Phenotype-Guided Dose Adjustment of Fluoropyrimidine-Based Chemotherapy in Dihydropyrimidine Dehydrogenase Deficient Gastrointestinal Cancer Patients

The primary objective of this study is to assess different strategies of **fluoropyrimidine (FP)**-dose adjustment according to pre-treatment uracilemia ([U]) in patients with dihydropyrimidine dehydrogenase (DPD) deficiency. This evaluation focuses on early severe FP-induced toxicity during the first two cycles of FOLFOX or CAPOX-based regimens. The aim is to generate guidelines for dose reduction in patients with DPD deficiency, which is clinically relevant as it seeks to minimize toxicity and improve treatment safety for gastrointestinal cancer patients who are FP-naive.

Secondary objectives include:

• Defining the recommended FP dose in DPD deficient patients based on plasma uracil levels, considering toxicity observed during the first four cycles of FP-based chemotherapy.
• Describing dose adjustments occurring during the first four cycles of FP-based chemotherapy.
• Describing the proportion of patients with dose modifications.
• Describing all grades of FP-induced toxicities observed during the first four cycles of FP-based chemotherapy.
• Assessing the impact of FP dose adaptations on disease outcomes in a homogeneous subgroup of patients, focusing on disease-free survival (DFS) and overall survival (OS) for stage III colon cancer, and progression-free survival (PFS) for stage IV colorectal cancer.

The clinical trial involves **Fluoropyrimidine (FP)-naive patients** diagnosed with gastrointestinal (GI) cancer who are beginning chemotherapy that combines FP (5FU or capecitabine) and oxaliplatin. The study population includes both male and female participants aged 18 years and older. Participants are required to have adequate bone marrow function, an estimated glomerular filtration rate of at least 60 ml/min, and liver function tests within specified limits. The trial does not specify the total number of participants, as this information was not provided by the sponsor. The selection criteria include pre-treatment screening based on uracilemia ([U]) values, and participants must be eligible for full standard doses of FP and oxaliplatin, regardless of DPD deficiency. Lifestyle considerations such as diet and physical activity are not detailed in the available data. The trial includes a vulnerable population, and participants must be affiliated with a Social Security System or equivalent. Women of childbearing potential are required to have a negative pregnancy test and agree to use effective contraception. Participants must provide informed consent and demonstrate willingness and ability to comply with the study protocol, including treatment and follow-up visits.

The clinical trial is designed to evaluate the efficacy of **fluoropyrimidine**-based chemotherapy dose adjustments in patients with gastrointestinal cancer who are deficient in dihydropyrimidine dehydrogenase (DPD). This is a Phase IV, randomized, double-blind, controlled study. The trial aims to assess different strategies for dose adjustment based on pre-treatment uracilemia ([U]) levels to mitigate early severe toxicity induced by fluoropyrimidine during the initial two cycles of chemotherapy. The study is expected to run from September 2024 to December 2029, with participant involvement lasting up to 14 weeks, depending on the treatment regimen.

Participants will undergo a series of study visits, beginning with an inclusion (screening) visit to confirm eligibility based on criteria such as age, ECOG performance status, and adequate organ function. The screening will also include a pregnancy test for women of childbearing potential and a review of the patient's ability to comply with the study protocol. Following the screening, participants will be randomized to receive either the standard or adjusted dose of chemotherapy, which includes **fluorouracil**, **capecitabine**, and **oxaliplatin**, administered intravenously or orally as per the regimen. The treatment period will consist of biweekly or three-weekly cycles, with follow-up visits scheduled to monitor for adverse events and treatment efficacy.

The primary endpoint is the proportion of patients experiencing grade ≥3 hematological and gastrointestinal toxicity after two cycles, assessed using the National Cancer Institute's Common Terminology Criteria for Adverse Events (NCI CTCAE) version 5.0. Secondary endpoints include the recommended dose estimation, description of administered doses, and treatment efficacy in terms of disease-free survival (DFS) and overall survival (OS) in specific patient subgroups. Participants may be withdrawn from the study if they experience unacceptable toxicity, fail to comply with the protocol, or withdraw consent. The trial's findings are anticipated to inform guidelines for dose reduction in DPD-deficient patients, enhancing the safety and effectiveness of chemotherapy in this population.

The clinical trial involves the administration of **FLUOROURACIL**, a chemical compound used as an experimental medication. It is provided in the form of a solution for injection or infusion. The maximum daily dose is 1200 mg/m², with a total maximum dose of 2800 mg/m² over a treatment period of 14 days. The route of administration is **intravenous**, and the dosing schedule is designed to ensure participant compliance through regular monitoring.

**FOLINIC ACID** is utilized as a non-experimental treatment in this study. It is also administered as a solution for injection or infusion. The maximum daily and total dose is 400 mg/m², administered intravenously over a 14-day period. This compound serves as an auxiliary treatment to enhance the efficacy of the primary experimental medication.

**CAPECITABINE** is another experimental medication used in the trial, provided in the form of film-coated tablets. The maximum daily dose is 2000 mg/m², with a total maximum dose of 28000 mg/m² over a treatment period of 3 weeks. The route of administration is **oral**, and participant compliance is monitored through scheduled dosing and follow-up assessments.

**OXALIPLATIN** is included as a non-experimental treatment, administered as a concentrate for solution for infusion. The maximum daily and total dose is 130 mg/m², delivered intravenously over a 14-day period. This compound is used in conjunction with the primary experimental medications to assess its impact on treatment outcomes.

Efficacy in this clinical trial will be assessed through several primary and secondary endpoints. The primary endpoint focuses on the proportion of **fluoropyrimidine (FP)**-induced grade ≥ 3 hematological and gastrointestinal toxicity after two cycles of treatment, evaluated according to the National Cancer Institute's Common Terminology Criteria for Adverse Events (NCI CTCAE) version 5.0. This assessment will be conducted in patients with gastrointestinal cancer undergoing treatment in either the (neo-)adjuvant or metastatic setting.

Secondary endpoints include the estimation of the recommended FP dose by comparing the rate of FP-induced grade ≥ 3 toxicities in DPD-deficient patients to those in non-DPD-deficient patients during the first four cycles of chemotherapy. Additionally, the trial will describe FP doses administered during these cycles, including reasons for dose modifications or treatment discontinuation due to toxicity. The percentage of patients experiencing dose adjustments during the first four cycles will also be recorded. All grades of FP-induced toxicities, whether related to DPD deficiency or not, will be documented, including neutropenia, febrile neutropenia, anemia, thrombocytopenia, diarrhea, mucositis, hand-foot syndrome, central neurotoxicity, and cardiotoxicity.

Treatment efficacy will be further evaluated in terms of disease-free survival (DFS), overall survival (OS), and progression-free survival (PFS). DFS is defined as the time from surgery to disease recurrence in patients with stage III colon cancer, with a particular focus on the 3-year DFS. OS is defined as the time from surgery until death from any cause in the same subgroup. PFS is defined as the time from inclusion to disease progression or death from any cause in patients with stage IV colorectal cancer.