Regorafenib, With Cetuximab or Panitumumab, for the Treatment of Unresectable, Locally Advanced, or Metastatic Colorectal Cancer

Inclusion Criteria: * Histologically proven, unresectable distant metastatic or locally advanced colorectal adenocarcinoma * KRAS, NRAS wild type * BRAF v600E wildtype * Measurable disease * Eastern Cooperative Oncology Group (ECOG) performance status (PS) 0, 1, or 2 * Life expectancy of \>= 3 months per estimation of treating physician * Absolute neutrophil count (ANC) \>= 1200/mm\^3 (obtained =\< 7 days prior to randomization) * Platelet count \>= 75,000/mm\^3 (obtained =\< 7 days prior to randomization) * Hemoglobin \>= 9.0 g/dL (obtained =\< 7 days prior to randomization) * Total bilirubin =\< 1.5 x upper limit of normal (ULN) (obtained =\< 7 days prior to randomization) * Alanine aminotransferase (ALT) and aspartate amino-transferase (AST) =\< 2.5 x ULN (=\< 5 x ULN for subjects with liver involvement of their cancer) (obtained =\< 7 days prior to randomization) * Serum creatinine =\< 1.5 x ULN (obtained =\< 7 days prior to randomization) * International normalized ratio (INR)/partial thromboplastin time (PTT) =\< 1.5 x ULN (obtained =\< 7 days prior to randomization) * NOTE: 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 * Alkaline phosphatas…