449TiP Evaluation of regorafenib treatment PERSOnalization based on therapeutic drug monitoring in patients with metastatic colorectal cancer (mCRC): RePERSO study

In randomized clinical trials, regorafenib (REG) has demonstrated a benefit in overall survival (OS) in mCRC patients, but limiting toxicities make treatment discontinuation frequent. Managing the high inter-patient variability of REG pharmacokinetics (PK) should help prevent toxicity and prolong the anti-tumor effect. In the prospective TEXCAN study, a sum of plasma concentrations of REG and its two main active metabolites M2 and M5 (Csum) at Day15 of Cycle 1 within 2.5 - 5.5 mg/L was associated with an improved OS (1). Applying a pharmacological prospective dosing optimization strategy, the present study intends to confirm whether Csum would be a valuable biomarker to individualize REG dosage and improve OS in mCRC patients. RePERSO is the first multicenter (12 sites), open-label, prospective single-arm phase II study, assessing the clinical impact of Csum as a biomarker of treatment benefit in mCRC patients. Patients ≥18 years, with mCRC, ECOG PS 0-1, treated with REG after failure of fluoropyrimidine-based chemotherapy combined with oxaliplatin and/or irinotecan as well as EGFR and/or VEGF inhibitors are eligible. The initial dose of REG is 120 mg/day for 3 weeks/4 (1 cycle). At cycles 2 and 3, the dose of REG is adjusted according to Csum, toxicity and radiological response. The primary objective of the trial is to determine whether an “optimal exposure” to REG, based on Csum, is associated with improved OS in mCRC patients. “Optimal exposure” is defined as a Csum within the predefined range of 2.5-5.5 mg/L at C1 and/or C2. Secondary objectives include comparison of objective response rate, disease control rate and progression-free survival between patients with or without “optimal exposure”. In addition, exploratory objectives include assessments of the prognostic value of the ratio of M2-concentrations C2/C1, the impact of genetic polymorphisms on the PK of REG, the influence of sarcopenia and the impact of endogenous biomarkers on REG response. It is planned to include 100 patients in 12 months with a 1-year follow-up. First patient was enrolled in October 2021 and 24/100 patients have been enrolled by 30th April 2022. 1. Rousseau et al. Eur J Cancer.2022. NCT04874207 EUDRACT no.: 2021-000252-18. Centre Hospitalier Universitaire de Rennes. Bayer Healthcare.