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Phase II Study of Preoperative Radiation With Concurrent Capecitabine, Oxaliplatin and Bevacizumab Followed by Surgery and Postoperative 5-FU, Leucovorin, Oxaliplatin (FOLFOX) and Bevacizumab in Patients With Locally Advanced Rectal Cancer

Phase 2
18 Years
Open (Enrolling)
Adenocarcinoma of the Rectum, Stage II Rectal Cancer, Stage III Rectal Cancer

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Trial Information

Phase II Study of Preoperative Radiation With Concurrent Capecitabine, Oxaliplatin and Bevacizumab Followed by Surgery and Postoperative 5-FU, Leucovorin, Oxaliplatin (FOLFOX) and Bevacizumab in Patients With Locally Advanced Rectal Cancer


I. Evaluate the pathological complete response rate in patients with T3 or T4 rectal cancer
treated with neoadjuvant bevacizumab in combination with radiotherapy, capecitabine, and
oxaliplatin followed by surgical resection and adjuvant bevacizumab in combination with
fluorouracil, leucovorin calcium, and oxaliplatin.


I. Evaluate the resection rate for T3 and T4 rectal cancers. II. Evaluate the expected
versus actual type of resection (abdominoperineal resection [APR] vs low anterior resection
[LAR] vs LAR/coloanal anastomosis) performed on these patients.

III. Determine, preliminarily, survival and patterns of recurrence in patients treated with
this regimen.

IV. Determine the toxicity and tolerability of this preoperative and postoperative regimen.

OUTLINE: This is a multicenter study. Patients are stratified according to primary tumor
size (T3 vs T4).

PREOPERATIVE CHEMORADIOTHERAPY: Patients undergo radiotherapy once daily 5 days a week and
receive oral capecitabine twice daily 5 days a week for 5.5 weeks. Patients also receive
oxaliplatin IV over 2 hours on days 1, 8, 15, 22, and 29 and bevacizumab 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 4-8 weeks after surgery, patients receive
oxaliplatin IV over 2 hours, leucovorin calcium IV over 2 hours, and bevacizumab IV over
30-90 minutes on day 1. Patients also receive fluorouracil (5-FU) 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, 5-FU, and bevacizumab.

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

Inclusion Criteria:

- Histologically confirmed adenocarcinoma of the rectum

- Locally advanced disease

- Must have primary T3 or T4 tumor

- Transmural penetration of tumor through the muscularis propria by CT scan plus
endorectal ultrasound or MRI

- An endorectal coil or pelvic MRI is allowed

- Distal border of the tumor must be at or below the peritoneal reflection,
defined as within12 cm of the anal verge by proctoscopic examination

- Tumors that are clinically fixed, clinical stage T4, N0-2, M0 are eligible if it
is believed that the tumors are potentially resectable after chemoradiotherapy,
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

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

- Vaginal or uterine involvement

- Nonmetastatic disease

- No evidence of tumor outside of the pelvis

- No liver metastases

- No peritoneal seeding

- No metastatic inguinal lymphadenopathy

- Resectable disease, defined as completely resectable disease with negative margins
based on routine examination of the non-anesthetized patient

- A surgeon must prospectively define the tumor as either initially resectable or
potentially resectable after preoperative chemoradiotherapy

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

- Carcinoembryonic antigen must be determined prior to initiation of therapy

- ECOG performance status 0-1

- Absolute neutrophil count ≥ 1,500/mm³

- Platelet count ≥ 100,000/mm³

- Creatinine clearance ≥ 50 mL/min

- Creatinine ≤ 1.5 times upper limit of normal (ULN)

- Bilirubin ≤ 1.5 times ULN

- Alkaline phosphatase < 2 times ULN

- SGOT < 2 times ULN

- Urine protein: creatinine ratio < 1

- Patients with a urine protein: creatinine ratio of ≥ 1 must demonstrate < 1 gm
of protein by 24-hour urine collection

- INR ≤ 1.5 unless patient is on full-dose anticoagulants and the following criteria is

- In range INR (usually between 2 and 3)

- On a stable dose of warfarin or on a stable dose of low molecular weight heparin

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

- Caloric intake > 1,500 kilocalories/day

- Albumin > 2 gm/dL

- No known dihydropyrimidine dehydrogenase deficiency

- Not pregnant or nursing

- Negative pregnancy test

- Fertile patients must use effective contraception during and for 6 months after
discontinuing bevacizumab

- No clinical evidence of high-grade (lumen diameter < 1 cm) large bowel obstruction,
unless diverting colostomy has been performed

- No active inflammatory bowel disease

- No history of cerebrovascular accident/transient ischemic attack

- No myocardial infarction or unstable angina within the past 12 months

- No peripheral neuropathy > grade 1

- No clinically significant peripheral vascular disease

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

- No New York Heart Association class II-IV congestive heart failure

- No evidence of bleeding diathesis/coagulopathy

- No serious nonhealing wound or bone fracture

- No abdominal fistula, gastrointestinal perforation, or intra-abdominal abscess within
the past 28 days

- No significant traumatic injury within the past 28 days

- No other malignancy within the past 5 years except for in situ carcinomas that were
completely removed

- No known allergy to study drugs

- No other serious medical illness or disease that might limit the patient's ability to
receive protocol therapy

- At least 28 days since prior major surgical procedure or open biopsy

- At least 7 days since prior core biopsy

- No prior chemotherapy for rectal cancer

- No prior pelvic irradiation

- No prior intra-operative radiotherapy (IORT) or brachytherapy treatment to the pelvis

- No concurrent intensity-modulated radiotherapy

- No concurrent full-dose anticoagulants

Type of Study:


Study Design:

Endpoint Classification: Efficacy Study, Intervention Model: Single Group Assignment, Masking: Open Label, Primary Purpose: Treatment

Outcome Measure:

Pathological complete response rate

Outcome Description:

A two-stage design will be used and 90% confidence intervals will be provided.

Outcome Time Frame:

Up to 10 years

Safety Issue:


Principal Investigator

Jerome Landry

Investigator Role:

Principal Investigator

Investigator Affiliation:

Eastern Cooperative Oncology Group


United States: Food and Drug Administration

Study ID:




Start Date:

July 2006

Completion Date:

Related Keywords:

  • Adenocarcinoma of the Rectum
  • Stage II Rectal Cancer
  • Stage III Rectal Cancer
  • Adenocarcinoma
  • Adenocarcinoma, Mucinous
  • Rectal Neoplasms



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