Randomised study to investigate FOLFOXIRI plus Cetuximab or FOLFOXIRI plus bevacizumab as first-line treatment of BRAF-mutated metastatic colorectal cancer (FIRE 4.5)

Phase 1

• Conditions: 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; Therapeutic area: Diseases [C] - Cancer [C04]; RAS wild-type tumour status (KRAS and NRAS exons 2, 3, 4) (proven in the primary tumour or metastasis); BRAF-mutated (V600E) tumour (proven in the primary tumour or metastasis); MedDRA version: 21.0Level: LLTClassification code 10052362Term: Metastatic colorectal cancerSystem Organ Class: 100000004864

• Registration Number: EUCTR2015-004849-11-DE
• Lead Sponsor: niversity Clinic od Munich-Großhadern (represented by the medical management)

Brief Summary

Not available

Detailed Description

Not available

Study Timeline

• Results First Posted: 1900-01-01
• Study Start: 2016-07-04
• Last Update Posted: 19 February 2024

Recruitment & Eligibility

• Status: ot Recruiting
• Sex: All
• Target Recruitment: 108

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 <1) for the duration of the study treatment and for at least 6 months after last administration of the study medication. A female subject will be considered to be of child-bearing potential unless she is = 50 years of age as well as has had a natural menopause for at least 2 years or has been surgically sterilised
• Adequate bone marrow function:
•Leukocytes = 3.0 x 109/L with neutrophils = 1.5 x 109/L
•Thrombocytes = 100 x 109/L,
•Haemoglobin = 5.6 mmol/L (equivalent to 9 g/dL)
•Adequate hepatic function:
- Serum bilirubin = 1.5 x upper limit of normal (ULN),
- ALAT and ASAT = 2.5 x ULN (in case of hepatic metastases, ALAT and ASAT = 5 x ULN)
•INR < 1.5 and aPTT < 1.5 x ULN (patients without anticoagulation). Therapeutic anticoagulation is allowed if INR and aPTT have remained stable within the therapeutic range for at least 2 weeks.
•Adequate renal function:
?Serum creatinine = 1.5 x ULN or creatinine clearance (calculated according to Cockcroft and Gault) = 50ml/min.
•Adequate cardiac function: ECG and echocardiogram with a LVEF of =55%
•No previous chemotherapy for metastatic disease (prior radiotherapy of metastasis/metastases without application of chemotherapy permitted provided that no radiated metastasis is selected as target lesion). Patients with need of immediate treatment (high tumour load, symptoms) may have received one cycle of FOLFOX, FOLFIRI or FOLFOXIRI prior to randomisation (Cycle 0).
•Time interval since last administration of any previous neoadjuvant/adjuvant chemotherapy or radiochemotherapy =3 months
• Any relevant toxicities of previous treatments must have subsided to grade 0

Are the trial subjects under 18? no
Number of subjects for this age range:
F.1.2 Adults (18-64 years) yes
F.1.2.1 Number of subjects for this age range
F.1.3 Elderly (>=65 years) yes
F.1.3.1 Number of subjects for this age range

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

Study & Design

• Study Type: Interventional clinical trial of medicinal product
• Study Design: Not specified