Randomised study of the efficacy of cetuximab rechallenge in patients with metastatic colorectal cancer (RAS wild-type) responding to first-line treatment with FOLFIRI plus cetuximab
- Conditions
- Histologically confirmed, UICC stage IV adenocarcinoma of the colon or rectum (metastatic colorectal cancer), primarily non-resectable or with surgery refused by the patientMedDRA version: 27.0Level: LLTClassification code 10052362Term: Metastatic colorectal cancerSystem Organ Class: 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps)Therapeutic area: Diseases [C] - Cancer [C04]
- Registration Number
- EUCTR2014-003787-21-DE
- Lead Sponsor
- Klinikum der Ludwig-Maximilians-Univ. Münch , Klinikum Großhadern (vertreten durch die kaufmännische Direktion)
- Brief Summary
Not available
- Detailed Description
Not available
Recruitment & Eligibility
- Status
- Authorised-recruitment may be ongoing or finished
- Sex
- All
- Target Recruitment
- 700
Criteria for inclusion in the study (Part 1 and 2)
- Histologically confirmed, UICC stage IV adenocarcinoma of the colon or rectum with metastases (metastatic colorectal cancer), metastases primarily non-resectable or surgery refused by the Patient
-RAS wild-type tumour status (KRAS and NRAS exon 2, 3, 4), proven in the primary tumour or metastasis prior to each randomisation time point.
Only for inclusion in part 2: If a repeated tumour biopsy is infeasible or poses an unacceptable risk to the patient as assessed by the investigator, RAS wild-type tumour status determined in liquid biopsy in Laboratory for Immunological Molecular Biology, Universitätsklinikum Knappschafts-krankenhaus Bochum GmbH permitted.
-Age =18
-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 tumour material (patients directly included in part 2 of the study in whom primary tumour material is no longer available may be included in the study. Molecular profiling of blood samples is optionally performed.
-Females of childbearing potential (FCBPs) and men must agree to use highly effective contraceptive measures (Pearl index <1) or practice true abstinence from any heterosexual intercourse (true abstinence is acceptable when this is in line with the preferred and usual lifestyle of the subject) for the duration of the study treatment and for at least 6 months after last administration of study medication. A woman will be considered as being of childbearing potential unless she is at least 50 years old and moreover has gone through menopause for at least 2 years or has been surgically sterilised.
-Adequate haematopoietic 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,
ALAT and ASAT = 2.5 x ULN (in the presence of hepatic metastases, ALAT and ASAT = 5 x uULN)
-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: Creatinine clearance (calculated according to Cockcroft and Gault) = 50ml/min.
- adequate cardiac function: ECG and echocardiogram with a LVEF of =55%
Inclusion criterion solely for Part 1:
-No previous chemotherapy for metastatic disease. Patient with need of immediate treatment (high tumour load, symptoms) may have received one application of FOLFIRI prior to study entry
-Time interval since last administration of any previous neoadjuvant/adjuvant chemotherapy or radiochemotherapy of the primary tumour in curative treatment intention = 6 months
-Any relevant toxicities of prior treatments must have resolved
Additional inclusion criteria solely for Part 2:
-Prior first-line treatment of the metastatic colorectal cancer with cetuximab or panitumumab in combination with FOLFIRI or FOLFOX or FOLFOXIRI; data available for the duration of treatment and the response within the context of first-line treatment
-Within the maintena
-Proof of a RAS mutation (KRAS/NRAS, exons 2, 3, 4 in the tumour (proven in the primary tumour or metastasis) or liquid biopsy (permitted only prior to Part 2) or absence of testing for RAS mutation- Primarily resect. metast. and the pat. wishes for resection
-= Grade II heart failure (NYHA classification)
-Myocardial infarction, balloon angioplasty (PTCA) with or without stenting, and cerebral vascular accident/stroke within the past 12 months before rando. 1 or before rando. 2, unstable angina pectoris, serious cardiac arrhythmia accord. to investigator’s judgement requiring medication
-Pre-existing pulmonary fibrosis or immune pneumonitis
-Pregnancy (absence of pregnancy to be ascertained by a negative beta hCG test) or breast feeding
-Medical or psychological impairments associated with restricted ability to give consent or not allowing conduct of the study
-Addit. cancer treat. (chemotherapy, radiation, immunotherapy or hormone treatment) during the study treat. in 1st-line and 3rd-line treat. (treat. that are conducted as part of an anthroposophic or homeopathic treatment approach, e.g. mistletoe therapy does not represent an excl. criterion)
-Previous chemotherapy for the CRC with the exception of adjuvant treat., complet. at least 6 months before entering the study (exclusion criterion solely for part 1)
-Toxicity > Grade 1 that has not yet resolved, attributed to a previous treat. or measure for treat. of the mCRC. However, alopecia (all grades) and oxaliplatin-induced neurotoxicity = Grade 2 are accept. (exclusion criterion only for part 2)
-Participation in a clinical study or experimental drug treat. 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 treat. prior to inclusion in the study, depending on which period is longest or simultaneous participation in another study while taking part in the study
-Known hypersensitivity or allergic reaction to any of the following substances: 5-fluorouracil, folinic acid, capecitabine, cetuximab, irinotecan, bevacizumab and chemically related substances and/or hypersensitivity to any of the components in the formulations of the aforementioned substances, including known hypersensitivity reactions to monoclonal antibodies NCI CTCAE Grade = 3.
-Known hypersensitivity to Chinese hamster ovary cell (CHO) – cellular products or other recombinant human or humanised monoclonal antibodies
-Pat. with known brain metast.. In case of clinical suspicion of brain metastasis a cranial CT or MRI must beperformed to rule out brain metastasis before study inclusion.
-History of acute or subacute intestinal occlusion, inflammatory bowel disease, immune colitis or chronic diarrhoea
-Symptomatic peritoneal carcinosis
-Severe, non-healing wounds, ulcers or bone fractures
-Pat. with active infection requiring systemic therapy
-Known history of testing positive for HIV or known acquired immunodeficiency syndrome.
-Active or chronic Hepatitis B virus (HBV) or hepatitis C virus (HCV) infection (positive HBV surface antigen or HCV RNA if anti-HCV antibody screening test positive; serologic tests required)
-Requirement for immunisation with live vaccine incl. attenuated live vaccine from at least 4 weeks before start of study treatment until 6 months after the administration of chemotherapeutic substances.
-Haemorrhagic diathesis or known thrombophilia
-Known complete DPD deficiency (specific screening
Study & Design
- Study Type
- Interventional clinical trial of medicinal product
- Study Design
- Not specified
- Primary Outcome Measures
Name Time Method
- Secondary Outcome Measures
Name Time Method