Ignite Creation Date:
2024-05-06 @ 4:07 PM
Last Modification Date:
2024-10-26 @ 2:03 PM
Study NCT ID:
NCT04874207
Status:
ACTIVE_NOT_RECRUITING
Last Update Posted:
2024-01-31
First Post:
2021-04-30
Brief Title:
Evaluation of Treatment PERSOnalization Based on Its Therapeutic Monitoring in Patients With Metastatic Colorectal Cancer Treated With REgorafenib
Sponsor:
Rennes University Hospital
Organization:
Rennes University Hospital
Study Overview
Official Title:
Evaluation of Treatment PERSOnalization Based on Its Therapeutic Monitoring in Patients With Metastatic Colorectal Cancer Treated With REgorafenib
Status:
ACTIVE_NOT_RECRUITING
Status Verified Date:
2024-08
Last Known Status:
None
Delayed Posting:
No
If Stopped, Why?:
Not Stopped
Has Expanded Access:
False
If Expanded Access, NCT#:
N/A
Has Expanded Access, NCT# Status:
N/A
Acronym:
RePERSO
Brief Summary:
Regorafenib has demonstrated a significant benefit in overall survival in metastatic colorectal cancer mCRC patients However more than 50 of patients had severe adverse events grade 3-4 leading to temporary or definitive discontinuation of treatment
The RePERSO study proposes to adapt the regorafenib dose regimen taking into account firstly the measurement of sum of metabolites M-2 and M-5 and secondly the occurrence of toxicity during treatment This treatment personalization through therapeutic drug monitoring pharmacological dosing optimization strategy aims at validating the proof of concept of regorafenib therapeutic drug monitoring and at improving the benefit in OS in patients using the previously defined Csum therapeutic range
The RePERSO study proposes to adapt the regorafenib dose regimen taking into account firstly the measurement of sum of metabolites M-2 and M-5 and secondly the occurrence of toxicity during treatment This treatment personalization through therapeutic drug monitoring pharmacological dosing optimization strategy aims at validating the proof of concept of regorafenib therapeutic drug monitoring and at improving the benefit in OS in patients using the previously defined Csum therapeutic range
Detailed Description:
Regorafenib has demonstrated in two multicenter phase III randomized clinical trials a significant benefit in overall survival OS in metastatic colorectal cancer mCRC patients treated with regorafenib at 160mgday 3 weeks4 3w4 However more than 50 of patients had severe adverse events grade 3-4 leading to temporary or definitive discontinuation of treatment in 23 of the patients and a reduction of the dosing in 20 of them Thus a part of the therapeutic failures could be explained by an insufficient exposure to regorafenib because of an early toxicity potentially linked to an initial overexposure The recent randomized phase II ReDOS study has shown that a gradual increase in the dose of regorafenib from 80 mg to 160 mgday 3w4 led to a significantly greater proportion of patients starting a third cycle of regorafenib and showed a trend toward improvement in overall survival of patients when compared to the standard administration schedule 160 mgday 3 w4 These results favored the dose-escalation strategy However due to the low correlation between dose and concentration a concentration-controlled study might be of better relevance
Regorafenib pharmacokinetics is characterized by a hepatic metabolism leading to the production of two main pharmacologically active metabolites M-2 and M-5 that may induce therapeutic and adverse effects The production of these metabolites shows a large inter-individual variability Pharmacokinetic data from phase III studies have suggested the existence of a relationship between exposure to regorafenib and its metabolites and the occurrence of some therapeutic and adverse effects In an ancillary pharmacokinetic study of the phase II prospective TEXCAN study in which regorafenib was evaluated in its mCRC indication it was shown a major benefit in OS in patients with an accumulation of M-2 between the first C1 and the second C2 cycle of regorafenib M2 C2C1 A significant correlation between M-2 C2C1 ratio and the sum of trough concentrations of regorafenib M-2 and M-5 measured at D15C1 C Sum RegoM-2M-5 was found which could be a pharmacological marker of efficacy earlier than the M-2 C2C1 ratio The assessment of the relationship between C Sum and in OS according to a Restricted Cubic Spline analysis showed that the benefit is optimal for a concentration between 25 mgL and 55 mgL median OS of 106 months versus 33 and 40 months in patients with a concentration 25 mgL and 55 mgL respectively The rate of serious adverse events was also lower in the group in the range 25 55 mgL 0 vs 43 and 20 respectively This interval seems to allow limiting the severe toxicities that cause treatment discontinuations andor early progressions that could explain the over-risk of death when the concentrations are outside
The RePERSO study proposes to adapt the regorafenib dose regimen taking into account firstly the measurement of Csum and secondly the occurrence of toxicity during treatment This treatment personalization through therapeutic drug monitoring pharmacological dosing optimization strategy aims at validating the proof of concept of regorafenib therapeutic drug monitoring and at improving the benefit in OS in patients using the previously defined Csum therapeutic range
Regorafenib pharmacokinetics is characterized by a hepatic metabolism leading to the production of two main pharmacologically active metabolites M-2 and M-5 that may induce therapeutic and adverse effects The production of these metabolites shows a large inter-individual variability Pharmacokinetic data from phase III studies have suggested the existence of a relationship between exposure to regorafenib and its metabolites and the occurrence of some therapeutic and adverse effects In an ancillary pharmacokinetic study of the phase II prospective TEXCAN study in which regorafenib was evaluated in its mCRC indication it was shown a major benefit in OS in patients with an accumulation of M-2 between the first C1 and the second C2 cycle of regorafenib M2 C2C1 A significant correlation between M-2 C2C1 ratio and the sum of trough concentrations of regorafenib M-2 and M-5 measured at D15C1 C Sum RegoM-2M-5 was found which could be a pharmacological marker of efficacy earlier than the M-2 C2C1 ratio The assessment of the relationship between C Sum and in OS according to a Restricted Cubic Spline analysis showed that the benefit is optimal for a concentration between 25 mgL and 55 mgL median OS of 106 months versus 33 and 40 months in patients with a concentration 25 mgL and 55 mgL respectively The rate of serious adverse events was also lower in the group in the range 25 55 mgL 0 vs 43 and 20 respectively This interval seems to allow limiting the severe toxicities that cause treatment discontinuations andor early progressions that could explain the over-risk of death when the concentrations are outside
The RePERSO study proposes to adapt the regorafenib dose regimen taking into account firstly the measurement of Csum and secondly the occurrence of toxicity during treatment This treatment personalization through therapeutic drug monitoring pharmacological dosing optimization strategy aims at validating the proof of concept of regorafenib therapeutic drug monitoring and at improving the benefit in OS in patients using the previously defined Csum therapeutic range
Study Oversight
Has Oversight DMC:
None
Is a FDA Regulated Drug?:
False
Is a FDA Regulated Device?:
False
Is an Unapproved Device?:
None
Is a PPSD?:
None
Is a US Export?:
None
Is an FDA AA801 Violation?:
None