The goal of this clinical research study is to find the highest tolerable dose of a combination of dasatinib, cetuximab and FOLFOX (5-fluorouracil [5-FU], leucovorin [LV], and Eloxatin [oxaliplatin]) that can be given to patients with metastatic colorectal cancer. The safety of these drugs in combination will also be studied.

Cetuximab is a drug designed to block the activity of EGFR, a protein on the surface of some tumor cells that may cause the cells to grow. Blocking EGFR may stop or slow the growth of tumor cells. Dasatinib is a drug that inhibits a protein called c-Src. High levels of c-Src may make it harder for chemotherapy to work against the cancer. If dasatinib can inhibit c-Src, the chemotherapy may be more effective against the cancer. FOLFOX is a drug combination frequently used to treat colon or rectal cancer that has spread to other parts of the body. FOLFOX is designed to kill rapidly dividing cells by preventing DNA (the genetic material of cells) from duplicating.

Before you can start taking the drugs on this study, you will have what are called "screening tests." These tests will help the doctor decide if you are eligible to take part in this study. Your complete medical history will be recorded, and you will be asked about any drugs you may be taking or have taken in the past. You will have a physical exam, including measurement of your vital signs (heart rate, temperature, breathing rate, and blood pressure), height, and weight. You will be asked how well you are able to perform the normal activities of daily living (a performance status evaluation). You will have an electrocardiogram (ECG - a test that measures the electrical activity of the heart). You will have a chest x-ray and either a computed tomography (CT) or magnetic resonance imaging (MRI) scan of your abdomen (stomach area) and pelvis to check the status of the disease. X-rays, CT scans, or MRIs may be taken of other areas of your body if your doctor thinks it is necessary. Blood (about 1-2 tablespoons) will be drawn for routine tests. This routine blood draw will include a pregnancy test for women who are able to have children. To be eligible to take part in this study, the pregnancy test must be negative.

Tumor tissue from a previous biopsy or surgery will be used to test a gene called KRAS. Recent studies have found that cetuximab, when given alone or in combination with other chemotherapy drugs, was not effective when given to patients with colorectal cancer that had a mutation of a certain type of gene called KRAS. If you have the KRAS gene mutation, you will not take part in this study.

If you are found to be eligible to take part in this study, you will begin receiving the study drugs at a dose based on when you join the study. Three (3) to 6 participants will be entered at each dose level. Each new group of participants will receive a higher dose, until the highest tolerable dose is found. Once the highest tolerable dose is found, 12 participants will be enrolled at that dose level. Your doctor will tell you what dose level you will be receiving and how this dose compares to the doses other participants have received. The starting dose of cetuximab and FOLFOX will be the same for all participants. The dose of dasatinib will be increased with the next group of 3-6 participants. Every 14 days is considered 1 study "cycle".

If you are enrolled at the highest tolerable dose level, you will have 2 core liver biopsies. The liver tissue will be studied to learn the effect of the study drugs on stopping the protein c-Src. You will have 2 liver biopsies collected. The first liver biopsy will be collected before you start the study drugs, and the second will be performed in either Cycle 2 or 3. Before the liver biopsy, you will receive fluids and drugs for relaxation and/or pain through an needle in your arm or hand. You will be awake during the biopsy. A radiologist will find the tumor in the liver with the help of radiographic imaging procedures such as an ultrasound or CT scan. Your skin around this area will be cleansed, and a local anesthetic will be given. A long, hollow needle will be inserted through the skin into the liver tumor, and a tissue sample(s) will be taken.

Before receiving the study drugs, you will have a central venous catheter (CVC) placed. A CVC is a sterile flexible tube that will be placed into a large vein while you are under local anesthesia. Your doctor will explain this procedure to you in more detail, and you will be required to sign a separate consent form for this procedure.

You will take dasatinib by mouth once a day, everyday during this study. Your study doctor and research nurse will tell you how many pills you will take. Dasatinib should be taken at the same time each day, with or without meals. If you miss a dose of dasatinib, you should not double the next dose. It is important to take dasatinib with water, and not fruit juices. You should not drink grapefruit juice or eat grapefruit while you are on this study. Dasatinib should not be touched by children, pregnant women, or women who are breastfeeding. If a caregiver must handle the drug, a protective glove should be worn.

While you are taking dasatinib, you will be given a drug diary. In this diary, you will write down the date, the time, and the number of dasatinib tablets taken. Certain drugs and herbal supplements may not be taken while you are receiving dasatinib. These drugs could affect how your body breaks down dasatinib, which could have a bad effect on you. Your doctor will give you a list of drugs and herbal supplements that you must not take while on this study. You must tell your doctor before taking any new drugs while on this study.

On Day 1 of every cycle, you will receive oxaliplatin and LV through the CVC over about 2 hours. On Day 1, you will receive 5-FU through the CVC over less than 5 minutes. You will then receive 5-FU through a portable pump for the next 46 hours. On Days 1 and 8, you will receive cetuximab through the CVC over about 2 hours.

On Day 8, blood (about 1-2 tablespoons) will be drawn for routine tests.

You will have extra blood samples drawn (1 tablespoon each time) before receiving the study drugs and on Day 8 of Cycles 2 and 4. This blood will be drawn at the same time as your routine blood tests are drawn. These blood samples will be used to develop tests that may help doctors be able to predict who will best benefit from dasatinib.

If you are enrolled in the group that receives the highest tolerable dose level, the Day 8 blood draw during cycle 2 will not be performed. Instead, blood will be collected at the time of the liver biopsy that is to be performed between Days 8-14 of cycle 2 or 3 about 2 to 6 hours after taking the daily dose of dasatinib.

Before each new cycle, you will be asked questions about any side effects you may have had. At each visit, it is important to tell the study staff about any drugs you are currently taking. You will have a physical exam, including measurement of your vital signs. You will have a performance status evaluation. Blood (about 1-2 tablespoons) will be drawn for routine tests.

You will also have either CT scans or MRIs of the tumor(s) every 8 weeks. Additional tests may be done during this study, if your study doctor thinks it is necessary.

If you experience severe side effects, the study drugs may be delayed, stopped, or you may receive smaller doses of the drugs.

You may remain on this study for as long as you are benefiting. You will be taken off this study if the disease gets worse or intolerable side effects occur.

Once you are off-study, you will have an end-of-study visit. At this visit, blood (about 3 tablespoons) and urine will be collected for routine tests. You will have a physical exam. You will have a CT scan or MRI scan of your abdomen and pelvis to check the status of the disease. If you are having side effects after you stop receiving the study drugs, you will be contacted by phone to check how you are feeling, or you will have follow-up visits until the side effects have gone away.

This is an investigational study. Dasatinib is FDA approved for the treatment of leukemia. Its use in this study, for this disease, is considered to be investigational. Cetuximab, 5-FU, LV, and oxaliplatin are all FDA approved and commercially available for the treatment of colorectal cancer. Up to 42 patients will take part in this study. All patients will be enrolled at M. D. Anderson.

• Drug: 5-FU
• Drug: Cetuximab
• Drug: Dasatinib
• Drug: Leucovorin
• Drug: Oxaliplatin

Inclusion Criteria:

1. Patient must have histologically or cytologically confirmed colorectal adenocarcinoma with metastatic disease documented on diagnostic imaging studies
2. Patient must have wild type KRAS.
3. Patient must have previously progressed, either clinically or radiographically, on systemic therapy for metastatic colorectal cancer, with no limit on the number of prior regimens.
4. 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.
5. Written informed consent obtained.
6. Age >/= 18 years to provide a uniform oncologic phenotype of adult-onset colorectal cancer.
7. ECOG performance status 0-1
8. Patients must have adequate organ and marrow function defined as: 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; serum creatinine < 2.0 mg/dL
9. 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.

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 28 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 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.
4. 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
5. Patients with known dihydropyrimidine dehydrogenase deficiency.
6. 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)
7. 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.
8. Patients with a history of allergic reactions attributed to cetuximab, oxaliplatin, 5-FU, or leucovorin.
9. 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, INR should be < 1.5.
10. Current or recent (<2 week) use of aspirin (at a dose greater than 81 mg/day) or clopidogrel.
11. Diagnosed or suspected congenital long QT syndrome
12. Any history of clinically significant ventricular arrhythmias (such as ventricular tachycardia, ventricular fibrillation, or Torsades de pointes).
13. Previous allergic reaction to a human monoclonal antibody.
14. 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
15. 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) .
16. 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
17. 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
18. Inability to take oral medications.
19. Inability to comply with study and/or follow-up procedures