Modulation of the FOLFIRI-based standard 1st-line therapy with cetuximab, controlled by monitoring the RAS mutation load by liquid biopsy in RAS-mutated mCRC patients
- Conditions
- C19Malignant neoplasm of rectosigmoid junction
- Registration Number
- DRKS00023034
- Lead Sponsor
- TheraOp gGmbH
- Brief Summary
Not available
- Detailed Description
Not available
Recruitment & Eligibility
- Status
- Complete
- Sex
- All
- Target Recruitment
- 6
Histologically confirmed, UICC stage IV adenocarcinoma of the left-sided colon or rectum with metastases (metastatic colorectal cancer), primarily non-resectable, confirmed RAS mutations proven in the primary tumor or metastasis (KRAS and NRAS exon 2, 3, 4)
- Age = 18 years on day of signing informed consent
- No previous chemotherapy for metastatic disease (1- 2 cycles FOLFIRI or mFOLFIRI are permitted before enrolment until RAS status is determined)
- Patients suitable for chemotherapy administration
- ECOG performance status 0-1
- Consent to liquid biopsy and mutation analysis
- Estimated life expectancy > 3 months
- Presence of at least one measurable reference lesion according to the RECIST 1.1 criteria (chest CT and abdominal CT 4 weeks or less before enrollment)
-Adequate bone marrow function defined as:
o Leukocytes 3.0 x 109/L with neutrophils 1.5 x 109/L
o Thrombocytes 100 x 109/L
o Hemoglobin 9 g/dL
- Adequate hepatic function defined as:
o Serum bilirubin 1.5 x ULN
o ALAT and ASAT 2.5 x ULN (in the presence of hepatic metastases, ALAT and ASAT 5 x ULN)
- Adequate renal function: Creatinine clearance =50 mL/min
- Adequate cardiac function defined as
o Normal ECG and echocardiogram with a left ventricular ejection fraction (LVEF) of 55%
- 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.
- Time interval of at least 6 months since last administration of any previous neoadjuvant/adjuvant chemotherapy or radiochemotherapy of the primary tumor in curative treatment intention to start of 1st line treatment
- Any relevant toxicities of prior treatments must have resolved to grade = 1 according to the CTCAE (version 5), except alopecia
- Women of childbearing potential (WOCBP) should have a negative urine pregnancy test within 72 hours prior to receiving the first dose of study medication.
- Highly effective contraception for both male and female patients throughout the study and for at least 3 months after last dose of study medication administration if the risk of conception exists. Highly effective contraception has to be in line with the definition of the CTFG (Clinical Trial Facilitation Group) recommendation
- Signed written informed consent and capacity of understanding the informed consent
- Right sided mCRC
- Primarily resectable metastases
- Previous chemotherapy for the colorectal cancer with the exception of adjuvant treatment, completed at least 6 months before entering the study
- Patients with known brain metastases
- Symptomatic peritoneal carcinosis
- Progressive disease before randomization
- History of acute or subacute intestinal occlusion, inflammatory bowel disease, immune colitis or chronic diarrhea
- 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 enrollment, unstable angina pectoris, serious cardiac arrhythmia according to investigator’s judgment requiring medication
- Active infection with hepatitis B or C
- Medical or psychological impairments associated with restricted ability to give consent or not allowing conduct of the study
- Additional cancer; Exceptions include adequately treated basal cell carcinoma of the skin, squamous cell carcinoma of the skin, or in situ cervical cancer that has undergone potentially curative therapy without evidence of recurrence
- Uncontrolled hypertension
- Marked proteinuria (nephrotic syndrome)
- Arterial thromboembolism or severe hemorrhage within 6 months prior to randomization (with the exception of tumor bleeding before tumor resection surgery)
- Hemorrhagic diathesis or tendency towards thrombosis
- Participation in a clinical study or experimental drug treatment within 30 days prior to study
- Known hypersensitivity or allergic reaction to any of the study medications
- Severe, non-healing wounds, ulcers, bone fractures or an infection requiring systemic therapy
- Known history of alcohol or drug abuse
- Complete dihydropyrimidine dehydrogenase (DPD) deficiency (phenotype and/or genotype test)
(Patients with partial DPD deficiency may be included in this clinical trial at the discretion of the investigator and should receive a reduced starting 5-FU dose)
- Known glucuronidation deficiency (Gilbert's syndrome) (specific screening not required)
- Absent or restricted legal capacity
- For female patients only: Pregnancy (absence to be confirmed by ß-HCG test) or lactating
Study & Design
- Study Type
- interventional
- Study Design
- Not specified
- Primary Outcome Measures
Name Time Method The primary objective is to evaluate efficacy in terms of progression free survival (PFS) from the date of randomization in the study according to Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1 criteria in experimental and control arms.
- Secondary Outcome Measures
Name Time Method - Overall survival (OS) in experimental and control arms from date of randomization<br>- Time to failure of treatment strategy (TFTS) in experimental and control arms after randomization<br>- PFS rate 1 year after date of randomization<br>- Depth of response in terms of reduction of tumor mass in experimental and control arms after start of 1st line treatment<br>- Metastasis resections in experimental and control arms after start of 1st line treatment<br>- Objective response rate (ORR) defined as patients with partial or complete response (CR + PR) in experimental and control arms after start of 1st line treatment<br>- Safety profile according to CTCAE, Version 5.0 criteria in experimental and control arms recorded from the date of signature of Informed Consent<br>