A Randomized Phase III Study Comparing 5-FU, Leucovorin and Oxaliplatin Versus 5-FU, Leucovorin, Oxaliplatin and Bevacizumab in Patients With Stage II Colon Cancer at High Risk for Recurrence to Determine Prospectively the Prognostic Value of Molecular Markers

Inclusion Criteria:

- Histologically confirmed adenocarcinoma of the colon

- Stage II disease (pT3, pT4a-b, N0, M0)

- At least 8 lymph nodes must have been evaluated

- Meets 1 of the following criteria:

- High risk for microsatellite instability (MSI) and loss of heterozygosity (LOH)
at chromosome 18q

- Microsatellite stable (MSS) with 18q LOH

- MSI-low grade (MSI-L) with 18q LOH

- Low risk for MSI and 18q LOH

- MSS with retention of 18q alleles

- MSI-L with retention of 18q alleles

- MSI-high grade (MSI-H) with retention of 18q alleles

- MSI-H without retention of 18q alleles

- MSI-H with 18q status uninformative

- Distal extent of tumor must be ≥ 12 cm from the anal verge by endoscopy or surgical
examination

- If tumor is located beyond sigmoid colon and centimeter distance is unavailable,
include anatomic region of the colon (e.g., right colon, transverse colon,
hepatic flexure, descending colon, or cecum)

- Has undergone surgical resection of the tumor between the past 28-60 days

- Must have had a complete resection (R0 resection)

- No history of isolated, distant, or noncontiguous intra-abdominal metastases

- Patients with synchronous tumors or appendiceal tumors are ineligible

- Hereditary non-polyposis colorectal cancer allowed

- Paraffin-embedded tumor specimen (one with normal mucosa and one from the resection
tumor) available

- Performance status - ECOG 0-2

- Absolute granulocyte count ≥ 1,500/mm^3*

- Platelet count ≥ 100,000/mm^3*

- No significant bleeding unrelated to tumor within the past 6 months*

- Bilirubin normal (unless due to Gilbert's disease or similar syndrome)*

- Alkaline phosphatase (AP) < 2.5 times upper limit of normal (ULN)*

- AST < 1.5 times ULN*

- PT INR > 1.5* allowed provided the following criteria are met:

- Patient is on full-dose anticoagulants

- INR in range (usually 2-3) on a stable dose of warfarin or low molecular weight
heparin

- No active bleeding or pathological condition associated with a high risk of
bleeding unrelated to primary colon tumor

- No systemic hepatic disease*

- Creatinine ≤ 1.5 times ULN*

- Urine protein:creatinine ratio < 1.0*

- Urine protein < 1 gm on 24-hour urine collection*

- No systemic renal disease*

- History of hypertension allowed provided blood pressure < 150/90 mm Hg while on a
stable regimen of anti-hypertensive therapy*

- No New York Heart Association class III or IV cardiac disease*

- No symptomatic arrhythmia*

- No history of transient ischemic attack*

- No history of cerebrovascular accident*

- No symptomatic peripheral vascular disease*

- No arterial thromboembolic events within the past 12 months*

- No unstable angina within the past 12 months*

- No myocardial infarction within the past 12 months*

- No other systemic cardiovascular disease*

- Not pregnant or nursing*

- Negative pregnancy test*

- Fertile patients must use effective contraception during and for 3 months after
completion of study treatment*

- No active gastroduodenal ulcer by endoscopy*

- No complete obstruction or perforation of the bowel

- No history of inflammatory bowel disease

- No prior or concurrent malignancy except for nonmelanoma skin cancer, carcinoma in
situ of the cervix, breast cancer in situ, treated non-pelvic cancer from which the
patient has been disease-free for > 5 years, or history of breast cancer (without
evidence of disease) and remain on hormonal therapy for > 5 years

- No other nonmalignant systemic disease that would preclude study compliance*

- No psychiatric or addictive disorder or other condition that would preclude study
participation*

- No serious or non-healing wound, skin ulcer, or bone fracture*

- No peripheral neuropathy ≥ grade 2*

- No significant traumatic injury within the past 4 weeks*

- No known allergy to platinum compounds

- No prior radiotherapy for this cancer

- No prior systemic therapy for this cancer

- More than 28 days since prior major surgery or open biopsy*

- More than 7 days since prior core biopsy or other minor procedure except placement of
a vascular access device*