Regorafenib and Nivolumab in Mismatch Repair (MMR) Refractory Colorectal Cancer

Inclusion Criteria:

* Histologically confirmed diagnosis of colorectal adenocarcinoma
* Proficient DNA mismatch repair (MMR) or stable microsatellite disease.
* Participants with the presence of at least one lesion with measurable disease as defined by 10mm in longest diameter for a soft tissue lesions or 15mm in short axis for a lymph node by RECIST 1.1 for response assessment.
* Participants must have received and progressed through or become intolerant to fluoropyrimidine, irinotecan, oxaliplatin, and bevacizumab, and if K-ras wild type, cetuximab or panitumumab containing therapies. Exceptions may apply.
* Eastern Cooperative Oncology Group (ECOG) Performance Score 0 or 1
* Estimated life expectancy over 3 months.
* Adequate bone marrow, liver and renal function.
* Participants must not have had chemotherapy, major surgery, monoclonal antibody therapy or experimental therapy within the 21 days prior to the start of regorafenib and nivolumab administration
* Women of childbearing potential must have a negative serum or urine pregnancy test (minimum sensitivity 25 IU/L or equivalent units of HCG) performed within 24 hours prior to the start of study drug and then every 4 weeks. Post-menopausal women (defined as no menses for at least 1 year) and surgically sterilized women are not required to undergo a pregnancy test.
* Participants (men and women) of childbearing potential must agree to use adequate contraception beginning at the signing of the Informed Consent Form (ICF) until at least 5 months for females and 7 months for males after the last dose of study drug
* Participants must be able to understand and be willing to sign the written informed consent form and be willing and able to comply with scheduled visits, treatment schedule, laboratory testing, and other study requirements.

Exclusion Criteria:

* Participants with active Central Nervous System (CNS) metastases If CNS metastases are treated and participants are at neurologic baseline for at least 2 weeks prior to enrollment, they will be eligible but will need a Brain MRI prior to enrollment.
* Uncontrolled hypertension (systolic pressure \>140 mm Hg or diastolic pressure \> 90 mm Hg \[NCI-CTCAE v5.0\] on repeated measurement) despite optimal medical management.
* Active or clinically significant cardiac disease.
* Women who are pregnant or breast-feeding
* Prior therapy with regorafenib, anti-PD-1, anti-PD-L1, anti-PD-L2, anti-CD137, or anti-CTLA-4 antibody (including ipilimumab or any other antibody or drug specifically targeting T-cell costimulation or checkpoint pathways).
* Previous or concurrent cancer within 3 years prior to treatment start EXCEPT for curatively treated cervical cancer in situ, non-melanoma skin cancer, superficial bladder tumors \[Ta (non-invasive tumor), Tis (carcinoma in situ) and T1 (tumor invades lamina propria)\].
* Active autoimmune disease that has required systemic treatment in the past 2 years. Replacement therapy (e.g., thyroxine, insulin, or physiologic corticosteroid replacement therapy for adrenal or pituitary insufficiency, etc.) is not considered a form of systemic treatment.
* Ascites, pleural effusion, or pericardial fluid requiring drainage in the last 4 weeks
* Participants with phaeochromocytoma
* Ongoing infection \> Grade 2
* Presence of a non-healing wound, or bone fracture.
* Renal failure requiring hemo-or peritoneal dialysis.
* Seizure disorder requiring medication.
* Interstitial lung disease with ongoing signs and symptoms at the time of informed consent.
* Pleural effusion or ascites that causes respiratory compromise.
* Any condition which, in the investigator's opinion, makes the subject unsuitable for trial participation.
* Known or suspected allergy or hypersensitivity to any of the study drugs, study drug classes, or excipients of the formulations given during the course of this trial.
* Persistent proteinuria ≥ Grade 3
* History of organ allograft
* Participants requiring warfarin or equivalent vitamin K antagonists (e.g. phenprocoumon)
* Participants with a condition requiring a strong CYP3A4 inhibitors or strong CYP3A4 inducers.
* Unresolved toxicity higher than CTCAE grade 1 attributed to any prior therapy or procedure, excluding alopecia.
* Any hemorrhage or bleeding event ≥ NCI CTCAE Grade 3 within 4 weeks prior to start of study medication.
* Substance abuse, medical, psychological or social conditions that may interfere with the patient's participation in the study or evaluation of the study results.
* Participants with an arterial thrombotic or thromboembolic event within 6 months of informed consent.
* Known history of human immunodeficiency virus (HIV) infection or current chronic or active hepatitis B or C infection.
* Child-Pugh B cirrhosis (or worse) or a history of hepatic encephalopathy
* History of stroke or intracranial hemorrhage within 6 months prior to enrollment.
* Major surgery or a wound that has not fully healed within 4 weeks of enrollment.
* Participants requiring concurrent anti-cancer therapy other than study treatment.
* Participants requiring hormonal therapy during the study or within 2 weeks of first study enrollment.