Regorafenib Plus 5-Fluorouracil/Leucovorin Beyond Progression in mCRC

Inclusion Criteria: 1. mCRC with prior progression on standard multi-agent combination chemotherapy and regorafenib as a standard approved monotherapy. Progression on prior regorafenib is required for inclusion in this clinical study. Prior regimens may include FOLFOX -/+ bevacizumab, FOLFIRI -/+ bevacizumab or -/+ cetuximab (if KRAS wild-type) or panitumumab (if KRAS wilt-type). Other prior regimens may include 5-FU or capecitabine -/+ bevacizumab, irinotecan -/+ cetuximab or panitumumab, FOLFIRI -/+ ziv-aflibercept or ramucirumab. 2. Patients treated with oxaliplatin in an adjuvant setting should have progressed during or within 6 months of completion of adjuvant therapy. Patients who progress more than 6 months after completion of oxaliplatin containing adjuvant treatment must be retreated. Patients who have withdrawn from standard treatment due to unacceptable toxicity warranting discontinuation of treatment and precluding retreatment with the same agent prior to progression of disease will also be allowed in the study. 3. Patients previously treated with chemotherapy must have at least 4 weeks period between the last dose of previous chemotherapy and the first dose in this clinical study. Patients previously treated with biologics such as Avastin, Zaltrap, Erbitux, and Vectibix must have at least 6 weeks period between the last dose of previous chemotherapy and the first dose in this clinical study. 4. Measurable metastatic disease that is refractory. 5. Eastern Cooperative Oncology Group (ECOG) performance status 0 or 1. 6. Patients are included regardless of KRAS/NRAS, BRAF, p53, or microsatellite instability (MSI) status 7. Age ≥ 18 years. 8. Life expectancy of at least 8 weeks (2 months). 9. Subjects must be able to understand and be willing to sign the written informed consent form. A signed informed consent form must be appropriately obtained prior to the conduct of any trial-specific procedure. 10. Adequate bone marrow, liver and renal function as assessed by the following laboratory requirements: * Total bilirubin ≤ 1.5 x the upper limits of normal (ULN) * Alanine aminotransferase (ALT) and aspartate amino-transferase (AST) ≤ 2.5 x ULN (≤ 5 x ULN for subjects with liver involvement of their cancer) * Alkaline phosphatase limit ≤ 2.5 x ULN (≤ 5 x ULN for subjects with liver involvement of their cancer) * Serum creatinine ≤ 1.5 x the ULN * International normalized ratio (INR)/ Partial thromboplastin time (PTT) ≤ 1.5 x ULN. * Platelet count \> 100000 /mm3, hemoglobin (Hb) \> 9 g/dL, absolute neutrophil count (ANC) ≥ 1500/mm3. Blood transfusion to meet the inclusion criteria will not be allowed. 11. Subject must be able to swallow and retain oral medication. 12. Up to 5 of the 15 patients will be allowed to have had other approved or investigational drugs after prior progression of Regorafenib monotherapy. (all patients enrolled in this trial must have had prior progression on regorafenib therapy). This may include TAS102, off-label therapy that may have been prescribed based on tumor genomic profiling or any investigational agents on a clinical trial. 13. No more than grade 2 toxicity with last previous cycle of regorafenib mono therapy. Exclusion Criteria: 1. Patients receiving any concurrent investigational agents 2. Previous assignment to treatment during this study. Subjects permanently withdrawn from study participation will not be allowed to re-enter study. 3. Uncontrolled hypertension (systolic pressure \>140 mm Hg or diastolic pressure \> 90 mm Hg \[NCI-CTCAE v4.0\] on repeated measurement) despite optimal medical management. 4. Active or clinically significant cardiac disease including: * Congestive heart failure - New York Heart Association (NYHA) \> Class II. * Active coronary artery disease. * Suspected Long QT syndrome defined as QTc interval \> 500 milliseconds at baseline. * Cardiac arrhythmias requiring anti-arrhythmic therapy other than beta blockers or digoxin. * Unstable angina (anginal symptoms at rest), new-onset angina within 3 months before randomization, or myocardial infarction within 6 months before randomization. 5. Evidence or history of bleeding diathesis or coagulopathy. 6. Any hemorrhage or bleeding event ≥ NCI CTCAE Grade 3 within 4 weeks prior to start of study medication. 7. Subjects diagnosed with thrombotic, embolic, venous, or arterial events, such as cerebrovascular accident (including transient ischemic attacks) deep vein thrombosis or pulmonary embolism within 3 months of start of study treatment. 8. Patients with any previously untreated or concurrent cancer that is distinct in primary site or histology except cervical cancer in-situ, treated ductal carcinoma in situ of the breast, curatively treated nonmelanoma skin carcinoma, noninvasive aerodigestive neoplasms, or superficial bladder tumor. Subjects surviving a cancer that was curatively treated and without evidence of disease for more than 3 years before registration are allowed; all cancer treatments must be completed at least 3 years prior to registration. 9. Patients with phaeochromocytoma. 10. Known history of human immunodeficiency virus (HIV) infection or current chronic or active hepatitis B or C infection requiring treatment with antiviral therapy. 11. Ongoing infection \> Grade 2 NCI-CTCAE v4.0. 12. Symptomatic metastatic brain or meningeal tumors. 13. Presence of a non-healing wound, non-healing ulcer, or bone fracture. 14. Major surgical procedure or significant traumatic injury within 28 days before start of study medication 15. Renal failure requiring hemo-or peritoneal dialysis. 16. Dehydration Grade ≥1 NCI-CTCAE v4.0. 17. Patients with seizure disorder requiring medication. 18. Persistent proteinuria ≥ Grade 3 per NCI-CTCAE v4.0 (\> 3.5 g/24 hrs, measured by urine protein: creatinine ratio on a random urine sample). 19. Interstitial lung disease with ongoing signs and symptoms at the time of informed consent. 20. Pleural effusion or ascites that causes respiratory compromise (≥ NCI-CTCAE version 4.0 Grade 2 dyspnea). 21. History of organ allograft (including corneal transplant). 22. 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. 23. Any malabsorption condition. 24. Women who are pregnant or breast-feeding. 25. Any condition which, in the investigator's opinion, makes the subject unsuitable for trial participation. 26. Substance abuse, medical, psychological or social conditions that may interfere with the subject's participation in the study or evaluation of the study results. 27. Therapeutic anticoagulation with Vitamin-K antagonists (e.g., warfarin) or with heparins and heparinoids. a. However, prophylactic anticoagulation as described below is allowed: i. Low dose warfarin (1 mg orally, once daily) with PT-INR ≤ 1.5 x ULN is permitted. ii. Low dose aspirin (≤ 100 mg daily). iii. Prophylactic doses of heparin. iv. Low molecular weight heparin Subjects who are prophylactically treated with an agent such as warfarin or heparin require close monitoring (day5 of cycle 1 and day 1 of each cycle) of their INR/PTT. If either of these values are above the therapeutic range, the doses should be modified and the assessments should be repeated weekly until they are stable.