Guadecitabine and Nivolumab in Treating Refractory Metastatic Colorectal Cancer

Inclusion Criteria:

* Histologically confirmed microsatellite stable (MSS) metastatic colorectal adenocarcinoma with prior treatment or intolerance to a fluoropyrimidine, oxaliplatin, irinotecan, bevacizumab, and an anti-EGFR agent (in patients with RAS wildtype tumors)
* CIMP+ status: A tumor sample will be classified as CIMP+ if \>= 3 of 5 CIMP reactions give a PMR (percent of methylated reference) \>= 10, using the MethylLight assay and following CIMP-defining panel - CACNA1G, IGF2, NEUROG1, RUNX3 and SOCS1
* No limit to number of prior lines of therapy
* Eastern Cooperative Oncology Group (ECOG) performance status 0-1
* Absolute neutrophil count (ANC) \>= 1,500/mcL
* Platelets \>= 100,000/mcl
* Serum total bilirubin =\< 1.5 upper limit normal (ULN)
* Serum albumin \>= 2.5 g/dL
* Aspartate aminotransferase (AST) (serum glutamic-oxaloacetic transaminase \[SGOT\])/alanine aminotransferase (ALT) (serum glutamate pyruvate transaminase \[SPGT\]) =\< 3 X ULN, unless liver metastases are present or patient has known chronic liver disease, in which case AST and ALT must be =\< 5 X ULN
* Serum creatinine clearance (CL) \> 40 mL/min by the Cockcroft-Gault formula (Cockcroft and Gault 1976) or by 24-hour urine collection for determination of creatinine clearance
* Women of childbearing potential (WOCBP) must agree to follow instructions for method(s) of contraception for the duration of study treatment with nivolumab and 5 months after the last dose of study treatment (i.e. 30 days \[duration of ovulatory cycle\] plus the time required for the investigational drug to undergo approximately five half-lives). Males who are sexually active with WOCBP must agree to follow instructions for method(s) of contraception for the duration of study treatment with nivolumab and 7 months after the last dose of study treatment (i.e. 90 days \[duration of sperm turnover\] plus the time required for the investigational drug to undergo approximately five half-lives). Should a woman become pregnant or suspect she is pregnant while participating in this study, she should inform her treating physician immediately

  * A female of child-bearing potential is any woman (regardless of sexual orientation, having undergone a tubal ligation, or remaining celibate by choice) who meets the following criteria:

    * Has not undergone a hysterectomy or bilateral oophorectomy; or
    * Has not been naturally postmenopausal for at least 12 consecutive months (i.e., has had menses at any time in the preceding 12 consecutive months)
* Ability to understand and the willingness to sign a written informed consent
* Patients with treated parenchymal brain metastases are eligible for study participation. Steroids, at stable dose for 2 weeks, not to exceed equivalent of prednisone 10 mg daily dose, are allowed. Anticonvulsants (at stable dose) are allowed. Treatment for brain metastases may be whole-brain radiotherapy, radiosurgery, neurosurgery, or a combination as deemed appropriate by the treating physician. Radiotherapy and stereotactic radiosurgery must be completed at least 28 days prior to randomization

Exclusion Criteria:

* Patients who have had chemotherapy or radiotherapy within 4 weeks prior to entering the study (or within 6 weeks for nitrosurea or mitomycin C) or those who have not recovered from adverse events due to agents administered more than 4 weeks earlier
* Patients may not be receiving any other investigational agents
* Any previous treatment with a hypomethylating agent, or with an anti-PD1 or anti-PD-L1 or anti-PD-L2 or anti-CTLA-4 inhibitor, including nivolumab (or any other antibody or drug specifically targeting T-cell co-stimulation or checkpoint pathways). Any immunomodulatory agent that is not described above should be cleared by the principal investigator (PI)
* Known hypersensitivity to any of the components of guadecitabine or nivolumab
* Receipt of live attenuated vaccination within 30 days prior to study entry
* History of leptomeningeal carcinomatosis or uncontrolled seizures
* 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
* Malignancies other than colorectal adenocarcinoma within 5 years prior to treatment, except for adequately treated carcinoma in situ (e.g. of the cervix), non-melanoma skin cancer, T1a or T1b prostate cancer treated with curative intent at least 1 year prior to study entry with normal prostate specific antigen (PSA), and ductal carcinoma in situ treated surgically with curative intent. Other early stage cancers that have a minimal chance of recurrence (i.e. stage I endometrial cancer, cervical cancer, etc.) may be cleared and should be discussed with the PI
* Renal insufficiency requiring dialysis
* Known positivity for human immunodeficiency virus (HIV)
* Active hepatitis B, hepatitis C
* Surgery (including open biopsy), significant traumatic injury within 28 days prior to randomization, or anticipation of the need for major surgery during study treatment
* Active or prior documented autoimmune disease. Subjects with vitiligo, Graves disease, or psoriasis not requiring systemic treatment (within the past 2 years) are not excluded
* Active or prior documented inflammatory bowel disease (e.g., Crohn?s disease, ulcerative colitis)
* History of allogeneic organ transplant
* Current or prior use of immunosuppressive medication within 28 days before the first dose of nivolumab, with the exceptions of intranasal and inhaled corticosteroids or systemic corticosteroids at physiological doses, which are not to exceed 10 mg/day of prednisone, or an equivalent corticosteroid. Live attenuated vaccines within 30 days of nivolumab dosing (i.e. 30 days prior to the first dose, during treatment with nivolumab and for 30 days post discontinuation of nivolumab. Inactivated vaccines, such as the injectable influenza vaccine, are permitted
* Known history or ongoing diagnosis of pneumonitis
* Known history of previous clinical diagnosis of tuberculosis
* Mean QT interval corrected for heart rate (QTc) \>= 470 ms calculated from 3 electrocardiograms (ECGs) using Fridericia?s correction
* Patients must not be pregnant or nursing due to the potential for congenital abnormalities and the potential of this regimen to harm nursing infants