Evaluation of Regorafenib Therapeutic Monitoring for Personalized Treatment in Metastatic Colorectal Cancer Patients

Trial ID: 2024-517241-13-00
Protocol: 35RC20_9803_RePERSO
Sponsor: Centre Hospitalier Universitaire De Rennes

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Diseases & Conditions

Colorectal cancer metastatic

Objectives

The primary objective of this study is to determine whether **optimal exposure** to regorafenib, based on plasma concentration of the drug and its metabolites, can improve overall survival in patients with metastatic colorectal cancer (mCRC). This is clinically relevant as it aims to enhance treatment efficacy and patient outcomes by personalizing therapy based on pharmacokinetic parameters.

Secondary objectives include:

Comparing overall survival at 10 months between patients with "optimal exposure" versus "non-optimal exposure" to regorafenib.
Evaluating the objective response to treatment between these two groups.
Assessing disease control and time to progression in relation to exposure levels.
Comparing the safety profile of regorafenib between the exposure groups.
Describing the number of patients with "optimal exposure" at each treatment cycle.
Assessing the prognostic value of the accumulation ratio of plasma concentration of M-2 C2/C1 on overall survival.
Evaluating the impact of genetic polymorphisms involved in drug metabolism on the pharmacokinetics of regorafenib and its metabolites.
Studying the relationships between body composition (sarcopenia and visceral fat surface) and early toxicities, efficacy of regorafenib, and trough blood concentrations.
Assessing the influence of plasma metabolomics biomarkers on regorafenib response.

These secondary objectives aim to provide a comprehensive understanding of the factors influencing the efficacy and safety of regorafenib in mCRC treatment.

Participants

The clinical trial involves participants diagnosed with **metastatic colorectal cancer**. The study population includes both male and female subjects aged 18 years and older. Participants are required to have a histologically confirmed diagnosis of metastatic colorectal cancer and must have previously undergone standard therapy, including treatment with a fluoropyrimidine, oxaliplatin, irinotecan, and specific targeted therapies depending on tumor characteristics. The trial does not involve a vulnerable population. Participants must demonstrate adequate bone marrow, renal, and hepatic function, and have an Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1. The sponsor has not provided the total number of participants. Lifestyle considerations include the requirement for women of childbearing potential and male participants to use adequate contraception during the study and for three months after therapy completion. Participants must be affiliated with the Social Security System and provide signed informed consent. The trial population was selected based on these criteria, ensuring participants are willing and able to comply with study procedures, including scheduled visits and laboratory tests.

Plans and Procedures

The clinical trial is designed to evaluate the **personalization** of treatment for patients with **metastatic colorectal cancer** using **regorafenib**. This is a Phase 4, randomized, double-blind, controlled trial aimed at determining whether optimal exposure to regorafenib, based on plasma concentration of the drug and its metabolites, can improve overall survival in patients. The trial is expected to run from October 2021 to June 2025, with a maximum treatment period of 24 months for each participant.

Participants will undergo a series of study visits, beginning with an inclusion (screening) visit to confirm eligibility based on specific criteria, such as age, previous treatments, and health status. Following the screening, participants will be randomized into two groups based on the trough concentration of regorafenib and its active metabolites. The primary endpoint is overall survival, defined as the time from inclusion to death from any cause. Secondary endpoints include the 10-month survival rate, objective response rate, disease control rate, progression-free survival, and the percentage of patients experiencing significant toxicities.

Study visits will include regular follow-up assessments to monitor treatment efficacy and safety, with evaluations of plasma concentrations and genetic polymorphisms related to regorafenib metabolism. Participants will also undergo imaging studies to assess tumor response and body composition. The end-of-study visit will occur after the completion of the treatment period or upon early termination, which may occur due to adverse events, disease progression, or withdrawal of consent. Participants are expected to be involved in the study for the duration of their treatment period, with additional follow-up for safety assessments.

Treatment

The clinical trial involves the administration of **Stivarga** 40 mg film-coated tablets, which contain the active substance **regorafenib**. This medication is classified as an antineoplastic tyrosine kinase inhibitor and is chemically synthesized. The pharmaceutical form of the medication is a film-coated tablet, designed for **oral use**. The maximum daily dose of regorafenib is 160 mg, with a total maximum dose of 80,640 mg over the course of the treatment. The treatment period is set to a maximum of 24 weeks. The primary objective of the trial is to evaluate the personalization of treatment based on therapeutic monitoring in patients with metastatic colorectal cancer.

In addition to the experimental medication, the study may include non-experimental treatments such as standard-of-care therapy, placebo, or comparator treatments, although specific details are not provided in the source data. Participant compliance with the dosing schedule will be monitored throughout the trial to ensure adherence to the prescribed regimen. The trial aims to determine whether optimal exposure to regorafenib, based on plasma concentration of the drug and its metabolites, can improve overall survival in patients with metastatic colorectal cancer.

Efficacy

Efficacy in this clinical trial will be assessed primarily through the measurement of **overall survival** in patients with metastatic colorectal cancer treated with regorafenib. The primary endpoint is defined as the time from inclusion to death from any cause. Patients will be categorized into two groups based on the trough concentration of regorafenib and its active metabolites: those with "optimal exposure" (Csum on C1 and/or Csum on C2 within the range [2.5 – 5.5 mg/L]) and those with "non-optimal exposure" (Csum on C1 and Csum on C2 outside the range [2.5 – 5.5 mg/L]).

Secondary endpoints include the 10-month survival rate, objective response rate (ORR), disease control rate (DCR), progression-free survival (PFS), and the percentage of patients experiencing significant toxicities (≥ grade 3). ORR and DCR will be assessed according to RECIST 1.1 criteria by investigators, while PFS will be calculated from the time of inclusion to the date of first observed disease progression or death. Additionally, the trial will evaluate the percentage of patients with "optimal exposure" at cycle 1 and cycle 2, overall survival based on plasma concentration ratios, genetic polymorphisms related to regorafenib metabolism, and plasma metabolomics biomarkers. Body composition will be determined using CT-scan imaging at baseline and during treatment for tumor response evaluation.

Inclusion and Exclusion Criteria

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Inclusion Criteria

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
INR/PTT ≤1.5 x ULN
Patients 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 patient 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
Signed and dated informed consent

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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