Nivolumab and Metformin in Patients With Treatment Refractory MSS Colorectal Cancer

Inclusion Criteria: * Patients must have histologically or cytologically confirmed stage IV colorectal adenocarcinoma with measurable disease * Prior treatment with 5 Fluorouracil (or capecitabine), oxaliplatin and irinotecan containing chemotherapy (needs to be treated with anti-epidermal growth factor receptor (EGFR) agent if extended RAS wild type) * Patients must have measurable disease, defined as at least one lesion that can be accurately measured in at least one dimension (longest diameter to be recorded for non-nodal lesions and short axis for nodal lesions) as ≥ 20 mm with conventional techniques or as ≥ 10 mm with spiral computed tomography (CT) scan, magnetic resonance imaging (MRI), or calipers by clinical exam * Eastern Cooperative Oncology Group (ECOG) performance status 0 or 1 (Karnofsky ≥ 70%) * Life expectancy of greater than 3 months * Absolute neutrophil count ≥ 1,500/µL * Platelets ≥ 100,000/µL * Hemoglobin ≥ 9 g/dL or ≥ 5.6 mmol/L without transfusion or erythropoietin (EPO) dependency (within 7 days of assessment) * Serum creatinine ≤ 1.5 x upper limit of normal (ULN) OR creatinine clearance ≥ 60 mL/min/1.73 m² for patients with creatinine levels \> 1.5 x ULN. Creatinine clearance should be calculated per institutional standard * Serum total bilirubin ≤ 1.5 x the upper limit of normal (ULN) OR direct bilirubin ≤ ULN for subjects with total bilirubin \> 1.5 ULN * Aspartate aminotransferase (AST) (serum glutamic oxaloacetic transaminase\[SGOT\])/alanine aminotransferase (ALT) (serum glutamate pyruvate transaminase \[SGPT\] ≤ 2.5 x institutional upper limit of normal * Serum albumin ≥ 2.5 mg/dl * International normalized ratio (INR) or prothrombin time (PT) ≤ 1.5 x ULN unless subject is receiving anticoagulant therapy as long as PT or partial thromboplastin time (PTT) is within therapeutic range of intended use of anticoagulants. Activated partial thromboplastin time (aPTT) ≤ 1.5 x ULN unless subject is receiving anticoagulant therapy as long as PT or PTT is within therapeutic range of intended use of anticoagulants * Patients with diabetes mellitus should be on a stable diabetic treatment regimen for at least 1 month prior to trial enrollment and keep a blood glucose level log at home for the first 4 weeks of the trial * Female subject of childbearing potential should have a negative urine or serum pregnancy within 72 hours prior to receiving the first dose of study medication; if the urine test is positive or cannot be confirmed as negative, a serum pregnancy test will be required * Male subjects of childbearing potential must agree to use an adequate method of contraception, starting with the first dose of study therapy through 120 days after the last dose of study therapy. * Note: Abstinence is acceptable if this is the usual lifestyle and preferred contraception for the subject * Female subjects of childbearing potential must be willing to use an adequate method of contraception for the course of the study through 120 days after the last dose of study medication * Note: Abstinence is acceptable if this is the usual lifestyle and preferred contraception for the subject * Ability to understand and the willingness to sign a written informed consent document Exclusion Criteria: * Patients who have had chemotherapy or radiotherapy within 4 weeks prior to entering the study or those who have not recovered from adverse events due to agents administered more than 4 weeks earlier * Note: Subjects with ≤ grade 2 neuropathy are an exception to this criterion and may qualify for the study * Note: If subject received major surgery, they must have recovered adequately from the toxicity and/or complications from the intervention prior to starting therapy * Metformin use in the last 3 months * Patients who are receiving any other investigational agents * Has known active central nervous system (CNS) metastases and/or carcinomatous meningitis; subjects with previously treated brain metastases may participate provided they are stable (without evidence of progression by imaging for at least four weeks prior to the first dose of trial treatment and any neurologic symptoms have returned to baseline), have no evidence of new or enlarging brain metastases, and are not using steroids for at least 7 days prior to trial treatment; this exception does not include carcinomatous meningitis which is excluded regardless of clinical stability * History of allergic reactions attributed to compounds of similar chemical or biologic composition to nivolumab and metformin * Has a known history of active tuberculosis (TB) (Bacillus tuberculosis) * Has a diagnosis of immunodeficiency or is receiving systemic steroid therapy or any other form of immunosuppressive therapy within 7 days prior to the first dose of trial treatment * Has active autoimmune disease that has required systemic treatment in the past 2 years (i.e. with use of disease modifying agents, corticosteroids or immunosuppressive drugs); replacement therapy (eg., thyroxine, insulin, or physiologic corticosteroid replacement therapy for adrenal or pituitary insufficiency, etc.) is not considered a form of systemic treatment * Has known history of, or any evidence of active, non-infectious pneumonitis * Has an active infection requiring systemic therapy * Has known substance abuse disorders that would interfere with cooperation with the requirements of the trial * Has received prior therapy with an anti-programmed death (PD)-1, anti-PD-L1, or anti-PD-L2 agent * Has a known history of human immunodeficiency virus (HIV) (HIV 1/2 antibodies) * Has known active hepatitis B (e.g., hepatitis surface antigen \[HBsAg\] reactive) or hepatitis C (e.g., hepatitis C virus \[HCV\] ribonucleic acid \[RNA\] \[qualitative\] is detected) * Has received a live vaccine within 30 days of planned start of study therapy. * Note: Seasonal influenza vaccines for injection are generally inactivated flu vaccines and are allowed; however intranasal influenza vaccines (e.g., Flu-Mist) are live attenuated vaccines, and are not allowed * Uncontrolled intercurrent illness including, but not limited to, ongoing or active infection, symptomatic congestive heart failure, unstable angina pectoris or myocardial infraction within 6 months of study entry, serious cardiac arrhythmia requiring medications, baseline corrected QT (QTc) \> 450 msec or previous history of QT prolongation while taking other medications * Other medications, or severe acute/chronic medical or psychiatric condition, or laboratory abnormality that may increase the risk associated with study participation or study drug administration, or may interfere with the interpretation of study results, and in the judgment of the investigator would make the subject inappropriate for entry into this study * Has a known additional malignancy that is progressing or requires active treatment; exceptions include basal cell carcinoma of the skin or squamous cell carcinoma of the skin that has undergone potentially curative therapy or in situ cervical cancer; subjects with prior malignancies are eligible if the subject has been disease free for \> 5 years * Is pregnant or breastfeeding, or expecting to conceive or father children within the projected duration of the trial, starting with the screening visit through 120 days after the last dose of trial treatment