• Written informed consent and HIPAA authorization for release of personal health information. NOTE: HIPAA authorization may be included in the informed consent or obtained separately.

• Age ≥ 18 years at the time of consent.

• ECOG Performance Status of 0-1 within 30 days prior to registration.

• Histologically proven stage I (T1N0), IIA (T2N0), IIB (T1/2N1), or IIIA (T3 N0/1) invasive squamous cell carcinoma of the anus by AJCC version 9. Stage IIIB/C (T4 N0/1) cancers will also be eligible if less than 5cm in diameter.

• Patient deemed ineligible for standard of care treatment with 5-fluorouracil (5FU) and mitomycin-C (MMC) concurrently with radiation per treating investigator.

• Patient is treatment naïve for anal cancer diagnosis.

• Evaluable disease according to RECIST v1.1 within 30 days prior to registration.

• Archival or newly obtained tissue available for planned correlative analysis. If tissue is not available, subjects may choose to have a standard of care biopsy to meet eligibility.

• Demonstrate adequate organ function as defined below. All screening labs to be obtained within 30 days prior to registration.

‣ White blood cell (WBC) ≥ 1500 /mm\^3

⁃ Absolute Neutrophil Count (ANC) ≥ 1500/mm\^3

⁃ Hemoglobin (Hgb)a ≥ 9 g/dL

⁃ Platelets (Plt) ≥ 100,000 g/dL

⁃ Creatinine ≤ 1.5 × upper limit of normal (ULN) OR Measured or calculated creatinine clearance (GFR can also be used in place of creatinine or CrCl) ≥30 mL/min for creatinine levels \>1.5 × institutional ULN

⁃ Total bilirubin ≤ 1.5 × ULN OR direct bilirubin ≤ULN for participants with total bilirubin levels \>1.5 × ULN

⁃ Aspartate aminotransferase (AST) ≤ 2.5 × ULN

⁃ Alanine aminotransferase (ALT) ≤ 2.5 × ULN

⁃ Females of childbearing potential who are sexually active with a male able to father a child must have a negative pregnancy test (serum or urine) within 14 days prior to registration.

⁃ Females of childbearing potential who are sexually active with a male able to father a child must be willing to abstain from heterosexual activity or use an effective method(s) of contraception. Males able to father a child who are sexually active with female of childbearing potential must be willing to abstain from heterosexual activity or to use an effective method(s) of contraception.

⁃ If a subject is HIV-infected, participants must have well-controlled HIV on antiretroviral therapy (ART), defined as:

• Participants on ART must have a CD4+ T-cell count ≥350 cells/mm3 at the time of screening

∙ Participants on ART must have achieved and maintained virologic suppression defined as confirmed HIV RNA level below 50 or the LLOQ (below the limit of detection) using the locally available assay at the time of screening and for at least 12 weeks before screening.

∙ Participants must not have had any AIDS-defining opportunistic infections within the past 12 months.

∙ Participants on ART must have been on a stable regimen, without changes in drugs or dose modification, for at least 4 weeks before study entry (Day 1) and agree to continue ART throughout the study. NOTE: HIV testing is not required for eligibility.

⁃ If a subject has evidence of chronic hepatitis B virus (HBV) infection, the HBV viral load must be undetectable on suppressive therapy, if indicated. If a subject has a history of hepatitis C virus (HCV) infection, it must have been treated and cured. For patients with HCV infection who are currently on treatment, the HCV viral load must be undetectable to be eligible for this trial. Testing is not required at screening unless mandated by local policy.

⁃ Ability of the subject to understand and comply with study procedures for the entire length of the study, as determined by the enrolling physician or protocol designee.