Primary Outcome Measures:
- Incidence of adverse events (Low-risk stratum) [Time Frame: Up to 5 years]
Evaluated by Common Terminology Criteria for Adverse Events (CTCAE) version 5.0. The adverse events will be summarized by overall, as well as by grade using frequency (percentage). A two-sided 95% confidence interval will be reported together with percentage estimates. The proportion of participants who experience grade 3-4 toxicities will be estimated using a binomial point estimate and its 95% confidence interval. - Incidence of adverse events (High-risk stratum) [Time Frame: Up to 5 years]
Evaluated by CTCAE version 5.0. The adverse events will be summarized by overall, as well as by grade using frequency (percentage). A two-sided 95% confidence interval will be reported together with percentage estimates. The proportion of participants who experience grade 3-4 toxicities will be estimated using a binomial point estimate and its 95% confidence interval.
Secondary Outcome Measures:
- Disease free survival (High-risk stratum) [Time Frame: Time from enrollment until progression of local disease, distant metastasis, secondary primary cancer or death, assessed at 2 years]
Will be estimated using Kaplan-Meier method. The 95% confidence interval will be estimated using Greenwood's formula. The cumulative incidence of pelvic disease relapse will also be estimated from Kaplan-Meier method and the corresponding 90% confidence interval will be estimated using Greenwood's formula. In the analyses above, a two-sided p-value of 0.05 will be used to assess statistical significance. - Disease control rate (Low-risk stratum) [Time Frame: Time from enrollment until first recurrence (locoregional or distant metastasis) or chemo-radiation-related death, assessed up to 5 years]
Will be estimated using Kaplan-Meier method. The 95% confidence interval will be estimated using Greenwood's formula. The cumulative incidence of pelvic disease relapse will also be estimated from Kaplan-Meier method and the corresponding 90% confidence interval will be estimated using Greenwood's formula. In the analyses above, a two-sided p-value of 0.05 will be used to assess statistical significance. - Change in CD4+ cell counts (High-risk stratum) [Time Frame: Baseline up to 5 years]
Will be assessed by evaluating the changes from baseline in CD4+ using the Wilcoxon signed rank test to allow for nonnormality. - Change in human immunodeficiency virus (HIV) viral load (Low-risk stratum) [Time Frame: Baseline up to 5 years]
Will be assessed by evaluating the changes from baseline in HIV viral load using the Wilcoxon signed rank test to allow for nonnormality. - Change in combination antiretroviral therapy (cART) adherence
[Time Frame: Baseline up to 5 years]
To assess cART adherence before, during, and after treatment with CRT and nivolumab to identify potential barriers to cART adherence when receiving concurrent oncological care.
Other Outcome Measures:
- Relationship between specific human papillomavirus (HPV) subtypes and clinical response to reduced intensity chemo-radiation therapy (CRT) or nivolumab [Time Frame: Up to 5 years]
Will be presented using descriptive statistics (with no inferential statistics involved). - 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 [ Time Frame: Up to 5 years]
Will be presented using descriptive statistics (with no inferential statistics involved). - Effect of reduced intensity CRT and nivolumab on viral HIV reservoirs [Time Frame: Up to 5 years]
Will be presented using descriptive statistics (with no inferential statistics involved). - Prevalence of cell-free plasma HPV deoxyribonucleic acid (DNA) before and after reduced intensity CRT and nivolumab [Time Frame: Up to 5 years]
Relationship with clinical response with be explored. Will be presented using descriptive statistics (with no inferential statistics involved). - Impact of reduced intensity CRT on quality of life [Time Frame: Up to 5 years]
Will be presented using descriptive statistics (with no inferential statistics involved).
Inclusion Criteria:
- HIGH-RISK STRATUM: Participant must have histologically proven stage (T3-T4N0M0 OR T2-4N1M0) invasive squamous cell carcinoma of the anus or anorectum as documented before CRT initiation
- HIGH-RISK STRATUM: HIV-positive. Documentation of HIV-1 infection by one of the following:
- Documentation of HIV diagnosis in the medical record by a licensed health care provider.
- HIV-1 ribonucleic acid (RNA) detection by a licensed HIV-1 RNA assay demonstrating > 1000 RNA copies/mL
- Any licensed HIV screening antibody and/or HIV antibody/antigen combination assay confirmed by a second licensed HIV assay.
- HIGH-RISK STRATUM: Age >= 18 years
- 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 before enrollment)
- 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 2 weeks before enrollment)
- HIGH-RISK STRATUM: Aspartate aminotransferase (AST) (serum glutamic oxaloacetic transaminase [SGOT]) / alanine aminotransferase (ALT) (serum glutamic pyruvic transaminase [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; or calculated creatinine clearance must be > 50 ml/min (within 2 weeks before enrollment)
- HIGH-RISK STRATUM: Females of childbearing potential (FOCBP) must agree to follow contraception requirements:
- FOCBP must agree to use adequate contraception (hormonal or barrier method of birth control; abstinence) before study entry, for the duration of study participation and 5 months after completion of nivolumab administration
- HIGH-RISK STRATUM: Participant must have a CD4 count of >= 100 cells/uL at least 2 weeks prior to enrollment OR >= 100 cells/uL before receiving prior 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 the regimen 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 the PTVp (primary) and 45 Gy to PTVn (elective nodal region) for the treatment of the anal cancer within 9 weeks before enrollment
- HIGH-RISK STRATUM: Participant must have =< grade 2 diarrhea
- HIGH-RISK STRATUM: Purified protein derivative (PPD) negative.
- HIGH-RISK STRATUM: The participant, in the opinion of the treating investigator, is able to receive IV contrast injections
- SCREENING ELIGIBILITY LOW-RISK STRATUM: Age >= 18 years
- SCREENING ELIGIBILITY LOW-RISK STRATUM: Participant must have histologically proven T1-2N0M0 invasive anal canal or anal margin squamous cell carcinoma with tumors measuring =< 4 cm within 6 weeks before pre-registration. Measurable disease is not required.
- SCREENING ELIGIBILITY LOW-RISK STRATUM: HIV positive. Documentation of HIV-1 infection by means of any one of the following:
- Documentation of HIV diagnosis in the medical record by a licensed health care provider.
- HIV-1 RNA detection by a licensed HIV-1 RNA assay demonstrating > 1000 RNA copies/mL
- Any licensed HIV screening antibody and/or HIV antibody/antigen combination assay confirmed by a second licensed HIV assay
- SCREENING ELIGIBILITY LOW-RISK STRATUM: Tumor size must be documented by digital rectal 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: 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 before enrollment)
- 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 2 weeks 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 creatinine clearance 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 be strongly advised to use accepted and effective method(s) of contraception or to abstain from sexual intercourse for the duration of their participation in the study and for at least 6 months after the completion of treatment
- LOW-RISK STRATUM: Participant must have a CD4 count of >= 100 cells/uL at least 2 weeks before enrollment
- LOW-RISK STRATUM: Participant must on a stable ART regimen for at least 2 weeks before enrollment and receive appropriate care and treatment for HIV infection under the 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 regimen within 2 weeks prior to enrollment if taking warfarin and considering capecitabine
- LOW-RISK STRATUM: Participant must agree to having phenytoin levels checked weekly if planning to receive capecitabine while taking phenytoin for a seizure disorder
- LOW-RISK STRATUM: The participant, in the opinion of the treating investigator, is able to receive IV contrast injections
Exclusion Criteria:
- HIGH-RISK STRATUM: Any live vaccines within 30 days prior to enrollment
- HIGH-RISK STRATUM: Participant has known interstitial lung disease that is symptomatic or may interfere with the detection or management of suspected drug-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 solid organ transplant
- HIGH-RISK STRATUM: Participant is receiving any other investigational agents
- HIGH-RISK STRATUM: History of allergic reactions attributed to compounds of similar chemical or biologic composition to nivolumab or other agents used in study
- HIGH-RISK STRATUM: Uncontrolled intercurrent illness
- HIGH-RISK STRATUM: Participant has a history of a different malignancy, unless he/she have been disease-free for at least 2 years and are deemed by the investigator to be at low risk of recurrence
- HIGH-RISK STRATUM: Pregnant or breastfeeding.
- 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 or experimental agent concurrently with the study drugs
- HIGH-RISK STRATUM: Participant has a known autoimmune disease
- HIGH-RISK STRATUM: Participant requires steroid treatment or other immunosuppressive treatment
- HIGH-RISK STRATUM: Any surgery must have been completed >= 4 weeks before treatment initiation
- 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 or investigational agents concurrently with study therapy
- LOW-RISK STRATUM: Significant cardiovascular disease within 6 months of enrollment
- LOW-RISK STRATUM: History of prior chemotherapy for this malignancy
- LOW-RISK STRATUM: Pregnant and/or breast-feeding women
- Other inclusion/exclusion criteria are present. Please contact the study team for a complete list.
Sponsor(s)
Aids Malignancy Consortium
Principal Investigator(s)
Dr. Sharad Goyal
Contact Phone Number
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