Inclusion Criteria:

• Age ≥18 years of age
• Histological or cytological documentation of adenocarcinoma of the colon or rectum with confirmed KRAS or BRAF mutation.
• Archived, paraffin-embedded tissue block (primary or metastatic) available for genomic studies required
• Metastatic disease not amenable to surgical resection with curative intent
• Progression during or within 3 months following administration of a regimen that must include a combination of 5-fluorouracil, leucovorin (or levoleucovorin), and oxaliplatin with or without bevacizumab for treatment of metastatic disease OR when used in the adjuvant setting. NOTE: Progression while on the oxaliplatin component of FOLFOX not required (e.g., oxaliplatin may have been withdrawn due to toxicity, and patient progressed during treatment with 5-flourouracil alone).
• Measurable disease, defined as at least 1 unidimensionally measurable lesion on a CT scan as defined by RECIST 1.1.
• Eastern Cooperative Oncology Group (ECOG) performance status ≤1 Life expectancy of at least 3 months

• Adequate bone marrow, renal, and hepatic function, as evidenced by the following within 7 days of study treatment initiation:

  • Absolute neutrophil count (ANC) ≥1,500/mm3
  • Platelets ≥100,000/mm3
  • Hemoglobin ≥9.0 g/dL
  • Serum creatinine ≤1.5 x upper limit of normal (ULN)
  • Glomerular filtration rate (GFR) ≥30 ml/min/1.73m2 (see Appendix A)
  • AST and ALT ≤2.5 x ULN ( ≤5.0 × ULN for patients with liver involvement of their cancer
  • Bilirubin ≤1.5 X ULN
  • Alkaline phosphatase ≤2.5 x ULN (≤5 x ULN with liver involvement of their cancer)
  • Amylase and lipase ≤1.5 x ULN
  • Spot urine must not show 1+ or more protein in urine or the patient will require a repeat urine analysis. If repeat urinanalysis shows 1+ protein or more, a 24-hour urine collection will be required and must show total protein excretion <1000 mg/24 hours
  • INR/PTT ≤1.5 x ULN
• Patients who are therapeutically treated with an agent such as warfarin or heparin will be allowed to participate provided that no prior evidence of underlying abnormality in coagulation parameters exists. Close monitoring of at least weekly evaluations will be performed until INR/PTT is stable based on a measurement that is pre-dose as defined by the local standard of care.
• Women of childbearing potential and male subjects must agree to use adequate contraception for the duration of study participation and up to 3 months following completion of therapy. Adequate contraception is defined as any medically recommended method (or combination of methods) as per standard of care.
• In the assessment of the investigator, subject is able to comply with study requirements
• Signed, IRB-approved written informed consent

Exclusion Criteria:

• Any subject meeting any of the following exclusion criteria at baseline will be ineligible for study participation:
• Prior treatment with regorafenib, or any other tyrosine kinase inhibitor for the treatment of malignancy
• More than 1 prior chemotherapy regimen for mCRC. Previous adjuvant FOLFOX based chemotherapy is allowed. Prior FOLFIRI or single agent irinotecan is prohibited.
• Known history of or concomitant malignancy likely to affect life expectancy in the judgment of the investigator
• Pregnant or breastfeeding patients. Women of childbearing potential must have a pregnancy test performed a maximum of 7 days before start of FOLFIRI treatment, and a negative result must be documented before start of treatment.
• History of Gilbert's syndrome
• Known DPD deficiency
• Pernicious anemia or other anemias due to vitamin B12 deficiency (due to potential masking of deficiency with leucovorin)
• Major surgical procedure, open biopsy, or significant traumatic injury within 28 days before start of Day 1 of treatment with FOLFIRI
• Radiotherapy within 4 weeks prior to first dose of FOLFIRI

• Active cardiac disease including any of the following:

  • Congestive heart failure (New York Heart Association [NYHA]) ≥Class 2 (see Appendix D)
  • Unstable angina (angina symptoms at rest), new-onset angina (begun within the last 3 months). Myocardial infarction less than 6 months before start of Day 1 of FOLFIRI
  • Cardiac arrhythmias requiring anti-arrhythmic therapy (beta blockers or digoxin are permitted)
  • Uncontrolled hypertension. (Systolic blood pressure >150 mmHg or diastolic pressure >90 mmHg despite optimal medical management)
• Patients with pheochromocytoma
• Arterial or venous thrombotic or embolic events such as cerebrovascular accident (including transient ischemic attacks), deep vein thrombosis, or pulmonary embolism within the 6 months before start of FOLFIRI.
• Ongoing infection >Grade 2 according to NCI Common Terminology Criteria for Adverse Events version 4.0 (CTCAE v. 4.0)
• Known history of human immunodeficiency virus (HIV) infection
• Known history of chronic hepatitis B or C
• Patients with seizure disorder requiring medication
• Symptomatic metastatic brain or meningeal tumors unless the patient is >6 months from definitive therapy, has a negative imaging study within 4 weeks of FOLFIRI initiation, and is clinically stable with respect to the tumor at the time of study entry. Also, the patient must not be undergoing acute steroid therapy or taper (chronic steroid therapy is acceptable provided that the dose is stable for one month prior to and following screening radiographic studies)
• History of organ allograft
• Evidence or history of bleeding diathesis. Any hemorrhage or bleeding event > Grade 4 within 4 weeks of start of FOLFIRI
• Non-healing wound, ulcer, or bone fracture
• Renal failure requiring hemo- or peritoneal dialysis
• Dehydration according to NCI-CTC v 4.0 Grade >1
• Substance abuse, medical, psychological, or social conditions that may interfere with the patient's participation in the study or evaluation of the study results
• Known hypersensitivity to any of the study drugs, study drug classes, or excipients in the formulation
• Interstitial lung disease with ongoing signs and symptoms at the time of informed consent
• Inability to swallow oral medications
• Any malabsorption condition
• Unresolved toxicity higher than CTCAE v. 4.0 Grade 1 attributed to any prior therapy/procedure excluding alopecia and oxaliplatin-induced neurotoxicity (which must be ≤Grade 2)
• Patients unable or unwilling to discontinue (and substitute if necessary) use of prohibited drugs for at least 2 weeks prior to Day 1 of FOLFIRI initiation (see Appendix B for list of prohibited drugs)
• Unwilling to provide consent for genetic studies of tumor, whole blood, or plasma specimens