Yttrium-90 Radioembolization + Nivolumab for Liver + Extra-hepatic Metastases From Colorectal Cancer

Inclusion Criteria:

* Patients must have histologically or cytologically confirmed metastatic colorectal cancer.
* Patients must have liver metastases and be appropriate for treatment with Y-90 radioembolization therapy as determined by the treating medical oncologist and interventional radiologist. Prior Y-90 therapy is not permitted.
* Patients must have measurable disease that is located outside of the Y-90 radioembolization field.
* Patients must have a metastatic focus amenable to biopsy that is located outside of the Y-90 radioembolization field. It is permissible to use the same lesion for biopsy as for assessment to tumor response.
* Patients must have received at least one line of prior chemotherapy and must have had resolution of all side effects to at least at Grade 1 prior to trial entry.
* Patients must have an Eastern Cooperative Oncology Group (ECOG) performance status of 0-1.
* Patients must have normal organ and marrow function as defined below:

  * Hemoglobin ≥ 9.0 g/dl
  * Leukocytes ≥ 2,000/mcL
  * Absolute neutrophil count ≥ 1,500/mcL
  * Platelet count ≥ 100,000/mcL
  * Total bilirubin ≤ 1.5 x upper limit of normal (ULN) (except in patients with Gilbert Syndrome, who can have a total bilirubin \< 3.0 mg/dL)
  * Aspartate aminotransferase (AST) (SGOT) ≤ 3 X institutional upper limit of normal
  * Alanine aminotransferase (ALT) (SGPT) ≤ 3 X institutional upper limit of normal
  * Serum creatinine ≤ 1.5 X ULN or creatinine clearance (CrCl) ≥ 40 mL/min (if using the Cockcroft-Gault formula below):

Female CrCl = (140 - age in years) x weight in kg x 1.00/ 72 x serum creatinine in mg/dL

Male CrCl = (140 - age in years) x weight in kg x 1.00/ 72 x serum creatinine in mg/dL

-Women of childbearing potential (WOCBP) must use appropriate method(s) of contraception. WOCBP should use an adequate method to avoid pregnancy for 23 weeks (30 days plus the time required for nivolumab to undergo five half-lives) after the last dose of investigational drug. Women of childbearing potential" is defined as any female who has experienced menarche and who has not undergone surgical sterilization (hysterectomy or bilateral oophorectomy) or who is not postmenopausal. Menopause is defined clinically as 12 months of amenorrhea in a woman over 45 in the absence of other biological or physiological causes. In addition, women under the age of 62 must have a documented serum follicle stimulating hormone (FSH) level less than 40 mili-international units/milliliter (mIU/mL).

Investigators shall counsel WOCBP and male subjects who are sexually active with WOCBP on the importance of pregnancy prevention and the implications of an unexpected pregnancy. Investigators shall advise on the use of highly effective methods of contraception, with have a failure rate of \< 1% when used consistently and correctly.

* Women of childbearing potential must have a negative serum or urine pregnancy test (minimum sensitivity 25 IU/L or equivalent units of HCG) within 24 hours prior to the start of nivolumab.
* Men who are sexually active with WOCBP must use any contraceptive method with a failure rate of less than 1% per year. Men receiving nivolumab and who are sexually active with WOCBP will be instructed to adhere to contraception for a period of 31 weeks after the last dose of investigational product. Women who are not of childbearing potential (i.e., who are postmenopausal or surgically sterile as well as azoospermic men do not require contraception).
* Patients must have the ability to understand and the willingness to sign a written informed consent document

Exclusion Criteria:

* Patients with ongoing toxicities \> grade 1 according to NCI CTCAE Version 4.0 (excluding alopecia and neuropathy) due to prior anti-cancer therapy.
* Patients receiving any other investigational agent or active chemotherapy.
* Patients who have previously been treated an anti-PD-1, anti-PD-L1, anti-PD-L2, anti-Cytotoxic T-lymphocyte associated protein (CTLA)-4 antibody, or any other antibody or drug specifically targeting T-cell co-stimulation or immune checkpoint pathways.
* Patients with a known autoimmune disease. Patients are permitted to enroll if they have vitiligo, type I diabetes mellitus, residual hypothyroidism due to autoimmune condition only requiring hormone replacement, psoriasis not requiring systemic treatment, or conditions not expected to recur in the absence of an external trigger.
* Patients having a condition requiring systemic treatment with either corticosteroids (\> 10 mg/day prednisone equivalents) or other immunosuppressive medications within 14 days of study drug administration. Inhaled or topical steroids and adrenal replacement doses \> 10 mg/day prednisone equivalents are permitted in the absence of active autoimmune disease.
* Patients who are positive for hepatitis B virus surface antigen (HBV sAg) or hepatitis C virus ribonucleic acid (HCV RNA) indicating acute or chronic infection.
* Patients with a known history of testing positive for human immunodeficiency virus (HIV) or known acquired immunodeficiency syndrome (AIDS).
* Patients who have received prior external beam radiation therapy to the liver.
* Patients who have clinical evidence of ascites or are in clinical liver failure.
* Patients who are known to have greater than 20% lung shunting of the hepatic artery blood flow determined by Technetium microaggregated albumin (MAA) scan (if conducted prior to study enrollment).
* Patients who have had a standard of care pre-assessment angiogram that demonstrates abnormal vascular anatomy that would result in significant reflux of hepatic arterial blood to the stomach, pancreas or bowel.
* Patients with known portal vein thrombosis.
* Patients with untreated brain metastases or leptomeningeal metastases will be excluded. Patients with brain metastases are eligible if metastases have been treated and there is no magnetic resonance imaging (MRI) evidence of progression for at least 4 weeks after treatment is complete and within 28 days prior to the first dose of nivolumab administration. There must also be no requirement for immunosuppressive doses of systemic corticosteroids (\> 10 mg/day prednisone equivalents) for at least 2 weeks prior to study drug administration.
* Patients with 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.
* Patients who are pregnant or breastfeeding will be excluded from the study due to the potential teratogenic or abortifacient effects that may result from nivolumab or Y-90 Theraspheres. Because there is an unknown, but potential risk for adverse events in nursing infants secondary to treatment of the mother with nivolumab and Y-90, breastfeeding should be discontinued if the mother is treated with nivolumab and Y-90. These potential risks may also apply to other agents used in this study.
* HIV-positive patients on combination antiretroviral therapy are ineligible because of the potential for pharmacokinetic interactions with nivolumab. In addition, these subjects are at increased risk of lethal infections when treated with immunosuppressive agents. Screening HIV testing is not required.