Preoperative chemoradiation leads to increased pelvic control and overall survival, but both distant and local disease control remain problematic in locally advanced rectal cancer patients. Enhancing the effect of chemotherapy and radiotherapy can increase tumor response as well as distant disease control. Patients who have complete response to therapy have increased sphincter preservation, and can possibly have more limited surgery (full thickness local excision). When combined with standard chemotherapy, bevacizumab has been shown to improve response and median survival in patients with metastatic colorectal cancer in a recent randomized trial, has led to increased activity in preclinical studies with radiotherapy, and has been found to be very well tolerated with chemoradiation in a phase I trial conducted at the M.D. Anderson Cancer Center (MDACC) in patients with locally advanced pancreatic cancer. Our hypothesis is that the addition of bevacizumab to standard chemoradiation will safely lead to increased tumor response in patients with locally advanced rectal cancer.

Condition	Treatment or Intervention	Phase
Rectal Cancer	Drug: Bevacizumab, Capecitabine, Radiation	Phase II

Further Study Details: 

Primary Outcomes: The primary endpoint is pathologic local tumor response. The expected pathologic complete response rate with capecitabine and radiotherapy is 22%. A clinically meaningful increase in pathologic complete response would be from 22% to 40%.
Secondary Outcomes: The trial will be terminated early if there is evidence that the Grade 4/5 toxicity rate is greater than 0.076.
Expected Total Enrollment:  50

RhuMAb VEGF (bevacizumab) will be administered intravenously every 2 weeks +/- 2 days at 5 mg/kg. The first dose will be given on day one of radiotherapy. A total of 3 doses will be given. Radiotherapy will be given for a total dose of 50.4 Gy over 28 treatment days. All patients will receive 45 Gy in 25 fractions to the pelvis followed by 5.4 Gy as a boost dose to the primary tumor with margin. Concurrent capecitabine will be given at 900 mg/m2 by mouth (PO) twice a day (BID) during days of radiation for all five weeks of therapy. Weekly dose adjustment of capecitabine will be made as needed. Surgical resection will take place 5-8 weeks after the end of chemoradiation therapy. Follow-up thereafter (every [Q] 3-4 months x 2 years, then Q 6 months for 3 years).

Ages Eligible for Study:  18 Years and above,  Genders Eligible for Study:  Both

Accepts Healthy Volunteers

Criteria

Inclusion Criteria:

• ECOG status of 0 or 1.
• Patients must be greater than or equal to 18 years of age.
• All patients must have histologically confirmed adenocarcinoma of the rectum. The clinical stage must be T3, T4, or recurrent based on computed tomography (CT), magnetic resonance imaging (MRI), or endoscopic ultrasound (EUS) criteria.
• All patients must have no distant metastatic disease on abdominopelvic CT scan performed with intravenous (IV) contrast.
• The rectal tumor must be either palpable on digital rectal exam or the inferior edge of the tumor must be within 12 cm of the anal verge based on rigid proctoscopy.
• Patients must have WBC > 4000 cells/mm3, ANC of >1500/L, platelets > 100,000/mm3, total serum bilirubin < 2.0 mg%, BUN < 30 mg%, creatinine < 1.5 mg% and/or creatinine clearance >30ml/min (estimated as calculated with Cockcroft-Gault equation).
• Hemoglobin of >9 gm/dL (may be transfused or receive Procrit to maintain or exceed this level)
• Patients must have signed informed consent.

Exclusion Criteria:

• Known compromised renal or hepatic function.
• Participation in any other experimental drug study.
• AST or ALT >5 times upper limit of normal for subjects with documented liver metastases; >2.5 times the upper limit of normal for subjects without evidence of liver metastases.
• Pregnant or lactating woman. Patients must agree to continue contraception for 30 days from the date of the last study drug administration.
• Any prior chemotherapy.
• Any prior radiation therapy.
• Serious, uncontrolled, concurrent infection(s) requiring IV antibiotics.
• Treatment for other carcinomas within the last five years, except cured non-melanoma skin cancer and treated in-situ cervical cancer.
• Clinically significant cardiac disease (e.g., uncontrolled hypertension [blood pressure of >160/110 mmHg on medication], any history of myocardial infarction, unstable angina), New York Heart Association (NYHA) Grade II or greater congestive heart failure, unstable symptomatic arrhythmia requiring medication (subjects with chronic atrial arrhythmia, i.e., atrial fibrillation or paroxysmal supraventricular tachycardia are eligible), or grade II or greater peripheral vascular disease
• Inability to to swallow oral medication.
• Evidence of bleeding diathesis or coagulopathy, INR greater than or equal to 1.5.
• Major surgical procedure, open biopsy, or significant traumatic injury within 28 days.
• Proteinuria at baseline.
• Currently has serious, nonhealing wound, ulcer, or bone fracture.
• Had aneurysms, strokes, transient ischemic attacks, and arteriovenous malformations within the past year.
• Patients who have had an organ allograft.
• Patients on Coumadin must be changed to Lovenox at least 1 week prior to starting capecitabine. Low dose (1 mg) Coumadin is allowed.
• Patients taking Sorivudine or Brivudine A must be off of these drugs for 4 weeks. Patients taking cimetidine must have this drug discontinued. Ranitidine or a drug from another anti-ulcer class can be substituted for cimetidine if necessary. If patient is currently receiving allopurinol, must discuss with the principal investigator (PI) to see if another agent may be substituted for it.

Please refer to this study by ClinicalTrials.gov identifier  NCT00113230

Christina Briggs, RN      713-792-3433  Ext. 2-3433    cbamos@mdanderson.org
SheaLynn M Foley, RN      713-745-0194  Ext. 5-0194    smfoley@mdanderson.org

Texas
      UT M. D. Anderson Cancer Center, Houston,  Texas,  77030,  United States; Recruiting

Study ID Numbers:  2003-0832
Record last reviewed:  June 2005
Last Updated:  June 6, 2005
Record first received:  June 6, 2005
ClinicalTrials.gov Identifier:  NCT00113230
Health Authority: United States: Food and Drug Administration
ClinicalTrials.gov processed this record on 2005-06-07