Cetuximab/FOLFIRI With or Without Oxaliplatin and FOLFOXIRI With or Without Bevacizumab in Neoadjuvant Treatment of Non-resectable Colorectal Liver Metastases
- Conditions
- Colorectal Cancer
- Interventions
- Registration Number
- NCT01802645
- Lead Sponsor
- Technische Universität Dresden
- Brief Summary
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.
- Detailed Description
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)
Recruitment & Eligibility
- Status
- UNKNOWN
- Sex
- All
- Target Recruitment
- 91
Not provided
-
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
Study & Design
- Study Type
- INTERVENTIONAL
- Study Design
- PARALLEL
- Arm && Interventions
Group Intervention Description Cetuximab/FOLFOXIRI Cetuximab 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 Cetuximab/FOLFIRI Folinic Acid 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 Cetuximab/FOLFIRI Cetuximab 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 Cetuximab/FOLFIRI Irinotecan 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 Cetuximab/FOLFIRI 5-FU 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 Cetuximab/FOLFOXIRI Irinotecan 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 Cetuximab/FOLFOXIRI Oxaliplatin 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 Cetuximab/FOLFOXIRI 5-FU 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 FOLFOXIRI Irinotecan 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 FOLFOXIRI Oxaliplatin 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 Cetuximab/FOLFOXIRI Folinic Acid 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 FOLFOXIRI Folinic Acid 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 FOLFOXIRI 5-FU 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 Bevacizumab/FOLFOXIRI Irinotecan 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 Bevacizumab/FOLFOXIRI Oxaliplatin 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 Bevacizumab/FOLFOXIRI 5-FU 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 Bevacizumab/FOLFOXIRI Bevacizumab 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 Bevacizumab/FOLFOXIRI Folinic Acid 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
- Primary Outcome Measures
Name Time Method Response rate up to 1 year after randomization Rate of patients with partial or complete response according to modified RECIST criteria.
- Secondary Outcome Measures
Name Time Method Rate of resected patients without early relaps 6 months after resection Rate of patients who had a R0 resection of all lesions and are disease free for at least 6 months in the ITT population.
Trial Locations
- Locations (15)
Klinikum Coburg GmbH
🇩🇪Coburg, Germany
Klinikum Landshut gGmbH
🇩🇪Landshut, Germany
Rems-Murr-Klinikum Winnenden
🇩🇪Winnenden, Germany
Universitätsklinikum der RWTH Aachen
🇩🇪Aachen, Germany
Klinikum der Johann Wolfgang Goethe Universität Frankfurt am Main
🇩🇪Frankfurt/ Main, Germany
Onkologie Dülmen GbR
🇩🇪Coesfeld, Germany
Universitätsmedizin Göttingen
🇩🇪Göttingen, Germany
University hospital Leipzig
🇩🇪Leipzig, Germany
Universitätsklinikum Würzburg
🇩🇪Würzburg, Germany
Johannes-Gutenberg-Universität
🇩🇪Mainz, Germany
Klinikum Oldenburg GmbH
🇩🇪Oldenburg, Germany
Überörtliche Gemeinschaftspraxis Hämatologie/ Onkologie
🇩🇪Bocholt, Germany
Charité Campus Virchow
🇩🇪Berlin, Germany
Universitätsklinikum Hamburg-Eppendorf
🇩🇪Hamburg, Germany
Universitätsklinikum Carl Gustav Carus
🇩🇪Dresden, Germany