Study of Pembrolizumab With Pemetrexed and Oxaliplatin in Chemo-Refractory Metastatic Colorectal Cancer Patients

Inclusion Criteria: * The patient must have consented to participate and, prior to beginning specific study procedures, must have signed and dated an appropriate IRB-approved consent form that conforms to federal and institutional guidelines for study treatment. * The ECOG performance status must be 0 or 1. * There must be histologic or cytologic confirmation of a diagnosis of microsatellite stable (MSS) colorectal adenocarcinoma using CLIA certified IHC or PCR-based MSI testing. * Metastatic or locally advanced disease not amenable to curative surgery and/or radiotherapy. * There must be documentation by PET/CT scan, CT scan, or MRI that the patient has evidence of measurable metastatic disease per RECIST 1.1. * Patients must have had prior treatment for metastatic or unresectable for cure of colorectal cancer with standard chemotherapy including fluoropyrimidine-, oxaliplatin- and irinotecan- based chemotherapy, and if RAS wild-type, an anti-EGFR therapy. * At the time of study entry, blood counts performed within 2 weeks prior to study entry must meet the following criteria: * ANC must be greater than or equal to 1500/mm3; * Platelet count must be greater than or equal to 100,000/mm3; and * Hemoglobin must be greater than or equal to 9 g/dL. * The following criteria for evidence of adequate hepatic function performed within 2 weeks prior to study entry must be met: * Total bilirubin must be less than or equal to 1.5 x ULN. * AST and ALT must be less than or equal to 2.5 x ULN for the lab except in the presence of known hepatic metastasis, wherein transaminases may be up to 5 x ULN. * Alkaline phosphatase must be less than or equal to 3 x ULN for the lab. * International normalized ratio of prothrombin time must be less than or equal to 1.5 times the ULN. Patients who are therapeutically treated with an agent such as warfarin or heparin will be allowed to participate if no underlying abnormality in coagulation parameters exists per medical history. For laboratories that do not report an ULN for the INR assay, use less than or equal to 1.2 as the value for the ULN. * Creatinine must be less than or equal to 1.5 x upper limit of normal (ULN) and measured or calculated creatinine clearance (CrCl) greater than or equal to 60mL/min. * All hematologic, gastrointestinal, and genitourinary chemotherapy toxicities must be less than grade 2 at the time study therapy is to begin. (Note: Transfusions may be used to correct hemoglobin for patients experiencing anemia from therapy who otherwise would be eligible for the study. * Patients must be able to interrupt nonsteroidal anti-inflammatory drugs (NSAIDS) 2 days before (5 days for long acting NSAIDS), the day of and 2 days following administration of pemetrexed. * Patients must be able to take folic acid, vitamin B12, and dexamethasone per protocol. * Female patients 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 and female patients with reproductive potential must agree to use accepted effective methods of contraception while receiving study therapy and for at least 120 days after the completion of study therapy. Note: Abstinence is acceptable if this is the usual lifestyle and preferred contraception for the patient. Exclusion Criteria: * Diagnosis of anal or small bowel carcinoma. * Colorectal cancer other than adenocarcinoma, e.g., sarcoma, lymphoma, carcinoid. * 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 study therapy. * Use and/or receipt of the last dose of anti-cancer therapy (chemotherapy, immunotherapy, endocrine therapy, targeted therapy, biologic therapy, tumor embolization, monoclonal anti-bodies) or radiation therapy within 4 weeks prior to receiving first dose of study therapy. * Prior monoclonal antibody therapy within 4 weeks prior to first dose of FC-10 study therapy or who has not recovered (i.e., less than or equal to grade 1 or at baseline) from adverse events due to a previously administered agent. * Neuropathy greater than grade 1. * Active autoimmune disease requiring systemic treatment within the past 3 months or a documented history of clinically severe autoimmune disease or a syndrome that requires systemic steroids or immunosuppressive agents. Note: steroid use is permitted only as indicated per protocol. * Receipt of live attenuated vaccination within 30 days prior to study entry or within 30 days of receiving study therapy. Administration of killed vaccines is allowed. * Known history of hepatitis B or hepatitis C. * Has known active central nervous system (CNS) metastases and/or carcinomatous meningitis. Patients 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 14 days prior to trial treatment. * Active infection or chronic infection requiring systemic therapy. * Known history of human immunodeficiency virus (HIV) or acquired immunodeficiency-related (AIDS) illnesses. * Prior therapy with an anti-PD-1, anti-PD-L1, anti-PD-L2, anti-CD137, or anti-Cytotoxic T-lymphocyte-associated antigen-4 (CTLA-4) antibody (including ipilimumab or any other antibody or drug specifically targeting T-cell co-stimulation or checkpoint pathways) is not allowed. * History of allogeneic organ transplantation. * Any of the following cardiac conditions: * Documented NYHA Class III or IV congestive heart failure, * Myocardial infarction within 6 months prior to study entry, * Unstable angina within 6 months prior to study entry, * Symptomatic arrhythmia. * Active or prior documented inflammatory bowel disease (e.g., Crohn's disease, ulcerative colitis). * Ongoing or active gastritis or peptic ulcer disease. * Presence of third space fluid which cannot be controlled by drainage. Active bleeding diatheses. * Known history of previous diagnosis of tuberculosis. * History of hypersensitivity to pembrolizumab, pemetrexed, or oxaliplatin or any excipients of these drugs. * Known history or confirmation of active pneumonia, non-infectious pneumonitis that requires steroids, current pneumonitis, symptomatic interstitial lung disease, or definitive evidence of interstitial lung disease described on CT scan, MRI, or chest x-ray in asymptomatic patients; dyspnea at rest requiring current continuous oxygen therapy. * Major surgical procedure, open biopsy, or significant traumatic injury within 28 days prior to randomization. * Other malignancies unless the patient is considered to be disease-free and has completed therapy for the malignancy greater than or equal to 12 months prior to study entry. Patients with the following cancers are eligible if diagnosed and treated within the past 12 months: carcinoma in situ of the cervix, and basal cell and squamous cell carcinoma of the skin. * Psychiatric or addictive disorders or other conditions that in the opinion of the investigator would preclude the patient from meeting the study requirements or interfere with interpretation of study results. * Pregnancy or lactation at the time of study entry. * Use of any investigational agent within 4 weeks prior to the first dose study therapy.