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

Inclusion Criteria:

• HIGH-RISK STRATUM: Participant is able to understand and willing to sign a writteninformed consent document

• HIGH-RISK STRATUM: Participant must have histologically proven stage (T3-T4N0M0 ORT2-4N1M0) invasive squamous cell carcinoma (SCC) of the anus or anorectum asdocumented before CRT initiation, according to the American Joint Committee onCancer (AJCC) 8th edition. Participants with squamous cell carcinoma of the analmargin are eligible if there is evidence of extension of the primary tumor into theanal canal. Participants with tumors of non-keratinizing histology such as basaloid,transitional cell or cloacogenic histology are permitted

• HIGH-RISK STRATUM: HIV-positive. Documentation of HIV-1 infection by means of anyone of the following:

• Documentation of HIV diagnosis in the medical record by a licensed health careprovider. If the record contains information that the patient is taking Foodand Drug Administration (FDA)-approved combination therapy for HIV infection,then this can be part of the record substantiating the HIV positive diagnosis

• HIV-1 ribonucleic acid (RNA) detection by a licensed HIV-1 RNA assaydemonstrating > 1000 RNA copies/mL

• Any licensed HIV screening antibody and/or HIV antibody/antigen combinationassay confirmed by a second licensed HIV assay such as a HIV-1 Western blotconfirmation or HIV rapid multispot antibody differentiation assay.

• NOTE: The term "licensed" refers to a kit that has been certified orlicensed by an oversight body within the participating country andvalidated internally (e.g., United States [U.S.] FDA)

• WHO (World Health Organization) and CDC (Centers for Disease Control andPrevention) guidelines mandate that confirmation of the initial testresult must use a test that is different from the one used for the initialassessment. A reactive initial rapid test must be confirmed by eitheranother type of rapid assay or an E/CIA that is based on a differentantigen preparation and/or different test principle (e.g., indirect versuscompetitive), or a Western blot or a plasma HIV-1 RNA viral load

• HIGH-RISK STRATUM: Age >= 18 years

• Because no dosing or adverse event data are currently available on the use ofnivolumab in participants < 18 years of age, children are excluded from thisstudy

• HIGH-RISK STRATUM: Eastern Cooperative Oncology Group (ECOG) performance status =< 2 (Karnofsky >= 50%)

• HIGH-RISK STRATUM: Life expectancy of greater than 6 months

• HIGH-RISK STRATUM: Hemoglobin > 10 g/dL (within 2 weeks before enrollment)

• HIGH-RISK STRATUM: Absolute neutrophil count: >= 1,500/mm^3 (within 2 weeks beforeenrollment)

• HIGH-RISK STRATUM: Platelets: >= 100,000/mm^3 (within 2 weeks before enrollment)

• HIGH-RISK STRATUM: Total bilirubin: < 2 X upper limit of normal (ULN) (within 2weeks before enrollment)

• HIGH-RISK STRATUM: Aspartate aminotransferase (AST) (serum glutamic oxaloacetictransaminase [SGOT]) / alanine aminotransferase (ALT) (serum glutamic pyruvictransaminase [SGPT]): =< 2.5 X institutional ULN (within 2 weeks before enrollment)

• HIGH-RISK STRATUM: Albumin >= 3.0 g/dL (within 2 weeks before enrollment)

• HIGH-RISK STRATUM: Creatinine levels =< 1.5 X normal institutional limits; orcalculated creatinine clearance must be > 50 ml/min (within 2 weeks beforeenrollment)

• HIGH-RISK STRATUM: Females of childbearing potential (FOCBP) must agree to followcontraception requirements:

• The effects of nivolumab on the developing human fetus are unknown. For thisreason and because other therapeutic agents used in this trial are known to beteratogenic, FOCBP must agree to use adequate contraception (hormonal orbarrier method of birth control; abstinence) before study entry, for theduration of study participation and 5 months after completion of nivolumabadministration. Should a woman become pregnant or suspect she is pregnant whileshe is participating in this study, she should inform her treating physicianimmediately

• NOTE: A female of childbearing potential is any woman, regardless ofsexual orientation or whether they have undergone tubal ligation, whomeets the following criteria: 1) has achieved menarche at some point, 2)has not undergone a hysterectomy or bilateral oophorectomy; or 2) has notbeen naturally postmenopausal (amenorrhea following cancer therapy doesnot rule out childbearing potential) for at least 24 consecutive months (i.e., has had menses at any time in the preceding 24 consecutive months)

• HIGH-RISK STRATUM: Participant must have a CD4 count of >= 100 cells/uL at least 2weeks prior to enrollment OR >= 100 cells/uL before receiving prior CRT, as CD4 maybe low due to the effects of CRT

• HIGH-RISK STRATUM: Participant must be on a stable antiretroviral therapy (ART)regimen for at least 2 weeks prior to enrollment with no intention to change theregimen within 12 weeks after enrollment

• HIGH-RISK STRATUM: Participant must have an HIV RNA viral load of < 200 copies/mL

• HIGH-RISK STRATUM: Participant must have received at least 54 Gy of radiation to thePTVp (primary) and 45 Gy to PTVn (elective nodal region) for the treatment of theanal cancer within 9 weeks before enrollment

• HIGH-RISK STRATUM: Participant must have =< grade 2 diarrhea

• Participants with grade 1 or grade 2 diarrhea are eligible provided stool forova/parasites and stool cryptosporidium studies are negative

• HIGH-RISK STRATUM: Purified protein derivative (PPD) negative. Alternatively, theQuantiFERON-tuberculosis (TB) Gold In-Tube (QFT-GIT) assay (Cellestis Limited,Carnegie, Australia) can be used. An individual is considered positive for M.tuberculosis infection if the interferon (IFN)-gamma response to TB antigens isabove the test cut-off (after subtracting the background IFN-gamma response in thenegative control). The result must be obtained within 20 weeks prior to enrollment.PPD positive (or QuantiFERON assay positive) participants are permitted ifprophylaxis has been completed prior to enrollment

• HIGH-RISK STRATUM: Participants with impaired decision-making capacity (IDMC) may beeligible for the study provided all other eligibility criteria are satisfied:

• The participant's legally authorized representative (LAR) is able and willingto sign consent in addition to the study candidate

• Both participant and LAR agree to follow study parameters per protocol

• HIGH-RISK STRATUM: The participant, in the opinion of the treating investigator, isable to receive IV contrast injections:

• All participants in the High-risk Stratum must have an oral contrast (rectalcontrast optional) and IV iodine contrast abdomen and pelvis contrast CT (A/PC+CT) and chest C+CT at baseline and for all clinical follow up time points.Imaging centers should follow their local routine guidelines for determinationof patient eligibility for IV contrast injection and appropriate post contrastfollow up renal function determinations

• SCREENING ELIGIBILITY LOW-RISK STRATUM: Participant is able to understand andwilling to sign a written informed consent document

• SCREENING ELIGIBILITY LOW-RISK STRATUM: Age >= 18 years

• Because no dosing or adverse event data are currently available on the use oflow-dose radiation concurrent with mitomycin-C/fluorouracil (5-FU) ormitomycin-C/capecitabine in participants < 18 years of age, children areexcluded from this study

• SCREENING ELIGIBILITY LOW-RISK STRATUM: Participant must have histologically provenT1-2N0M0 invasive anal canal or anal margin squamous cell carcinoma with tumorsmeasuring =< 4 cm within 6 weeks before pre-registration. Measurable disease is notrequired. Participants with tumors of non-keratinizing histology such as basaloid,transitional cell, or cloacogenic histology are permitted. Participants who arestatus/post local excision or excisional biopsy procedure are eligible providedthere was tumor involvement of the anal canal and/or anal verge prior to thereaction, if the margins were positive, and/or if the stage is T2N0 based on tumorsize before the procedure. This means that participants with T1N0M0 anal marginsquamous cell carcinoma who underwent surgical excision with negative margins and noinvolvement of the anal verge and/or anal canal are not eligible Baseline imagingincluding, FDG-PET/CT and A/P C+CT must be submitted for central review forconfirmation of no lymph node involvement. Results of central review (includingdiscrepancies between local read and central review) will be returned to the sitewithin 5 business days of submission, allowing participants with imaging suspiciousfor lymph node (LN) involvement determined by central review to undergo a fineneedle aspirate (FNA) or core biopsy at their local center confirming no lymph nodeinvolvement (N0) for eligibility

• SCREENING ELIGIBILITY LOW-RISK STRATUM: HIV positive. Documentation of HIV-1infection by means of any one of the following:

• Documentation of HIV diagnosis in the medical record by a licensed health careprovider. If the record contains information that the patient is takingFDA-approved combination therapy for HIV infection, then this can be part ofthe record substantiating the HIV positive diagnosis

• HIV-1 RNA detection by a licensed HIV-1 RNA assay demonstrating > 1000 RNAcopies/mL

• Any licensed HIV screening antibody and/or HIV antibody/antigen combinationassay confirmed by a second licensed HIV assay such as a HIV-1 Western blotconfirmation or HIV rapid multispot antibody differentiation assay.

• NOTE: The term "licensed" refers to a kit that has been certified orlicensed by an oversight body within the participating country andvalidated internally (e.g., U.S. FDA)

• WHO (World Health Organization) and CDC (Centers for Disease Control andPrevention) guidelines mandate that confirmation of the initial testresult must use a test that is different from the one used for the initialassessment. A reactive initial rapid test must be confirmed by eitheranother type of rapid assay or an E/CIA that is based on a differentantigen preparation and/or different test principle (e.g., indirect versuscompetitive), or a Western blot or a plasma HIV-1 RNA viral load

• SCREENING ELIGIBILITY LOW-RISK STRATUM: Tumor size must be documented by digitalrectal exam and anoscopy/proctoscopy within 6 weeks prior to pre-registration

• SCREENING ELIGIBILITY LOW-RISK STRATUM: Life expectancy of greater than 6 months

• LOW-RISK STRATUM: Participant satisfies all criteria in Eligibility for ScreeningLow-Risk Stratum. Participants with imaging suspicious for LN involvement determinedby central review must undergo a fine needle aspirate (FNA) or core biopsyconfirming no lymph node involvement (N0)

• LOW-RISK STRATUM: ECOG performance status =< 2 (Karnofsky >= 50%)

• LOW-RISK STRATUM: Hemoglobin > 10 g/dL (within 2 weeks before enrollment)

• LOW-RISK STRATUM: Absolute neutrophil count: >= 1,500/mm^3 (within 2 weeks beforeenrollment)

• LOW-RISK STRATUM: Platelets: >= 100,000/mm^3 (within 2 weeks before enrollment)

• LOW-RISK STRATUM: Total bilirubin: < 2 X ULN (within 2 weeks before enrollment)

• LOW-RISK STRATUM: AST (SGOT) / ALT (SGPT): =< 2.5 X institutional ULN (within 2weeks before enrollment)

• LOW-RISK STRATUM: Albumin >= 3.0 g/dL (within 2 weeks before enrollment)

• LOW-RISK STRATUM: Serum creatinine levels =< 1.5 X ULN or calculated creatinineclearance must be > 50 ml/min (within 2 weeks before enrollment)

• LOW-RISK STRATUM: Participant must agree to follow contraception requirements:

• Females of childbearing potential (FOCBP) and sexually active males must bestrongly advised to use accepted and effective method(s) of contraception or toabstain from sexual intercourse for the duration of their participation in thestudy and for at least 6 months after the completion of treatment

• NOTE: FOCBP is defined as a sexually mature woman, regardless of sexualorientation or whether they have undergone tubal ligation who: 1) has notundergone a hysterectomy or bilateral oophorectomy; or 2) has not beennaturally postmenopausal for at least 24 consecutive months, i.e., has hadmenses at any time in the preceding 24 consecutive months

• LOW-RISK STRATUM: Participant must have a CD4 count of >= 100 cells/uL at least 2weeks before enrollment

• LOW-RISK STRATUM: Participant must on a stable ART regimen for at least 2 weeksbefore enrollment and receive appropriate care and treatment for HIV infection underthe care of a physician experienced in HIV management

• LOW-RISK STRATUM: Participant has a HIV RNA viral load of < 200 copies/mL

• LOW-RISK STRATUM: Participant has started an alternative anti-coagulant regimenwithin 2 weeks prior to enrollment if taking warfarin and considering capecitabine

• NOTE: Low molecular weight heparin is permitted provided the participantsprothrombin time (PT)/international normalized ratio (INR) is < 1.5

• LOW-RISK STRATUM: Participant must agree to having phenytoin levels checked weeklyif planning to receive capecitabine while taking phenytoin for a seizure disorder

• LOW-RISK STRATUM: Participants with IDMC may be eligible for the study provided allother eligibility criteria are satisfied:

• The participant's legally authorized representative (LAR) is able and willingto sign consent in addition to the study candidate

• Both participant and LAR agree to follow study parameters

• LOW-RISK STRATUM: The participant, in the opinion of the treating investigator, isable to receive IV contrast injections:

All participants in the Low-risk Stratum must have an oral contrast (rectal contrast optional) and IV iodine contrast CT (A/P C+CT and chest C+CT) at baseline and for all clinical follow up time points. Imaging centers should follow their local routine guidelines for determination of patient eligibility for IV contrast injection and appropriate post contrast follow up renal function determinations

Exclusion Criteria:

• HIGH-RISK STRATUM: Any live vaccines within 30 days prior to enrollment

• Examples of live vaccines include, but are not limited to, the following:measles, mumps, rubella, chicken pox, yellow fever, rabies, BacillusCalmette-Guerin (BCG), and typhoid (oral) vaccine. Seasonal influenza vaccinesfor injection are generally killed virus vaccines and are allowed; however,intranasal influenza vaccines (e.g., Flu-Mist) are live attenuated vaccines andare not allowed

• NOTE: No live vaccines may be administered while participating in the trial.

• HIGH-RISK STRATUM: Participant has known interstitial lung disease that issymptomatic or may interfere with the detection or management of suspecteddrug-related pulmonary toxicity

• HIGH-RISK STRATUM: Prior treatment with an immune checkpoint inhibitor (anti-PD-1,anti-PD-L1, anti-PD-L2, anti-CTLA4 monoclonal antibody)

• HIGH-RISK STRATUM: Participant with an allogenic bone marrow/stem, cell or solidorgan transplant

• HIGH-RISK STRATUM: Participant is receiving any other investigational agents

• HIGH-RISK STRATUM: History of allergic reactions attributed to compounds of similarchemical or biologic composition to nivolumab or other agents used in study

• HIGH-RISK STRATUM: Uncontrolled intercurrent illness including, but not limited to,ongoing or active infection, symptomatic congestive heart failure, unstable anginapectoris, cardiac arrhythmia or psychiatric illness/social situations that wouldlimit compliance with study requirements

• HIGH-RISK STRATUM: Participant has a history of a different malignancy, unlesshe/she have been disease-free for at least 2 years and are deemed by theinvestigator to be at low risk of recurrence

• NOTE: Individuals with the following cancers are eligible if diagnosed andtreated within the past 5 years: cervical cancer in situ, basal cell orsquamous cell carcinoma of the skin, and stage I and IIA/IIB resected melanoma.In addition, participants on hormonal treatment for breast/gynecological andprostate tumors with no evidence of active disease are permitted, as well asparticipants with controlled Kaposi sarcoma (KS) not requiring systemic KSdirected therapy

• HIGH-RISK STRATUM: Pregnant or breastfeeding.

• Pregnant women are excluded from this study because nivolumab is ananti-PD-1MAb agent with the potential for teratogenic or abortifacient effects.Because there is an unknown but potential risk for adverse events in nursinginfants secondary to treatment of the mother with nivolumab, breastfeedingshould be discontinued if the mother is treated with nivolumab

• All FOCBP must have a blood test or urine study within 2 weeks prior toenrollment to rule out pregnancy

• HIGH-RISK STRATUM: Participant has not recovered from adverse events due to CRT (i.e., have residual toxicity > grade 1), excluding alopecia

• HIGH-RISK STRATUM: Participant has had prior potentially curative surgery (i.e.,abdominal-perineal resection) for carcinoma of the anus

• HIGH-RISK STRATUM: Participant is receiving other standard anti-cancer therapy orexperimental agent concurrently with the study drugs

• HIGH-RISK STRATUM: Participant has a known autoimmune disease

• Participants with active autoimmune disease or history of autoimmune diseasethat might recur, which may affect vital organ function or require immunesuppressive treatment including systemic corticosteroids, should be excluded.These include but are not limited to participants with a history of immunerelated neurologic disease, multiple sclerosis, autoimmune (demyelinating)neuropathy, Guillain-Barre syndrome, myasthenia gravis; systemic autoimmunedisease such as systemic lupus erythematosus (SLE), connective tissue diseases,scleroderma, inflammatory bowel disease (IBD), Crohn's, ulcerative colitis,hepatitis; and participants with a history of toxic epidermal necrolysis (TEN),Stevens-Johnson syndrome, or phospholipid syndrome should be excluded becauseof the risk of recurrence or exacerbation of disease. Participants withvitiligo, endocrine deficiencies including thyroiditis managed with replacementhormones including physiologic corticosteroids are eligible. Participants withrheumatoid arthritis and other arthropathies, Sjogren's syndrome and psoriasiscontrolled with topical medication and participants with positive serology,such as antinuclear antibodies (ANA), anti-thyroid antibodies should beevaluated for the presence of target organ involvement and potential need forsystemic treatment but should otherwise be eligible

• HIGH-RISK STRATUM: Participant requires steroid treatment or other immunosuppressivetreatment

• Participants will be excluded if they have a condition requiring systemictreatment with either corticosteroids (> 10 mg daily prednisone equivalents) orother immunosuppressive medications within 7 days of study drug administration.Topical corticosteroid or occasional inhaled corticosteroids are allowed

• HIGH-RISK STRATUM: Any surgery must have been completed >= 4 weeks before treatmentinitiation

• LOW-RISK STRATUM: Has undergone prior potentially curative surgery (i.e.,abdominal-perineal resection) for carcinoma of the anus

• LOW-RISK STRATUM: Receiving any other standard anti-cancer therapy orinvestigational agents concurrently with study therapy

• LOW-RISK STRATUM: Significant cardiovascular disease including myocardialinfarction, unstable angina, stroke, transient ischemic attack, symptomatic coronaryartery disease, symptomatic congestive heart failure, or uncontrolled cardiacarrhythmia within 6 months of enrollment

• LOW-RISK STRATUM: History of prior chemotherapy for this malignancy

• LOW-RISK STRATUM: Pregnant and/or breast-feeding women

• Pregnant and/or breast-feeding women are excluded from this study because thestudy treatment administered