A Phase 1 Trial Utilizing a Pharmacokinetic Endpoint to Determine the Optimal Dose of Ramucirumab in Children and Adolescents With Relapsed or Refractory Solid Tumors, Including Central Nervous System Tumors

Authors

Kristy L Pilbeam
Kamnesh Pradhan
James Croop
Charles G Minard
Xiaowei Liu
Stephan D Voss
Emasenyie Isikwei
Stacey L Berg
Joel M Reid
Elizabeth Fox
Brenda J Weigel

Publication Date

3-1-2024

Journal

Pediatric Blood & Cancer

DOI

10.1002/pbc.30817

PMID

38189770

PMCID

PMC11220737

PubMedCentral® Posted Date

3-1-2025

PubMedCentral® Full Text Version

Author MSS

Published Open-Access

yes

Keywords

Adult, Child, Humans, Adolescent, Ramucirumab, Vascular Endothelial Growth Factor A, Neoplasm Recurrence, Local, Neoplasms, Antibodies, Monoclonal, Central Nervous System Neoplasms, Maximum Tolerated Dose, Anti-angiogenesis, ramucirumab, pediatric cancer, pharmacokinetics

Abstract

Background: Ramucirumab is a monoclonal antibody that binds the extracellular domain of vascular endothelial growth factor receptor (VEGFR-2) and prevents binding of VEGF ligands. Based on population pharmacokinetic (PK) analysis and correlation with efficacy in adults, a target steady state trough concentration (Css,min ) ≥ 50 µg/mL was established.

Procedures: This phase 1 trial (ADVL1416) used a rolling six design and a PK primary endpoint to define the recommended phase 2 dose (RP2D) of ramucirumab in children with recurrent/refractory solid tumors. Two dose levels (DL) were planned (DL1: 8 mg/kg, DL2: 12 mg/kg administered intravenously [IV] every 2 weeks). Toxicity during the initial 6 weeks was used to assess maximum tolerated dose (MTD). Cycle 1 Day 42 trough (Cmin ) ≥ 50 µg/mL was the target concentration for the PK endpoint. At the RP2D, cohorts for PK expansion and children with central nervous tumors were planned.

Results: Twenty-nine patients were enrolled; 28 were eligible; median age [range] = 13.5 [1-21] years; 22 were evaluable for the PK endpoint. Dose-limiting proteinuria occurred at both DLs; however, the MTD was not exceeded. At DL2 (12 mg/kg), the median Day 42 Cmin (n = 16) was 87.8 µg/mL; 15 of 16 patients achieved a Cmin ≥ 50 µg/mL.

Conclusion: Ramucirumab was well tolerated in children and adolescents with solid tumors. The RP2D for ramucirumab was 12 mg/kg IV every 2 weeks. This trial demonstrates the feasibility of incorporating a primary PK endpoint to determine dose escalation and the RP2D in children. Studies of ramucirumab in children with selected solid tumors are ongoing.