| Eligibility |
Inclusion Criteria:
- 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)
- 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
- Primary tumour tissue available and patient consents to storage and molecular and
genetic profiling of tumour material. Molecular profiling of blood samples is
optionally performed.
- Females of childbearing potential (FCBPs) and men must agree to use highly effec-tive
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 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 the presence of hepatic metastases, ALAT and ASAT =
5 x ULN)
- INR < 1.5 and aPTT < 1.5 x ULN (patients without anticoagulation). Therapeu-tic
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) = 50 mL/min
- Adequate cardiac function: ECG and echocardiogram with a LVEF of = 55%
- 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
chemo-therapy or radiochemotherapy of the primary tumour in curative treatment
intention = 6 months.
- Any relevant toxicities of prior treatments must have resolved
Exclusion Criteria:
- Proof of a RAS mutation (KRAS or NRAS, exons 2, 3, 4 in the tumor (proven in the
primary tumor or metastasis) or absence of testing for RAS mutation
- Primarily resectable metastases and the patient wishes for resection
- = Grade II heart failure (NYHA classification)
- Myocardial infarction, balloon angioplasty (PTCA) with or without stenting, and
cere-bral vascular accident/stroke within the past 12 months before start of study
treat-ment, unstable angina pectoris, serious cardiac arrhythmia according to
investigator's judgement requiring medication.
- Pre-existing pulmonary fibrosis or immune pneumonitis
- Active autoimmune disease that might be negatively affected by an immune check-point
inhibitor. Patients with diabetes type I, vitiligo, psoriasis, or hypo- or
hyperthyroid diseases not requiring immunosuppressive treatment are eligible.
- Prior organ transplantation, including allogeneic stem cell transplantation
- Current use of immunosuppressive medication, except for the following:
- Intranasal, inhaled, topical steroids, or local steroid injection (e.g.,
intra-articular injection);
- Systemic corticosteroids at physiologic doses = 10 mg/day of prednisone or
equivalent;
- Steroids as premedication for hypersensitivity reactions (e.g., CT scan
pre-medication).
- 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
con-sent or not allowing conduct of the study
- Additional cancer treatment (chemotherapy, radiation, immunotherapy or hormone
treatment) during the study treatment in first-line and third-line treatment
(treatments that are conducted as part of an anthroposophic or homeopathic treatment
approach, e.g. mistletoe therapy do not represent an exclusion criterion)
- Previous chemotherapy for the colorectal cancer with the exception of adjuvant
treatment, completed at least 6 months before entering the study
- Toxicity > Grade 1 that has not yet resolved, attributed to a previous treatment or
measure for treatment of the mCRC. However, alopecia (all grades) and
oxaliplatin-induced neurotoxicity = Grade 2 are acceptable.
- 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
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,
avelumab and chemically related substances and/or hypersensitivity to any of the
components in the formulations of the aforementioned substances, including known
hypersensitivi-ty 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
- Patients with known brain metastases. In case of clinical suspicion of brain
metastasis a cranial CT or MRI must be performed to rule out brain metastasis before
study in-clusion.
- History of acute or subacute intestinal occlusion, inflammatory bowel disease, im-mune
colitis or chronic diarrhoea
- Symptomatic peritoneal carcinosis
- Severe, non-healing wounds, ulcers or bone fractures
- Patients with active infection requiring systemic therapy
- Known history of testing positive for HIV or known acquired immunodeficiency
syn-drome.
- 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;
sero-logic tests required).
- Requirement for immunisation with live vaccine under the study treatment.
- Haemorrhagic diathesis or known thrombophilia
- Known DPD deficiency (specific screening not required)
- Known glucuronidation deficiency (Gilbert's syndrome) (specific screening not
re-quired)
- History of a second primary malignancy during the past 5 years before inclusion in the
study or during participation in the study, with the exception of a basal cell or
squamous cell carcinoma of the skin or cervical carcinoma in situ, if these were
treated curatively.
- Known history of alcohol or drug abuse
- Any other severe acute or chronic concomitant disease or medical condition including
psychiatric conditions (including recent i.e. within the past year or active suicidal
idea-tion or behavior) or laboratory abnormalities that may increase the risk
associated with study participation or study treatment administration or may interfere
with the in-terpretation of study results and, in the judgment of the investigator,
would make the patient inappropriate for entry into this study.
- Absent or restricted legal capacity
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