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

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ClinicalTrials.gov Identifier: NCT01802645
Recruitment Status : Active, not recruiting
First Posted : March 1, 2013
Last Update Posted : September 11, 2019
Sponsor:
Information provided by (Responsible Party):
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.

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

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Study Type : Interventional  (Clinical Trial)
Actual Enrollment : 91 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (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.
Actual Study Start Date : March 2013
Estimated Primary Completion Date : September 2019
Estimated Study Completion Date : December 2020

Resource links provided by the National Library of Medicine


Arm Intervention/treatment
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




Primary Outcome Measures :
  1. Response rate [ Time Frame: up to 1 year after randomization ]
    Rate of patients with partial or complete response according to modified RECIST criteria.


Secondary Outcome Measures :
  1. Rate of resected patients without early relaps [ Time Frame: 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.


Other Outcome Measures:
  1. R0 resection rate [ Time Frame: up to 1 year after randomization ]
    Resection rate, defined as patients with microscopically complete (R0) resection (ITT- population)

  2. Resection rate [ Time Frame: up to 1 year after randomization ]
    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)

  3. Progression free survival [ Time Frame: up to 3 years after randomization ]
    Progression free survival (Medium, Kaplan-Meier-estimation, ITT- population)

  4. Disease free survival after resection [ Time Frame: up to 3 years after resection ]
    Disease free survival after resection (Medium, Kaplan-Meier-estimation, resected patients)

  5. Overall survival [ Time Frame: up to 5 year after randomization ]
    Overall survival (Kaplan-Meier-estimation, ITT- population)

  6. Toxicity [ Time Frame: up to 1 year after randomization ]
    Toxicity according to NCI-CTC criteria v. 4.0 Perioperative toxicity according to Clavien

  7. Pathological response [ Time Frame: up to 1 year after randomization ]
    Pathological response in the resected tumour tissue

  8. Molecular markers [ Time Frame: up to 1 year after randomization ]
    Evaluation of molecular predictive markers for response (i.e. other mutations in EGFR signalling pathway, EGFR ligands) and toxicity



Information from the National Library of Medicine

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, Learn About Clinical Studies.


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Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
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

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT01802645


Locations
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Germany
Universitätsklinikum der RWTH Aachen
Aachen, Germany, 52074
Charité Campus Virchow
Berlin, Germany, 13353
Überörtliche Gemeinschaftspraxis Hämatologie/ Onkologie
Bocholt, Germany, 46397
Klinikum Coburg GmbH
Coburg, Germany, 96450
Onkologie Dülmen GbR
Coesfeld, Germany, 48653
Universitätsklinikum Carl Gustav Carus
Dresden, Germany, 01307
Klinikum der Johann Wolfgang Goethe Universität Frankfurt am Main
Frankfurt/ Main, Germany, 60590
Universitätsmedizin Göttingen
Göttingen, Germany, 37075
Universitätsklinikum Hamburg-Eppendorf
Hamburg, Germany, 20246
Klinikum Landshut gGmbH
Landshut, Germany, 84034
University hospital Leipzig
Leipzig, Germany, 04103
Johannes-Gutenberg-Universität
Mainz, Germany, 55131
Klinikum Oldenburg GmbH
Oldenburg, Germany, 26133
Rems-Murr-Klinikum Winnenden
Winnenden, Germany, 71364
Universitätsklinikum Würzburg
Würzburg, Germany, 97080
Sponsors and Collaborators
Technische Universität Dresden
Investigators
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Principal Investigator: Gunnar Folprecht, PD Dr. University hospital "Carl Gustav Carus" Dresden
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Responsible Party: Technische Universität Dresden
ClinicalTrials.gov Identifier: NCT01802645    
Other Study ID Numbers: TUD-CELIM2-050
2011-003288-31 ( EudraCT Number )
First Posted: March 1, 2013    Key Record Dates
Last Update Posted: September 11, 2019
Last Verified: September 2019
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:
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Neoplasm Metastasis
Neoplasms
Neoplastic Processes
Pathologic Processes
Leucovorin
Folic Acid
Bevacizumab
Cetuximab
Fluorouracil
Oxaliplatin
Irinotecan
Levoleucovorin
Antineoplastic Agents, Immunological
Antineoplastic Agents
Angiogenesis Inhibitors
Angiogenesis Modulating Agents
Growth Substances
Physiological Effects of Drugs
Growth Inhibitors
Antimetabolites
Molecular Mechanisms of Pharmacological Action
Antimetabolites, Antineoplastic
Immunosuppressive Agents
Immunologic Factors
Topoisomerase I Inhibitors
Topoisomerase Inhibitors
Enzyme Inhibitors
Antidotes
Protective Agents
Vitamin B Complex