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Primary objective:
To evaluate the overall survival of fruquintinib plus BSC compared to placebo plus BSC in subjects with refractory mCRC.

Inclusion Criteria:

1. Provide written informed consent;
2. Age >=18 years;
3. Histologically and/or cytologically documented metastatic colorectal adenocarcinoma. RAS, BRAF, and microsatellite instability microsatellite instability (MSI)/mismatch repair (MMR) status for each patient must be documented, according to country level guidelines;
4. Subjects must have progressed on or been intolerant to treatment with either trifluridine/tipiracil (TAS-102) or regorafenib. Subjects are considered intolerant to TAS-102 or regorafenib if they have received at least 1 dose of either agents and were discontinued from therapy for reasons other than disease progression. Subjects who have been treated with both TAS-102 and regorafenib are permitted. Subjects must also have been previously treated with standard approved therapies: fluoropyrimidine-, oxaliplatin-, and irinotecan-based chemotherapy, an anti-VEGF biological therapy, and, if RAS wild-type, an anti-EGFR therapy;
5. Subjects with microsatellite-high (MSI-H) or mismatch repair deficient (dMMR) tumors must have been treated with immune checkpoint inhibitors if approved and available in the subject's country unless the patient is ineligible for treatment with a checkpoint inhibitor;
6. Subjects who received oxaliplatin in the adjuvant setting and developed metastatic disease during or within 6 months of completing adjuvant therapy are considered eligible without receiving oxaliplatin in the metastatic setting. Subjects who developed metastatic disease more than 6 months after completion of oxaliplatin-containing adjuvant treatment must be treated with oxaliplatin-based therapy in the metastatic setting to be eligible;
7. Body weight >=40kg;
8. Eastern Cooperative Oncology Group (ECOG) performance status of 0-1;
9. Have measurable disease according to RECIST Version 1.1, assessed locally. Tumors that were treated with radiotherapy are not measurable per RECIST Version 1.1, unless there has been documented progression of those lesions;
10. Expected survival >12 weeks.
11. For female subjects of childbearing potential and male subjects with partners of childbearing potential, agreement to use a highly effective form(s) of contraception, that results in a low failure rate (<1% per year) when used consistently and correctly, starting during the screening period, continuing throughout the entire study period, and for 90 days after taking the last dose of study drug. Such methods include: oral hormonal contraception (combined estrogen/ progestogen, or progestogen-only) associated with inhibition of ovulation, intrauterine device (IUD), intrauterine hormone-releasing system (IUS), bilateral tubal ligation, vasectomized partner, or true sexual abstinence in line with the preferred and usual lifestyle of the subject. Highly effective contraception should always be combined with an additional barrier method (eg, diaphragm, with spermicide). The same criteria are applicable to male subjects involved in this clinical trial if they have a partner of childbirth potential, and male subjects must always use a condom.
12. Subjects with BRAF-mutant tumors must have been treated with a BRAF inhibitor if approved and available in the subject's home country unless the patient is ineligible for treatment with a BRAF inhibitor.

Primary objective:
To compare overall survival in metastatic prostate cancer patients who are randomized to standard systemic therapy (SST) plus definitive treatment of the primary tumor versus standard systemic therapy alone.

Secondary objectives:

1. To compare overall survival in metastatic prostate cancer patients who received SST plus surgical excision of the primary tumor versus SST alone in the subset who specify the surgical intent stratification factor.
2. To compare the rate of symptomatic local progression between the treatment arms.
3. To compare progression-free survival (PFS) between the two treatment arms.
4. To compare rates of progression-free survival between arms for the subsets of patients with and without metastasis directed therapy (MDT) to oligometastatic sites.

Inclusion Criteria:

1. All patients must have a histologically or cytologically proven diagnosis of adenocarcinoma of the prostate. Patients with pure small cell carcinoma* (SCC), sarcomatoid, or squamous cell carcinoma are not eligible. (*morphology must be consistent with SCC; synaptophysin or chromogranin positive by immunohistochemical staining is insufficient to diagnose SCC).
2. Patients must have an intact prostate. No prior local therapy for prostate adenocarcinoma is allowed (e.g., brachytherapy, high-intensity focused ultrasound [HIFU], cryotherapy, laser ablative therapies). Any prior therapy for benign conditions, such as obstruction, are acceptable (e.g., transurethral resection of the prostate, greenlight laser ablation, microwave ablation).
3. Patients must have evidence of metastatic disease on technetium bone scan and computed tomography (CT) or magnetic resonance imaging (MRI) within 42 days prior to starting standard systemic therapy. Metastatic disease that is detected by positron emission tomography (PET) scan only (sodium fluoride [NaF], prostate-specific membrane antigen [PSMA], anti-1-amino-3-18F-fluorocyclobutane-1-carboxylic acid [FACBC], carbon [C]11) but not conventional imaging (technetium [Tc]99 bone scan, CT or MRI) or solitary metastases by conventional imaging, must be confirmed histologically or cytologically.
4. Patients with known brain metastases are not eligible. Brain imaging studies are not required for eligibility if the patient has no neurologic signs or symptoms suggestive of brain metastasis. If brain imaging studies are performed, they must be negative for disease.
5. Patients must have received no more than 28 weeks of standard systemic therapy (SST). SST is defined as current National Comprehensive Cancer Network (NCCN) guidelines for metastatic prostate cancer.
6. Patients must not have progressed while on SST.
7. Patients with oligometastatic prostate cancer may receive metastasis directed therapy to up to four sites of disease prior to randomization.
8. Patients must have a complete physical examination and medical history within 28 days prior to registration.
9. Patients must have a PSA documented prior to initiation of SST and within 28 days prior to registration. Any additional PSAs measured while receiving SST should be recorded.
10. Patients must have a testosterone lab documented within 28 days prior to randomization. Any additional testosterone labs measured while receiving SST should be recorded as well as pretreatment initiation if available.
11. No other prior malignancy is allowed except for the following: adequately treated basal cell or squamous cell skin cancer, adequately treated stage 0, I or II cancer from which the patient is currently in complete remission, or any other cancer from which the patient has been disease free for three years.
12. Patients must be offered the opportunity to participate in translational medicine studies and specimen banking for future studies.
13. Patients who can complete Patient-Reported Outcome instruments in English, Spanish or French, must participate in the quality of life studies.
14. Patients must be informed of the investigational nature of this study and must sign and give written informed consent in accordance with institutional and federal guidelines.

Primary objective:
To compare the overall survival (OS) in patients with metastatic RCC treated with ipilimumabnivolumab followed by either nivolumab versus cabozantinib-nivolumab.

Secondary objectives:

• To determine PFS of patients treated with nivolumab versus nivolumab-cabozantinib
• To evaluate the 12-month complete response rate in patients treated with ipilimumabnivolumab followed by cabozantinib-nivolumab versus ipilimumab-nivolumab followed by nivolumab (patients who have CR and relapse before 12 months will not be counted as a CR at 12-months)
• To evaluate the rates of discontinuing therapy at 1 year
• To compare objective response rates (ORR, assessed by RECIST 1.1 and irRECIST criteria) for patients treated with ipilimumab-nivolumab followed by cabozantinib-nivolumab versus ipilimumab-nivolumab followed by nivolumab.
• To document the adverse event profile of ipilimumab-nivolumab followed by cabozantinibnivolumab.

Inclusion Criteria:

1. Histologically documented renal cell carcinoma with clear cell component, including patients who have sarcomatoid features.
2. Any metastatic disease, including visceral, lymph node, other soft tissue and bone, measurable per RECIST 1.1.
3. Measurable disease as defined in the protocol.
4. Must be intermediate or poor risk patient per International Metastatic Renal Cell Carcinoma Database (IMDC) criteria (1 or more of the following: Karnofsky performance status [KPS] < 80, < 1 year from diagnosis [including initial nephrectomy] to systemic treatment for metastatic disease, hemoglobin less than lower limit of normal [LLN], corrected calcium concentration greater than upper limit of normal [ULN], absolute neutrophil count greater than ULN, platelet count > ULN).
5. Central nervous system (CNS) disease permitted, if stable and not otherwise causing symptoms or needing active treatment.
6. Karnofsky performance status >= 70%.
7. No prior treatment with PD-1, PD-L1, or CTLA-4 targeting agents (including but not limited to nivolumab, pembrolizumab, pidilizumab, durvalumab, atezolizumab, tremelimumab, and ipilimumab), or any other drug or antibody specifically targeting T-cell co-stimulation or checkpoint pathways. The only exception is for prior treatment with nivolumab or other PD-1/PD-L1/CTLA-4 targeting therapy on pre- or post-operative trials, as long as > 1 year since completion of systemic therapy.
8. No prior previous systemic therapy for renal cell carcinoma (prior HD IL-2 [> 28 days] and prior adjuvant sunitinib > 180 days since completion and prior immunotherapy as above are allowed).
9. No cancer therapy less than 28 days prior to registration; this includes radiation therapy, except for bone lesions less than 14 days prior to registration. There must be a complete recovery and no ongoing complications from radiotherapy.
10. Not pregnant and not nursing, because this study involves an agent that has known genotoxic, mutagenic and teratogenic effects. Therefore, for women of childbearing potential only, a negative serum or urine pregnancy test done =< 14 days prior to registration is required.
11. Age >= 18 years
12. Absolute neutrophil count (ANC) >= 1,500/mm^3.
13. Platelet count >= 100,000/mm^3.
14. Hemoglobin >= 8 g/dL.
15. Calculated (Calc.) creatinine clearance >= 30 mL/min.
16. Urine protein =< 1+ or urine protein to creatinine (UPC) ratio < 1.
17. Total bilirubin =< 1.5 x upper limit of normal (ULN).
18. Aspartate aminotransferase/alanine aminotransferase (AST/ALT) =< 2.5 x upper limit of normal (ULN) or < 5 x ULN if hepatic metastases present.
19. STEP 2 REGISTRATION ELIGIBILITY CRITERIA
20. Successful completion of at least 1 cycle of ipilimumab/nivolumab.
21. Resolution of any treatment-related adverse events to grade 1 or less per dose modification section (this criteria does not include any adverse events [AEs] not attributable to treatment which are present due to disease). Exceptions for this criteria include patients receiving replacement hormone treatments (such as levothyroxine for treatment-related hypothyroidism or glucocorticoid replacement for adrenal insufficiency). Please contact study chair if further discussion is needed.
22. No more than 70 days from last dose of ipilimumab/nivolumab.

Primary objective:
To assess the efficacy of concurrent definitive therapy followed by nivolumab compared with concurrent definitive therapy followed by observation in terms of progression-free survival (PFS). (Phase II) II. To assess the efficacy of concurrent definitive therapy followed by nivolumab compared with concurrent definitive therapy followed by observation in terms of overall survival (OS). (Phase III)

Secondary objectives:

1. To further assess the efficacy of nivolumab compared with observation in terms of:
   • The relationship of baseline PD-L1 expression to clinical outcome.
   • To evaluate the association of 12 week post therapy fludeoxyglucose F-18 (FDG) positron emission tomography (PET)/computed tomography (CT) with PFS and OS.
   • To establish the prognostic value of standardized uptake value (SUV)max of primary tumor or neck nodal metastasis of baseline FDG PET/CT for OS (and/or PFS).
   • To correlate SUVmax of primary tumor or nodal metastasis of baseline FDG PET/CT with PD-L1 expression (positive vs. negative).
   • To compare the PET based therapy response assessment (Hopkins criteria) to the Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 assessment at 12 week post chemoradiation therapy, for patients who have a PET/CT scan at 12 weeks.

Inclusion Criteria:

1. Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1.
2. Patients must have oropharynx cancer (AJCC 8) that is p16-positive by immunohistochemistry with smoking status: >= 10 pack-years, stage T1-2N2-N3 or T3-4N0-3 (less than 10 pack-years is considered a non-smoker) OR < 10 pack-years, stage T4N0-N3 or T1-3N2-3.
3. Patients must not have known hypersensitivity to nivolumab or compounds of similar chemical or biologic composition.
4. Patients with a history of allergic reactions attributed to platinum-based chemotherapy agents are excluded.
5. Patients must not have had prior systemic therapy, radiation treatment or surgery for p16 positive oropharyngeal squamous cell carcinoma (OPSCC).
6. Patients must not have received previous irradiation for head and neck tumor, skull base, or brain tumors.
7. Patients must not receive investigational agents within 4 weeks of enrollment or at any time while on study.
8. Patients with evidence of distant metastases or leptomeningeal disease (LMD) are excluded.
9. Patients with uncontrolled inter-current illnesses which in the opinion of the investigator will interfere with the ability to undergo therapy including chemotherapy are excluded.
10. Patients with a history of prior or second malignancy are excluded, with the exception of curatively treated non-melanoma skin cancer, or curatively treated cervical cancer; additionally, patients curatively treated for malignancy who remain disease-free at > 2 years of follow up, are not excluded.
11. Absolute neutrophil count (ANC) >= 1500/mm^3 (must be obtained =< 2 weeks prior to randomization).
12. Hemoglobin (Hgb) >= 8.0 g/dL (must be obtained =< 2 weeks prior to randomization).
13. Platelet count >= 100,000/mm^3 (must be obtained =< 2 weeks prior to randomization).
14. Creatinine clearance of >= 60 ml/min (must be obtained =< 2 weeks prior to randomization). Creatinine clearance may be measured or calculated. If calculating, creatinine clearance, use the Cockcroft-Gault formula.
15. Total bilirubin within 1.5 times the normal limits (must be obtained =< 2 weeks prior to randomization).
16. Serum glutamic oxaloacetic transaminase (SGOT) (aspartate aminotransferase [AST]) or serum glutamate pyruvate transaminase (SGPT) (alanine aminotransferase [ALT]) within 2.0 times the normal limits (must be obtained =< 2 weeks prior to randomization).
17. Alkaline phosphatase within 1.5 times the normal limits (must be obtained =< 2 weeks prior to randomization).
18. Women must not be pregnant or breast-feeding as chemotherapy, radiation, and immunotherapy may have possible teratogenicity effects; in addition, complications from pregnancy may interfere with the ability of patients to have an uninterrupted therapy.
19. All women of childbearing potential must have a blood test or urine study within 2 weeks prior to randomization to rule out pregnancy.
20. A woman of childbearing potential is any female, regardless of sexual orientation or whether they have undergone tubal ligation, who meets the following criteria: 1) has achieved menarche at some point, 2) has not undergone a hysterectomy or bilateral oophorectomy or 3) has not been naturally postmenopausal (amenorrhea following cancer therapy does not rule out childbearing potential) for at least 24 consecutive months.
21. Women of childbearing potential (WOCBP) and males who are sexually active with WOCBP must use an accepted and effective method of contraception or abstain from sexual intercourse for at least one week prior to the start of treatment, and continue for 5 months after the last dose of protocol treatment for women of childbearing potential and 7 months after the last dose of protocol treatment for males who are sexually active with WOCBP.
22. Patients must have measurable disease as defined.
23. Patients must have tumor measurements with CT of neck and CT of chest within 4 weeks prior to Step 1 randomization.

Primary objective:
To compare the progression-free survival (PFS) of patients receiving high-dose cholecalciferol (vitamin D3) in combination with standard chemotherapy (leucovorin calcium, fluorouracil, and oxaliplatin [FOLFOX] or leucovorin calcium, fluorouracil, and irinotecan hydrochloride [FOLFIRI]) and bevacizumab versus those receiving standard-dose vitamin D3 in combination with standard chemotherapy and bevacizumab.

Secondary objectives:

1. To compare the objective response rate (ORR) of patients receiving high-dose vitamin D3 in combination with standard chemotherapy + bevacizumab versus those receiving standard-dose vitamin D3 in combination with standard chemotherapy + bevacizumab.
2. To compare the overall survival (OS) of patients receiving high-dose vitamin D3 in combination with standard chemotherapy + bevacizumab versus those receiving standard-dose vitamin D3 in combination with standard chemotherapy + bevacizumab.
3. To evaluate and compare the toxicity of adding high-dose vitamin D3 versus standard-dose vitamin D3 to chemotherapy + bevacizumab.
4. To assess the influence of diet, body mass index, physical activity, and other lifestyle habits on PFS among patients with locally advanced/metastatic colorectal cancer.
5. To evaluate the incidence of vitamin D3 deficiency in participants with previously untreated metastatic colorectal cancer.
6. To compare the efficacy of high-dose vitamin D3 versus standard-dose vitamin D3 in subgroups of patients defined by baseline plasma calcifediol (25[OH]D) levels.
7. To evaluate the prognostic effect of highest-achieved 25(OH)D levels with PFS.

Inclusion Criteria:

1. Histologically confirmed advanced/metastatic colorectal adenocarcinoma for which metastasectomy is not planned.
2. No mismatch repair deficiency (dMMR) or high-frequency microsatellite instability (MSI-H) disease.
3. Measurable disease per Response Evaluation Criteria in Solid Tumors (RECIST) version (v) 1.1.
4. No prior systemic treatment for metastatic disease.
5. Patients may have received prior neoadjuvant or adjuvant chemotherapy and/or chemoradiation. The last course of adjuvant therapy must have been completed > 12 months prior to colorectal cancer recurrence.
6. Patients may have received prior standard rectal cancer chemoradiation so long as prior radiotherapy was to =< 25% of bone marrow. Previous radiation therapy must have been completed >= 4 weeks prior to registration.
7. No continuous daily use of vitamin D supplements >= 2,000 IU per day for the 12 months prior to registration. Patients may have had continuous daily use of vitamin D supplements >= 2,000 IU per day if total duration < 12 months in the 12 months prior to registration. Patients may have had continuous daily use of vitamin D supplements < 2,000 IU per day for any duration prior to registration.
8. Patients must have completed any major surgery or open biopsy >= 4 weeks prior to registration and must have completed any minor surgery or core biopsy >= 1 week prior to registration. (Note: insertion of a vascular access device is not considered major or minor surgery.) Patients must have recovered from the effects of any surgery (e.g. wound is healed, no active infection, no drains, etc.) prior to registration.
9. Not pregnant and not nursing. This study involves an agent that has known genotoxic, mutagenic, and teratogenic effects. Therefore, for women of childbearing potential only, a negative serum or urine pregnancy test done =< 14 days prior to registration is required.
10. Eastern Cooperative Oncology Group (ECOG) performance status: 0-1.
11. Absolute neutrophil count >= 1,500/mm^3.
12. Platelet count >= 100,000/mm^3.
13. Hemoglobin >= 9 g/dL.
14. Creatinine =< 1.5 x upper limit of normal (ULN) OR calculated (Calc.) creatinine clearance (CrCl) > 30 mL/min.
15. Calcium =< 1.0 x ULN.
16. Corrected for albumin level if albumin not within institutional limits of normal.
17. Total bilirubin =< 1.5 x ULN.
18. If Gilbert's disease, use direct bilirubin instead of total bilirubin; direct bilirubin =< 1.5 x ULN if patient to receive FOLFIRI; direct bilirubin =< 3.0 x ULN if patient to receive leucovorin, infusional fluorouracil, and oxaliplatin (modified [m]FOLFOX6).
19. Aspartate aminotransferase (AST)/alanine aminotransferase (ALT) =< 2.5 x ULN.
20. AST/ALT < 5 x ULN if clearly attributable to liver metastases.
21. Urine protein to creatinine (UPC) ratio < 1 OR urine protein =< 1.

Primary outcome measurements:
Overall survival (OS) [Time Frame: Up to 2 years post treatment]

Secondary outcome measurements:
Instrumental Activities of Daily Living (IADL) [Time Frame: Up to 2 years post treatment]

Inclusion Criteria:

1. Newly diagnosed untreated metastatic adenocarcinoma of the pancreas. However, previous surgery, adjuvant chemotherapy and/or radiation therapy will be allowed, provided radiation therapy is completed at least 2 weeks prior to registration and adjuvant therapy was administered more than 6 months prior to registration. Patients with the following histology are excluded: acinar cell; adenosquamous carcinoma
2. Eastern Cooperative Oncology Group (ECOG) performance status 0-2
3. Patient is an English speaker with the ability to understand and complete the informed consent and questionnaires
4. Leukocytes >= 3,000/mcL (obtained within 4 weeks of registration)
5. Absolute neutrophil count >= 1,500/mcL (obtained within 4 weeks of registration)
6. Platelets >= 100,000/mcL (obtained within 4 weeks of registration)
7. Total bilirubin =< institutional upper limit of normal (ULN) (obtained within 4 weeks of registration)
8. Aspartate aminotransferase (AST) (serum glutamic oxaloacetic transaminase [SGOT])/alanine aminotransferase (ALT) (serum glutamate pyruvate transaminase [SGPT]) =< 2.5 x institutional ULN (obtained within 4 weeks of registration)
9. Creatinine =< institutional ULN unless data exists supporting safe use at lower kidney function values, no lower than 30 mL/min/1.73 m^2 (obtained within 4 weeks of registration)
10. Glomerular filtration rate (GFR) >= 40 mL/min/1.73 m^2 unless data exists supporting safe use at lower kidney function values, no lower than 30 mL/min/1.73 m^2 (obtained within 4 weeks of registration)
11. Human immunodeficiency virus (HIV)-infected patients on effective anti-retroviral therapy with undetectable viral load within 6 months of registration are eligible for this protocol. HIV positive (+) patients who are on ritonavir or/and cobicistat-based regimen must be switched to alternative anti-retroviral therapy (ART)
12. For patients with evidence of chronic hepatitis B virus (HBV) infection, the HBV viral load must be undetectable on suppressive therapy, if indicated
13. Patients with a history of hepatitis C virus (HCV) infection must have been treated and cured. For patients with HCV infection who are currently on treatment, they are eligible if they have an undetectable HCV viral load
14. Male patients must agree not to father children while on study
15. Patients with known history or current symptoms of cardiac disease, or history of treatment with cardiotoxic agents, should have a clinical risk assessment of cardiac function using the New York Heart Association functional classification. To be eligible for this protocol, patients should be class 2B or better
16. Patients must have measurable disease and scans must be done within 4 weeks of registration
17. Patients classified to have mild-moderate abnormalities in any of the domains evaluated in the screening geriatric assessment and are classified as "vulnerable" are eligible. Patients classified without any abnormalities ("fit") or with severe cognitive/functional impairment or high co-morbidity score ("frail") on the screening geriatric assessment are ineligible
18. Patients must agree not to take any medications or substances that are strong inhibitors or inducers of CYP3A4. Those who are randomized to liposomal irinotecan treatment arm should avoid drugs that are UGT1A1 inhibitors

Primary objective:
To evaluate whether the reconstruction complication rate at 24 months post radiation is non-inferior with hypofractionation.

Secondary objectives:

1. To evaluate the incidence of acute and late radiation complications, based on Common Terminology Criteria for Adverse Events (CTCAE) 4.0 toxicity.
2. To evaluate the local and local regional recurrence rate. III. To compare reconstruction complication rates based on reconstruction method (autologous +/- implant versus [vs] implant only) and timing of reconstruction received (immediate vs. intent for delayed).

Inclusion Criteria:

1. Histologically confirmed invasive carcinoma of the breast of any of the following histologies (ductal, lobular, mammary, medullary, or tubular); patients with metaplastic breast cancer are not eligible
2. Patients will be staged according to the TNM staging system
   1. For patients not receiving neoadjuvant chemotherapy, pathologic staging must be T0N1-2a, T1N1-2a, T2N1-2a, T3N0-2a, and all M0 status
   2. For patients receiving neoadjuvant chemotherapy, clinical pre-chemo staging and post mastectomy pathological staging is required for all patients; patients who have received neoadjuvant chemotherapy and are pathologically cT0-2 and N0 are only eligible if biopsy-proven clinically N1 or N2 disease is documented prior to the start of neoadjuvant chemotherapy; cT3N0 patients or ypT3N0 patients who receive neoadjuvant chemotherapy may be eligible based on clinical or pathological T stage, and do not require pathologically positive lymph nodes
   3. Note: Higher of the clinical or pathological T and N stage are used for final staging, if receiving neoadjuvant chemotherapy; all patients with clinical, radiographic or pathological T4, N3 or involved internal mammary disease (N1b, N1c, and N2b) are not eligible
3. No prior therapeutic radiation therapy to the chest, neck or axilla; prior radioactive oral iodine is permitted
4. No prior history of ipsilateral breast cancer (invasive disease or ductal breast carcinoma in situ [DCIS]); lobular carcinoma in situ (LCIS) and benign breast disease is allowed
5. No history of prior or concurrent contralateral invasive breast cancer; benign breast disease, LCIS or DCIS of contralateral breast is allowed
6. No active collagen vascular diseases, such as: systemic lupus erythematous, scleroderma, or dermatomyositis
7. Negative inked histologic margins from mastectomy pathology (no invasive cells at margin)
8. No significant post mastectomy complications in the ipsilateral breast requiring an unplanned re-operation or admission for intravenous (IV) antibiotics; re-operation for margins evaluation, nodal completion and routine reconstruction is acceptable
9. Radiation oncologist intends to treat all target volumes and respect all normal tissues in accordance with the dosimetric constraints described (simulation before registration recommended)
10. Radiation oncologist is planning to treat regional lymph nodes including internal mammary nodes and meet acceptable protocol dosimetric requirements
11. Radiation oncologist is NOT planning to utilize a chest wall/scar boost
12. Patient must have undergone immediate reconstruction at the time of mastectomy or be planning to undergo reconstruction within 18 months after radiation
13. If a tissue expander is utilized it needs to be a fluid filled expander, NO air expander (unless completely deflated) during radiation therapy
14. For patients with diabetes, hemoglobin A1C test must have been performed =< 90 days prior to registration
15. No co-existing medical conditions with life expectancy < 5 years
16. No other malignancy within 5 years of registration with the exception of basal cell or squamous cell carcinoma of the skin treated with local resection only or carcinoma in situ of the cervix
17. Negative serum or urine beta-human chorionic gonadotropin (HCG) in women of child-bearing potential =< 7 days prior to registration
18. Women of child-bearing potential must agree to utilize a form of birth control or agree to undergo sexual abstinence during radiation therapy
19. Eastern Cooperative Oncology Group (ECOG) (Zubrod) performance status 0-1
20. Patients must be able to read and comprehend English, in order to be able to complete study questionnaires; however, patients participating through Canadian Cancer Trials Group (CCTG) institutions who can read and comprehend French are eligible

Primary outcome measures:
Pathologic complete response (pCR) rate assessed by independent central pathology review [Time Frame: Up to 12 weeks]

Secondary outcome measures:

1. Major pathologic response (mPR) rate assessed by independent central pathology review [Time Frame: Up to 12 weeks]
2. pCR rate assessed by local pathology review [Time Frame: Up to 12 weeks]
3. mPR rate assessed by local pathology review [Time Frame: Up to 12 weeks]
4. Objective response rate (ORR) prior to surgery, according to investigator assessment using RECIST 1.1 [Time Frame: Up to 12 weeks]
5. Event free survival (EFS) [Time Frame: Up to 50 months]
6. Disease free survival (DFS) [Time Frame: Up to 47 months]
7. Overall survival (OS) [Time Frame: Up to 50 months]
8. Incidence of adverse events (AEs) [Time Frame: Up to 52 months]
9. Incidence of serious adverse events (SAEs) [Time Frame: Up to 52 months]
10. Incidence of deaths [Time Frame: Up to 52 months]
11. Incidence of laboratory abnormalities [Time Frame: Up to 52 months]
12. Change in surgical plan in the screening period versus actual surgery after neoadjuvant cemiplimab [Time Frame: Up to 12 weeks]
13. Change in post-surgical management plan in the screening period versus actual post-surgical management [Time Frame: Up to 14 weeks]

Key Inclusion Criteria:

1. Stage II to IV (M0) CSCC, for which surgery would be recommended in routine clinical practice. For stage II patients, lesion must be ≥3 cm at the longest diameter.
2. At least 1 lesion that is measurable by RECIST 1.1
3. Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1
4. Adequate organ, bone marrow function, and hepatic function as defined in the protocol

Key Exclusion Criteria:

1. Solid malignancy within 5 years of the projected enrollment date, or hematologic malignancy (including chronic lymphocytic leukemia [CLL]) at any time
2. Distant metastatic disease (M1), visceral and/or distant nodal
3. Prior radiation therapy for CSCC
4. Patients with a condition requiring corticosteroid therapy (>10 mg prednisone/day or equivalent) within 14 days of the first dose of study drug.
5. Patients with active, known, or suspected autoimmune disease that has required systemic therapy within 5 years of the projected enrollment date.
6. History of interstitial lung disease (eg, idiopathic pulmonary fibrosis, organizing pneumonia) or active, noninfectious pneumonitis that required immune-suppressive doses of glucocorticoids to assist with management.
7. Uncontrolled infection with human immunodeficiency virus (HIV), hepatitis B or hepatitis C virus (HBV or HCV) infection; or diagnosis of immunodeficiency
8. Active tuberculosis

NOTE: Other protocol-defined Inclusion/Exclusion Criteria apply

Primary objective:
To evaluate whether therapy with nivolumab following combined modality therapy (CMT) improves disease-free survival (DFS) compared with observation in patients with high risk anal carcinoma.

Secondary objectives:

• 1a. To compare nivolumab following combined modality therapy (CMT) with observation in patients with high risk anal carcinoma with regard to:
• 1b. Objective response rate (complete [CR] and partial [PR]), stable disease and progression.
• 1c. Severe toxicity interval.
• 1d. Colostomy-free survival.
• 1e. Overall survival.
• 1f. Toxicity.

Inclusion Criteria:

1. Patients must have histologically proven stage IIB (T3N0M0 only), IIIA (T2N1M0), IIIB (T4N0M0), or IIIC (T3N1M0, T4N1M0) invasive squamous cell carcinoma of the anus or anorectum, according to the American Joint Committee on Cancer (AJCC) 8th edition; this may include tumors of non-keratinizing histology such as basaloid, transitional cell, or cloacogenic histology; individuals with squamous cell carcinoma of the anal margin are eligible if there is evidence of extension of the primary tumor into the anal canal
2. Patients must have Eastern Cooperative Oncology Group (ECOG) performance status of 0-2
3. Patients must have hemoglobin levels of > 9 g/dL (within 2 weeks prior to registration)
4. Patient must have a platelet count of > 100,000/mm^3 (within 2 weeks prior to registration)
5. Patient's absolute neutrophil count (ANC) level must be > 1500/mm^3 (within 2 weeks prior to registration)
6. Serum creatinine must be =< 1.5 X upper limit of normal (ULN) (within 2 weeks prior to registration)
7. Total bilirubin must be < 2 X ULN (within 2 weeks prior to registration)
8. Aspartate aminotransferase (AST) (serum glutamic oxaloacetic transaminase [SGOT])/alanine aminotransferase (ALT) (serum glutamic pyruvic transaminase [SGPT]) =< 2.5 X institutional upper limit of normal (within 2 weeks prior to registration)
9. Albumin >= 3.0 g/dL (within 2 weeks prior to registration)
10. Patients known to be human immunodeficiency virus (HIV)+ are permitted; patients with CD4 > 200 and serum HIV viral load of < 200 copies/mm^3 are eligible, and SEE PROTOCOL FOR ADDITIONAL TESTING REQUIREMENTS FOR HIV+ SUBJECTS.
    
    NOTE: HIV testing is not required for eligibility
11. For patients registering prior to start of chemoradiotherapy, baseline scans must have been completed within 4 weeks prior to registration
12. Women of child bearing potential and sexually active males must use accepted and effective method(s) of contraception and/or abstain from sexual intercourse while on protocol treatment and for at least 5 months after the last dose of nivolumab (for female patients) and for at least 7 months after the last dose of nivolumab (for male patients)
13. Any surgery must have been completed >= 4 weeks prior to starting study treatment
14. No uncontrolled intercurrent illness including, but not limited to ongoing or active infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac arrhythmia, or psychiatric illness/social situations that would limit compliance with study requirements
15. No prior treatment with an immune checkpoint inhibitor (anti-PD-1, anti-PD-L1, anti-PD-L2, anti-CTLA4 monoclonal antibody)
16. No patients with immunodeficiency or receiving systemic steroid therapy equivalent to > 10 mg prednisone per day or any other form of immunosuppressive therapy within 7 days prior to Step 1 registration; topical corticosteroid or occasional inhaled corticosteroids are allowed
17. No live vaccines within 30 days prior to registration; examples of live vaccines include, but are not limited to, the following: measles, mumps, rubella, chicken pox, yellow fever, rabies, BCG, and typhoid (oral) vaccine; seasonal influenza vaccines for injection are generally killed virus vaccines and are allowed; however, intranasal influenza vaccines (e.g., Flu-Mist) are live attenuated vaccines and are not allowed
    
    NOTE: no live vaccines may be administered while participating in the trial
18. Previously irradiated patients (Arm S) must have received radiation per National Comprehensive Cancer Network guidelines; radiation therapy delivered on protocol (Arm T) will be reviewed