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

Colorectal Cancer Clinical Trial

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

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT00153998
• Other study ID #: CELIM
• Status: Completed
• Phase: Phase 2
• First received: September 8, 2005
• Last updated: February 26, 2009
• Start date: November 2004

Study information

• Verified date: April 2007
• Source: Technische Universität Dresden
• Contact: n/a
• Is FDA regulated: No
• Health authority: Germany: Paul-Ehrlich-Institut
• Study type: Interventional

Clinical Trial 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

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.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 135
• Est. primary completion date: March 2008
• Accepts healthy volunteers: No
• Gender: Both
• Age group: 18 Years and older

Eligibility

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)

Study Design

Allocation: Randomized, Endpoint Classification: Efficacy Study, Intervention Model: Parallel Assignment, Masking: Open Label, Primary Purpose: Treatment

Related Conditions & MeSH terms

• Colorectal Cancer
• Liver Metastases
• Liver Neoplasms
• Neoplasm Metastasis

Intervention

Drug:
• Cetuximab

Procedure:
• Liver resection

Drug:
• 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.)
• 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.)

Locations

Country	Name	City	State
Austria	Medizinische Universitaet Wien, Universitaetsklinik für Chirurgie	Wien
Germany	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	Duesseldorf
Germany	Universitaet Erlangen-Nuernberg, Chirurgie	Erlangen
Germany	Westdeutsches Tumorzentrum, Universitaetsklinikum Essen	Essen
Germany	Johann Wolfgang Goethe Universitaet, Chirurgie	Frankfurt 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	Muenchen
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	Tuebingen
Germany	Universitaetsklinikum Wuerzburg, Chirurgie	Wuerzburg

Sponsors (1)

Lead Sponsor	Collaborator
Technische Universität Dresden

Countries where clinical trial is conducted

Austria,  Germany, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	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	Rate of R0 liver resection (ITT- population)
Secondary	Progression free survival (ITT- population)
Secondary	Disease free survival after resection (ITT- population)
Secondary	Overall survival (ITT- population)
Secondary	Safety (all patients that received any study drug)
Secondary	Molecular predictive markers for response and toxicity