Cetuximab/FOLFIRI With or Without Oxaliplatin and FOLFOXIRI With or Without Bevacizumab in Neoadjuvant Treatment of Non-resectable Colorectal Liver Metastases (CELIM2)

This study is currently recruiting participants. (see Contacts and Locations)
Verified September 2014 by Technische Universität Dresden
Sponsor:
Information provided by (Responsible Party):
Technische Universität Dresden
ClinicalTrials.gov Identifier:
NCT01802645
First received: February 11, 2013
Last updated: September 25, 2014
Last verified: September 2014
  Purpose

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.

Condition Intervention Phase
Colorectal Cancer
Drug: Cetuximab
Drug: Bevacizumab
Drug: Irinotecan
Drug: Oxaliplatin
Drug: 5-FU
Drug: Folinic Acid
Phase 2

Study Type: Interventional
Study Design: Allocation: Randomized
Endpoint Classification: Efficacy Study
Intervention Model: Parallel Assignment
Masking: Open Label
Primary Purpose: Treatment
Official Title: 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.

Resource links provided by NLM:


Further study details as provided by Technische Universität Dresden:

Primary Outcome Measures:
  • Response rate [ Time Frame: up to 1 year after randomization ] [ Designated as safety issue: No ]
    Rate of patients with partial or complete response according to modified RECIST criteria.


Secondary Outcome Measures:
  • Rate of resected patients without early relaps [ Time Frame: 6 months after resection ] [ Designated as safety issue: No ]
    Rate of patients who had a R0 resection of all lesions and are disease free for at least 6 months in the ITT population.


Other Outcome Measures:
  • R0 resection rate [ Time Frame: up to 1 year after randomization ] [ Designated as safety issue: No ]
    Resection rate, defined as patients with microscopically complete (R0) resection (ITT- population)

  • Resection rate [ Time Frame: up to 1 year after randomization ] [ Designated as safety issue: No ]
    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)

  • Progression free survival [ Time Frame: up to 3 years after randomization ] [ Designated as safety issue: No ]
    Progression free survival (Medium, Kaplan-Meier-estimation, ITT- population)

  • Disease free survival after resection [ Time Frame: up to 3 years after resection ] [ Designated as safety issue: No ]
    Disease free survival after resection (Medium, Kaplan-Meier-estimation, resected patients)

  • Overall survival [ Time Frame: up to 5 year after randomization ] [ Designated as safety issue: Yes ]
    Overall survival (Kaplan-Meier-estimation, ITT- population)

  • Toxicity [ Time Frame: up to 1 year after randomization ] [ Designated as safety issue: Yes ]
    Toxicity according to NCI-CTC criteria v. 4.0 Perioperative toxicity according to Clavien

  • Pathological response [ Time Frame: up to 1 year after randomization ] [ Designated as safety issue: No ]
    Pathological response in the resected tumour tissue

  • Molecular markers [ Time Frame: up to 1 year after randomization ] [ Designated as safety issue: No ]
    Evaluation of molecular predictive markers for response (i.e. other mutations in EGFR signalling pathway, EGFR ligands) and toxicity


Estimated Enrollment: 256
Study Start Date: February 2013
Estimated Study Completion Date: July 2020
Estimated Primary Completion Date: July 2017 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Active Comparator: 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

Drug: Cetuximab
Other Name: Erbitux
Drug: Irinotecan
Other Name: Campto
Drug: 5-FU
Other Name: 5-Fluorouracil
Drug: Folinic Acid
Other Name: Leukovorin
Experimental: 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

Drug: Cetuximab
Other Name: Erbitux
Drug: Irinotecan
Other Name: Campto
Drug: Oxaliplatin
Other Name: Eloxatin
Drug: 5-FU
Other Name: 5-Fluorouracil
Drug: Folinic Acid
Other Name: Leukovorin
Active Comparator: 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

Drug: Irinotecan
Other Name: Campto
Drug: Oxaliplatin
Other Name: Eloxatin
Drug: 5-FU
Other Name: 5-Fluorouracil
Drug: Folinic Acid
Other Name: Leukovorin
Experimental: 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

Drug: Bevacizumab
Other Name: Avastin
Drug: Irinotecan
Other Name: Campto
Drug: Oxaliplatin
Other Name: Eloxatin
Drug: 5-FU
Other Name: 5-Fluorouracil
Drug: Folinic Acid
Other Name: Leukovorin

  Show Detailed Description

  Eligibility

Ages Eligible for Study:   18 Years and older
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No
Criteria

Patients can be enrolled, if all of these conditions apply:

  1. Non-resectable, histologically confirmed, synchronous or metachronous colorectal liver metastases.
  2. 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)

  3. Patients with simultaneous liver metastases are eligible,

    1. if the primary tumour was resected at least 1 month prior to chemotherapy or
    2. 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.

  4. WHO PS ≤ 1
  5. Written informed consent
  6. 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)
  7. Age ≥ 18 years

Exclusion Criteria:

  1. Any evidence of extrahepatic metastases, distant lymph node metastases and primary tumour recurrence
  2. (deleted)
  3. 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)
  4. Radiotherapy or major abdominal or thoracic surgery (excluding diagnostic interventions or venous port implantation) ≤ 4 weeks before study entry
  5. 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
  6. Hypertension with an arterial blood pressure > 150/90 mmHg
  7. 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)
  8. Known proteinuria > 1 g/day (to be tested if proteinuria more than 1+ in the urinary dipstick analysis)
  9. Peripheral neuropathy > CTC grade I
  10. Concurrent systemic immune therapy, chemotherapy, hormone therapy, or patients receiving immune suppressive treatment (i.e. for transplantation, severe rheumatologic disease)
  11. Participation in clinical trials with investigational agents within 30 days before start of the treatment in study
  12. Active treatment of

    1. peptic ulcers or bleeding erosive esophagitis / gastritis within 3 months before study
    2. pulmonary embolism, severe or unstable angina pectoris or myocardial infarction, stroke or transient ischemic attack within 12 months before study
    3. deep vein thrombosis within 4 weeks before study
  13. Inflammatory bowel disease
  14. 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
  15. History of brain metastases
  16. History of severe psychiatric illness
  17. Active drug- or alcohol abuse
  18. Known hepatitis B or C or HIV infection
  19. Breast- feeding or pregnant women
  20. Lack of effective contraception (for male and female patients)
  21. Known intolerance to one of the following drugs: cetuximab, bevacizumab, oxaliplatin, irinotecan, 5-FU, folinic acid
  Contacts and Locations
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT01802645

Contacts
Contact: Gunnar Folprecht, PD Dr. +49 351 458 4794 Gunnar.Folprecht@uniklinikum-dresden.de
Contact: Olga Schubert +49 351 79 656 20 Olga.Schubert@uniklinikum-dresden.de

Locations
Germany
Universitätsklinikum der RWTH Aachen Recruiting
Aachen, Germany, 52074
Contact: Ulf-Peter Neumann, Prof. Dr.    0241 8085660    chirurgie@ukaachen.de   
Principal Investigator: Ulf-Peter Neumann, Prof. Dr.         
Charité Campus Virchow Recruiting
Berlin, Germany, 13353
Contact: Daniel Seehofer, PD Dr. med.    030/ 450 652062    daniel.seehofer@charite.de   
Principal Investigator: Daniel Seehofer, PD Dr. med.         
Überörtliche Gemeinschaftspraxis Hämatologie/ Onkologie Not yet recruiting
Bocholt, Germany, 46397
Contact: Volker Burstedde, Dr. med.    02871/2182669    Dr.burstedde@gmx.de   
Klinikum Coburg GmbH Not yet recruiting
Coburg, Germany, 96450
Contact: Christof Lamberti, PD Dr. med.    09561 / 22-5413    christof.lamberti@klinikum-coburg.de   
Onkologie Dülmen GbR Not yet recruiting
Coesfeld, Germany, 48653
Contact: Manfred Glados, Dr. med.    02541/971893    onko-studien@glados.eu   
Universitätsklinikum Carl Gustav Carus Recruiting
Dresden, Germany, 01307
Contact: Gunnar Folprecht, PD Dr. med.    +49 351 458 4794    Gunnar.Folprecht@uniklinikum-dresden.de   
Contact: Olga Schubert    +49 351 7965620    olga.schubert@uniklinikum-dresden.de   
Principal Investigator: Gunnar Folprecht, PD Dr. med.         
Klinikum der Johann Wolfgang Goethe Universität Frankfurt am Main Recruiting
Frankfurt/ Main, Germany, 60590
Contact: Wolf Otto Bechstein, Prof. Dr.       wolf.bechstein@kgu.de   
Universitätsmedizin Göttingen Recruiting
Göttingen, Germany, 37075
Contact: Torsten Liersch, PD Dr. med.    0551/ 398323    tliersch@chirurgie-goettingen.de   
Principal Investigator: Torsten Liersch, PD Dr. med.         
Universitätsklinikum Hamburg-Eppendorf Recruiting
Hamburg, Germany, 20246
Contact: Dirk Arnold, Prof. Dr.    040/ 7410 55489    d.arnold@uke.de   
Principal Investigator: Dirk Arnold, Prof. Dr.         
Klinikum Landshut gGmbH Recruiting
Landshut, Germany, 84034
Contact: Florian Loehe, Prof. Dr.    0871 698 3338    florian.loehe@klinikum-landshut.de   
University hospital Leipzig Recruiting
Leipzig, Germany, 04103
Contact: Florian Lordick, Pr.    +49 341 97 12560    Florian.Lordick@medizin.uni-leipzig.de   
Principal Investigator: Florian Lordick, Pr.         
Johannes-Gutenberg-Universität Recruiting
Mainz, Germany, 55131
Contact: Markus Möhler, PD Dr.    +49 6131 17 6863    markus.moehler@unimedizin-mainz.de   
Principal Investigator: Markus Möhler, PD Dr.         
Klinikum Oldenburg GmbH Recruiting
Oldenburg, Germany, 26133
Contact: Claus-Henning Köhne, Prof. Dr.    +49 441 403-2610    onkologie@klinikum-oldenburg.de   
Principal Investigator: Claus-Henning Köhne, Prof.         
Rems-Murr-Klinikum Winnenden Not yet recruiting
Winnenden, Germany, 71364
Contact: Markus Schaich, Prof. Dr.    07195-591 39240    Markus.Schaich@rems-murr-kliniken.de   
Universitätsklinikum Würzburg Recruiting
Würzburg, Germany, 97080
Contact: Volker Kunzmann, PD Dr. med.    0931/20140746    kunzmann_v@medizin.uni-wuerzburg.de   
Principal Investigator: Volker Kunzmann, PD Dr. med.         
Sponsors and Collaborators
Technische Universität Dresden
Investigators
Principal Investigator: Gunnar Folprecht, PD Dr. University hospital "Carl Gustav Carus" Dresden
  More Information

No publications provided

Responsible Party: Technische Universität Dresden
ClinicalTrials.gov Identifier: NCT01802645     History of Changes
Other Study ID Numbers: TUD-CELIM2-050, 2011-003288-31
Study First Received: February 11, 2013
Last Updated: September 25, 2014
Health Authority: Germany: Paul-Ehrlich-Institut

Keywords provided by Technische Universität Dresden:
neoadjuvant
cetuximab
irinotecan
bevacizumab
oxaliplatin
5-FU
Resection
colorectal liver metastases
liver resection
Chemotherapy
k-ras
non-resectable

Additional relevant MeSH terms:
Colorectal Neoplasms
Neoplasm Metastasis
Colonic Diseases
Digestive System Diseases
Digestive System Neoplasms
Gastrointestinal Diseases
Gastrointestinal Neoplasms
Intestinal Diseases
Intestinal Neoplasms
Neoplasms
Neoplasms by Site
Neoplastic Processes
Pathologic Processes
Rectal Diseases
Bevacizumab
Cetuximab
Folic Acid
Irinotecan
Levoleucovorin
Oxaliplatin
Angiogenesis Inhibitors
Angiogenesis Modulating Agents
Antidotes
Antineoplastic Agents
Antineoplastic Agents, Phytogenic
Enzyme Inhibitors
Growth Inhibitors
Growth Substances
Hematinics
Hematologic Agents

ClinicalTrials.gov processed this record on October 29, 2014