Histologically confirmed, UICC stage IV adenocarcinoma of the left-sided colon or rectum with metastases (metastatic colorectal cancer), primarily non-resectable or surgery refused by the patient, confirmed RAS mutations proven in the primary tumor or metastasis (KRAS and NRAS exon 2, 3, 4) MedDRA version: 21.0 Level: PT Classification code 10061451 Term: Colorectal cancer System Organ Class: 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Conditions
Interventions
Trade Name: Erbitux
Pharmaceutical Form: Infusion
INN or Proposed INN: CETUXIMAB
CAS Number: 205923-56-4
Concentration unit: mg/ml milligram(s)/millilitre
Concentration type: equal
Concentration numbe
Sponsors
TheraOp gGmbH
Eligibility
Sex/Gender
All
Inclusion criteria
Inclusion criteria: • 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 =65 years) yes F.1.3.1 Number of subjects for this age range 75
Exclusion criteria
Exclusion criteria: • 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 (1- 2 cycles FOLFIRI or mFOLFIRI are permitted before enrolment) • 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
Design outcomes
Primary
| Measure | Time frame |
|---|---|
| Main Objective: The aim of this randomized study is to evaluate whether patients with left sided RAS-mutant mCRC at diagnosis will derive a benefit from the adaptation of adding cetuximab to first-line therapy (FOLFIRI) after RAS-mutation status has changed to wild-type and changing back to FOLFIRI, as required if RAS-mutation status has changed to mutant, depending upon, and monitored by longitudinal ctDNA liquid biopsies. The primary objective is to evaluate efficacy in terms of progression free survival (PFS) from 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 Objective: • Overall survival (OS) in experimental and control arms from date of randomization • Time to failure of treatment strategy (TFTS) in experimental and control arms after randomization • PFS rate 1 year after date of randomization • Depth of response in terms of reduction of tumor mass in experimental and control arms after start of 1st line treatment • Metastasis resections in experimental and control arms after start of 1st line treatment • 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 • Safety profile according to CTCAE, Version 5.0 criteria in experimental and control arms recorded from the date of signature of Informed Consent ;Primary end point(s): 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.;Timepoint(s) of evaluation of this end point: PFS from the date of randomization until date of progression or date of death, whichever occurs first. | — |
Secondary
| Measure | Time frame |
|---|---|
| Secondary end point(s): • OS in experimental and control arms • TFTS in experimental and control arms • PFS rate • Depth of response in terms of reduction of tumor mass in experimental and control arms • Percentage of patients with metastasis resections in experimental and control arms • ORR defined as patients with partial or complete response (CR + PR) in experimental and control arms • Safety profile according to CTCAE, Version 5.0 criteria in experimental and control arms;Timepoint(s) of evaluation of this end point: • OS: until death from any cause • TFTS: after randomization to failure of treatment strategy • PFS rate: 1 year after date of randomization • Depth of response (DpR): The time for DpR assessment varies between patients relating to the individual achievement of maximal tumor shrinkage, which typically occurs 4–6 months after the start of 1st-line therapy. • Percentage of patients with metastasis resections: until the end of the treatment strategy. • ORR: from start of 1st line therapy until documentation of CR or PR as best response • Safety: during whole study | — |
Countries
Germany
Contacts
Public ContactPD Dr. med. Alexander Baraniskin
Evangelisches Krankenhaus Hamm
Outcome results
None listed