FOLFOX Chemotherapy Regimen (5-FU, Leucovorin, Oxaliplatin) in Metastatic Colorectal Cancer

Inclusion Criteria:

1. Patient must have histologically or cytologically confirmed colorectal adenocarcinoma with metastatic disease documented on diagnostic imaging studies
2. Phase IB: Patient must have wild type KRAS.
3. Phase IB: For the expansion cohort, only patients with liver metastases \>/= 2.0 cm amenable to percutaneous CT or U/S guided biopsy and who agree to having 2 liver biopsies done are eligible.
4. Phase II: Patient must have known KRAS (exon 1, codon 12, 13) or sufficient available tumor tissue from the primary tumor or metastatic site for KRAS mutation analysis \[Phase II only\].
5. Patient must have previously progressed on systemic therapy for metastatic colorectal cancer, with no limit on the number of prior regimens. For patients in the Phase II cohort, they must have progressed on 5-FU or capecitabine and oxaliplatin \[patients with KRAS mutated tumors\], and either cetuximab or panitumumab \[patients with KRAS wild type tumors\].
6. (Continued from # 5) The following criteria must be met for progression. • Baseline imaging was performed 1 month or less prior to starting regimen. • Average treatment intensity (number of cycles received/number of cycles anticipated in absence of delays) of greater than 70%. • Restaging study demonstrating progression 6 weeks or less from last dose of oxaliplatin and EGFR inhibitor (if applicable). • Progression may be by RECIST criteria or, with PI approval, clinical progression.
7. Written informed consent obtained
8. Age \>/= 18 years to provide a uniform oncologic phenotype of adult-onset colorectal cancer.
9. Eastern Cooperative Oncology Group (ECOG) performance status 0-1 (Appendix E)
10. Patients must have adequate organ and marrow function defined as: absolute neutrophil count (ANC) \>/= 1,500/mm\^3; platelets \>/= 100,000/ mm\^3; hemoglobin \>/= 9 gm/dL (may be transfused to maintain or exceed this level); total bilirubin \</= 1.5 mg/dL; AST (SGOT)/ALT(SGPT) \</= 2.5 times institution's upper limit of normal (IULN), or \</= 5 times IULN if known liver metastases; · Creatinine clearance \> 60mL/min using Cockcroft-Gault formula.
11. Women of childbearing potential must have a negative serum or urine pregnancy test within 72 hours prior to the start of study medications. Childbearing potential is defined as a woman who is not post-menopausal for 12 months or longer or is not surgically sterile. Patients must agree to practice acceptable contraceptive methods as outlined in the protocol.

Exclusion Criteria:

1. Recent (within 4 weeks of the first infusion of study drugs on this study), or planned participation in another experimental therapeutic drug study. Patients who have had any systemic chemotherapy, radiotherapy, or major surgery within 21 days prior to the first infusion of study drugs.
2. Patients who have not recovered to \</= grade 2 for neuropathy or \</= grade 1 for other side effects due to prior treatment.
3. Patients with radiographic evidence of pleural effusions in the last 30 days prior to enrollment.
4. Patients with known brain metastases because of their poor prognosis and because they often develop progressive neurologic dysfunction that would confound the evaluation of neurologic and other adverse events.
5. Female patients who are pregnant or lactating or men and women of reproductive potential not willing to employ an effective method of birth control during treatment and for 3 weeks after discontinuing study treatment
6. Patients with known dihydropyrimidine dehydrogenase deficiency.
7. Patients with a history of significant bleeding disorder unrelated to cancer, including: Diagnosed congenital bleeding disorders (e.g., von Willebrand's disease); Diagnosed acquired bleeding disorder within one year (e.g., acquired anti-factor VIII antibodies)
8. Patients currently taking the following drugs that are generally accepted to have a risk of causing Torsades de Pointes:haloperidol, methadone, amiodarone, sotalol, erythromycins, clarithromycin cisapride, chlorpromazine, bepridil, droperidol, arsenic, chloroquine, domperidone, halofantrine, levomethadyl, pentamidine, sparfloxacin, lidoflazine, quinidine, procainamide, disopyramide, ibutilide, dofetilide. Subjects who have discontinued any of these medications must have a wash-out of at least 5 days (or 14 days for amiodarone) prior to the first dose of dasatinib.
9. Patients with wild type KRAS tumors with a history of allergic reactions attributed to cetuximab, oxaliplatin, 5-FU, capecitabine, or leucovorin that, previously, have not been adequately prevented with premedications.
10. Current use of full-dose warfarin (except as required to maintain patency of preexisting, permanent indwelling IV catheters). For subjects receiving warfarin for catheter patency, international normalized ratio (INR) should be \< 1.5.
11. Current or recent (\<2 week) use of aspirin (at a dose greater than 81 mg/day) or clopidogrel.
12. Diagnosed or suspected congenital long QT syndrome
13. Any history of clinically significant ventricular arrhythmias (such as ventricular tachycardia, ventricular fibrillation, or Torsades de pointes).
14. Previous allergic reaction to a human monoclonal antibody.
15. Prolonged QTc interval on pre-entry electrocardiogram (\> 450 msec) on both the Fridericia \[QTc = QT/RR\^1/3\] and Bazett's \[QTc = QT/sqrtRR\] correction. Bazett's correction is calculated automatically by institutional EKG machines
16. Any of the following concurrent severe and/or uncontrolled medical conditions which could compromise participation in the study: Uncontrolled high blood pressure (systolic blood pressure \>/= 140 and diastolic blood pressure \>/= 90), history of labile hypertension, or history of poor compliance with an antihypertensive regimen. Unstable angina or stable angina markedly limiting ordinary physical activity. (Angina occurs on walking one to two blocks on the level and climbing one flight of stairs in normal conditions and at a normal pace) .
17. Any of the following concurrent severe and/or uncontrolled medical conditions which could compromise participation in the study: New York Heart Association (NYHA) \>/= grade 2 congestive heart failure; Myocardial infarction within 6 months of study enrollment; History of stroke within 6 months of study enrollment; Unstable symptomatic arrhythmia requiring medication (Patients with chronic atrial arrhythmia, i.e., atrial fibrillation or paroxysmal SVT are eligible); Clinically significant peripheral vascular disease; Uncontrolled diabetes; Serious active or uncontrolled infection
18. History of other disease, metabolic dysfunction, physical examination finding, or clinical laboratory finding giving reasonable suspicion of a disease or condition that contraindicates the use of a study drug or that might affect the interpretation of the results of the study or render the subject at high risk from treatment complications
19. Inability to take oral medications.
20. Inability to comply with study and/or follow-up procedures.