Avelumab Dose Selection for Clinical Studies in Pediatric Patients with Solid Tumors

Abstract

Background and objective: A phase I/II trial evaluated the safety, antitumor activity, and pharmacokinetics of avelumab (anti-PD-L1 antibody) in pediatric patients with refractory/relapsed solid tumors (NCT03451825). This study aimed to inform avelumab dose selection in pediatric populations using population pharmacokinetic modeling and simulations.

Methods: Patients aged < 18 years with refractory/relapsed solid tumors enrolled in phase I received avelumab 10 or 20 mg/kg intravenously every 2 weeks. A pediatric population pharmacokinetic model was developed via the frequentist prior approach.

Results: Pharmacokinetic parameters from 21 patients who received avelumab 10 mg/kg (n = 6) or 20 mg/kg (n = 15) were analyzed. Patients had a wide range of weights and ages (medians, 37.3 kg and 12 years). Exposures with 10-mg/kg dosing were lower vs adult dosing, particularly in patients weighing < 40 kg, whereas 20-mg/kg dosing achieved or exceeded adult exposures, irrespective of body weight. A two-compartment linear model with time-varying clearance using body weight as a covariate, with the frequentist prior approach, best described pediatric data. In this model, optimal overlap in exposure with adult data was achieved with 800 mg every 2 weeks for patients aged ≥ 12 years and weighing ≥ 40 kg, and 15 mg/kg every 2 weeks for patients aged < 12 years or weighing < 40 kg.

Conclusions: Based on exposure matching, the recommended doses for further avelumab studies, including combination studies, are 15 mg/kg every 2 weeks for pediatric patients aged < 12 years or weighing < 40 kg and the adult flat dose of 800 mg every 2 weeks for pediatric patients aged ≥ 12 years and weighing ≥ 40 kg.

Clinical trial registration: ClinicalTrials.gov NCT03451825.

Conflict of interest statement

YV is an employee of EMD Serono Research & Development Institute, Inc., Billerica, MA, USA, an affiliate of Merck KGaA. AMG and PR are employees of Merck Healthcare KGaA, Darmstadt, Germany. MR was an employee of EMD Serono Research & Development Institute, Inc., Billerica, MA, USA, an affiliate of Merck KGaA at the time of the study, and holds stock in Bristol Myers Squibb. BB and AK are employees of Merck Healthcare KGaA, Darmstadt, Germany and hold stock in Merck. HD was an employee of EMD Serono Research & Development Institute, Inc., Billerica, MA, USA, an affiliate of Merck KGaA at the time of the study.

© 2022. The Author(s).

Figures

Fig. 1

Dose-normalized, noncompartmental-derived pharmacokinetic parameters following first infusion of avelumab (10- or 20-mg/kg dose), by body weight (A Maximum observed serum concentration (Cmax). B Area under the concentration–time curve (AUC0–τ). C Trough concentration (Ctrough). Boxes represent interquartile range, solid lines within the box are arithmetic means, whereas the dotted lines are medians. Individual values beyond the interquartile range tails are shown as outlying dots

Fig. 2

Simulations with the pediatric population pharmacokinetic model vs observations after a single dose of avelumab at 10 or 20 mg/kg every 2 weeks (q2w). A Serum concentration. B Trough concentration (Ctrough). C Area under the concentration–time curve (AUC). D Clearance (CL). In Apink dots are individual observations, and the shaded blue areas represent predicted concentrations at each dose. In B–D, boxes represent interquartile range; horizontal lines within the box are medians; whiskers extend to the most extreme point, which is no more than 1.5 times the length of the box away from the box; pink dots are observations; and blue dots are observations that are outside 1.5 times the length of the box away from the box

Fig. 3

Simulations of A trough concentration (Ctrough) and B area under the concentration–time curve (AUC) in subgroups defined by age and body weight and CCtrough, and D AUC in subgroups defined by body weight after a single dose of avelumab at different doses in pediatric patients. Boxes represent interquartile range; horizontal lines are medians; whiskers extend to the most extreme point, which is no more than 1.5 times the length of the box away from the box; points are observations that are outside 1.5 times the length of the box away from the box. The pink dashed line represents the median for adult 800-mg data. For C and D, ages ranged from 2 to 9 years for the 10–20 kg 15-mg/kg subgroup, 3–12 years for the 20–30 kg 15-mg/kg subgroup, and 5–15 years for the 30–40 kg 15-mg/kg subgroup

Fig. 4.

Simulations of A concentration–time profiles and B population fractions that achieved trough concentration (Ctrough) associated with maximal PD-L1 target occupancy with avelumab recommended doses after a single dose. Lines are medians, shaded areas are 90% prediction intervals, and dashed horizontal lines are target concentrations of 6 µg/mL