Postoperative Chemotherapy With or Without Bevacizumab for Patients With Stage II or III Rectal Cancer

PRIMARY OBJECTIVES:

I. Compare the overall survival of patients who have undergone prior surgery and neoadjuvant
chemoradiotherapy for clinical stage II or III rectal cancer treated with adjuvant
oxaliplatin, leucovorin calcium, fluorouracil with vs without bevacizumab.

SECONDARY OBJECTIVES:

I. Evaluate tolerance of treatment, patterns of failure, and disease-free survival in
patients treated with these regimens.

II. Assess long-term rectal function using the Patient Bowel Function/Uniscale questionnaire
and the Functional Assessment of Cancer (FACT)-Diarrhea subscale in patients treated with
these regimens.

III. Validate the FACT-Diarrhea subscale.

IV. Assess long-term symptoms of oxaliplatin-related neurotoxicity using the
FACT/Gynecologic Oncology Group (GOG)-Neurotoxicity subscale in patients treated with these
regimens.

V. Correlate TS, DPD and TP expression (key targets for fluorouracil); retention of
chromosome 18q alleles and microsatellite instability (MSI) with TGFβ1RII mutation (markers
for fluorouracil efficacy); ERCC1, ERCC2, and XPF expression (participants in repair of
adducts from oxaliplatin); and p53 gene mutation and possibly other molecular markers
pertinent to vascular endothelial growth factor in tumor tissue specimens with treatment
efficacy in these patients.

VI. Correlate tumor molecular prognostic markers (chromosome 18q allelic loss and MSI) with
survival in patients treated with this regimen.

OUTLINE:

This is a randomized study. Patients are stratified according to Eastern Cooperative
Oncology Group (ECOG) performance status (0 vs 1), clinical staging (high risk [T3, N+, M0
or T4, any N, M0] vs low risk [T1-2, N+, M0 or T3, N0, M0]), prior pre-operative oxaliplatin
(yes vs no), and prior radiotherapy dose (40-50 Gy vs > 50-55.8 Gy). Patients are randomized
to 1 of 2 treatment arms in a 1:1 ratio.

ARM I: Patients receive oxaliplatin intravenously (IV) over 2 hours, leucovorin calcium IV
over 2 hours, and fluorouracil IV on day 1 followed by fluorouracil IV continuously over 46
hours on days 1 and 2. Treatment repeats every 2 weeks for up to 12 courses* in the absence
of disease progression or unacceptable toxicity.

ARM II: Patients receive bevacizumab** IV over 30-90 minutes on day 1. Patients also receive
oxaliplatin, leucovorin calcium, and fluorouracil as in arm I*.

[Note: *Patients who received prior neoadjuvant oxaliplatin including patients on protocol
NSABP-R-04 receive up to 9 courses of treatment followed by leucovorin calcium IV and
fluorouracil IV with (arm II) or without (arm I) bevacizumab for up to 3 courses.]

[Note: **Patients no longer receive bevacizumab as of 4/29/2009 when accrual was terminated
due to slow accrual for the study)]

Patients complete 10-15 minute questionnaires about bowel function at randomization, end of
treatment, 12 months post-treatment and then annually to 5 years post-treatment.

After completion of study treatment, patients are followed periodically for approximately 10
years.

PROJECTED ACCRUAL: 2100 patients

Inclusion Criteria:

- Histologically confirmed adenocarcinoma of the rectum meeting 1 of the following
clinical (e.g., before neoadjuvant therapy) or pathologic staging criteria:

- T3, N+, M0

- T3, N0, M0

- T4, N0, M0

- Any T, N1-2, M0

- T4, N0-2, M0 disease must meet 1 of the following criteria:

- Clinically fixed tumor on rectal examination with tumor adherent to the pelvic
sidewall or sacrum

- Hydronephrosis on Computed Tomography (CT) scan or Intravenous Pyelogram (IVP)

- Ureteric or bladder invasion as documented by cystoscopy and cytology or biopsy

- Invasion into prostate

- Vaginal or uterine involvement

- Must have undergone complete tumor resection >= 28 days ago and able to begin
treatment by day 56

- Must have undergone concurrent neoadjuvant chemoradiotherapy*

- NOTE: *Neoadjuvant chemoradiotherapy received on protocol NSABP-R-04 allowed
provided it met these criteria

- Must have undergone prior radiotherapy at 40-55.8 Gy** AND received 1 of the
following chemotherapy regimens:

- Continuous infusion of fluorouracil with or without oxaliplatin; fluorouracil
and leucovorin calcium

- Capecitabine with or without oxaliplatin; capecitabine with or without
oxaliplatin OR a continuous infusion of fluorouracil with or without oxaliplatin
received on protocol NSABP-R-04

- NOTE: **Intensity-modulated radiotherapy allowed

- ECOG performance status 0-1

- Platelet count >= 100,000/mm^3

- Absolute granulocyte count >= 1,500/mm^3

- Bilirubin normal (unless chronic grade 1 bilirubin elevation due to Gilbert's disease
or similar syndrome due to slow conjugation of bilirubin)

- Alkaline phosphatase (AP) < 2.5 times upper limit of normal (ULN) and aspartate
aminotransferase (AST) < 1.5 times ULN

- Hepatitis B and C negative (for patients with AP > normal) unless previously
vaccinated

- Serum creatinine =< 1.5 times ULN

- Urine protein:creatinine (UPC) ratio < 1.0 OR urine protein < 1 g on 24-hour urine
collection

- International Normalized Ratio (INR) =< 1.5

- INR > 1.5 allowed provided patient is on full-dose anticoagulants AND meets all of
the following criteria:

- In-range INR (i.e., between 2 and 3) on a stable dose of warfarin or low
molecular weight heparin

- No active bleeding or pathological condition that is associated with a high risk
of bleeding

- Negative pregnancy test

- Fertile patients must use effective contraception during and for at least 3 months
after study treatment

- No other previous or concurrent malignancy except nonmelanoma skin cancer, breast
cancer in situ, carcinoma in situ of the cervix, or previously treated nonpelvic
cancer that has been disease-free for > 5 years

- Patients with a history of breast cancer (without evidence of disease) who remain on
hormonal therapy for > 5 years are eligible

- Patients with a history of hypertension must have blood pressure < 150/90 mm Hg AND
be on a stable regimen of antihypertensive therapy

- No other prior chemotherapy or pelvic radiotherapy except as neoadjuvant treatment
for current diagnosis of rectal cancer

- Concurrent participation on protocol NSABP-R-04 allowed

Exclusion Criteria:

- Pregnant or nursing

- Evidence of metastatic disease on the surgical/intraoperative examination

- Evidence of metastatic disease confirmed by CT scan, Magnetic resonance imaging
(MRI), or ultrasound of the liver or chest CT scan or chest x-ray within the past 6
months

- Evidence of tumor outside of the pelvis, including liver metastases, peritoneal
seeding, or metastatic inguinal lymphadenopathy

- Concurrent major surgery

- Active bleeding not related to the primary rectal tumor within the past 6 months

- Active inflammatory bowel disease or other serious medical illness which might limit
the ability of the patient to receive protocol therapy

- Active gastroduodenal ulcer determined by endoscopy

- Serious or nonhealing wound, skin ulcer, or bone fracture

- Clinically significant peripheral sensory or motor neuropathy >= grade 2

- Nonmalignant systemic disease (e.g., cardiovascular, renal, or hepatic) that would
preclude study treatment including, but not limited to, any of the following:

- New York Heart Association class III or IV congestive heart failure

- Concurrent symptomatic arrhythmia

- Transient ischemic attack or cerebrovascular accident

- Arterial thromboembolic event, unstable angina, or myocardial infarction within the
past 12 months

- Significant peripheral vascular disease

- Psychiatric or addictive disorders or other conditions that, in the opinion of the
investigator, would preclude study requirements

- Significant traumatic injury within the past 28 days

- Known allergy to platinum compounds

- Prior invasive procedure, including either of the following:

- Major surgical procedure or open biopsy within the past 28 days

- Core biopsy or other minor procedure, except placement of a vascular access
device, within the past 7 days