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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)

9 settembre 2019 aggiornato da: Technische Universität Dresden

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.

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.

Panoramica dello studio

Stato

Sconosciuto

Condizioni

Intervento / Trattamento

Descrizione dettagliata

Patients with liver metastases from colorectal and without known extrahepatic metastases will be screened for this study including ras status (b-raf status according to local standard).

Patients receive chemotherapy according to the allocation and are re-evaluated for resectability every 8 weeks for a maximum of 6 months. Resectable patients will be resected and receive an adjuvant treatment to complete 12 cycles.

In certain circumstances, a second resection is allowed within the study.

Patients will be randomized using a web-based computer system that allows randomization if the key basic characteristics are entered.

Patients with ras wild-type tumours will be randomized to receive:

  • Cetuximab/FOLFIRI or
  • Cetuximab/FOLFOXIRI

Patients with ras mutations will be randomized to receive:

  • FOLFOXIRI or
  • FOLFOXIRI/bevacizumab

Chemotherapy doses are adjusted to the risk of toxicity in all treatment arms.

Stratification will be performed according to:

  • Number of metastases (< 5 vs. ≥ 5 metastases)
  • Primary tumour in situ
  • Centre

Treatment regimens For dose reductions and conditions to continue please refer to the full protocol.

All drugs are used within the label and approved doses.

B-raf mutations are determined according to local standard. If a b-raf mutation is known before randomization, the investigator can consider the patient as ras wildtype OR as ras mutant patient.

Cetuximab/FOLFIRI :

Cetuximab 400 mg/m² (first dose, 2 h), then 250 mg/m² (1 h) weekly Irinotecan 180 mg/m², 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

Cetuximab/FOLFOXIRI:

Cetuximab 400 mg/m² (first dose, 2 h), then 250 mg/m² (1 h) weekly Irinotecan 125 mg/m² , 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

FOLFOXIRI:

Irinotecan 165 mg/m², 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

Bevacizumab/FOLFOXIRI:

Bevacizumab 5 mg/kg (90 - 30 min i.v.), Irinotecan 165 mg/m², 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

Evaluation for response and resections Patients are evaluated for response by the same imaging technique as at baseline every 8 weeks. The findings will be discussed for resectability within two weeks after tumour assessment in a local multidisciplinary team.

Technically resectable patients should be offered liver resection. The treatment will continue until liver resection or for a maximum of six months (12 cycles).

Adjuvant treatment After liver resection, an adjuvant treatment is recommended with the same schedule as preoperatively, for a maximum combined pre- and postoperative treatment of 12 cycles. If less than three postoperative cycles remain, no postoperative treatment will be started (see chapter 9.10).

Follow up After resection, patients will be followed up for 5 years after randomization. This includes

  • imaging and clinical investigation every three months for the first 2 years, then every six months (patients without tumour progression / recurrence)
  • survival status and surgical/medical treatment every three months for the first 2 years and then every six months (all patients)

Tipo di studio

Interventistico

Iscrizione (Effettivo)

91

Fase

  • Fase 2

Contatti e Sedi

Questa sezione fornisce i recapiti di coloro che conducono lo studio e informazioni su dove viene condotto lo studio.

Luoghi di studio

  • Germania
      • Aachen, Germania, 52074
        • Universitätsklinikum der RWTH Aachen
      • Berlin, Germania, 13353
        • Charité Campus Virchow
      • Bocholt, Germania, 46397
        • Überörtliche Gemeinschaftspraxis Hämatologie/ Onkologie
      • Coburg, Germania, 96450
        • Klinikum Coburg GmbH
      • Coesfeld, Germania, 48653
        • Onkologie Dülmen GbR
      • Dresden, Germania, 01307
        • Universitätsklinikum Carl Gustav Carus
      • Frankfurt/ Main, Germania, 60590
        • Klinikum der Johann Wolfgang Goethe Universität Frankfurt am Main
      • Göttingen, Germania, 37075
        • Universitatsmedizin Gottingen
      • Hamburg, Germania, 20246
        • Universitatsklinikum Hamburg-Eppendorf
      • Landshut, Germania, 84034
        • Klinikum Landshut gGmbH
      • Leipzig, Germania, 04103
        • University Hospital Leipzig
      • Mainz, Germania, 55131
        • Johannes-Gutenberg-Universität
      • Oldenburg, Germania, 26133
        • Klinikum Oldenburg GmbH
      • Winnenden, Germania, 71364
        • Rems-Murr-Klinikum Winnenden
      • Würzburg, Germania, 97080
        • Universitatsklinikum Wurzburg

Criteri di partecipazione

I ricercatori cercano persone che corrispondano a una certa descrizione, chiamata criteri di ammissibilità. Alcuni esempi di questi criteri sono le condizioni generali di salute di una persona o trattamenti precedenti.

Criteri di ammissibilità

Età idonea allo studio

18 anni e precedenti (Adulto, Adulto più anziano)

Accetta volontari sani

No

Sessi ammissibili allo studio

Tutto

Descrizione

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

Piano di studio

Questa sezione fornisce i dettagli del piano di studio, compreso il modo in cui lo studio è progettato e ciò che lo studio sta misurando.

Come è strutturato lo studio?

Dettagli di progettazione

  • Scopo principale: Trattamento
  • Assegnazione: Randomizzato
  • Modello interventistico: Assegnazione parallela
  • Mascheramento: Nessuno (etichetta aperta)

Armi e interventi

Gruppo di partecipanti / Arm
Intervento / Trattamento
Comparatore attivo: 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
Droga: Cetuximab
Altri nomi:
  • Erbitux
Droga: Irinotecano
Altri nomi:
  • Campto
Droga: 5-FU
Altri nomi:
  • 5-Fluorouracile
Droga: Acido folinico
Altri nomi:
  • Leucovorin
Sperimentale: 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
Droga: Oxaliplatino
Altri nomi:
  • Eloxatina
Droga: Cetuximab
Altri nomi:
  • Erbitux
Droga: Irinotecano
Altri nomi:
  • Campto
Droga: 5-FU
Altri nomi:
  • 5-Fluorouracile
Droga: Acido folinico
Altri nomi:
  • Leucovorin
Comparatore attivo: 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
Droga: Oxaliplatino
Altri nomi:
  • Eloxatina
Droga: Irinotecano
Altri nomi:
  • Campto
Droga: 5-FU
Altri nomi:
  • 5-Fluorouracile
Droga: Acido folinico
Altri nomi:
  • Leucovorin
Sperimentale: 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
Droga: Oxaliplatino
Altri nomi:
  • Eloxatina
Droga: Bevacizumab
Altri nomi:
  • Avastin
Droga: Irinotecano
Altri nomi:
  • Campto
Droga: 5-FU
Altri nomi:
  • 5-Fluorouracile
Droga: Acido folinico
Altri nomi:
  • Leucovorin

Cosa sta misurando lo studio?

Misure di risultato primarie

Misura del risultato
Misura Descrizione
Lasso di tempo
Response rate
Lasso di tempo: up to 1 year after randomization
Rate of patients with partial or complete response according to modified RECIST criteria.
up to 1 year after randomization

Misure di risultato secondarie

Misura del risultato
Misura Descrizione
Lasso di tempo
Rate of resected patients without early relaps
Lasso di tempo: 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.
6 months after resection

Altre misure di risultato

Misura del risultato
Misura Descrizione
Lasso di tempo
R0 resection rate
Lasso di tempo: up to 1 year after randomization
Resection rate, defined as patients with microscopically complete (R0) resection (ITT- population)
up to 1 year after randomization
Resection rate
Lasso di tempo: 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)
up to 1 year after randomization
Progression free survival
Lasso di tempo: up to 3 years after randomization
Progression free survival (Medium, Kaplan-Meier-estimation, ITT- population)
up to 3 years after randomization
Disease free survival after resection
Lasso di tempo: up to 3 years after resection
Disease free survival after resection (Medium, Kaplan-Meier-estimation, resected patients)
up to 3 years after resection
Overall survival
Lasso di tempo: up to 5 year after randomization
Overall survival (Kaplan-Meier-estimation, ITT- population)
up to 5 year after randomization
Toxicity
Lasso di tempo: up to 1 year after randomization
Toxicity according to NCI-CTC criteria v. 4.0 Perioperative toxicity according to Clavien
up to 1 year after randomization
Pathological response
Lasso di tempo: up to 1 year after randomization
Pathological response in the resected tumour tissue
up to 1 year after randomization
Molecular markers
Lasso di tempo: 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
up to 1 year after randomization

Collaboratori e investigatori

Qui è dove troverai le persone e le organizzazioni coinvolte in questo studio.

Sponsor

Technische Universität Dresden

Investigatori

  • Investigatore principale: Gunnar Folprecht, PD Dr., University hospital "Carl Gustav Carus" Dresden

Studiare le date dei record

Queste date tengono traccia dell'avanzamento della registrazione dello studio e dell'invio dei risultati di sintesi a ClinicalTrials.gov. I record degli studi e i risultati riportati vengono esaminati dalla National Library of Medicine (NLM) per assicurarsi che soddisfino specifici standard di controllo della qualità prima di essere pubblicati sul sito Web pubblico.

Studia le date principali

Inizio studio (Effettivo)

1 marzo 2013

Completamento primario (Anticipato)

1 settembre 2019

Completamento dello studio (Anticipato)

1 dicembre 2020

Date di iscrizione allo studio

Primo inviato

11 febbraio 2013

Primo inviato che soddisfa i criteri di controllo qualità

28 febbraio 2013

Primo Inserito (Stima)

1 marzo 2013

Aggiornamenti dei record di studio

Ultimo aggiornamento pubblicato (Effettivo)

11 settembre 2019

Ultimo aggiornamento inviato che soddisfa i criteri QC

9 settembre 2019

Ultimo verificato

1 settembre 2019

Maggiori informazioni

Termini relativi a questo studio

Parole chiave

Termini MeSH pertinenti aggiuntivi

Altri numeri di identificazione dello studio

  • TUD-CELIM2-050
  • 2011-003288-31 (Numero EudraCT)

Queste informazioni sono state recuperate direttamente dal sito web clinicaltrials.gov senza alcuna modifica. In caso di richieste di modifica, rimozione o aggiornamento dei dettagli dello studio, contattare register@clinicaltrials.gov. Non appena verrà implementata una modifica su clinicaltrials.gov, questa verrà aggiornata automaticamente anche sul nostro sito web .

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Condizioni

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Sponsor / Collaboratori

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