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

NCT ID: NCT00153998

Last Updated: 2009-02-27

Basic Information

• Recruitment Status: COMPLETED
• Clinical Phase: PHASE2
• Total Enrollment: 135 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2004-11-30

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.

Conditions

Colorectal Cancer; Liver Metastases

Keywords

Cetuximab; Oxaliplatin; Irinotecan; 5-FU; Chemotherapy; Resection; Liver resection; Neoadjuvant

Study Design

• Allocation Method: RANDOMIZED
• Intervention Model: PARALLEL
• Primary Study Purpose: TREATMENT
• Blinding Strategy: NONE

Study Groups

1

Cetuximab and FOLFIRI

Group Type: ACTIVE_COMPARATOR

Cetuximab

Intervention Type: DRUG

Liver resection

Intervention Type: PROCEDURE

Cetuximab and FOLFIRI

Intervention Type: DRUG

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.)

2

Cetuximab and FOLFOX

Group Type: ACTIVE_COMPARATOR

Cetuximab

Intervention Type: DRUG

Liver resection

Intervention Type: PROCEDURE

Cetuximab and FOLFOX

Intervention Type: DRUG

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.)

Interventions

Cetuximab

Intervention Type: DRUG

Liver resection

Intervention Type: PROCEDURE

Cetuximab and FOLFIRI

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

Cetuximab and FOLFOX

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.)

Intervention Type: DRUG

Other Intervention Names

Cetuximab(C225, Erbitux®, Merck KGaA); Irinotecan (irinotecan HCl, CPT-11 or Campto®, Aventis); 5-Fluorouracil (5-FU); Folinic acid (FA, i.e. Leucovorin®, Wyeth); Cetuximab(C225, Erbitux®, Merck KGaA); Oxaliplatin (L-OHP, Eloxatin®, Sanofi-Synthelabo); 5-Fluorouracil (5-FU); Folinic acid (FA, i.e. Leucovorin®, Wyeth)

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)

• Minimum Eligible Age: 18 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: No

Sponsors

Technische Universität Dresden

OTHER

Sponsor Role: lead

Responsible Party

now: Klinikum Oldenburg gGmbH

Principal Investigators

Claus-Henning Köhne, Prof. Dr.

Role: PRINCIPAL_INVESTIGATOR

Klinikum Oldenburg GmbH, Dr.-Eden-Str.10; 26133 Oldenburg

Gunnar Folprecht, Dr.

Role: PRINCIPAL_INVESTIGATOR

University Hospital Dresden, Fetscherstr. 74, 01307 Dresden, Germany

Locations

Medizinische Universitaet Wien, Universitaetsklinik für Chirurgie

Vienna, , Austria

Kreiskrankenhaus Aschersleben

Aschersleben, , Germany

Charite-Campus Benjamin Franklin, Innere Medizin

Berlin, , Germany

Charite-Campus, Virchow-Klinikum, Innere Medizin

Berlin, , Germany

Allgemeines Krankenhaus Celle

Celle, , Germany

University Hospital "Carl Gustav Carus"

Dresden, , Germany

Florence-Nightingale-Krankenhaus

Düsseldorf, , Germany

Universitaet Erlangen-Nuernberg, Chirurgie

Erlangen, , Germany

Westdeutsches Tumorzentrum, Universitaetsklinikum Essen

Essen, , Germany

Johann Wolfgang Goethe Universitaet, Chirurgie

Frankfurt am Main, , Germany

Westpfalz-Klinikum GmbH Innere Medizin I

Kaiserslautern, , Germany

UKSH Campus Kiel, II. Medizinische Klinik

Kiel, , Germany

Staedtisches Klinikum Magdeburg-Olvenstedt

Magdeburg, , Germany

Universitaetsklinik Mannheim gGmbH, III. Medizinische Klinik

Mannheim, , Germany

Klinikum Grosshadern, III. Medizinische Klinik

München, , Germany

Klinikum Oldenburg GmbH

Oldenburg, , Germany

Klinikum Passau, II. Medizinische Klinik

Passau, , Germany

Klinikum der Hansestadt Stralsund GmbH, Medizinische Klinik

Stralsund, , Germany

Krankenhaus der Barmherzigen Brueder Trier, Chirurgie

Trier, , Germany

Universitaetsklinikum Tuebingen

Tübingen, , Germany

Universitaetsklinikum Wuerzburg, Chirurgie

Würzburg, , Germany

Countries

Austria; Germany

References

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.

Reference Type: DERIVED

PMID: 24585720 (View on PubMed)

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.

Reference Type: DERIVED

PMID: 19942479 (View on PubMed)

Other Identifiers

CELIM

Identifier Type: -

Identifier Source: org_study_id