Dihydropyrimidine dehydrogenase phenotype-guided dose individualization of fluoropyrimidine in gastrointestinal cancers: PRODIGE100-UCGI48-FUDOSE phase II study

BACKGROUND: Pre-treatment screening for dihydropyrimidine dehydrogenase (DPD) deficiency based on plasma uracil concentration ([U]) is mandatory in France before fluoropyrimidine (FP) administration. However, dose-adjustment strategies according to [U] in case of partial DPD deficiency remain empirical, heterogeneous across centers and lacking clear recommendations. METHODS: This national, multicenter, open-label phase II trial will enroll approximately 400 patients schedule to receive FP-based chemotherapy combined with oxaliplatin, with or without targeted therapy. Patients will be stratified by pre-treatment [U] into one control arm (non-DPD-deficient, [U] <16 ng/mL) receiving a full standard FP starting dose, and four DPD-deficient cohorts ([16-20[, [20-50[, [50-100[, and [100-150[ ng/mL) receiving prespecified starting dose. The primary endpoint is FP-induced grade ≥3 hematological and gastrointestinal toxicity during the first two treatment cycles, compared between DPD-deficient cohorts vs control arm within a Bayesian framework. Interim analyses with sequential toxicity monitoring are planned to allow protocol adaptation if safety concerns arise. Secondary endpoints include overall toxicity profiles, dose adaptations, survival outcomes, pharmacokinetic analyses, and correlations between [U] levels and DPYD genotypes. CONCLUSIONS: This trial addresses a major gap between mandatory preemptive DPD phenotyping and actionable FP dosing recommendations, to generate prospective evidence supporting safer and harmonized FP use in routine clinical practice. TRIAL REGISTRATION: FUDOSE is registered at Clinicaltrials.gov (NCT06475352).