A Randomized Phase III Trial of Oxaliplatin (OXAL) Plus 5-Fluorouracil (5-FU)/Leucovorin (CF) With or Without Cetuximab (C225) After Curative Resection for Patients With Stage III Colon Cancer
试验速览
- 阶段
- 3 期
- 状态
- 已完成
- 入组人数
- 3,397
- 试验地点
- 1,764
- 主要终点
- Disease-free Survival (Arms A and D: Wild-type KRAS Patients)
研究概览
简要总结
This randomized phase III trial was originally designed to compare three different combination chemotherapy regimens to see how well they work. As of September 1, 2004, the study was expanded to a total of 6 arms (the original 3 arms (A, B, C) and 3 additional arms which were the same as the first 3 but with cetuximab) in treating patients who have undergone surgery for stage III colon cancer. Drugs used in chemotherapy, such as irinotecan hydrochloride, fluorouracil, leucovorin calcium, and oxaliplatin, work in different ways to stop tumor cells from dividing so they stop growing or die. Monoclonal antibodies such as cetuximab can locate tumor cells and either kill them or deliver tumor-killing substances to them without harming normal cells. Combining more than one chemotherapy drug with monoclonal antibody therapy and giving them after surgery may kill any remaining tumor cells. It was not known at the time this study was developed which combination chemotherapy regimen is more effective after surgery in treating colon cancer. This study had several key changes, based on the results of other phase III trials. As of 6/1/2005, patients no longer received irinotecan on this study and treatment arms B, C, E, and F were discontinued. Patients on arms B and C crossed to arm A. Patients on arms E and F crossed to arm D. Patients on arms C and F who had not gotten to irinotecan continued on arms A and D, respectively. As of 8/18/2008, pre-screening for Kirsten rat sarcoma (KRAS) status was added with mutant KRAS (or KRAS not evaluable) patients put on arm G and wild-type KRAS patients randomized between arm A and arm D. Patients on arm G were treated per physician discretion and followed for disease and survival status. KRAS was determined in a central laboratory and was process for all patients on this study. The primary endpoint of this study was modified on 8/18/2008 to focus on patients having wild-type KRAS tumors. All modifications were approved by the Central Institution Review Board, local Institutional Review Boards, NCI, and the NCCTG Data Safety Monitoring Board.
详细描述
PRIMARY OBJECTIVES:
I. Disease-free Survival (Arms A and D: Wild-type KRAS Patients)
SECONDARY OBJECTIVES:
I. Disease-free Survival (Arms A and D: Mutant KRAS Patients) II. Disease-free Survival III. Overall Survival IV. Toxicity
OUTLINE: This is a randomized, multicenter study. Patients are stratified according to positive lymph node involvement (1-3 vs 4 or more), histology (high [poorly differentiated or undifferentiated] vs low [well to moderately differentiated]), and clinical T stage (T1 or T2 vs T3 vs T4). Patients are randomized to 1 of 6 treatment arms (as of 6/1/2005, patients are randomized to treatment arms I and IV only; arms II, III, V, and VI are closed to accrual). As of 8/18/2008, pre-screening for KRAS status was added with mutant KRAS (or KRAS not evaluable) patients put on arm G and wild-type KRAS patients randomized between arm A and arm D.
研究设计
- 研究类型
- Interventional
- 分配方式
- Randomized
- 干预模型
- Parallel
- 主要目的
- Treatment
- 盲法
- None
入排标准
- 年龄范围
- 18 Years 至 99 Years（Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •Histologically confirmed adenocarcinoma of the colon
- •Stage III disease
- •No resected stage IV disease
- •No rectal cancer
- •Gross inferior (caudad) margin of the primary tumor must be ≥ 12 cm from the anal verge by rigid proctoscopy
- •Stage III tumor must have been completely resected within the past 56 days
- •Must have documented en bloc resection in patients with tumor adherence to adjacent structures
- •Tumor-related obstructions and colonic perforation are allowed
- •Tumor samples must be available
- •At least 1 pathologically confirmed positive lymph node
- •No evidence of residual involved lymph node disease
- •Synchronous primary colon cancer allowed
- •No distant metastatic disease
- •Performance status - Eastern Cooperative Oncology Group (ECOG) 0-2
- •Absolute neutrophil count ≥ 1,500/mm^3
- •Platelet count ≥ 100,000/mm^3
- •Hemoglobin ≥ 9 g/dL
- •Bilirubin ≤ 1.5 times upper limit of normal (ULN)
- •Creatinine ≤ 1.5 times ULN
- •No uncontrolled high blood pressure
- •No unstable angina
- •No symptomatic congestive heart failure
- •No myocardial infarction with the past 6 months
- •No New York Heart Association class III or IV heart disease
- •No symptomatic pulmonary fibrosis
- •No symptomatic interstitial pneumonitis
- •No prior allergic reaction (known sensitivity) to chimerized or murine monoclonal antibody therapy
- •No known allergy to platinum compounds
- •No documented presence of human anti-mouse antibodies (HAMA)
- •No active uncontrolled bacterial, viral, or systemic fungal infection
- •HIV negative
- •No clinically defined AIDS
- •Not pregnant or nursing
- •Negative pregnancy test
- •No men or women of childbearing potential who are unwilling to employ adequate contraception
- •No inadequately treated gastrointestinal bleeding
- •No ≥ grade 2 pre-existing peripheral sensory or motor neuropathy
- •No other malignancy within the past 5 years except adequately treated basal cell or squamous cell skin cancer, carcinoma in situ of the cervix, or lobular carcinoma in situ in 1 breast
- •No other concurrent medical condition that would preclude study participation
- •No concurrent biologic therapy
- •No prior chemotherapy for colon cancer
- •No other concurrent chemotherapy
- •No prior radiotherapy for colon cancer
- •No concurrent targeted agents
- •No prior agents directed against epidermal growth factor-receptor
- •No other concurrent anticancer therapy
排除标准
- 未提供
研究组 & 干预措施
Arm A (combination chemotherapy)
Patients received oxaliplatin IV over 2 hours, leucovorin calcium IV over 2 hours, and fluorouracil IV continuously over 46-48 hours on days 1. Treatment repeated every 14 days for up to 12 courses in the absence of unacceptable toxicity or recurrent disease.
干预措施: leucovorin calcium (Drug)
Arm B (combination chemotherapy)
Patients received irinotecan IV over 2 hours on day 1 and leucovorin calcium and fluorouracil as in arm A. Treatment repeated every 14 days for up to 12 courses in the absence of unacceptable toxicity or recurrent disease.
干预措施: leucovorin calcium (Drug)
Arm A (combination chemotherapy)
Patients received oxaliplatin IV over 2 hours, leucovorin calcium IV over 2 hours, and fluorouracil IV continuously over 46-48 hours on days 1. Treatment repeated every 14 days for up to 12 courses in the absence of unacceptable toxicity or recurrent disease.
干预措施: oxaliplatin (Drug)
Arm A (combination chemotherapy)
Patients received oxaliplatin IV over 2 hours, leucovorin calcium IV over 2 hours, and fluorouracil IV continuously over 46-48 hours on days 1. Treatment repeated every 14 days for up to 12 courses in the absence of unacceptable toxicity or recurrent disease.
干预措施: fluorouracil (Drug)
Arm B (combination chemotherapy)
Patients received irinotecan IV over 2 hours on day 1 and leucovorin calcium and fluorouracil as in arm A. Treatment repeated every 14 days for up to 12 courses in the absence of unacceptable toxicity or recurrent disease.
干预措施: fluorouracil (Drug)
Arm C (combination chemotherapy)
Patients received the same treatment as in arm A for 6 courses followed by the same treatment as in arm B for 6 courses (total of 12 courses). Treatment continues in the absence of unacceptable toxicity or recurrent disease.
干预措施: irinotecan hydrochloride (Drug)
Arm C (combination chemotherapy)
Patients received the same treatment as in arm A for 6 courses followed by the same treatment as in arm B for 6 courses (total of 12 courses). Treatment continues in the absence of unacceptable toxicity or recurrent disease.
干预措施: oxaliplatin (Drug)
Arm C (combination chemotherapy)
Patients received the same treatment as in arm A for 6 courses followed by the same treatment as in arm B for 6 courses (total of 12 courses). Treatment continues in the absence of unacceptable toxicity or recurrent disease.
干预措施: leucovorin calcium (Drug)
Arm D (combination chemotherapy, monoclonal antibody)
Patients received cetuximab IV over 1 hour on days 1 and 8 and oxaliplatin, leucovorin calcium, and fluorouracil as in arm A. Treatment repeated every 14 days for up to 12 courses in the absence of unacceptable toxicity or recurrent disease.
干预措施: leucovorin calcium (Drug)
Arm D (combination chemotherapy, monoclonal antibody)
Patients received cetuximab IV over 1 hour on days 1 and 8 and oxaliplatin, leucovorin calcium, and fluorouracil as in arm A. Treatment repeated every 14 days for up to 12 courses in the absence of unacceptable toxicity or recurrent disease.
干预措施: cetuximab (Biological)
Arm C (combination chemotherapy)
Patients received the same treatment as in arm A for 6 courses followed by the same treatment as in arm B for 6 courses (total of 12 courses). Treatment continues in the absence of unacceptable toxicity or recurrent disease.
干预措施: fluorouracil (Drug)
Arm D (combination chemotherapy, monoclonal antibody)
Patients received cetuximab IV over 1 hour on days 1 and 8 and oxaliplatin, leucovorin calcium, and fluorouracil as in arm A. Treatment repeated every 14 days for up to 12 courses in the absence of unacceptable toxicity or recurrent disease.
干预措施: oxaliplatin (Drug)
Arm D (combination chemotherapy, monoclonal antibody)
Patients received cetuximab IV over 1 hour on days 1 and 8 and oxaliplatin, leucovorin calcium, and fluorouracil as in arm A. Treatment repeated every 14 days for up to 12 courses in the absence of unacceptable toxicity or recurrent disease.
干预措施: fluorouracil (Drug)
Arm E (combination chemotherapy, monoclonal antibody)
Patients received cetuximab as in arm D and irinotecan, leucovorin calcium, and fluorouracil as in arm B. Treatment repeated every 14 days for up to 12 courses in the absence of unacceptable toxicity or recurrent disease.
干预措施: leucovorin calcium (Drug)
Arm E (combination chemotherapy, monoclonal antibody)
Patients received cetuximab as in arm D and irinotecan, leucovorin calcium, and fluorouracil as in arm B. Treatment repeated every 14 days for up to 12 courses in the absence of unacceptable toxicity or recurrent disease.
干预措施: cetuximab (Biological)
Arm F (combination chemotherapy, monoclonal antibody)
Patients received cetuximab as in arm D and chemotherapy as in arm C.
干预措施: leucovorin calcium (Drug)
Arm E (combination chemotherapy, monoclonal antibody)
Patients received cetuximab as in arm D and irinotecan, leucovorin calcium, and fluorouracil as in arm B. Treatment repeated every 14 days for up to 12 courses in the absence of unacceptable toxicity or recurrent disease.
干预措施: irinotecan hydrochloride (Drug)
Arm E (combination chemotherapy, monoclonal antibody)
Patients received cetuximab as in arm D and irinotecan, leucovorin calcium, and fluorouracil as in arm B. Treatment repeated every 14 days for up to 12 courses in the absence of unacceptable toxicity or recurrent disease.
干预措施: fluorouracil (Drug)
Arm F (combination chemotherapy, monoclonal antibody)
Patients received cetuximab as in arm D and chemotherapy as in arm C.
干预措施: irinotecan hydrochloride (Drug)
Arm F (combination chemotherapy, monoclonal antibody)
Patients received cetuximab as in arm D and chemotherapy as in arm C.
干预措施: oxaliplatin (Drug)
Arm G (Locally directed therapy)
Patients determined to have mutated KRAS (or KRAS not evaluable) were assigned to an event monitoring arm in which adjuvant therapy was determined and assigned by the treating oncologist. The determination of the type of therapy, duration of treatment, and dose modification was the responsibility of the treating oncologists.
干预措施: Locally Directed Therapy (Drug)
Arm F (combination chemotherapy, monoclonal antibody)
Patients received cetuximab as in arm D and chemotherapy as in arm C.
干预措施: cetuximab (Biological)
Arm F (combination chemotherapy, monoclonal antibody)
Patients received cetuximab as in arm D and chemotherapy as in arm C.
干预措施: fluorouracil (Drug)
Arm B (combination chemotherapy)
Patients received irinotecan IV over 2 hours on day 1 and leucovorin calcium and fluorouracil as in arm A. Treatment repeated every 14 days for up to 12 courses in the absence of unacceptable toxicity or recurrent disease.
干预措施: irinotecan hydrochloride (Drug)
结局指标
主要结局
Disease-free Survival (Arms A and D: Wild-type KRAS Patients)
时间窗: At 3 years
The primary endpoint for this study was to compare the disease-free survival (DFS) in patients with stage III colon cancer who are KRAS wild-type randomized to one of two treatment regimens: 1) oxaliplatin, leucovorin calcium, and fluorouracil (Arm A) or 2) oxaliplatin, leucovorin calcium, fluorouracil and cetuximab (Arm D). Participants treated according to Arms B, C, E, and F treatment schedules received treatment which included irinotecan hydrochloride and therefore were not analyzed for this endpoint. Disease-free survival is defined as the time from randomization until tumor recurrence or death, whichever is first. Estimated by the method of Kaplan and Meier.
次要结局
- Toxicity, Assessed Using National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) Version 3.0 (v3) (Arms A and D: Mutant KRAS Patients)(Assessed up to 8 years)
- Toxicity, Assessed Using National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) Version 3.0 (v3) (Arms A and D: Wild-type KRAS Patients)(Assessed up to 8 years)
- Disease-free Survival (Arms A and D: Mutant KRAS Patients)(At 3 years)
- Overall Survival as Measured by the 3-year Event-free Rate (Arms A and D: Mutant KRAS Patients)(Up to 3 years)
- Overall Survival as Measured by the 3-year Event-free Rate (Arms A and D: Wild-type KRAS Patients)(Up to 3 years)