Neoadjuvant Chemoradiation With RHUMAB VEGF (Avastin) for Rectal Cancer
Condition: Rectal Cancer
MeSH terms: Rectal Neoplasms
Intervention: Avastin (Bevacizumab, RHUMAB VEGF); Capecitabine; Radiation Therapy
Intervention description: Starting Dose 5 mg/kg intravenously on day one of radiotherapy, given every 2 weeks +/- 2 days for a total of 3 doses.; 900 mg/m^2 by mouth twice a day during days of radiation for all five weeks of therapy.; 45 Gy in 25 fractions to the pelvis followed by 5.4 Gy as a boost dose to the primary tumor with margin, for a total dose of 50.4 Gy over 28 treatment days.
Intervention MeSH terms: Bevacizumab; Capecitabine
Phase: Phase 2
Study type: Interventional
Primary purpose: Treatment
Allocation: Non-Randomized
Intervention model: Single Group Assignment
Masking: None (Open Label)
Enrollment: 25.0
Sex: All
Minimum age: 18 Years
Healthy volunteers: Accepts Healthy Volunteers
Keywords: Rectal Cancer; Bevacizumab; RHUMAB VEGF; Avastin; Capecitabine; Neoadjuvant Concurrent Capecitabine; Xeloda; Radiation; Radiotherapy; Radiation Therapy; XRT

Summary:

      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 [RHUMAB VEGF, Avastin]
      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. The hypothesis is that the addition of bevacizumab to standard
      chemoradiation will safely lead to increased tumor response in patients with locally advanced
      rectal cancer.
    

Eligibility criteria:

        Inclusion Criteria:

          1. ECOG status of 0 or 1.

          2. Patients must be greater than or equal to 18 years of age.

          3. All patients must have histologically confirmed adenocarcinoma of the rectum with
             pathologic material reviewed by the Department of Pathology at MDACC. The clinical
             stage must be T3, T4, or recurrent based on CT, MRI or EUS criteria.

          4. All patients must have no distant metastatic disease on abdominopelvic CT scan
             performed with IV contrast. If the CT was performed outside of MDACC, the slice
             thickness is 7.5 mm. Criteria for pathologic enlargement of lymph nodes is > 15 mm on
             short axis dimension. If CT findings of lung, liver, or peritoneal metastases are
             equivocal, patients are eligible to participate.

          5. 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.

          6. 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). Note: In
             patients with moderate renal impairment (estimated creatinine clearance 30-50 mL/min)
             at baseline, a dose reduction to 75% of the capecitabine starting dose is recommended.

          7. Hemoglobin of >9 gm/dL (may be transfused or receive Procrit to maintain or exceed
             this level)

          8. Patients must have signed informed consent indicating that they are aware of the
             investigational nature of the study, and are aware that participation is voluntary.

        Exclusion Criteria:

          1. Known compromised renal or hepatic function.

          2. Participation in any other experimental drug study.

          3. 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.

          4. Pregnant or lactating woman. Woman of childbearing potential with either a positive or
             no pregnancy test at baseline. Woman / men of childbearing potential not using a
             reliable contraceptive method. (Postmenopausal woman must have been amenorrheic for at
             least 12 months to be considered of non-childbearing potential). Patients must agree
             to continue contraception for 30 days from the date of the last study drug
             administration.

          5. Any prior chemotherapy.

          6. Any prior radiation therapy.

          7. Serious, uncontrolled, concurrent infection(s) requiring IV antibiotics.

          8. Treatment for other carcinomas within the last five years, except cure non-melanoma
             skin cancer and treated in-situ cervical cancer.

          9. 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 (see Appendix H), 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(see Appendix H).

         10. Inability to to swallow oral medication.

         11. Evidence of bleeding diathesis or coagulopathy, INR greater than or equal to 1.5.

         12. Major surgical procedure, open biopsy, or significant traumatic injury within 28 days
             prior to Day 0, or anticipation of need for major surgical procedure during the course
             of the study; fine needle aspirations or core biopsies within 7 days prior to Day 0.

         13. Proteinuria at baseline or clinically significant impairment of renal function
             Subjects unexpectedly discovered to have 1+ proteinuria at baseline should undergo a
             24-hour urine collection, which must be an adequate collection and must demonstrate
             <500 mg of protein/24 hr to allow participation in the study (see appendix F).

         14. Currently has serious, nonhealing wound, ulcer, or bone fracture.

         15. Had aneurysms, strokes, transient ischemic attacks, and arteriovenous malformations
             within the past year.

         16. Patients who have had an organ allograft.

         17. Patients on Coumadin must be changed to Lovenox at least 1 week prior to starting
             capecitabine. Low dose (1 mg) Coumadin is allowed.

         18. 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 PI to see of another agent may
             substitute for it.