Evaluation of Treatment PERSOnalization Based on Its Therapeutic Monitoring in Patients With Metastatic Colorectal Cancer Treated With REgorafenib (RePERSO)

August 4, 2025 updated by: Rennes University Hospital

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.

Study Overview

Status

Status

Indicates the current recruitment status or the expanded access status.
Completed

Conditions

Conditions

The disease, disorder, syndrome, illness, or injury that is being studied. On ClinicalTrials.gov, conditions may also include other health-related issues, such as lifespan, quality of life, and health risks.

Intervention / Treatment

Intervention / Treatment

A process or action that is the focus of a clinical study. Interventions include drugs, medical devices, procedures, vaccines, and other products that are either investigational or already available. Interventions can also include noninvasive approaches, such as education or modifying diet and exercise.

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 160mg/day 3 weeks/4 (3w/4). However, more than 50% of patients had severe adverse events (grade 3-4), leading to temporary or definitive discontinuation of treatment in 2/3 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 mg/day 3w/4) 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 mg/day 3 w/4). 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 C2/C1). A significant correlation between M-2 C2/C1 ratio and the sum of trough concentrations of regorafenib, M-2 and M-5 measured at D15C1 (C Sum (Rego+M-2+M-5)) was found, which could be a pharmacological marker of efficacy, earlier than the M-2 C2/C1 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 2.5 mg/L and 5.5 mg/L (median OS of 10.6 months versus 3.3 and 4.0 months in patients with a concentration <2.5 mg/L and ≥5.5 mg/L, respectively). The rate of serious adverse events was also lower in the group in the range [≥2.5; <5.5 mg/L] (0% vs 43% and 20% respectively). This interval seems to allow limiting the severe toxicities that cause treatment discontinuations and/or 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 Type

Study Type

Describes the nature of a clinical study. Study types include interventional studies (also called clinical trials), observational studies (including patient registries), and expanded access.
Interventional

Enrollment (Actual)

Enrollment

The number of participants in a clinical study. The "anticipated" enrollment is the target number of participants that the researchers need for the study.
110

Phase

Phase

The stage of a clinical trial studying a drug or biological product, based on definitions developed by the U.S. Food and Drug Administration (FDA). The phase is based on the study's objective, the number of participants, and other characteristics. There are five phases: Early Phase 1 (formerly listed as Phase 0), Phase 1, Phase 2, Phase 3, and Phase 4. Not Applicable is used to describe trials without FDA-defined phases, including trials of devices or behavioral interventions.
  • Phase 4

Contacts and Locations

This section provides the contact details for those conducting the study, and information on where this study is being conducted.

Study Contact

Study Contact

The name and contact information for the person who can answer enrollment questions for a clinical study. Each location where the study is being conducted may also have a specific contact, who may be better able to answer those questions.

Study Locations

  • France
      • Caen, France
        • CHU CAEN
      • Créteil, France
        • AP-HP Henri Mondor
      • Grenoble, France
        • Institut Daniel Hollard, Groupe Hospitalier Mutualiste de Grenoble
      • Nantes, France
        • CHU Nantes
      • Paris, France
        • AP-HP St Antoine
      • Rennes, France
        • Centre Eugène Marquis
      • Rennes, France
        • CHU Rennes
      • Rouen, France
        • CHU Rouen
      • Tours, France
        • CHU Tours

Participation Criteria

Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.

Eligibility Criteria

Eligibility Criteria

The key requirements that people who want to participate in a clinical study must meet or the characteristics they must have. Eligibility criteria consist of both inclusion criteria (which are required for a person to participate in the study) and exclusion criteria (which prevent a person from participating). Types of eligibility criteria include whether a study accepts healthy volunteers, has age or age group requirements, or is limited by sex.

Ages Eligible for Study

18 years and older (Adult, Older Adult)

Accepts Healthy Volunteers

No

Description

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, an anti-VEGF (bevacizumab or aflibercept) and an anti-EGFR (cetuximab or panitumumab) for patients who had a RAS wild-type tumor
  • In mCRC with MSI-H, the patient must have received immunotherapy. For mCRC with BRAF mutation, the patient should have received a BRAF inhibitor if eligible.
  • 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 :

    1. Absolute neutrophil count ≥ 1.3 Giga/L
    2. Platelets > 100 Giga/L
    3. Hemoglobin ≥ 9 g/dL
    4. 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
    5. AST and ALT ≤3 x ULN (≤5.0 × ULN for patients with liver involvement of their cancer)
    6. Total Bilirubin ≤2 X ULN
    7. 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 (or >5 ULN in patient with liver involvement of their cancer and/or with bone metastases), hepatic isoenzymes 5-nucleotidase or GGT tests must be performed; hepatic isoenzymes 5-nucleotidase must be within the normal range and/or GGT < 3 x ULN
    8. No argument for acute pancreatitis within 3 months before the start of study medication
    9. No proteinuria: Spot urine ≥ 1+ protein will require a 24-hour urine collection that must show total protein excretion <1000 mg/24 hours
  • INR/PTT ≤1.5 x ULN
  • Patient who are therapeutically treated with an agent such as warfarin or heparin will be allowed to participate provided that no prior evidence of underlying abnormality in coagulation parameters exists. For patients treated with VKA, close monitoring of at least weekly evaluations will be performed until INR/PTT is stable based on a measurement that is pre-dose as defined by the local standard of care
  • Women of childbearing potential and male patients must agree to use adequate contraception for the duration of study participation and up to 3 months following completion of therapy
  • Women of childbearing potential must have a negative serum β-HCG pregnancy test within 7 days prior randomization
  • Patients must be willing and able to comply with scheduled visits, treatment plan, laboratory tests and other study procedures
  • Patients affiliated to the Social Security System

Exclusion Criteria:

  • - Prior treatment with regorafenib, and with any prior antiangiogenic inhibitor except bevacizumab
  • Hypersensitivity to the active substance or to any of the excipients
  • Systemic cancer therapy with unfinished washout (in general 3 weeks except for example for capecitabin which has a 1 week washout)
  • 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 hepatitis B or C or chronic hepatitis B or C requiring treatment with antiviral therapy
  • Breastfeeding
  • Uncontrolled hypertension (systolic blood pressure >140 mmHg or diastolic pressure >90 mmHg despite optimal medical management)
  • Arterial thrombotic or embolic events such as cerebrovascular accident (including transient ischemic attacks), 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, anemia, hypothyroidism 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

Study Plan

This section provides details of the study plan, including how the study is designed and what the study is measuring.

How is the study designed?

Design Details

  • Primary Purpose: Treatment
  • Allocation: N/A
  • Interventional Model: Single Group Assignment
  • Masking: None (Open Label)

Arms and Interventions

Participant Group / Arm

Participant Group / Arm

A group or subgroup of participants in a clinical trial that receives a specific intervention/treatment, or no intervention, according to the trial's protocol.
Intervention / Treatment

Intervention / Treatment

A process or action that is the focus of a clinical study. Interventions include drugs, medical devices, procedures, vaccines, and other products that are either investigational or already available. Interventions can also include noninvasive approaches, such as education or modifying diet and exercise.
Experimental: Patients
Drug: Regorafenib
Dose adaptation at the beginning of cycle 2 and cycle 3 after regorafenib dosage at day 15

What is the study measuring?

Primary Outcome Measures

Primary Outcome Measures

In a clinical study's protocol, the planned outcome measure that is the most important for evaluating the effect of an intervention/treatment. Most clinical studies have one primary outcome measure, but some have more than one.
Outcome Measure
Measure Description
Time Frame
Time from inclusion to death
Time Frame: 12 months
Determine whether "optimal exposure" to regorafenib based on plasma concentration of the drug and its metabolites can improve overall survival in mCRC patients
12 months

Secondary Outcome Measures

Secondary Outcome Measures

In a clinical study's protocol, a planned outcome measure that is not as important as the primary outcome measure for evaluating the effect of an intervention but is still of interest. Most clinical studies have more than one secondary outcome measure.
Outcome Measure
Measure Description
Time Frame
Ten months survival rate
Time Frame: 10 months
Percentage of patients alive 10 months after inclusion
10 months
Objective response Rate
Time Frame: 12 months
Objective response Rate (ORR) defined as the rate of patients with complete or partial response
12 months
Disease Control Rate
Time Frame: 12 months
Disease Control Rate (DCR) is defined as the rate of patients with complete response, partial response or stable disease,
12 months
Progression-free survival
Time Frame: 12 months
Progression-free survival (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.
12 months
Severe toxicities
Time Frame: 12 months
Percentage of patients with significant toxicities (≥ grade 3). Adverse events will be assessed from inclusion to 28 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.
12 months
Percentage of optimal exposure
Time Frame: 2 months
Percentage of patients with "optimal exposure" - i.e. with Csum at day 15 within the range [2.5 - 5.5 mg/L]) - at cycle 1 and cycle 2
2 months
Difference in overall survival between patient with different metabolite 2 plasma ratio
Time Frame: 2 months
Overall survival for the half of patients with a low ratio of plasma concentration of Metabolite 2 Cycle2/Ccyle1 compared to the overall survival for the half of patients with a high ratio of plasma concentration of Metabolite 2 Cycle2/Cycle1
2 months
Genetic polymorphism impact
Time Frame: 12 months
Genetic polymorphisms in gene involved in regorafenib metabolism and plasma concentrations of regorafenib and its metabolites
12 months
Body composition
Time Frame: 12 months
Body composition will be determined on Computerized Tomography scan (CT-scan) imaging done at baseline and for tumor response evaluation during treatment.
12 months

Collaborators and Investigators

This is where you will find people and organizations involved with this study.

Sponsor

Sponsor

The organization or person who initiates the study and who has authority and control over the study.
Rennes University Hospital

Study record dates

These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.

Study Major Dates

Study Start (Actual)

Study Start

The actual date on which the first participant was enrolled in a clinical study. The "anticipated" study start date is the date that the researchers think will be the study start date.
October 22, 2021

Primary Completion (Actual)

Primary Completion

The date on which the last participant in a clinical study was examined or received an intervention to collect final data for the primary outcome measure. Whether the clinical study ended according to the protocol or was terminated does not affect this date. For clinical studies with more than one primary outcome measure with different completion dates, this term refers to the date on which data collection is completed for all the primary outcome measures. The "anticipated" primary completion date is the date that the researchers think will be the primary completion date for the study.
April 11, 2025

Study Completion (Actual)

Study Completion

The date on which the last participant in a clinical study was examined or received an intervention/treatment to collect final data for the primary outcome measures, secondary outcome measures, and adverse events (that is, the last participant's last visit). The "anticipated" study completion date is the date that the researchers think will be the study completion date.
April 11, 2025

Study Registration Dates

First Submitted

First Submitted

The date on which the study sponsor or investigator first submitted a study record to ClinicalTrials.gov. There is typically a delay of a few days between the first submitted date and the record's availability on ClinicalTrials.gov (the first posted date).
April 30, 2021

First Submitted That Met QC Criteria

First Submitted That Met QC Criteria

The date on which the study sponsor or investigator first submits a study record that is consistent with National Library of Medicine (NLM) quality control (QC) review criteria. The sponsor or investigator may need to revise and submit a study record one or more times before NLM's QC review criteria are met. It is the responsibility of the sponsor or investigator to ensure that the study record is consistent with the NLM QC review criteria.
April 30, 2021

First Posted (Actual)

First Posted

The date on which the study record was first available on ClinicalTrials.gov after National Library of Medicine (NLM) quality control (QC) review has concluded. There is typically a delay of a few days between the date the study sponsor or investigator submitted the study record and the first posted date.
May 5, 2021

Study Record Updates

Last Update Posted (Actual)

Last Update Posted

The most recent date on which changes to a study record were made available on ClinicalTrials.gov. There may be a delay between when the changes were submitted to ClinicalTrials.gov by the study's sponsor or investigator (the last update submitted date) and the last update posted date.
August 8, 2025

Last Update Submitted That Met QC Criteria

Last Update Submitted That Met QC Criteria

The most recent date on which the study sponsor or investigator submitted changes to a study record that are consistent with National Library of Medicine (NLM) quality control (QC) review criteria. It is the responsibility of the sponsor or investigator to ensure that the study record is consistent with the NLM QC review criteria.
August 4, 2025

Last Verified

Last Verified

The most recent date on which the study sponsor or investigator confirmed the information about a clinical study on ClinicalTrials.gov as accurate and current. If a study with a recruitment status of recruiting; not yet recruiting; or active, not recruiting has not been confirmed within the past 2 years, the study's recruitment status is shown as unknown.
August 1, 2025

More Information

Terms related to this study

Additional Relevant MeSH Terms

Other Study ID Numbers

Other Study ID Numbers

Identifiers or ID numbers other than the NCT number that are assigned to a clinical study by the study's sponsor, funders, or others. These numbers may include unique identifiers from other trial registries and National Institutes of Health grant numbers.
  • 35RC20_9803_RePERSO

Plan for Individual participant data (IPD)

Plan to Share Individual Participant Data (IPD)?

NO

Drug and device information, study documents

Studies a U.S. FDA-regulated drug product

No

Studies a U.S. FDA-regulated device product

No

product manufactured in and exported from the U.S.

No

This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.

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