Title: ECOG E5202 - A Randomized Phase III Study Comparing 5-FU, Leucovorin and Oxaliplatin versus 5-FU, Leucovorin, Oxaliplatin and Bevacizumab in Patients with Stage II Colon Cancer at High Risk for Recurrence to Determine Prospectively the Prognostic Value of Molecular Markers
Principal Investigator: Carla I. Falkson, M.D.
Sponsor: National Cancer Institute (NCI), Genentech, Sanofi-Aventis
OBJECTIVES
1. To demonstrate an improvement in 3-year disease-free survival for high-risk Stage II colon cancer patients randomly assigned to 5-FU, Leucovorin, Oxaliplatin versus 5-FU, Leucovorin, Oxaliplatin and bevacizumab.
2. To compare overall survival between the regimens.
3. To further define the toxicity profiles of the regimens.
4. To prospectively determine the impact of tumor biological characteristics on the survival of patients with Stage II colon cancer.
PATIENT SELECTION
Initial Registration
1. The distal extent of the tumor must be ≥ 12cm from the anal verge on endoscopy. If the patient is not a candidate for endoscopy, then the distal extent of the tumor must be ≥ 12cm from the anal verge as determined by surgical examination.
2. Patients must have paraffin-embedded tumor specimen available for evaluation of microsatellite instability and loss of heterozygosity at 18q to determine high risk versus low risk. High risk patients will be randomized to Treatment Arm A or B. Low risk patients will be registered to Arm C for observation.
3. Patients must have no history of isolated, distant, or non-contiguous intra-abdominal metastases, even if restricted.
4. Patients must have histologically confirmed adenocarcinoma of the colon that meets the criteria below:
a. Stage II Carcinoma (T3,4 N0 M0): The tumor invades through the muscularis propria into the subserosa or into non-peritonealized pericolic or perirectal tissues (T3) or directly invades other organs or structures and/or perforates visceral peritoneum (T4).
5. Patients must have ≥ 8 lymph nodes evaluated and reported.
6. Patients must not have presented with obstruction or perforation of the bowel.
7. Patients must not have had any systemic or radiation therapy initiated for this malignancy.
8. Patients with prior malignancies, including colorectal cancers, are eligible if they have been disease-free for ≥ 5 years and are deemed by their physician to be at low risk for recurrence. Patients with squamous or basal cell carcinoma of the skin, melanoma in situ, carcinoma in situ of the cervix. Or carcinoma in situ of the colon or rectum that have been effectively treated are eligible, even if these conditions were diagnosed within 5 years prior to randomization.
9. Patients must be ≥ 18 years old.
10. Patients must have ECOG Performance Status of 0-2.
Randomization (High Risk Patients - Arm A and B Only)
1. Within 2 weeks prior to randomization, postoperative absolute granulocyte count (AGC) must be ≥ 1500/mm3 (or < 1500/mm3 if, in the opinion of the investigator, this represents an ethnic or racial variation of normal).
2. Within 2 weeks prior to randomization, the postoperative platelet count must be ≥ 100,000/mm3.
3. Within 2 weeks prior to randomization, there must be postoperative evidence of adequate hepatic function.
a. Bilirubin must be ≤ ULN unless the patient has a chronic Grade 1 bilirubin elevation due to Gilbert's disease or similar syndrome due to slow conjugation or bilirubin.
b. Alkaline phosphatase must be < 2.5 x ULN
d. AST must be < 1.5 x ULN
e. If alkaline phosphatase or AST is > ULN, serologic testing for Hepatitis B and C must be obtained and results must be negative
4. Within 2 weeks prior to randomization, there must be postoperative evidence of adequate renal function.
a. Serum creatinine ≤ 1.5 x ULN
b. Urine protein/creatinine (UPC) ratio of < 1.0. Patients with a UPS ratio ³ 1.0 must undergo a 24-hour urine collection, which must be an adequate collection and must demonstrate < 1gm of protein in order to participate.
5. Patients with any significant bleeding that is not related to the primary colon tumor within 6 months prior to study entry are not eligible.
6. Patients with gastroduodenal ulcer(s) determined to be active by endoscopy are not eligible.
7. Patients with a history of hypertension must measure < 150/90 mmHg and be on a stable regimen of anti-hypertensive therapy.
8. Patients must not have a serious or non-healing wound, skin ulcers or bone fracture.
9. Patients receiving concomitant halogenated antiviral agents are not eligible.
10. Patients experiencing clinically significant peripheral neuropathy at the time of Step 2 randomization are not eligible.
11. Patients must not have had invasive procedures, defined below:
a. Major surgical procedure, open biopsy or significant traumatic injury within 28 days prior to randomization.
b. Core biopsy or other minor procedure, excluding placement of a vascular access device within 7 days prior to randomization.
12. Patients must begin adjuvant treatment no less than 28 days and no more than 60 days from surgery.
13. Eligible patients of reproductive potential (both sexes) must agree to use an accepted and effective method of contraception during study therapy and for at least 3 months after the completion of bevacizumab.
Women must not be pregnant or breastfeeding because the study drugs administered may cause harm to an unborn fetus or breastfeeding child. All females of child-bearing potential must have a serum pregnancy test to rule out pregnancy within 2 weeks prior to Step 2 randomization.
14. Patients with PT (INR) > 1.5 are not eligible unless the patient is on full dose anti-coagulants. If so, the following criteria must be met for enrollment:
a. The subject must have an in-range INR (usually between 2 and 3) on a stable dose of warfarin or on a stable dose of low molecular weight heparin.
b. The subject must not have active bleeding or a pathological condition that is associated with a high risk of bleeding.
15. Patients with non-malignant systemic disease (cardiovascular, renal, hepatic, etc.) that would preclude any of the study drugs are not eligible. Specifically excluded are the following conditions:
a. Class III or IV Cardiac Disease
b. Current Symptomatic Arrhythmia
c. Any non-malignant systemic disease
16. Patients with a history of transient ischemic attack (TIA) or cerebrovascular accident (CVA) are not eligible.
17. Patients with a history of the following within twelve months of study entry are not eligible:
a. Arterial thromboembolic events
b. Unstable Angina
c. Myocardial Infarction
18. Patients with symptomatic peripheral vascular disease are not eligible.
19. Patients with psychiatric or addictive disorders or other conditions that, in the opinion of the investigator, would preclude them from meeting the study requirements are not eligible.
Registration (Low-Risk Patients - Arm C)
1. Patients determined to be low risk are eligible.
ADDITIONAL INFORMATION
Contact: Robyn Wilson, RN
Telephone: 205-975-6347
Email: robyn.wilson@ccc.uab.edu