A Phase I, Open-Label, Dose Escalation Study of Enoblituzumab in Children and Young Adults with B7-H3-Expressing Relapsed or Refractory Solid Tumors

Purpose:This multi-center, phase 1, cohort expansion study was performed to characterize the safety, pharmacokinetics, pharmacodynamics, immunogenicity and preliminary anti-tumor activity of enoblituzumab in children with relapsed/refractory tumors expressing B7-H3 above a predetermined threshold. Patients and Methods:Samples from 101 patients were screened for B7-H3 expression. Twenty-five patients were enrolled with a median age of 14.8 years (range 6 – 24 years). Enoblituzumab was administered IV weekly at 10 or 15 mg/kg. Serum concentrations of enoblituzumab were monitored using a quantitative sandwich enzyme-linked immunosorbent assay. Pharmacokinetic model building and evaluation was conducted using NONMEM Version 7 level 4 and followed standard model building approaches to define the structure, intersubject variability, and covariate dependence of the model. Safety assessments were performed on all patients who received >/= 1 dose of enoblituzumab. Disease assessment occurred after the eighth enoblituzumab infusion and every 8 weeks thereafter. Results: B7-H3 expression was documented in 96% of evaluable tumors. The maximum administered dose of enoblituzumab was the protocol-specified maximum dose of 15 mg/kg. The main toxicities encountered were infusion-related reactions including fever, chills, hypotension and rash. Pharmacokinetic studies showed that drug plasma concentrations fit a linear 2 compartment model with a mean elimination half-life of 67 days. No objective tumor responses were documented. Conclusions:B7-H3 is expressed on a high proportion of pediatric solid tumors. While enoblituzumab could be safely administered at a weekly dose of 15 mg/kg, no objective tumor responses were observed. Alternative strategies to target B7-H3 in children with relapsed solid tumors should be considered.