A phase 2 pharmacokinetic and pharmacodynamic dose-finding study of oral NEPA for chemotherapy-induced nausea and vomiting in pediatric patients with cancer.

PURPOSE: Chemotherapy-induced nausea and vomiting (CINV) remains a significant challenge in pediatric oncology, with limited data guiding optimal antiemetic regimens. This phase 2 study evaluated pharmacokinetics (PK), pharmacodynamics, efficacy, and safety of oral netupitant combined with oral palonosetron (NEPA) in pediatric patients receiving highly or moderately emetogenic chemotherapy. METHODS: In this multicenter, randomized, double-blind, dose-finding study, pediatric patients (< 18 years) were stratified by age, chemotherapy emetogenicity, and schedule. Patients received one of two netupitant doses (1.33 or 4 mg/kg) with palonosetron (20 µg/kg). Efficacy was assessed via complete response (CR; no emesis and no rescue medication) during acute (0-24h), delayed (> 24-120h), and overall (0-120h) phases. PK parameters were derived from plasma concentrations of netupitant, its metabolites, and palonosetron. Safety was monitored through adverse events and clinical assessments. RESULTS: Among 65 evaluable patients, CR rates were 85.3%, 70.6%, and 70.6% in the lower netupitant dose group, and 87.1%, 71.0%, and 67.7% in the higher dose group, for the acute, delayed, and overall phases, respectively. CR was mostly consistent across age groups and chemotherapy emetogenicity. A trend toward increased CR with higher netupitant exposure (AUC0-inf) was observed in the delayed phase. The safety profile was consistent with expectations for cytotoxic chemotherapy, and no new safety signals were observed. CONCLUSION: A single dose of 4 mg/kg oral netupitant with oral palonosetron was effective and well-tolerated for CINV prevention in pediatric patients, supporting further investigation of NEPA in this population. TRIAL REGISTRATION: NCT03204279 [2 July 2017 registration date].