metastatic colorectal cancer MedDRA version: 21.0 Level: LLT Classification code 10052362 Term: Metastatic colorectal cancer System Organ Class: 100000004864
Conditions
Interventions
Trade Name: Stivarga
Product Name: regorafenib
Pharmaceutical Form: Tablet
Sponsors
Rennes University Hospital
Eligibility
Sex/Gender
All
Inclusion criteria
Inclusion criteria: - Signed and dated informed consent - Male or female patients = 18 years-old at time of Informed Consent Form (ICF) signature - Patients must have a histologically proven metastatic colorectal cancer - Patients who have previously been treated with standard therapy including a fluoropyrimidine, oxaliplatin, irinotecan, bevacizumab and cetuximab or panitumumab for patients who had a RAS wild-type tumour - ECOG PS = 0 or 1 - Imaging target greater than one cm must be visible on CT - Patients must have adequate bone marrow, renal, and hepatic function, as evidenced by the pre-therapeutic check-up performed within 7 days before regorafenib initiation: Normal organ functions as defined below : a. Absolute neutrophil count = 1.3 Giga/L b. Platelets > 100 Giga/L c. Hemoglobin = 9 g/dL d. Serum creatinine = 1.5 x ULN (Upper Limit of Normal) or Glomerular filtration rate (GFR) =30 ml/min/1.73m2 according to the modified Diet in Renal Disease (MDRD) or CKD-EPI (Chronic Kidney Disease Epidemiology Collaboration) abbreviated formula e. AST and ALT =2.5 x ULN (=5.0 × ULN for patients with liver involvement of their cancer) f. Total Bilirubin =1.5 X ULN OR Direct bilirubin = ULN for patients with total bilirubin levels > 1.5 ULN (except for patients with Gilbert disease for whom a total serum bilirubin = 3ULN is acceptable) g. Alkaline phosphatase =3 x ULN (=5 x ULN in patient with liver involvement of their cancer and/or with bone metastases). If Alkaline phosphatase > 3 ULN, hepatic isoenzymes 5-nucleotidase or GGT tests must be performed; hepatic isoenzymes 5-nucleotidase must be within the normal range and/or GGT =65 years) no F.1.3.1 Number of subjects for this age range
Exclusion criteria
Exclusion criteria: - Prior treatment with regorafenib, and with any prior antiangiogenic inhibitor - Hypersensitivity to the active substance or to any of the excipients - Systemic anticancer therapy including cytotoxic therapy, antibodies, immunotherapy =3 weeks prior to start of regorafenib - Concomitant treatment with a cytochrome P450 3A4 (CYP3A4) inducer or inhibitor or UGT1A9 inhibitor - Patients unable to swallow oral medication - Digestive obstruction, chronic inflammatory bowel disease or any malabsorption condition - Previous or concurrent cancer that is distinct in primary site or histology from colorectal cancer within 5 years prior to inclusion, except for curatively treated cervical cancer in situ, non-melanoma skin cancer and superficial bladder tumors (Ta [non-invasive tumor], Tis [carcinoma in situ] and T1 [tumor invades lamina propria]) - Ongoing uncontrolled infection (viral, bacterial or fungal) - Known history of human immunodeficiency virus (HIV) infection, active or chronic hepatitis B or C - Breastfeeding - Uncontrolled hypertension (systolic blood pressure >140 mmHg or diastolic pressure >90 mmHg despite optimal medical management) - Arterial or venous thrombotic or embolic events such as cerebrovascular accident (including transient ischemic attacks), deep vein thrombosis or pulmonary embolism within 6 months before the start of study medication - Unstable angina (angina symptoms at rest), new-onset angina (begun within the last 3 months) - Myocardial infarction less than 6 months before the start of study medication - Any hemorrhage or bleeding event = Grade 3, NCI-CTCAE v 5.0 within 4 weeks prior to the start of study medication - Major surgical procedure, open biopsy or significant traumatic injury within 28 days before start of study medication - Non-healing wound, ulcer or bone fracture - Unresolved toxicity higher than Grade 1, NCI-CTCAE v 5.0, attributed to any prior therapy/procedure excluding alopecia and oxaliplatin induced neuropathy - Any psychological, familial, sociological or geographical condition potentially hampering compliance with the study protocol and follow-up schedule - Adults legally protected (judicial protection, guardianship or supervision), person deprived of their liberty
Design outcomes
Primary
| Measure | Time frame |
|---|---|
| Main Objective: The primary objective of the trial is to determine whether “optimal exposure” to regorafenib based on plasma concentration of the drug and its metabolites can improve overall survival in mCRC patients.;Secondary Objective: To compare between patients with “optimal exposure” versus patients with “non optimal exposure” to regorafenib: 1.the overall survival at 10 months 2.the objective response to treatment 3.the disease control to treatment 4.the time to progression 5.the safety profile of regorafenib To described: 6.the number of patients with “optimal exposure” at each cycle (C1 and C2) To assessed: 7.the prognostic value on overall survival of the accumulation ratio of plasma concentration of M-2 C2/C1 8.the impact of genetic polymorphisms involved in drug metabolism on the pharmacokinetic of regorafenib and its metabolites 9.study the relationships between body composition (sarcopenia and surface of visceral fat) and oa) early toxicities and efficacy of regorafenib and ob) trough blood concentrations of regorafenib 10.the influence of plasma metabolomics biomarkers on regorafenib response;Primary end point(s): The primary endpoint is the overall survival defined as the time from inclusion to death from any cause. Two groups of patients will be defined a posteriori based on trough concentration of regorafenib and active metabolites: •Group with “optimal exposure”: Csum on C1 and/or Csum on C2 within the range [2.5 – 5.5 mg/L]. •Group with “non optimal exposure”: Csum on C1 and Csum on C2 outside the range [2.5 – 5.5 mg/L]. Csum is defined – for each cycle – as the sum of plasma trough concentrations of regorafenib, M-2 and M-5 at steady state of each cycle. The steady state occurs at the latest at D15 of each cycle. So Csum could be measured in a range of 3 days post-D15 (D15-D18). ;Timepoint(s) of evaluation of this end point: 12 months | — |
Secondary
| Measure | Time frame |
|---|---|
| Secondary end point(s): They include: 1. 10-month survival rate (defined as the percentage of patients alive 10 months after inclusion) 2. Objective response Rate (ORR) according to RECIST 1.1 and assessed by the investigators. ORR is be defined as the rate of patients with complete or partial response, 3. Disease Control Rate (DCR) according to RECIST 1.1 and assessed by the investigators. DCR is defined as the rate of patients with complete response, partial response or stable disease, 4. Progression-free survival (PFS) according to RECIST 1.1, assessed by the investigators. PFS is defined as the time from inclusion to date of first observed disease progression (radiological or clinical) or death due to any cause, if death occurs before progression is documented. The actual date that the tumor scan was performed will be used for this calculation. PFS for patients without disease progression or death at the time of analysis will be censored at the last date of tumor evaluation. 5. Percentage of patients with significant toxicities (= grade 3). AEs will be assessed from inclusion to 30 day after the discontinuation of the study drug and classified according to the National Cancer Institute Common Terminology Criteria for Adverse Events (NCI-CTCAE) version 5.0. 6. Percentage of patients with “optimal exposure” – i.e. with Csum at D15 within the range [2.5 – 5.5 mg/L]) – at cycle 1 and cycle 2 7. Overall survival for the half of patients with a low ratio of plasma concentration of M2 C2/C1 compared to the overall survival for the half of patients with a high ratio of plasma concentration of M2 C2/C1 8. Genetic polymorphisms in gene involved in regorafenib metabolism and plasma concentrations of regorafenib and its metabolites 9. Body composition will be determined on Computerized Tomography scan (CT-scan) imaging done at baseline and for tumor response evaluation during treatment. One axial image at the 3rd lumbar vertebra will selected for analysis of total muscle | — |
Countries
France
Contacts
Public ContactSponsor
Rennes University Hospital
Outcome results
None listed