Pharmacokinetic Analysis of Capecitabine and Oxaliplatin in CES1 Variant Carriers with Advanced Gastrointestinal Carcinoma

The primary objective of this study is to demonstrate an increase of 25% in the **area under the curve (AUC)** 0-6h of 5-FU at the last day of **capecitabine** administration in cycle 1 between carriers of the CES1 1165–33 C>A (rs2244613) SNP and wild type patients. This is clinically relevant as it may provide insights into the pharmacokinetic variability and potential efficacy of capecitabine in patients with locally advanced or metastatic **gastro-intestinal carcinoma**.

Secondary objectives include:

• Identifying differences in AUC of other metabolites of capecitabine in carriers of the CES1 1165–33 C>A SNP.
• Identifying differences in dermal and urinary pharmacokinetics of capecitabine and its metabolites in carriers of the CES1 1165–33 C>A SNP.
• Analyzing the contribution of other SNPs in the metabolic pathway of capecitabine to inter-individual differences in capecitabine pharmacokinetics.
• Studying differences in the development of toxicity, such as hand-foot syndrome (HFS), among carriers versus wild types for CES1 1165–33 C>A.
• Performing an exploratory analysis of endogenous pyrimidine metabolites using metabolomics to search for new markers of capecitabine toxicity.
• Studying inter-individual differences in the pharmacokinetics of **oxaliplatin**, in relation to pharmacogenetics and the development of toxicity.

The clinical trial involves participants diagnosed with **locally advanced or metastatic gastro-intestinal carcinoma**. The study population includes both male and female subjects, aged 18 years and older, who are planned to start treatment with concomitant capecitabine and oxaliplatin according to the standard of care. Participants are required to be fit for treatment as judged by the treating physician and capable of understanding and complying with protocol requirements. The trial does not include a vulnerable population. The sponsor has not provided information regarding the total number of participants or specific lifestyle considerations such as diet or physical activity. The selection of the trial population is based on the ability to understand and sign the informed consent form, ensuring participants are adequately informed about the study. Key inclusion criteria focus on age, planned treatment regimen, and overall fitness for the prescribed therapy.

The clinical trial is designed to evaluate the pharmacokinetics of **capecitabine** and the incidence of hand-foot syndrome in carriers of the CES1 variant, specifically in patients with locally advanced or metastatic gastro-intestinal carcinoma. This study is a randomized, double-blind, controlled trial, categorized as a low-risk interventional trial, utilizing registered medicinal products within their authorized use. The trial is expected to commence recruitment on September 1, 2024, and conclude by December 31, 2026, with an estimated duration of participant involvement of up to 120 days for **capecitabine** and 6 days for **oxaliplatin**.

Participants will undergo a series of study visits, beginning with an inclusion (screening) visit to assess eligibility based on criteria such as age (≥18 years), planned treatment with **capecitabine** and **oxaliplatin**, and the ability to comply with protocol requirements. Following the screening, participants will be randomized to receive either the investigational treatment or a control. The primary endpoint is the difference in the area under the curve (AUC) 0-6 hours of 5-FU on the last day of **capecitabine** administration in cycle 1 between CES1 variant carriers and wild-type patients. Secondary endpoints include differences in the pharmacokinetics of **capecitabine** and its metabolites, as well as the pharmacokinetics of **oxaliplatin**.

Study visits will include follow-up assessments to monitor pharmacokinetic parameters and toxicity, with specific evaluations on day 1 and day 14 of cycle 1. The end-of-study visit will occur after the completion of the treatment period, where final assessments will be conducted. Participants may be withdrawn from the study early if they experience unacceptable toxicity, are unable to comply with study procedures, or withdraw consent. The trial aims to provide valuable insights into the pharmacogenetic factors influencing the efficacy and safety of **capecitabine** and **oxaliplatin** in this patient population.

The clinical trial involves the administration of **CAPECITABINE**, an anti-neoplastic agent, in the form of a **film-coated tablet**. The active substance, capecitabine, is of chemical origin. The medication is administered **orally** with a maximum daily dose of 2000 mg/m². The total maximum dose over the treatment period is 5,000,000 mg/m². The treatment duration is set for a maximum of 120 days. Compliance with the dosing schedule will be monitored throughout the trial to ensure adherence to the protocol.

Additionally, the trial includes the administration of **OXALIPLATIN**, another anti-neoplastic agent, provided as a **concentrate for solution for infusion**. The active substance, oxaliplatin, is also of chemical origin. This medication is administered via **intravenous infusion** with a maximum daily dose of 85 mg/m². The total maximum dose over the treatment period is 1020 mg/m², with a treatment duration of up to 6 cycles. Participant compliance with the dosing regimen will be closely monitored to maintain the integrity of the study data.

Efficacy in this clinical trial will be assessed by evaluating the pharmacokinetics of **capecitabine** and its metabolites, with a focus on the area under the curve (AUC) 0-6 hours of 5-FU on the last day of capecitabine administration in cycle 1. The primary endpoint is the difference in AUC0-6 of 5-FU between carriers and wild-type patients for the CES1 1165–33 C>A (rs2244613) single nucleotide polymorphism (SNP) on cycle 1, day 14 (C1D14). Secondary endpoints include differences in AUC0-6 of capecitabine and its other metabolites, such as 5DFCR, 5DFUR, DHFU, FBAL, and FAC, among carriers versus wild-types for the same SNP on C1D14. Additionally, differences in concentrations of 5-FU and other metabolites in dermal biopsies and urine will be assessed, along with genotyping of SNPs in genes related to the metabolic pathway of capecitabine.

The trial will also evaluate the incidence of toxicity in respective subgroups using the HFS-14 questionnaire scores and differences in the pharmacokinetics of **oxaliplatin** in relation to pharmacogenetics and the development of toxicity. Plasma concentrations will be measured on C1D1 (post-infusion) and C1D14. These assessments will be conducted using validated laboratory tests and patient-reported outcomes at specified timepoints to ensure accurate and reliable data collection and analysis.