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Cetuximab in Neoadjuvant Treatment of Non-Resectable Colorectal Liver Metastases (CELIM)

Primary Purpose

Colorectal Cancer, Liver Metastases

Status
Completed
Phase
Phase 2
Locations
International
Study Type
Interventional
Intervention
Cetuximab
Liver resection
Cetuximab and FOLFIRI
Cetuximab and FOLFOX
Sponsored by
Technische Universität Dresden
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional treatment trial for Colorectal Cancer focused on measuring Cetuximab, Oxaliplatin, Irinotecan, 5-FU, Chemotherapy, Resection, Liver resection, Neoadjuvant

Eligibility Criteria

18 Years - undefined (Adult, Older Adult)All SexesDoes not accept healthy volunteers

Inclusion Criteria: Patients with non-resectable, histologically confirmed, synchronous or metachronous colorectal liver metastases. Patients with non-resectable metastases are defined as; patients with five or more liver metastases; and/or patients with liver metastases that are technically non-resectable (local surgeon in cooperation with local radiologist will define non-resectability on the basis of remaining functional liver tissue, infiltration of all liver veins, infiltration of both liver arteries, both portal branches or both bile ducts). Patients with simultaneous liver metastases are eligible, if the primary tumor has been resected at least 1 month prior to chemotherapy. Karnofsky Performance Status ≥ 80 Informed consent Adequate bone marrow function, liver and renal function (neutrophils > 1.5 x 10^9/l; thrombocytes > 100 x 10^9/l; hemoglobin > 8.0 g/l; bilirubin ≤ 1.5 x upper limit of normal [ULN] and not increasing more than 25% within the last 4 weeks; ALAT and ASAT < 5 x UNL; serum creatinine ≤ 1.5 x UNL) Age ≥ 18 years Exclusion Criteria: Any evidence of extrahepatic metastases, lymph node metastases and primary tumor recurrence Prior chemotherapy (except adjuvant chemotherapy with an interval of ≥ 6 months) Previous exposure to EGFR (epidermal growth factor receptor)-targeting therapy Radiotherapy or major abdominal or thoracic surgery (excluding diagnostic biopsy or port implantation) ≤ 4 weeks before study entry Concurrent systemic immune therapy, chemotherapy, or hormone therapy Investigational agents or participation in clinical trials within 30 days before start of the treatment in study Clinically relevant coronary disease or myocardial infarction within 12 months before study entry Peripheral neuropathy > CTC grade I Inflammatory bowel disease Previous malignancy (except colorectal cancer, history of basal cell carcinoma of skin or pre-invasive carcinoma of the cervix with adequate treatment) History of severe psychiatric illness Drug or alcohol abuse Breast feeding or pregnant women, no effective contraception if risk of conception exists (male and female patients)

Sites / Locations

  • Medizinische Universitaet Wien, Universitaetsklinik für Chirurgie
  • Kreiskrankenhaus Aschersleben
  • Charite-Campus Benjamin Franklin, Innere Medizin
  • Charite-Campus, Virchow-Klinikum, Innere Medizin
  • Allgemeines Krankenhaus Celle
  • University Hospital "Carl Gustav Carus"
  • Florence-Nightingale-Krankenhaus
  • Universitaet Erlangen-Nuernberg, Chirurgie
  • Westdeutsches Tumorzentrum, Universitaetsklinikum Essen
  • Johann Wolfgang Goethe Universitaet, Chirurgie
  • Westpfalz-Klinikum GmbH Innere Medizin I
  • UKSH Campus Kiel, II. Medizinische Klinik
  • Staedtisches Klinikum Magdeburg-Olvenstedt
  • Universitaetsklinik Mannheim gGmbH, III. Medizinische Klinik
  • Klinikum Grosshadern, III. Medizinische Klinik
  • Klinikum Oldenburg GmbH
  • Klinikum Passau, II. Medizinische Klinik
  • Klinikum der Hansestadt Stralsund GmbH, Medizinische Klinik
  • Krankenhaus der Barmherzigen Brueder Trier, Chirurgie
  • Universitaetsklinikum Tuebingen
  • Universitaetsklinikum Wuerzburg, Chirurgie

Arms of the Study

Arm 1

Arm 2

Arm Type

Active Comparator

Active Comparator

Arm Label

1

2

Arm Description

Cetuximab and FOLFIRI

Cetuximab and FOLFOX

Outcomes

Primary Outcome Measures

Tumor response, defined as partial and complete response according to RECIST (Response Evaluation Criteria in Solid Tumors) - criteria in the intention-to-treat [ITT-] population

Secondary Outcome Measures

Rate of R0 liver resection (ITT- population)
Progression free survival (ITT- population)
Disease free survival after resection (ITT- population)
Overall survival (ITT- population)
Safety (all patients that received any study drug)
Molecular predictive markers for response and toxicity

Full Information

First Posted
September 8, 2005
Last Updated
February 26, 2009
Sponsor
Technische Universität Dresden
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1. Study Identification

Unique Protocol Identification Number
NCT00153998
Brief Title
Cetuximab in Neoadjuvant Treatment of Non-Resectable Colorectal Liver Metastases (CELIM)
Official Title
Open, Randomized, Multicenter, Randomized Phase II Trial Comparing the Combination of Cetuximab With Oxaliplatin/5-FU/FA Versus the Combination of Cetuximab With Irinotecan/5-FU/FA as Neoadjuvant Treatment in Patients With Non-Resectable Colorectal Liver Metastases
Study Type
Interventional

2. Study Status

Record Verification Date
April 2007
Overall Recruitment Status
Completed
Study Start Date
November 2004 (undefined)
Primary Completion Date
March 2008 (Actual)
Study Completion Date
undefined (undefined)

3. Sponsor/Collaborators

Name of the Sponsor
Technische Universität Dresden

4. Oversight

Data Monitoring Committee
No

5. Study Description

Brief Summary
General Objectives: To test the feasibility of neoadjuvant treatment with cetuximab/chemotherapy followed by liver resection To determine the optimal combination (cetuximab/FOLFOX versus cetuximab/FOLFIRI) for further trials in preoperative chemotherapy
Detailed Description
Patients with liver metastasis will be screened for this study. Eligible patients will complete the pretreatment evaluation including an abdominal CT scan that will be presented to the local surgeon and the radiologist for proving of resectability of hepatic lesions. Additionally, CT scans will be reviewed by three reference surgeons. In case of non-resectability, as defined above, CT- or ultrasound- guided biopsy of one of the liver metastases will be performed, unless biopsy material is available from prior biopsy of one of the liver metastases. Instead of an ultrasound-guided biopsy, a CT-guided biopsy may be performed. Formalin-fixed, paraffin embedded metastatic tissue will be sent to reference laboratory (Prof. Störkel, Wuppertal) for immunohistochemical analysis of EGFR- expression. Additionally tissue will be stored in "RNA later" for gene expression analysis if agreed by the patient. Additionally, the primary tumor will be collected and sent to the reference laboratory for analysis of EGFR- expression (if agreement of the patient exists). Patients will be randomized to a combination of: Cetuximab/FOLFIRI (irinotecan/5-FU/FA) or Cetuximab/FOLFOX6 (oxaliplatin/5-FU/FA) All patients receive a four month treatment (eight cycles) of the allocated treatment. Resection is planned after completion of neoadjuvant treatment and should be performed between 4 and 6 weeks after the last dose of chemotherapy. Probes of the resected material (in liquid nitrogen and paraffin embedded material will be collected). If a resection is not possible after eight administrations of chemotherapy, chemotherapy will be continued until tumor progression (maximal duration of treatment 2 years) and the patient will be evaluated for a potential resection every two months. After resection, postoperative treatment is planned for 3 months (6 cycles). Treatment start is planned between 4 and 8 weeks after the operation.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Colorectal Cancer, Liver Metastases
Keywords
Cetuximab, Oxaliplatin, Irinotecan, 5-FU, Chemotherapy, Resection, Liver resection, Neoadjuvant

7. Study Design

Primary Purpose
Treatment
Study Phase
Phase 2
Interventional Study Model
Parallel Assignment
Masking
None (Open Label)
Allocation
Randomized
Enrollment
135 (Actual)

8. Arms, Groups, and Interventions

Arm Title
1
Arm Type
Active Comparator
Arm Description
Cetuximab and FOLFIRI
Arm Title
2
Arm Type
Active Comparator
Arm Description
Cetuximab and FOLFOX
Intervention Type
Drug
Intervention Name(s)
Cetuximab
Intervention Type
Procedure
Intervention Name(s)
Liver resection
Intervention Type
Drug
Intervention Name(s)
Cetuximab and FOLFIRI
Other Intervention Name(s)
Cetuximab(C225, Erbitux®, Merck KGaA), Irinotecan (irinotecan HCl, CPT-11 or Campto®, Aventis), 5-Fluorouracil (5-FU), Folinic acid (FA, i.e. Leucovorin®, Wyeth)
Intervention Description
Cetuximab 400 mg/m² (2.0 h i.v.) (first dose only), followed by: Cetuximab 250 mg/m² (1.0 h i.v.) weekly Irinotecan 180 mg/m² (2.0 h i.v.) all compounds day 1, repeated at day 15 Folinic acid (D,L) 400 mg/m² (2.0 h i.v.) 5-FU 400 mg/m² (bolus i.v.) 5-FU 2400 (-3000) mg/m² (46 h i.v.)
Intervention Type
Drug
Intervention Name(s)
Cetuximab and FOLFOX
Other Intervention Name(s)
Cetuximab(C225, Erbitux®, Merck KGaA), Oxaliplatin (L-OHP, Eloxatin®, Sanofi-Synthelabo), 5-Fluorouracil (5-FU), Folinic acid (FA, i.e. Leucovorin®, Wyeth)
Intervention Description
Cetuximab 400 mg/m² (2.0 h i.v.) (first dose only), followed by: Cetuximab 250 mg/m² (1.0 h i.v.) weekly Oxaliplatin 100 mg/m² (2.0 h i.v.) all compounds day 1, repeated at day 15 Folinic acid (D,L) 400 mg/m² (2.0 h i.v.) 5-FU 400 mg/m² (bolus i.v.) 5-FU 2400 (-3000) mg/m² (46 h i.v.)
Primary Outcome Measure Information:
Title
Tumor response, defined as partial and complete response according to RECIST (Response Evaluation Criteria in Solid Tumors) - criteria in the intention-to-treat [ITT-] population
Secondary Outcome Measure Information:
Title
Rate of R0 liver resection (ITT- population)
Title
Progression free survival (ITT- population)
Title
Disease free survival after resection (ITT- population)
Title
Overall survival (ITT- population)
Title
Safety (all patients that received any study drug)
Title
Molecular predictive markers for response and toxicity

10. Eligibility

Sex
All
Minimum Age & Unit of Time
18 Years
Accepts Healthy Volunteers
No
Eligibility Criteria
Inclusion Criteria: Patients with non-resectable, histologically confirmed, synchronous or metachronous colorectal liver metastases. Patients with non-resectable metastases are defined as; patients with five or more liver metastases; and/or patients with liver metastases that are technically non-resectable (local surgeon in cooperation with local radiologist will define non-resectability on the basis of remaining functional liver tissue, infiltration of all liver veins, infiltration of both liver arteries, both portal branches or both bile ducts). Patients with simultaneous liver metastases are eligible, if the primary tumor has been resected at least 1 month prior to chemotherapy. Karnofsky Performance Status ≥ 80 Informed consent Adequate bone marrow function, liver and renal function (neutrophils > 1.5 x 10^9/l; thrombocytes > 100 x 10^9/l; hemoglobin > 8.0 g/l; bilirubin ≤ 1.5 x upper limit of normal [ULN] and not increasing more than 25% within the last 4 weeks; ALAT and ASAT < 5 x UNL; serum creatinine ≤ 1.5 x UNL) Age ≥ 18 years Exclusion Criteria: Any evidence of extrahepatic metastases, lymph node metastases and primary tumor recurrence Prior chemotherapy (except adjuvant chemotherapy with an interval of ≥ 6 months) Previous exposure to EGFR (epidermal growth factor receptor)-targeting therapy Radiotherapy or major abdominal or thoracic surgery (excluding diagnostic biopsy or port implantation) ≤ 4 weeks before study entry Concurrent systemic immune therapy, chemotherapy, or hormone therapy Investigational agents or participation in clinical trials within 30 days before start of the treatment in study Clinically relevant coronary disease or myocardial infarction within 12 months before study entry Peripheral neuropathy > CTC grade I Inflammatory bowel disease Previous malignancy (except colorectal cancer, history of basal cell carcinoma of skin or pre-invasive carcinoma of the cervix with adequate treatment) History of severe psychiatric illness Drug or alcohol abuse Breast feeding or pregnant women, no effective contraception if risk of conception exists (male and female patients)
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Claus-Henning Köhne, Prof. Dr.
Organizational Affiliation
Klinikum Oldenburg GmbH, Dr.-Eden-Str.10; 26133 Oldenburg
Official's Role
Principal Investigator
First Name & Middle Initial & Last Name & Degree
Gunnar Folprecht, Dr.
Organizational Affiliation
University Hospital Dresden, Fetscherstr. 74, 01307 Dresden, Germany
Official's Role
Principal Investigator
Facility Information:
Facility Name
Medizinische Universitaet Wien, Universitaetsklinik für Chirurgie
City
Wien
ZIP/Postal Code
A-1090
Country
Austria
Facility Name
Kreiskrankenhaus Aschersleben
City
Aschersleben
ZIP/Postal Code
06449
Country
Germany
Facility Name
Charite-Campus Benjamin Franklin, Innere Medizin
City
Berlin
ZIP/Postal Code
12200
Country
Germany
Facility Name
Charite-Campus, Virchow-Klinikum, Innere Medizin
City
Berlin
ZIP/Postal Code
13353
Country
Germany
Facility Name
Allgemeines Krankenhaus Celle
City
Celle
ZIP/Postal Code
29223
Country
Germany
Facility Name
University Hospital "Carl Gustav Carus"
City
Dresden
ZIP/Postal Code
01307
Country
Germany
Facility Name
Florence-Nightingale-Krankenhaus
City
Duesseldorf
ZIP/Postal Code
40489
Country
Germany
Facility Name
Universitaet Erlangen-Nuernberg, Chirurgie
City
Erlangen
ZIP/Postal Code
91054
Country
Germany
Facility Name
Westdeutsches Tumorzentrum, Universitaetsklinikum Essen
City
Essen
ZIP/Postal Code
45112
Country
Germany
Facility Name
Johann Wolfgang Goethe Universitaet, Chirurgie
City
Frankfurt Main
ZIP/Postal Code
60596
Country
Germany
Facility Name
Westpfalz-Klinikum GmbH Innere Medizin I
City
Kaiserslautern
ZIP/Postal Code
67653
Country
Germany
Facility Name
UKSH Campus Kiel, II. Medizinische Klinik
City
Kiel
ZIP/Postal Code
24116
Country
Germany
Facility Name
Staedtisches Klinikum Magdeburg-Olvenstedt
City
Magdeburg
ZIP/Postal Code
39130
Country
Germany
Facility Name
Universitaetsklinik Mannheim gGmbH, III. Medizinische Klinik
City
Mannheim
ZIP/Postal Code
68167
Country
Germany
Facility Name
Klinikum Grosshadern, III. Medizinische Klinik
City
Muenchen
ZIP/Postal Code
81377
Country
Germany
Facility Name
Klinikum Oldenburg GmbH
City
Oldenburg
ZIP/Postal Code
26133
Country
Germany
Facility Name
Klinikum Passau, II. Medizinische Klinik
City
Passau
ZIP/Postal Code
94032
Country
Germany
Facility Name
Klinikum der Hansestadt Stralsund GmbH, Medizinische Klinik
City
Stralsund
ZIP/Postal Code
18435
Country
Germany
Facility Name
Krankenhaus der Barmherzigen Brueder Trier, Chirurgie
City
Trier
ZIP/Postal Code
54292
Country
Germany
Facility Name
Universitaetsklinikum Tuebingen
City
Tuebingen
ZIP/Postal Code
72076
Country
Germany
Facility Name
Universitaetsklinikum Wuerzburg, Chirurgie
City
Wuerzburg
ZIP/Postal Code
97080
Country
Germany

12. IPD Sharing Statement

Citations:
PubMed Identifier
24585720
Citation
Folprecht G, Gruenberger T, Bechstein W, Raab HR, Weitz J, Lordick F, Hartmann JT, Stoehlmacher-Williams J, Lang H, Trarbach T, Liersch T, Ockert D, Jaeger D, Steger U, Suedhoff T, Rentsch A, Kohne CH. Survival of patients with initially unresectable colorectal liver metastases treated with FOLFOX/cetuximab or FOLFIRI/cetuximab in a multidisciplinary concept (CELIM study). Ann Oncol. 2014 May;25(5):1018-25. doi: 10.1093/annonc/mdu088. Epub 2014 Feb 27.
Results Reference
derived
PubMed Identifier
19942479
Citation
Folprecht G, Gruenberger T, Bechstein WO, Raab HR, Lordick F, Hartmann JT, Lang H, Frilling A, Stoehlmacher J, Weitz J, Konopke R, Stroszczynski C, Liersch T, Ockert D, Herrmann T, Goekkurt E, Parisi F, Kohne CH. Tumour response and secondary resectability of colorectal liver metastases following neoadjuvant chemotherapy with cetuximab: the CELIM randomised phase 2 trial. Lancet Oncol. 2010 Jan;11(1):38-47. doi: 10.1016/S1470-2045(09)70330-4. Epub 2009 Nov 26.
Results Reference
derived

Learn more about this trial

Cetuximab in Neoadjuvant Treatment of Non-Resectable Colorectal Liver Metastases (CELIM)

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