BAY 43-9006 Plus Cetuximab to Treat Colorectal Cancer

* INCLUSION CRITERIA: * Patients must have histologically or cytologically documented metastatic colorectal cancer, which has recurred or progressed following at least one prior chemotherapy regimen administered for the treatment of metastatic disease. The diagnosis should be confirmed by the Laboratory of Pathology at the Clinical Center, NIH (National Institutes of Health). * Tumor should express epidermal growth factor receptor (EGFR), defined as any membrane staining for EGFR in tumor cells by immunohistochemistry (IHC) done on archival tumor blocks or slides. * Tumor blocks or unstained slides from archival pathological specimen suitable for the isolation of genomic DNA (deoxyribonucleic acid) must be available to determine the status of mutations in KRAS in the tumor. (For the initial 13 evaluable patients already enrolled and treated on this study, every effort will be made to re-acquire these blocks from patients or their referring physicians for evaluation of KRAS.) * Patients must have measurable disease, defined as at least one lesion that can be accurately measured in at least one dimension (longest diameter to be recorded) as greater than or equal to 20 mm with conventional techniques or as greater than or equal to 10 mm with spiral computed tomography (CT) scan. * Patients must have received or been offered and declined at least one prior Fluorouracil (5FU)-containing combination chemotherapy regimen for metastatic disease, unless available chemotherapy regimens were for some reason contraindicated for a particular patient. Patients who have received chemotherapy and/or biologic therapy, excluding BAY 43-9006 or cetuximab, are eligible. This therapy must have been completed greater than or equal to 4 weeks prior to enrollment on protocol, and the patient must have recovered to eligibility levels from prior toxicity. Prior radiation or surgery should have been completed greater than or equal to 4 weeks prior to study enrollment and all associated toxicities resolved to eligibility levels. * Age greater than or equal to18 years. Colorectal cancer does not usually occur in patients less than 18 years of age. * Life expectancy greater than 3 months. * ECOG (Eastern Cooperative Oncology Group) performance status 0 or 1. * Patients must have normal organ and marrow function as defined below: * absolute neutrophil count greater than or equal to 1,500/ microliter * platelets greater than or equal to 100,000/ microliter * total bilirubin less than or equal to 1.5 times the institutional upper limits of normal * AST (aspartate aminotransferase) (SGOT (serum glutamic oxaloacetic transaminase))/ALT (alanine aminotransferase) (SGPT (serum glutamic pyruvic transaminase) less than or equal to 2.5 times the institutional upper limit of normal * creatinine less than or equal to 1.5 times the institutional upper limits of normal OR * creatinine clearance greater than or equal to 60 mL/min/1.73 m\^2 * PT (prothrombin time)/PTT (partial thromboplastin time) less than or equal to 1.5 times the institutional upper limits of normal * Patients must have at least one lesion amenable to biopsy, as determined by an associate investigator after discussion with a member of the interventional radiology team. This lesion should be different from target lesion(s) being followed on imaging studies to evaluate response to treatment. * The effects of the combination of BAY 43-9006 and cetuximab on the developing human fetus at the recommended therapeutic doses are unknown. For this reason and because raf kinase inhibitor agents used in this trial are known to be teratogenic, women of child-bearing potential and men must agree to use adequate contraception (hormonal or barrier method of birth control; abstinence) prior to study entry, for the duration of study participation, and for at least 2 months following completion of study. Should a woman become pregnant or suspect she is pregnant while participating in this study, she should inform her treating physician immediately. * Ability to understand and the willingness to sign a written informed consent document and the ability to comply with daily oral self administration schedule. * Patients must have systolic blood pressure less than or equal to 150 mm Hg and diastolic blood pressure less than or equal to 90 mmHg. Concomitant antihypertensive medications to achieve control of blood pressure are allowed. EXCLUSION CRITERIA: * Patients who have had chemotherapy, biologic therapy, or radiotherapy within 4 weeks prior to entering the study or those who have not recovered to at least eligibility levels from adverse events due to agents administered more than 4 weeks earlier. Patients must be greater than or equal to 2 weeks since any investigational agent administered as part of a Phase 0 study (also referred to as an early Phase I study or pre-Phase I study where a sub-therapeutic dose of drug is administered) at the PIs (principal investigator's) discretion, and should have recovered to eligibility levels from any toxicities * Patients who have received any other investigational agents within 4 weeks prior to entering the study or those who have not recovered to at least eligibility levels from adverse events due to agents administered more than 4 weeks earlier. * Patients with known brain metastases would be excluded from this clinical trial, with the exception of patients whose brain metastatic disease status remains stable for greater than or equal to 6 months after treatment of the brain metastases without steroids or anti seizure medications. These patients may be enrolled at the discretion of the principal investigator. * History of allergic reactions attributed to compounds of similar chemical or biologic composition to BAY 43-9006 (for example, other multi-targeted kinase inhibitors, such as sunitinib) or cetuximab (for example, other drugs containing murine proteins, such as bevacizumab) used in the study. * Prior therapy with cetuximab or BAY 43-9006. * Patients on therapeutic anticoagulation are excluded. Prophylactic anticoagulation (i.e. low dose warfarin) of venous or arterial access devices is allowed provided that the requirements for PT, INR (International normalized ratio) or PTT are met. * Evidence of bleeding diathesis. * Uncontrolled intercurrent illness including, but not limited to, ongoing or active serious infection, symptomatic congestive heart failure, unstable angina pectoris, uncontrolled cardiac arrhythmia, uncontrolled hypertension, or psychiatric illness/social situations that would limit compliance with study requirements. * Pregnant women are excluded from this study because BAY 43-9006 is a kinase inhibitor agent with the potential for teratogenic or abortifacient effects. Because there is an unknown but potential risk for adverse events in nursing infants secondary to treatment of the mother with BAY 43-9006, breastfeeding should be discontinued if the mother is treated with BAY 43-9006. * Human immunodeficiency virus (HIV)-positive patients receiving anti-retroviral therapy are excluded from this study due to the possibility of pharmacokinetic interactions between anti-retroviral medications and BAY 43-9006. HIV positive patients not receiving antiretroviral therapy are excluded due to the possibility that BAY 43-9006 may worsen their condition and the likelihood that the underlying condition may obscure the attribution of adverse events with respect to BAY 43-9006. * History of another malignancy within the past 5 years, apart from adequately treated non-melanoma skin cancers, superficial bladder cancer or in situ cervical cancer. * Patients with conditions that would impair their ability to swallow tablets are excluded. * Use of the following medications will be not be allowed within 4 weeks prior to enrollment on the study and during the study: ketoconazole, itraconazole, ritonavir, cyclosporine, carbamazepine, phenytoin, phenobarbital, rifampin, St. Johns Wort, and prophylactic use of filgrastim and sargramostim. Products containing grapefruit juice will not be allowed while on study. BAY 43-9006 tosylate is metabolized by the P450 CYP3A enzyme; therefore, it is possible that BAY 43-9006 tosylate may interact with the above medications. Efforts should be made to switch patients who are taking enzyme-inducing anticonvulsant agents to other medications. * Patients in whom resection is indicated and can be performed safely (unless surgery is declined by the patient for other reasons). * For the optional PET/CT imaging with (89)Zr-panitumumab correlative study, participants with severe claustrophobia not relieved by oral anxiolytic medication or patients weighing \> 136 kg (weight limit for scanner table). Inclusion of Women and Minorities: Both men and women and members of all races and ethnic groups are eligible for this trial.