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] © The Author(s) 2026.