A 2x2 Factorial Randomized Phase III Study of Intermittent Oral Capecitabine in Combination With Intravenous Oxaliplatin (Q3W) ("XELOX") With/Without Intravenous Bevacizumab (Q3W) Versus Bolus and Continuous Infusion Fluorouracil/Intravenous Leucovorin With Intravenous Oxaliplatin (Q2W) ("FOLFOX-4") With/Without Intravenous Bevacizumab (Q2W) as First-line Treatment for Patients With Metastatic Colorectal Cancer
试验速览
- 阶段
- 3 期
- 状态
- 已完成
- 入组人数
- 2,035
- 主要终点
- PFS as Assessed by the Investigator According to Response Evaluation Criteria in Solid Tumors (RECIST) by General Approach (Participants With Curative Surgery Censored) - Superiority of Chemotherapy Plus BV Over Chemotherapy Alone
研究概览
简要总结
This 4 arm study assessed the efficacy and safety of oral capecitabine (Xeloda) or intravenous (iv) fluorouracil/leucovorin, in combination with iv oxaliplatin (Eloxatin) with or without iv bevacizumab (Avastin), as a first-line treatment in patients with metastatic colorectal cancer. Patients were randomized to receive 1) XELOX (Xeloda 1000 mg/m^2 orally [po] twice a day [bid] on Days 1-15 + oxaliplatin in 3 week cycles), 2) FOLFOX-4 (oxaliplatin + leucovorin + fluorouracil [5-FU] in 2 week cycles), 3) XELOX + bevacizumab (7.5 mg iv on Day 1 in 3 week cycles), or 4) FOLFOX-4 + bevacizumab (5 mg iv on Day 1 in 2 week cycles).
详细描述
This study was conducted in 2 parts: An initial 2-arm part in which patients were randomized to 1 of 2 different treatment groups (XELOX or FOLFOX-4), and a subsequent 2 x 2 factorial part, added to the study through a protocol amendment, in which additional patients were randomized into one of 4 different treatment groups (XELOX + placebo, FOLFOX-4 + placebo, XELOX + bevacizumab, or FOLFOX-4 + bevacizumab). Due to the comparison of the oral agent capecitabine with bolus and infused fluorouracil, the study was not blinded with respect to these 2 treatments. The study was double-blind with regard to the administration of bevacizumab, ie, there was a placebo control for bevacizumab in the second part of the study.
The study consisted of 3 phases, a Primary Study Treatment Phase, a Post-Study Treatment Phase, and a Follow-Up Phase.
Primary Study Treatment Phase
Patients were to receive up to 16 cycles (2-arm part of the study) or 24 cycles (4-arm part of the study) of treatment during the Primary Study Treatment Phase (48 weeks).
Post-Study Treatment Phase
研究设计
- 研究类型
- Interventional
- 分配方式
- Randomized
- 干预模型
- Factorial
- 主要目的
- Treatment
- 盲法
- Double (Participant, Investigator)
入排标准
- 年龄范围
- 18 Years 至 —（Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •Adult patients ≥ 18 years of age.
- •Metastatic colorectal cancer.
- •≥ 1 target lesion.
排除标准
- •Previous treatment with oxaliplatin or bevacizumab.
- •Previous systemic chemotherapy or immunotherapy for advanced or metastatic disease.
- •Progressive disease during or within 6 months of completion of previous adjuvant therapy.
研究组 & 干预措施
XELOX (oxaliplatin+capecitabine)
Patients in the 2-arm part of the study received oxaliplatin 130 mg/m^2 intravenously (iv) on Day 1 of every 3 week cycle + capecitabine 1000 mg/m^2 orally twice a day for the first 2 weeks of every 3 week cycle. Patients in the 4-arm part of the study received the same treatments plus placebo for bevacizumab 7.5 mg/kg iv on Day 1 of every 3 week cycle.
干预措施: Oxaliplatin 130 mg/m^2 (Drug)
XELOX (oxaliplatin+capecitabine)
Patients in the 2-arm part of the study received oxaliplatin 130 mg/m^2 intravenously (iv) on Day 1 of every 3 week cycle + capecitabine 1000 mg/m^2 orally twice a day for the first 2 weeks of every 3 week cycle. Patients in the 4-arm part of the study received the same treatments plus placebo for bevacizumab 7.5 mg/kg iv on Day 1 of every 3 week cycle.
干预措施: Capecitabine 1000 mg/m^2 (Drug)
XELOX (oxaliplatin+capecitabine)
Patients in the 2-arm part of the study received oxaliplatin 130 mg/m^2 intravenously (iv) on Day 1 of every 3 week cycle + capecitabine 1000 mg/m^2 orally twice a day for the first 2 weeks of every 3 week cycle. Patients in the 4-arm part of the study received the same treatments plus placebo for bevacizumab 7.5 mg/kg iv on Day 1 of every 3 week cycle.
干预措施: Placebo for bevacizumab 7.5 mg/kg (Drug)
XELOX (oxaliplatin+capecitabine) + bevacizumab
Patients in the 4-arm part of the study received oxaliplatin 130 mg/m^2 intravenously (iv) on Day 1 of every 3 week cycle + capecitabine 1000 mg/m^2 orally twice a day for the first 2 weeks of every 3 week cycle + bevacizumab 7.5 mg/kg iv on Day 1 of every 3 week cycle.
干预措施: Oxaliplatin 130 mg/m^2 (Drug)
XELOX (oxaliplatin+capecitabine) + bevacizumab
Patients in the 4-arm part of the study received oxaliplatin 130 mg/m^2 intravenously (iv) on Day 1 of every 3 week cycle + capecitabine 1000 mg/m^2 orally twice a day for the first 2 weeks of every 3 week cycle + bevacizumab 7.5 mg/kg iv on Day 1 of every 3 week cycle.
干预措施: Capecitabine 1000 mg/m^2 (Drug)
XELOX (oxaliplatin+capecitabine) + bevacizumab
Patients in the 4-arm part of the study received oxaliplatin 130 mg/m^2 intravenously (iv) on Day 1 of every 3 week cycle + capecitabine 1000 mg/m^2 orally twice a day for the first 2 weeks of every 3 week cycle + bevacizumab 7.5 mg/kg iv on Day 1 of every 3 week cycle.
干预措施: Bevacizumab 7.5 mg/kg (Drug)
FOLFOX-4 (oxaliplatin+leucovorin+fluorouracil)
Patients in the 2-arm part of the study received oxaliplatin 85 mg/m^2 intravenously (iv) + leucovorin 200 mg/m^2 iv on Day 1 of every 2 week cycle + fluorouracil 400 mg/m^2 bolus injection over 2 to 4 min followed by 600 mg/m^2 continuous infusion over 22 h on Days 1 and 2 of every 2 week cycle. Patients in the 4-arm part of the study received the same treatments plus placebo for bevacizumab 5 mg/kg iv on Day 1 of every 2 week cycle.
干预措施: Oxaliplatin 85 mg/m^2 (Drug)
FOLFOX-4 (oxaliplatin+leucovorin+fluorouracil)
Patients in the 2-arm part of the study received oxaliplatin 85 mg/m^2 intravenously (iv) + leucovorin 200 mg/m^2 iv on Day 1 of every 2 week cycle + fluorouracil 400 mg/m^2 bolus injection over 2 to 4 min followed by 600 mg/m^2 continuous infusion over 22 h on Days 1 and 2 of every 2 week cycle. Patients in the 4-arm part of the study received the same treatments plus placebo for bevacizumab 5 mg/kg iv on Day 1 of every 2 week cycle.
干预措施: Leucovorin 200 mg/m^2 (Drug)
FOLFOX-4 (oxaliplatin+leucovorin+fluorouracil)
Patients in the 2-arm part of the study received oxaliplatin 85 mg/m^2 intravenously (iv) + leucovorin 200 mg/m^2 iv on Day 1 of every 2 week cycle + fluorouracil 400 mg/m^2 bolus injection over 2 to 4 min followed by 600 mg/m^2 continuous infusion over 22 h on Days 1 and 2 of every 2 week cycle. Patients in the 4-arm part of the study received the same treatments plus placebo for bevacizumab 5 mg/kg iv on Day 1 of every 2 week cycle.
干预措施: Fluorouracil 400 mg/m^2 (Drug)
FOLFOX-4 (oxaliplatin+leucovorin+fluorouracil)
Patients in the 2-arm part of the study received oxaliplatin 85 mg/m^2 intravenously (iv) + leucovorin 200 mg/m^2 iv on Day 1 of every 2 week cycle + fluorouracil 400 mg/m^2 bolus injection over 2 to 4 min followed by 600 mg/m^2 continuous infusion over 22 h on Days 1 and 2 of every 2 week cycle. Patients in the 4-arm part of the study received the same treatments plus placebo for bevacizumab 5 mg/kg iv on Day 1 of every 2 week cycle.
干预措施: Placebo for bevacizumab 5 mg/kg (Drug)
FOLFOX-4 (oxaliplatin+leucovorin+fluorouracil) + bevacizumab
Patients in the 4-arm part of the study received oxaliplatin 85 mg/m^2 intravenously (iv) + leucovorin 200 mg/m^2 iv + bevacizumab 5 mg/kg iv on Day 1 of every 2 week cycle + fluorouracil 400 mg/m^2 bolus injection over 2 to 4 min followed by 600 mg/m^2 continuous infusion over 22 h on Days 1 and 2 of every 2 week cycle.
干预措施: Oxaliplatin 85 mg/m^2 (Drug)
FOLFOX-4 (oxaliplatin+leucovorin+fluorouracil) + bevacizumab
Patients in the 4-arm part of the study received oxaliplatin 85 mg/m^2 intravenously (iv) + leucovorin 200 mg/m^2 iv + bevacizumab 5 mg/kg iv on Day 1 of every 2 week cycle + fluorouracil 400 mg/m^2 bolus injection over 2 to 4 min followed by 600 mg/m^2 continuous infusion over 22 h on Days 1 and 2 of every 2 week cycle.
干预措施: Leucovorin 200 mg/m^2 (Drug)
FOLFOX-4 (oxaliplatin+leucovorin+fluorouracil) + bevacizumab
Patients in the 4-arm part of the study received oxaliplatin 85 mg/m^2 intravenously (iv) + leucovorin 200 mg/m^2 iv + bevacizumab 5 mg/kg iv on Day 1 of every 2 week cycle + fluorouracil 400 mg/m^2 bolus injection over 2 to 4 min followed by 600 mg/m^2 continuous infusion over 22 h on Days 1 and 2 of every 2 week cycle.
干预措施: Fluorouracil 400 mg/m^2 (Drug)
FOLFOX-4 (oxaliplatin+leucovorin+fluorouracil) + bevacizumab
Patients in the 4-arm part of the study received oxaliplatin 85 mg/m^2 intravenously (iv) + leucovorin 200 mg/m^2 iv + bevacizumab 5 mg/kg iv on Day 1 of every 2 week cycle + fluorouracil 400 mg/m^2 bolus injection over 2 to 4 min followed by 600 mg/m^2 continuous infusion over 22 h on Days 1 and 2 of every 2 week cycle.
干预措施: Bevacizumab 5 mg/kg (Drug)
结局指标
主要结局
PFS as Assessed by the Investigator According to Response Evaluation Criteria in Solid Tumors (RECIST) by General Approach (Participants With Curative Surgery Censored) - Superiority of Chemotherapy Plus BV Over Chemotherapy Alone
时间窗: Baseline until disease progression or death, approximately 2 years 6 months
PFS was defined as the time from randomization to progressive disease or death. Participants with neither disease progression nor death were censored at the last date of the last tumor assessment that confirmed that their disease had not progressed. Participants with no tumor assessments after baseline who were alive at the time of clinical cutoff were censored at the date of randomization. Participants who underwent surgical resection with curative intent without prior progression were censored at the date of surgery. PFS was based on tumor assessments made by the investigators according to the RECIST criteria. Superiority analysis that followed the general approach took into account all tumor assessments obtained during the primary study treatment phase, the post-study treatment phase and those obtained during the follow-up phase. Superiority of the BV-containing arms was compared with the chemotherapy alone arms.
Progression-free Survival (PFS) as Assessed by the Investigator According to Response Evaluation Criteria in Solid Tumors (RECIST) by General Approach (Participants With Curative Surgery Censored): Non-inferiority of XELOX Versus FOLFOX-4
时间窗: Baseline until disease progression or death, approximately 2 years 6 months
PFS was defined as the time from randomization to progressive disease or death. Participants with neither disease progression nor death were censored at the last date of the last tumor assessment that confirmed that their disease had not progressed. Participants with no tumor assessments after baseline who were alive at the time of clinical cutoff were censored at the date of randomization. Participants who underwent surgical resection with curative intent without prior progression were censored at the date of surgery. PFS was based on tumor assessments made by the investigators according to the RECIST criteria. Non-inferiority analysis that followed the general approach took into account all tumor assessments obtained during the primary study treatment phase, the post-study treatment phase and those obtained during the follow-up phase. Non-inferiority of the XELOX-containing arms compared with the FOLFOX-4- containing arms was investigated.
次要结局
- PFS as Assessed by the Independent Review Committee (IRC) (General Approach, Participants With Curative Surgery Censored) - Non-inferiority of XELOX Versus FOLFOX-4(Baseline until disease progression or death, approximately 2 years 6 months)
- PFS as Assessed by the Independent Review Committee (IRC) (General Approach, Participants With Curative Surgery Censored) - Superiority of Chemotherapy Plus BV Over Chemotherapy Alone(Baseline until disease progression or death, approximately 2 years 6 months)
- PFS (On-treatment Approach): Non-inferiority of XELOX Versus FOLFOX-4(Baseline until disease progression or death, approximately 2 years 6 months)
- PFS by General Approach, Participants With Curative Surgery Not Censored: Superiority of Chemotherapy Plus BV Over Chemotherapy Alone(Baseline until disease progression or death, approximately 2 years 6 months)
- PFS (On-treatment Approach): Superiority of Chemotherapy Plus BV Over Chemotherapy Alone(Baseline until disease progression or death, approximately 2 years 6 months)
- PFS by General Approach, Participants With Curative Surgery Not Censored: Non-inferiority of XELOX Versus FOLFOX-4(Baseline until disease progression or death, approximately 2 years 6 months)
- Overall Survival: Non-inferiority of XELOX Versus FOLFOX-4(Baseline until disease progression or death, approximately 2 years 6 months)
- Overall Survival: Superiority of Chemotherapy Plus BV Over Chemotherapy Alone(Baseline until disease progression or death, approximately 2 years 6 months)
- BOR as Assessed by the IRC According to RECIST: Non-inferiority of XELOX Versus FOLFOX-4(From baseline until disease progression/recurrence, approximately 2 years 6 months)
- Time to Treatment Failure (TTF) as Assessed by the Investigator According to RECIST: Non-inferiority of XELOX Versus FOLFOX-4(From baseline until disease progression/recurrence, approximately 2 years 6 months)
- Time to Treatment Failure as Assessed by the Investigator According to RECIST: Superiority of Chemotherapy Plus BV Over Chemotherapy Alone(From baseline until disease progression/recurrence, approximately 2 years 6 months)
- Time to Response as Assessed by the Investigator According to RECIST: Non-inferiority of XELOX Versus FOLFOX-4(Week 1 to Week 54)
- Duration of Overall Response as Assessed by the Investigator According to RECIST: Superiority Analysis of Chemotherapy Plus Bevacizumab Versus Chemotherapy Alone(From baseline until disease progression/recurrence, approximately 2 years 6 months)
- Best Overall Response (BOR) as Assessed by the Investigator According to Response Evaluation Criteria in Solid Tumors (RECIST): Non-inferiority of XELOX Versus FOLFOX-4(From baseline until disease progression/recurrence, approximately 2 years 6 months)
- Best Overall Response (BOR) as Assessed by the Investigator According to RECIST: Superiority of Chemotherapy Plus BV Over Chemotherapy Alone(From baseline until disease progression/recurrence, approximately 2 years 6 months)
- Duration of Overall Response as Assessed by the Investigator According to RECIST: Non-inferiority of XELOX Versus FOLFOX-4(From baseline until disease progression/recurrence, approximately 2 years 6 months)
- BOR as Assessed by the IRC According to RECIST: Superiority of Chemotherapy Plus BV Over Chemotherapy Alone(From baseline until disease progression/recurrence, approximately 2 years 6 months)
- Time to Response as Assessed by the Investigator According to RECIST: Superiority of Chemotherapy Plus BV Over Chemotherapy Alone(Week 1 to Week 54)
- Duration of Complete Response as Assessed by the Investigator According to RECIST: Non-inferiority of XELOX Versus FOLFOX-4(From baseline until disease progression/recurrence, approximately 2 years 6 months)
- Duration of Complete Response as Assessed by the Investigator According to RECIST: Superiority of Chemotherapy Plus BV Over Chemotherapy Alone(From baseline until disease progression/recurrence, approximately 2 years 6 months)