Model-informed approach to support Pediatric Dosing for the Pan-PI3K Inhibitor Copanlisib in Children and Adolescents with Relapsed/Refractory Solid Tumors.

Copanlisib is an intravenously administered PI3K inhibitor which was investigated in pediatric patients with relapsed/refractory solid tumors. A model-informed approach was undertaken to support and confirm an empirically selected starting dose of 28 mg/m 2 for pediatric patients ≥ 1 year old, corresponding to 80% of the adult recommended dose adjusted for body surface area. An adult physiologically-based pharmacokinetic (PBPK) model was initially established using copanlisib physicochemical and disposition properties and clinical PK data and was shown to adequately capture clinical PK across a range of copanlisib doses in adult cancer patients. The adult PBPK model was then extended to the pediatric population through incorporation of age-dependent anatomical and physiological changes and used to simulate copanlisib exposures in pediatric cancer patient age groups. The pediatric PBPK model predicted that the copanlisib 28 mg/m 2 dose would achieve similar copanlisib exposures across pediatric ages when compared with historical adult exposures following the approved copanlisib 60 mg dose administered on Days 1, 8, and 15 of a 28-day cycle. Clinical PK were collected from a Phase 1 study in pediatric patients with relapsed/refractory solid tumors (≥ 4 years). An established adult population PK model was extended to incorporate an allometrically-scaled effect of body surface area and confirmed that the copanlisib maximum tolerated dose (MTD) of 28 mg/m 2 was appropriate to achieve uniform copanlisib exposures across the investigated pediatric age range and consistent exposures to historical data in adult cancer patients. The model-informed approach successfully supported and confirmed the copanlisib pediatric dose recommendation.