Protocol for a prospective feasibility study investigating phenoconversion ofCYP3A4,CYP2C19andCYP2D6genotypes in paediatric and adolescent and young adult patients with an acute diagnosis of Hodgkin or Non-Hodgkin Lymphoma [PEGASUS]
Authors: Conyers Rachel , Stenta Tayla , Felmingham Ben , Somogyi Andrew , Kirkpatrick Carl , Halman Andreas , Moore Claire , Khatri Dhrita , Williams Elizabeth , Dyas Roxanne , Elliott David A. , Gwee Amanda , Alexander Marliese 
Published: June 2024

ABSTRACTIntroductionPhenoconversion is the discrepancy between the predicted phenotype based on genotyping (genotype-based phenotype) and the actual phenotype influenced by non-genetic factors (clinical phenotype). Despite its potential impact on drug selection, efficacy, toxicity, and cancer treatment outcomes, research in this area is limited. This study aimed to assess the acceptability and feasibility of investigating phenoconversion using probe medications in a paediatric and adolescent and young adult oncology patient population.Methods and AnalysisThis prospective, single-arm, partially blinded, non-randomized feasibility study will enrol individuals aged 6-25 with a new diagnosis of Hodgkin Lymphoma or Non-Hodgkin Lymphoma. Genotyping will be performed at baseline using whole genome sequencing or targeted panel testing. Longitudinal phenotyping will be conducted throughout the cancer treatment journey using exogenous oral enzyme-specific probes, specifically subtherapeutic doses of dextromethorphan (CYP2D6) and omeprazole (CYP2C19, CYP3A4) for enzyme activity assessment. The primary outcome measure will be the proportion of patients who consent to the study and successfully complete baseline and at least two longitudinal time points with valid probe drug metabolic ratio measurements. Secondary outcomes include classification of clinical phenotypes based on probe drug metabolic ratios, probe drug safety, barriers to consent, acceptability of pharmacogenomic and phenoconversion testing, longitudinal genotype/phenotype concordance and inflammatory profiles, and investigation of patient and disease factors influencing phenoconversion.Ethics and DisseminationThe ethics approval of the trial has been obtained from the Sydney Childrens Ethics Committee (2023/ETH1954). Findings will be disseminated through peer-reviewed publications and professional conference presentations.Trial RegistrationClinicalTrials.gov NCT 06383338STRENGTHS AND LIMITATIONS OF THIS STUDYPioneering study: This is the first study to conduct longitudinal phenotype assessments in a paediatric and adolescent and young adult oncology population.Primary outcome focus: The primary outcome includes patient consent and successful longitudinal probe drug derived clinical-phenotype assessments, crucial for designing future clinical trials.Generalisability: Conducting the study within both paediatric and adult hospital systems will enhance generalisability.Blinding: Probe drug metabolic ratio assessments are conducted blinded to genotype.Power: The trial is not powered to assess outcomes of or factors influencing phenoconversion, however secondary outcome evaluations may help prioritise outcomes/factors for further investigation.