A Phase I, Pharmacological, and Biological Study of OSI-774 in Combination With FOLFOX 4 (5-FU, Leucovorin, and Oxaliplatin) and Bevacizumab (Avastin) in Patients With Advanced Colorectal Cancer

Inclusion Criteria:

* Histologically or cytologically confirmed diagnosis of colorectal adenocarcinoma with metastatic or locally advanced disease not amenable to curative therapy
* The patients may have therapy for advanced disease completed no less than 28 days prior to enrolling on this protocol; chemotherapy in the adjuvant setting may be allowed, but must have been completed at least 120 days prior to enrollment onto this protocol; prior bevacizumab is allowed
* ECOG performance status =\< 1 (Karnofsky \>= 60%)
* Life expectancy of greater than 12 weeks
* Leukocytes \>= 3,000/ul
* Absolute neutrophil count \>= 1,500/ul
* Platelets \>= 100,000/ul
* Total bilirubin =\< 2 mg/dL
* AST(SGOT)/ALT(SGPT) =\< 2.5 X institutional upper limit of normal (=\< 5 X institutional upper limit of normal for patients with liver metastatsis)
* Creatinine =\< 1.5 mg/dL OR creatinine clearance \>= 60 mL/min/1.73 m\^2 for patients with creatinine levels above institutional normal
* In addition, those patients consenting to have a tumor biopsy and enrolling on that portion of the protocol must have:

  * PTT \< 40 seconds
  * PT \< 2 seconds more than ULN
* Patients must have unidimensionally-measurable disease, defined as at least one lesion that can be accurately measured in at least one dimension (longest diameter to be recorded) as \>= 20 mm with conventional techniques or as \>= 10 mm with spiral CT scan
* Ability to understand and the willingness to sign a written informed consent document
* After the MTD has been defined and 10-20 patients have been treated at this dose level, enrollment will be restricted to patients who have tumor lesions amenable to sequential sampling, if less than 10 patients have had this performed
* Patients undergoing tumor biopsies must not be taking any anti-platelet agents or anticoagulants for at least 5 days prior to biopsy; tumor that will be considered for biopsy will include skin lesions, liver metastases, and peripheral lymph nodes (excluding supraclavicular and high cervical nodes), but will not include lung nodules; if a liver biopsy is being performed, the patient's films (CT or MRI) must be reviewed by the radiologist performing the biopsy (Dr Macura), who must feel that a biopsy is safe and carry minimal risk
* No concurrent nephritic syndrome, uncontrolled hypertension, congestive heart failure

Exclusion Criteria:

* Previous oxaliplatin therapy for metastatic disease; (prior adjuvant therapy with oxaliplatin is allowed as long as 120 days have elapsed since the last oxaliplatin treatment)
* Less than 120 days elapsed time between chemotherapy treatment for adjuvant disease and enrollment onto this protocol or less than 28 days between therapy for metastatic disease and enrollment onto this protocol
* Patients with known brain metastases should be excluded from this clinical trial because of their poor prognosis and because they often develop progressive neurologic dysfunction that would confound the evaluation of neurologic and other adverse events
* History of allergic reactions attributed to compounds of similar chemical or biologic composition to OSI-774, oxaliplatin, 5-FU, or leucovorin
* Patients with a significant neuropathy (greater than grade 2) not controlled despite medications
* Prior treatment with EGFR targeting therapies
* Major surgery or significant traumatic injury occurring within 28 days prior to treatment; all surgical wounds must be healed
* Abnormalities of the cornea based on history (e.g., dry eye syndrome, Sjogren's syndrome), congenital abnormality (e.g., Fuch's dystrophy), abnormal slit-lamp examination using a vital dye (e.g., fluorescein, Bengal Rose), and/or an abnormal corneal sensitivity test (Schirmer test or similar tear production test)
* Gastrointestinal tract disease resulting in an inability to take oral medication or a requirement for IV alimentation, prior surgical procedures affecting absorption, or active peptic ulcer disease
* Uncontrolled intercurrent illness including, but not limited to, ongoing or active infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac arrhythmia, or psychiatric illness/social situations that would limit compliance with study requirements
* Pregnant women are excluded from this study because OSI-774 is an epidermal growth factor inhibitor with the potential for teratogenic or abortifacient effects based on the data suggesting that EGFR expression is important for normal organ development; because there is an unknown but potential risk for adverse events in nursing infants secondary to treatment of the mother with OSI-774, breastfeeding should be discontinued if the mother is treated with OSI-774; because patients with immune deficiency are at increased risk of lethal infections when treated with marrow-suppressive therapy, HIV-positive patients receiving combination anti-retroviral therapy are excluded from the study because of possible pharmacokinetic interactions with OSI-774; appropriate studies will be undertaken in patients receiving combination anti-retroviral therapy when indicated
* Patients with only non-measurable disease, defined as all other lesions, including small lesions (longest diameter \< 20 mm with conventional techniques or \<10 mm with spiral CT scan) and truly non-measurable lesions, which include the following:

  * Bone lesions;
  * Leptomeningeal disease;
  * Ascites;
  * Pleural/pericardial effusion;
  * Inflammatory breast disease;
  * Lymphangitis cutis/pulmonis;
  * Abdominal masses that are not confirmed and followed by imaging techniques;
  * Cystic lesions
* Patients without sufficient central venous access for therapy
* Patients with thromboembolic events (MI, TIA, stroke, or angina) occurring within the past 6 months prior to the start of therapy