Histologically confirmed, UICC stage IV adenocarcinoma of the colon or rectum with metastases (metastatic colorectal cancer, mCRC), primarily non-resectable or surgery refused by the patient
Conditions
Interventions
Trade Name: Erbitux (100 mg)
Pharmaceutical Form: Solution for infusion
INN or Proposed INN: CETUXIMAB
CAS Number: 205923-56-4
Concentration unit: mg/ml milligram(s)/millilitre
Concentration type: equ
Sponsors
University Clinic od Munich-Großhadern (represented by the medical management)
Eligibility
Sex/Gender
All
Inclusion criteria
Inclusion criteria: • Histologically confirmed, UICC stage IV adenocarcinoma of the colon or rectum with metastases (metastatic colorectal cancer, mCRC), primarily non-resectable or surgery refused by the patient • RAS wild-type tumour status (KRAS and NRAS exons 2, 3, 4) (proven in the primary tumour or metastasis) • BRAF V600E mutation-positive tumour (proven in the primary tumour or metastasis) • Age =18 years • ECOG performance status 0-1 • Patients suitable for chemotherapy administration • Patient's written declaration of consent obtained • Estimated life expectancy > 3 months • Presence of at least one measurable reference lesion according to the RECIST 1.1 – criteria (chest X-ray in two planes or chest CT and abdominal CT 4 weeks or less before randomisation) • Primary tumour tissue available and patient consents to storage and molecular and genetic profiling of the tumour material. Molecular profiling of blood samples is optionally performed. • Females of childbearing potential (FCBP) and men must agree to use effective contraceptive measures (Pearl index =65 years) yes F.1.3.1 Number of subjects for this age range
Exclusion criteria
Exclusion criteria: • Grade III or IV heart failure (NYHA classification) • Myocardial infarction, unstable angina pectoris, balloon angioplasty (PTCA) with or without stenting within the past 12 months before randomisation • Pregnancy (absence of pregnancy has to be ascertained by a beta hCG test) or breast feeding • Medical or psychological impairments associated with restricted ability to give consent or not allowing conduct of the study • Additional cancer treatment (chemotherapy, radiation, immune therapy or hormone treatment) during the study treatment. Treatments that are conducted as part of an anthroposophical or homeopathic treatment approach, e.g. mistletoe therapy, do not represent an exclusion criterion. • Previous chemotherapy for the colorectal cancer with exception of chemotherapy or radiochemotherapy given as neoadjuvant or adjuvant treatment with curative intent, completed =3 months before randomisation Further exception: Patients with metastatic disease and need of immediate treatment (high tumour load, symptoms) may have received one cycle of FOLFOX, FOLFIRI or FOLFOXIRI prior to randomisation (Cycle 0). • Participation in a clinical study or experimental drug treatment within 30 days prior to study inclusion or within a period of 5 half-lives of the substances administered in a clinical study or during an experimental drug treatment prior to inclusion in the study, depending on which period is longest, or simultaneous participation in another clinical study while taking part in the study • Known hypersensitivity or allergic reaction to any of the following substances: 5-fluorouracil, folinic acid, cetuximab, irinotecan, bevacizumab, oxaliplatin and chemically related substances and/or hypersensitivity to any of the excipients of any of the aforementioned substances • Known hypersensitivity to CHO (Chinese hamster ovary cells) - cell products or other recombinant human or humanised antibodies • Patients with confirmed cerebral metastases. In case of clinical suspicion of brain metastases, a cranial CT or MRI must be performed to rule out brain metastases before study inclusion. • History of acute or subacute intestinal occlusion or chronic inflammatory bowel disease or chronic diarrhoea. • Symptomatic peritoneal carcinosis • Severe, non-healing wounds, ulcers or bone fractures • Patients with active infection (including confirmed HIV and/or HBV/HCV infection). In case of clinical suspicion of the presence of HIV or HBV/HCV infection, the latter should be ruled out before study inclusion. • Requirement for immunisation with live vaccine including attenuated live vaccine from at least 4 weeks before start of study treatment until 6 months after the administration of the last study medication. • Uncontrolled hypertension • Marked proteinuria (nephrotic syndrome) • Arterial thromboembolism or severe haemorrhage within 6 months prior to randomisation (with the exception of tumour bleeding before tumour resection surgery) • Haemorrhagic diathesis or tendency towards thrombosis • Known complete DPD deficiency (specific screening according to the recommendations of the SmPC in effect for 5-FU or capecitabine, respectively; patients with a known complete DPD deficiency must be excluded; patients with a known partial DPD deficiency may be included at the discretion of the investigator) • Known glucuronidation deficiency (Gilbert's syndrome) (specific screening not required) • Treatment with nucleoside analogues including sorivudine or brivudi
Design outcomes
Primary
| Measure | Time frame |
|---|---|
| Main Objective: To compare the objective response rate (ORR) according to RECIST 1.1 of treatment with FOLFOXIRI plus cetuximab versus treatment with FOLFOXIRI plus bevacizumab in BRAF-mutated patients.;Secondary Objective: • Investigation of progression-free survival (PFS) from randomisation • Investigation of overall survival (OS) from randomisation • Investigation of early tumour shrinkage (ETS) and depth of response (DpR) • Investigation of molecular biomarkers for prediction of sensitivity and secondary resistance of an anti-EGFR treatment with cetuximab (including tumour biopsies and liquid biopsies from blood samples) • Investigation of prospective analysis of tumour marker level evolution (CEA and CA 19-9) • Recording of the safety and tolerability (NCI-CTCAE version 4.03 criteria) of the treatment • Investigation of the sequence of therapy after 1st-line treatment and its impact on OS;Primary end point(s): To compare the objective response rate (ORR) according to RECIST 1.1 of treatment with FOLFOXIRI plus cetuximab versus treatment with FOLFOXIRI plus bevacizumab in BRAF-mutated patients.;Timepoint(s) of evaluation of this end point: Restaging according to RECIST 1.1 will be performed after treatment week 8, 16, 24 and every 12 treatment weeks thereafter. | — |
Secondary
| Measure | Time frame |
|---|---|
| Secondary end point(s): • Investigation of progression-free survival (PFS) from randomisation • Investigation of overall survival (OS) from randomisation • Investigation of early tumour shrinkage (ETS) and depth of response (DpR) • Investigation of molecular biomarkers for prediction of sensitivity and secondary resistance of an anti-EGFR treatment with cetuximab (including tumour biopsies and liquid biopsies from blood samples) • Investigation of prospective analysis of tumour marker evolution (CEA and CA 19-9) • Recording of the safety and tolerability (NCI-CTCAE version 4.03 criteria) of the treatment • Investigation of the sequence of therapy after 1st-line treatment and its impact on OS ;Timepoint(s) of evaluation of this end point: - PFS, ETS and DpR will be analysed according to RECIST 1.1. Restaging will be performed after treatment week 8, 16, 24 and every 12 weeks thereafter - OS will be evaluated in a continously manner, after study treatment every 3 months for up to 2.5 years after last study treatment - tumor markers will be evaluated after treatment week 8, 16, 26, thereafter every 12 weeks, at end of treatment and every 3 months in Follow Up but only untill progression occurs - safety and tolerability will be evaluated in a continously manner - molecular biomarkers will be evaluated before study treatment, after 8 weeks of treatment, after termination of study and on progression | — |
Countries
Germany
Contacts
Public Contactstudy secretariat
Klinikum der Ludwig-Maximilians-Univ. München, Klinikum Großhadern
Outcome results
None listed