergo digital rectal exam, anoscopy/proctoscopy and CT throughout the study, receive fludeoxyglucose F-18 (FDG) IV and undergo positron emission tomography (PET)/CT, PET/magnetic resonance imaging (MRI) and /or MRI during screening and follow-up as well as blood sample collection during screening and EOT. Some patients undergo lymph node biopsy during screening at the discretion of the treating physician. After completion of study treatment, patients are followed up at 6 weeks, every 3 months for years 1-2, every 6 months for year 3, and then annually for years 4-5.