Cetuximab/FOLFIRI With or Without Oxaliplatin and FOLFOXIRI With or Without Bevacizumab in Neoadjuvant Treatment of Non-resectable Colorectal Liver Metastases (CELIM2)
Open, Randomized, Multicenter Phase II Trial With Cetuximab /5-FU/FA/Irinotecan or Cetuximab/5-FU/FA /Irinotecan/Oxaliplatin in K-ras/B-raf Wild Type Patients or With Irinotecan/Oxaliplatin/5-FU/FA With or Without Bevacizumab in K-ras Mutant Patients as Neoadjuvant Treatment in Patients With Non- Resectable Colorectal Liver Metastases.
The aim of this study is to investigate the following schedules for efficacy with regard to response rate in neoadjuvant treatment of patients with non-resectable liver metastases:
- Cetuximab/FOLFOXIRI and cetuximab/FOLFIRI in patients with ras wild type tumours and
- Bevacizumab/FOLFOXIRI and FOLFOXIRI in patients with ras mutant tumours.
研究概览
详细说明
Patients with liver metastases from colorectal and without known extrahepatic metastases will be screened for this study including ras status (b-raf status according to local standard).
Patients receive chemotherapy according to the allocation and are re-evaluated for resectability every 8 weeks for a maximum of 6 months. Resectable patients will be resected and receive an adjuvant treatment to complete 12 cycles.
In certain circumstances, a second resection is allowed within the study.
Patients will be randomized using a web-based computer system that allows randomization if the key basic characteristics are entered.
Patients with ras wild-type tumours will be randomized to receive:
- Cetuximab/FOLFIRI or
- Cetuximab/FOLFOXIRI
Patients with ras mutations will be randomized to receive:
- FOLFOXIRI or
- FOLFOXIRI/bevacizumab
Chemotherapy doses are adjusted to the risk of toxicity in all treatment arms.
Stratification will be performed according to:
- Number of metastases (< 5 vs. ≥ 5 metastases)
- Primary tumour in situ
- Centre
Treatment regimens For dose reductions and conditions to continue please refer to the full protocol.
All drugs are used within the label and approved doses.
B-raf mutations are determined according to local standard. If a b-raf mutation is known before randomization, the investigator can consider the patient as ras wildtype OR as ras mutant patient.
Cetuximab/FOLFIRI :
Cetuximab 400 mg/m² (first dose, 2 h), then 250 mg/m² (1 h) weekly Irinotecan 180 mg/m², d-l Folinic acid 400 mg/m² (2 h), 5-FU 400 mg/m² (Bolus), 5-FU 2400 mg/m² (46 h) every 2 weeks
Cetuximab/FOLFOXIRI:
Cetuximab 400 mg/m² (first dose, 2 h), then 250 mg/m² (1 h) weekly Irinotecan 125 mg/m² , Oxaliplatin 85 mg/m² (2 h), d-l Folinic acid 400 mg/m² (2 h), 5-FU 3200 mg/m² (46 h) every 2 weeks
FOLFOXIRI:
Irinotecan 165 mg/m², Oxaliplatin 85 mg/m² (2 h), d-l Folinic acid 400 mg/m² (2 h), 5-FU 3200 mg/m² (46 h) every 2 weeks
Bevacizumab/FOLFOXIRI:
Bevacizumab 5 mg/kg (90 - 30 min i.v.), Irinotecan 165 mg/m², Oxaliplatin 85 mg/m² (2 h), d-l Folinic acid 400 mg/m² (2 h), 5-FU 3200 mg/m² (46 h) every 2 weeks
Evaluation for response and resections Patients are evaluated for response by the same imaging technique as at baseline every 8 weeks. The findings will be discussed for resectability within two weeks after tumour assessment in a local multidisciplinary team.
Technically resectable patients should be offered liver resection. The treatment will continue until liver resection or for a maximum of six months (12 cycles).
Adjuvant treatment After liver resection, an adjuvant treatment is recommended with the same schedule as preoperatively, for a maximum combined pre- and postoperative treatment of 12 cycles. If less than three postoperative cycles remain, no postoperative treatment will be started (see chapter 9.10).
Follow up After resection, patients will be followed up for 5 years after randomization. This includes
- imaging and clinical investigation every three months for the first 2 years, then every six months (patients without tumour progression / recurrence)
- survival status and surgical/medical treatment every three months for the first 2 years and then every six months (all patients)
研究类型
注册 (实际的)
阶段
- 阶段2
联系人和位置
学习地点
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Aachen、德国、52074
- Universitatsklinikum der RWTH Aachen
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Berlin、德国、13353
- Charite Campus Virchow
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Bocholt、德国、46397
- Überörtliche Gemeinschaftspraxis Hämatologie/ Onkologie
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Coburg、德国、96450
- Klinikum Coburg GmbH
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Coesfeld、德国、48653
- Onkologie Dülmen GbR
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Dresden、德国、01307
- Universitätsklinikum Carl Gustav Carus
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Frankfurt/ Main、德国、60590
- Klinikum der Johann Wolfgang Goethe Universität Frankfurt am Main
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Göttingen、德国、37075
- Universitatsmedizin Gottingen
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Hamburg、德国、20246
- Universitätsklinikum Hamburg-Eppendorf
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Landshut、德国、84034
- Klinikum Landshut gGmbH
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Leipzig、德国、04103
- University Hospital Leipzig
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Mainz、德国、55131
- Johannes-Gutenberg-Universität
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Oldenburg、德国、26133
- Klinikum Oldenburg GmbH
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Winnenden、德国、71364
- Rems-Murr-Klinikum Winnenden
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Würzburg、德国、97080
- Universitätsklinikum Würzburg
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参与标准
资格标准
适合学习的年龄
接受健康志愿者
有资格学习的性别
描述
Patients can be enrolled, if all of these conditions apply:
- Non-resectable, histologically confirmed, synchronous or metachronous colorectal liver metastases.
Non-resectability will be documented by a local multidisciplinary tumour board with participation of a surgeon experienced in liver surgery. Patients can be enrolled if they
a) are technically non-resectable (locally determined by a multi-disciplinary team discussion based on remaining functional liver tissue after resection, i.e. i) involvement of both portal veins, all hepatic veins, portal vein of the liver lobe and hepatic veins draining the segments of the other liver lobe, or ii) other reasons for less than 30% remaining functional liver tissue after resection) and / or b) have ≥ 5 liver metastases and / or c) are regarded as non-resectable for other reasons (description necessary)
Patients with simultaneous liver metastases are eligible,
- if the primary tumour was resected at least 1 month prior to chemotherapy or
- all of the following conditions apply:
i) the primary tumour is clearly resectable, ii) no radiation therapy is planned, iii) liver resection is planned before resection of the primary or at the same operation as the resection of the primary, iv) no two-stage liver resection is planned, and v) all efforts were made to exclude additional distant metastases.
- WHO PS ≤ 1
- Written informed consent
- Adequate bone marrow function, liver function (neutrophils > 1.5 x 109/l; platelets > 100 x 109/l; haemoglobin > 5.0 mmol/l (8.0 g/dl); bilirubin ≤ ULN or ≤ 1.5 x ULN and not increasing more than 25 % within the last 4 weeks; SGOT and SGPT < 5 x UNL)
- Age ≥ 18 years
Exclusion Criteria:
- Any evidence of extrahepatic metastases, distant lymph node metastases and primary tumour recurrence
- (deleted)
- Prior systemic anti-tumour therapy with anti- EGFR-, anti-angiogenetic drugs or with chemotherapy (except adjuvant chemotherapy with an interval of ≥ 6 months or in combination with radiation as radio sensitizer)
- Radiotherapy or major abdominal or thoracic surgery (excluding diagnostic interventions or venous port implantation) ≤ 4 weeks before study entry
- Renal insufficiency with serum creatinine ≥ 1.5 x UNL. If serum creatinine is between 1.0 and 1.5 x UNL, the creatinine clearance according to the Cockroft-Gault formula should be ≥ 60 ml/min
- Hypertension with an arterial blood pressure > 150/90 mmHg
- Severe or uncontrolled cardiovascular disease (congestive heart failure NYHA III or IV, unstable angina pectoris, history of myocardial infarction within the last 12 months, significant arrhythmias)
- Known proteinuria > 1 g/day (to be tested if proteinuria more than 1+ in the urinary dipstick analysis)
- Peripheral neuropathy > CTC grade I
- Concurrent systemic immune therapy, chemotherapy, hormone therapy, or patients receiving immune suppressive treatment (i.e. for transplantation, severe rheumatologic disease)
- Participation in clinical trials with investigational agents within 30 days before start of the treatment in study
Active treatment of
- peptic ulcers or bleeding erosive esophagitis / gastritis within 3 months before study
- pulmonary embolism, severe or unstable angina pectoris or myocardial infarction, stroke or transient ischemic attack within 12 months before study
- deep vein thrombosis within 4 weeks before study
- Inflammatory bowel disease
- History of other malignancies, from which the patient is not 5 years disease free, with the exception of colorectal cancer, or adequately treated basal cell or squamous cell carcinoma of skin or in-situ cervical cancer within 5 years before study
- History of brain metastases
- History of severe psychiatric illness
- Active drug- or alcohol abuse
- Known hepatitis B or C or HIV infection
- Breast- feeding or pregnant women
- Lack of effective contraception (for male and female patients)
- Known intolerance to one of the following drugs: cetuximab, bevacizumab, oxaliplatin, irinotecan, 5-FU, folinic acid
学习计划
研究是如何设计的?
设计细节
- 主要用途:治疗
- 分配:随机化
- 介入模型:并行分配
- 屏蔽:无(打开标签)
武器和干预
参与者组/臂 |
干预/治疗 |
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有源比较器:Cetuximab/FOLFIRI
Cetuximab 250 mg/m² (1 h) weekly Irinotecan 180 mg/m² (1 h)*, d-l Folinic acid 400 mg/m² (2 h), 5-FU 400 mg/m² (Bolus), 5-FU 2400 mg/m² (46 h) every 2 weeks *reduced in UGT1A1 7/7 patients |
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实验性的:Cetuximab/FOLFOXIRI
Cetuximab 250 mg/m² (1 h) weekly Irinotecan 125 mg/m² (1 h),* Oxaliplatin 85 mg/m² (2 h), d-l Folinic acid 400 mg/m² (2 h), 5-FU 3200 mg/m² (46 h) every 2 weeks *reduced in UGT1A1 7/7 patients |
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有源比较器:FOLFOXIRI
Irinotecan 165 mg/m² (1 h)*, Oxaliplatin 85 mg/m² (2 h), d-l Folinic acid 400 mg/m² (2 h), 5-FU 3200 mg/m² (46 h) every 2 weeks *reduced in UGT1A1 7/7 patients |
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实验性的:Bevacizumab/FOLFOXIRI
Bevacizumab 5 mg/kg (30-90 min i.v.), Irinotecan 165 mg/m² (1 h),* Oxaliplatin 85 mg/m² (2 h), d-l Folinic acid 400 mg/m² (2 h), 5-FU 3200 mg/m² (46 h) every 2 weeks *reduced in UGT1A1 7/7 patients |
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研究衡量的是什么?
主要结果指标
结果测量 |
措施说明 |
大体时间 |
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Response rate
大体时间:up to 1 year after randomization
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Rate of patients with partial or complete response according to modified RECIST criteria.
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up to 1 year after randomization
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次要结果测量
结果测量 |
措施说明 |
大体时间 |
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Rate of resected patients without early relaps
大体时间:6 months after resection
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Rate of patients who had a R0 resection of all lesions and are disease free for at least 6 months in the ITT population.
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6 months after resection
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其他结果措施
结果测量 |
措施说明 |
大体时间 |
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R0 resection rate
大体时间:up to 1 year after randomization
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Resection rate, defined as patients with microscopically complete (R0) resection (ITT- population)
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up to 1 year after randomization
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Resection rate
大体时间:up to 1 year after randomization
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Rate of liver resection with macroscopically tumour free margins and/or RFA (all patients with R0 or R1 resection and/or complete RFA of all lesion, ITT- population)
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up to 1 year after randomization
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Progression free survival
大体时间:up to 3 years after randomization
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Progression free survival (Medium, Kaplan-Meier-estimation, ITT- population)
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up to 3 years after randomization
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Disease free survival after resection
大体时间:up to 3 years after resection
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Disease free survival after resection (Medium, Kaplan-Meier-estimation, resected patients)
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up to 3 years after resection
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Overall survival
大体时间:up to 5 year after randomization
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Overall survival (Kaplan-Meier-estimation, ITT- population)
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up to 5 year after randomization
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Toxicity
大体时间:up to 1 year after randomization
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Toxicity according to NCI-CTC criteria v. 4.0 Perioperative toxicity according to Clavien
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up to 1 year after randomization
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Pathological response
大体时间:up to 1 year after randomization
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Pathological response in the resected tumour tissue
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up to 1 year after randomization
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Molecular markers
大体时间:up to 1 year after randomization
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Evaluation of molecular predictive markers for response (i.e.
other mutations in EGFR signalling pathway, EGFR ligands) and toxicity
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up to 1 year after randomization
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合作者和调查者
调查人员
- 首席研究员:Gunnar Folprecht, PD Dr.、University hospital "Carl Gustav Carus" Dresden
研究记录日期
研究主要日期
学习开始 (实际的)
初级完成 (预期的)
研究完成 (预期的)
研究注册日期
首次提交
首先提交符合 QC 标准的
首次发布 (估计)
研究记录更新
最后更新发布 (实际的)
上次提交的符合 QC 标准的更新
最后验证
更多信息
与本研究相关的术语
其他相关的 MeSH 术语
其他研究编号
- TUD-CELIM2-050
- 2011-003288-31 (EudraCT编号)
此信息直接从 clinicaltrials.gov 网站检索,没有任何更改。如果您有任何更改、删除或更新研究详细信息的请求,请联系 register@clinicaltrials.gov. clinicaltrials.gov 上实施更改,我们的网站上也会自动更新.
奥沙利铂的临床试验
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Hospices Civils de Lyon未知