Cetuximab/FOLFIRI With or Without Oxaliplatin and FOLFOXIRI With or Without Bevacizumab in Neoadjuvant Treatment of Non-resectable Colorectal Liver Metastases (CELIM2)
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.
Visão geral do estudo
Status
Condições
Descrição detalhada
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 de estudo
Inscrição (Real)
Estágio
- Fase 2
Contactos e Locais
Locais de estudo
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Aachen, Alemanha, 52074
- Universitatsklinikum der RWTH Aachen
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Berlin, Alemanha, 13353
- Charité Campus Virchow
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Bocholt, Alemanha, 46397
- Überörtliche Gemeinschaftspraxis Hämatologie/ Onkologie
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Coburg, Alemanha, 96450
- Klinikum Coburg GmbH
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Coesfeld, Alemanha, 48653
- Onkologie Dülmen GbR
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Dresden, Alemanha, 01307
- Universitatsklinikum Carl Gustav Carus
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Frankfurt/ Main, Alemanha, 60590
- Klinikum der Johann Wolfgang Goethe Universität Frankfurt am Main
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Göttingen, Alemanha, 37075
- Universitätsmedizin Göttingen
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Hamburg, Alemanha, 20246
- Universitätsklinikum Hamburg-Eppendorf
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Landshut, Alemanha, 84034
- Klinikum Landshut gGmbH
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Leipzig, Alemanha, 04103
- University Hospital Leipzig
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Mainz, Alemanha, 55131
- Johannes-Gutenberg-Universität
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Oldenburg, Alemanha, 26133
- Klinikum Oldenburg GmbH
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Winnenden, Alemanha, 71364
- Rems-Murr-Klinikum Winnenden
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Würzburg, Alemanha, 97080
- Universitatsklinikum Wurzburg
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Critérios de participação
Critérios de elegibilidade
Idades elegíveis para estudo
Aceita Voluntários Saudáveis
Gêneros Elegíveis para o Estudo
Descrição
Patients can be enrolled, if all of these conditions apply:
- Non-resectable, histologically confirmed, synchronous or metachronous colorectal liver metastases.
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)
Patients with simultaneous liver metastases are eligible,
- if the primary tumour was resected at least 1 month prior to chemotherapy or
- 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.
- WHO PS ≤ 1
- Written informed consent
- 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)
- Age ≥ 18 years
Exclusion Criteria:
- Any evidence of extrahepatic metastases, distant lymph node metastases and primary tumour recurrence
- (deleted)
- 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)
- Radiotherapy or major abdominal or thoracic surgery (excluding diagnostic interventions or venous port implantation) ≤ 4 weeks before study entry
- 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
- Hypertension with an arterial blood pressure > 150/90 mmHg
- 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)
- Known proteinuria > 1 g/day (to be tested if proteinuria more than 1+ in the urinary dipstick analysis)
- Peripheral neuropathy > CTC grade I
- Concurrent systemic immune therapy, chemotherapy, hormone therapy, or patients receiving immune suppressive treatment (i.e. for transplantation, severe rheumatologic disease)
- Participation in clinical trials with investigational agents within 30 days before start of the treatment in study
Active treatment of
- peptic ulcers or bleeding erosive esophagitis / gastritis within 3 months before study
- pulmonary embolism, severe or unstable angina pectoris or myocardial infarction, stroke or transient ischemic attack within 12 months before study
- deep vein thrombosis within 4 weeks before study
- Inflammatory bowel disease
- 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
- History of brain metastases
- History of severe psychiatric illness
- Active drug- or alcohol abuse
- Known hepatitis B or C or HIV infection
- Breast- feeding or pregnant women
- Lack of effective contraception (for male and female patients)
- Known intolerance to one of the following drugs: cetuximab, bevacizumab, oxaliplatin, irinotecan, 5-FU, folinic acid
Plano de estudo
Como o estudo é projetado?
Detalhes do projeto
- Finalidade Principal: Tratamento
- Alocação: Randomizado
- Modelo Intervencional: Atribuição Paralela
- Mascaramento: Nenhum (rótulo aberto)
Armas e Intervenções
Grupo de Participantes / Braço |
Intervenção / Tratamento |
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Comparador Ativo: 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 |
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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 |
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Comparador Ativo: 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 |
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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 |
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O que o estudo está medindo?
Medidas de resultados primários
Medida de resultado |
Descrição da medida |
Prazo |
|---|---|---|
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Response rate
Prazo: up to 1 year after randomization
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Rate of patients with partial or complete response according to modified RECIST criteria.
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up to 1 year after randomization
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Medidas de resultados secundários
Medida de resultado |
Descrição da medida |
Prazo |
|---|---|---|
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Rate of resected patients without early relaps
Prazo: 6 months after resection
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Rate of patients who had a R0 resection of all lesions and are disease free for at least 6 months in the ITT population.
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6 months after resection
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Outras medidas de resultado
Medida de resultado |
Descrição da medida |
Prazo |
|---|---|---|
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R0 resection rate
Prazo: up to 1 year after randomization
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Resection rate, defined as patients with microscopically complete (R0) resection (ITT- population)
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up to 1 year after randomization
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Resection rate
Prazo: up to 1 year after randomization
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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)
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up to 1 year after randomization
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Progression free survival
Prazo: up to 3 years after randomization
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Progression free survival (Medium, Kaplan-Meier-estimation, ITT- population)
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up to 3 years after randomization
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Disease free survival after resection
Prazo: up to 3 years after resection
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Disease free survival after resection (Medium, Kaplan-Meier-estimation, resected patients)
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up to 3 years after resection
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Overall survival
Prazo: up to 5 year after randomization
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Overall survival (Kaplan-Meier-estimation, ITT- population)
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up to 5 year after randomization
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Toxicity
Prazo: up to 1 year after randomization
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Toxicity according to NCI-CTC criteria v. 4.0 Perioperative toxicity according to Clavien
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up to 1 year after randomization
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Pathological response
Prazo: up to 1 year after randomization
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Pathological response in the resected tumour tissue
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up to 1 year after randomization
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Molecular markers
Prazo: up to 1 year after randomization
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Evaluation of molecular predictive markers for response (i.e.
other mutations in EGFR signalling pathway, EGFR ligands) and toxicity
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up to 1 year after randomization
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Colaboradores e Investigadores
Patrocinador
Investigadores
- Investigador principal: Gunnar Folprecht, PD Dr., University hospital "Carl Gustav Carus" Dresden
Datas de registro do estudo
Datas Principais do Estudo
Início do estudo (Real)
Conclusão Primária (Antecipado)
Conclusão do estudo (Antecipado)
Datas de inscrição no estudo
Enviado pela primeira vez
Enviado pela primeira vez que atendeu aos critérios de CQ
Primeira postagem (Estimativa)
Atualizações de registro de estudo
Última Atualização Postada (Real)
Última atualização enviada que atendeu aos critérios de controle de qualidade
Última verificação
Mais Informações
Termos relacionados a este estudo
Palavras-chave
Termos MeSH relevantes adicionais
- Processos Patológicos
- Neoplasias
- Processos Neoplásicos
- Neoplasia Metástase
- Efeitos Fisiológicos das Drogas
- Mecanismos Moleculares de Ação Farmacológica
- Inibidores Enzimáticos
- Antimetabólitos, Antineoplásicos
- Antimetabólitos
- Agentes Antineoplásicos
- Agentes imunossupressores
- Fatores imunológicos
- Agentes de proteção
- Inibidores da Topoisomerase
- Agentes Antineoplásicos Imunológicos
- Inibidores de angiogênese
- Agentes Moduladores da Angiogênese
- Substâncias de crescimento
- Inibidores de crescimento
- Micronutrientes
- Vitaminas
- Inibidores da Topoisomerase I
- Antídotos
- Complexo de Vitamina B
- Hematínicos
- Fluorouracil
- Oxaliplatina
- Bevacizumabe
- Leucovorina
- Irinotecano
- Levoleucovorina
- Ácido fólico
- Cetuximabe
Outros números de identificação do estudo
- TUD-CELIM2-050
- 2011-003288-31 (Número EudraCT)
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