Bevacizumab, Radiation Therapy, and Combination Chemotherapy in Treating Patients Who Are Undergoing Surgery for Locally Advanced Nonmetastatic Rectal Cancer

PRIMARY OBJECTIVES:

I. To evaluate the pathological complete response rate in patients with T3 and T4 rectal
cancers when treated preoperatively with capecitabine, oxaliplatin, bevacizumab, and
concurrent radiotherapy (XRT).

II. To evaluate the resection rate for T3 and T4 rectal cancers and the expected versus
actual type of resection (abdominoperinal resection [APR] vs. low anterior resection [LAR]
vs. LAR/coloanal anastomosis).

III. To make preliminary observations of patient survival and patterns of recurrence for this
treatment combination.

IV. To gain additional experience regarding the toxicity and tolerability of this
preoperative and postoperative regimen.

OUTLINE:

PREOPERATIVE CHEMORADIOTHERAPY: Patients undergo radiotherapy (total dose to the tumor bed
was 5040 cGy) once daily (QD) 5 days a week and receive capecitabine 825 mg/m^2 orally (PO)
twice daily (BID) 5 days a week for 5.5 weeks. Patients also receive oxaliplatin 50 mg/m^2
intravenously (IV) over 2 hours on days 1, 8, 15, 22, and 29 and bevacizumab 5 mg/kg IV over
30-90 minutes on days 1, 15, and 29 during radiotherapy.

SURGERY: Approximately 6-8 weeks after completion of chemoradiotherapy, patients undergo
surgical resection. Patients whose tumors are not completely resected or who have metastatic
disease discontinue protocol therapy.

POSTOPERATIVE CHEMOTHERAPY: Approximately 4-12 weeks after surgery, patients receive
oxaliplatin IV over 2 hours, leucovorin calcium 400 mg/m^2 IV over 2 hours, and bevacizumab 5
mg/kg IV over 30-90 minutes on day 1. Patients also receive fluorouracil 2400 mg/m^2 IV
continuously over 46 hours beginning on day 1. Treatment repeats every 2 weeks for 9 courses
in the absence of disease progression or unacceptable toxicity. Patients then receive up to 3
additional courses of leucovorin calcium, fluorouracil, and bevacizumab.

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

Inclusion Criteria:

- Patients must have histologically confirmed, locally advanced, non-metastatic primary
T3 or T4 adenocarcinoma of the rectum

- Patients must not have evidence of tumor outside of the pelvis including liver
metastases, peritoneal seeding, or metastatic inguinal lymphadenopathy

- Patients must not have intra-operative radiotherapy (IORT) or brachytherapy treatment
to the pelvis

- The distal border of the tumor must be at or below the peritoneal reflection, defined
as within 12 centimeters of the anal verge by proctoscopic examination

- Transmural penetration of tumor through the muscularis propria must be demonstrated by
either of the following: computed tomography (CT) scan plus endorectal ultrasound, or
a magnetic resonance imaging (MRI); an endorectal coil or pelvic MRI is allowed

- For the patient to be eligible, the surgeon must prospectively define the tumor as
either initially resectable or potentially resectable after pre-operative
chemoradiation; clinically resectable tumors are defined as completely resectable with
negative margins based on routine examination of the non-anesthetized patient;
patients whose tumors are not resectable are not eligible; before pre-operative (op)
treatment, the surgeon should estimate and record the type of resection anticipated:
pelvic exenteration, posterior pelvic exenteration, APR, LAR, or LAR/coloanal
anastomosis

- Patients with tumors that are clinically fixed, clinical stage T4N0-2, M0 are eligible
if it is believed that their tumors are potentially resectable after chemoradiation;
based on the following:

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

- Sciatica attributed to sacral root invasion with CT scan/MRI evidence of the lack
of clear tissue plane will be considered evidence of fixation

- Hydronephrosis on CT scan or intravenous pyelogram (IVP) or ureteric or bladder
invasion as documented by cystoscopy and cytology or biopsy, or invasion into
prostate

- Vaginal or uterine involvement

- Patients must have Eastern Cooperative Oncology Group (ECOG) performance status 0-1

- A surgical evaluation must confirm patient's ability to tolerate the proposed surgical
procedure

- Patients must have a caloric intake > 1500 kilocalories/day (d)

- Within 4 weeks prior to registration, the patient's absolute neutrophil count (ANC)
level must be >= 1,500/mm^3

- Within 4 weeks prior to registration, the patients platelet level must be >=
100,000/mm^3

- Within 4 weeks prior to registration, serum creatinine must be < 1.5 X upper limit of
normal (ULN); if serum creatinine > 1.5 x ULN, then creatinine clearance must be >= 50
mL/mm

- Within 4 weeks prior to registration, serum bilirubin must be =< 1.5 X ULN

- Within 4 weeks prior to registration, alkaline phosphatase (alk phos) must be < 2 x
ULN

- Within 4 weeks prior to registration, serum glutamic oxaloacetic transaminase (SGOT)
must be < 2 x ULN

- Carcinoembryonic antigen (CEA) must be determined prior to initiation of therapy

- Within 4 weeks prior to registration, urine protein/creatinine (UPC) ratio must be <
1; patients with a ratio of >= 1 must undergo a 24-hour urine collection which must be
an adequate collection and must demonstrate < 1 gram (gm) of protein in order to
participate

- Within 4 weeks prior to registration, albumin must be >= 2 gm/dl

- Absence of clinical evidence of high-grade (lumen diameter < 1 cm) large bowel
obstruction, unless diverting colostomy has been performed

- Eligible patients of reproductive potential (both sexes) must agree to use an accepted
and effective method of contraceptive during study therapy and for at least 6 months
after the completion of bevacizumab

- Women must not be pregnant or breast-feeding; all females of childbearing potential
must have a serum pregnancy test to rule out pregnancy within 2 weeks of registration

- Patients must have had no prior chemotherapy for rectal cancer or pelvic irradiation
therapy

- Patients with prior malignancies, including pelvic cancer, are eligible if they have
been disease free for > 5 years; patients with prior in situ carcinomas are eligible
provided there was complete removal

- Patients must have no active inflammatory bowel disease or other serious medical
illness or disease that might limit the patient's ability to receive protocol therapy

- Patients with a history of cerebrovascular accident (CVA)/transient ischemic attack
(TIA) at any time, or myocardial infarction/unstable angina within 12 months of study
entry are not eligible

- Patients with > grade 1 peripheral neuropathy are not eligible

- Patients must have urine protein/creatinine (UPC) ratio of < 1.0; patients with a UPC
ratio >= 1.0 must undergo a 24-hour urine collection, which must be an adequate
collection and must demonstrate < 1 gm of protein in order to participate

- Patients with a history of hypertension must measure < 150/90 mmHg and be on a stable
regimen of anti-hypertensive therapy

- Patients with clinically significant peripheral vascular disease are not eligible

- Patients must not have any of the following:

- Unstable angina (within 12 months of study entry)

- New York Heart Association (NYHA) grade II or higher congestive heart failure

- Evidence of bleeding diathesis/coagulopathy

- Serious non-healing wound or bone fracture

- Patients with a history of the following within 28 days prior to registration are not
eligible:

- Abdominal fistula

- Gastrointestinal perforation

- Intrabdominal abscess

- Patients with a history of the following within 28 days prior to day 0 (first
treatment day) are not eligible:

- Major surgical procedure

- Open biopsy

- Significant traumatic injury

- Patients must not have core biopsy within 7 days prior to day 0 (first treatment day)

- Patients with prothrombin time (PT) (international normalized ratio [INR]) > 1.5 are
not eligible, unless the patient is on full-dose anticoagulants; if so, the following
criteria must be met for enrollment:

- The subject must have an in-range INR (usually between 2 and 3), be on a stable
dose of warfarin or on a stable dose of low molecular weight heparin

- The subject must not have active bleeding or a pathological condition that is
associated with a high risk of bleeding