A phase 1/2 study of pepinemab in children, adolescents, or young adults with recurrent or refractory solid tumors: A children's oncology group consortium report (ADVL1614)

Emily Greengard, Robin Williams, Branden Moriarity, Xiaowei Liu, Charles G. Minard, Joel M. Reid, Terrence Fisher, Elizabeth Evans, Desa Rae Pastore, Maurice Zauderer, Stephan Voss, Elizabeth Fox, Brenda J. Weigel

Research output: Contribution to journalArticlepeer-review

Abstract

Purpose: Pepinemab, a humanized IgG4 monoclonal antibody, targets the SEMA4D (CD100) antigen to inhibit binding to its high-affinity receptors (plexin B1/PLXNB1, plexin B2/PLXNB2) and low-affinity receptor (CD72). SEMA4D blockade leads to increased cytotoxic T-cell infiltration, delayed tumor growth, and durable tumor rejection in murine tumor models. Pepinemab was well tolerated and improved T cell infiltration in clinical studies in adults with refractory tumors. SEMA4D was identified as a strong candidate proto-oncogene in a model of osteosarcoma. Based on these preclinical and clinical data, we conducted a phase 1/2 study to determine the recommended phase 2 dose (RP2D), pharmacokinetics, pharmacodynamics, and immunogenicity, of pepinemab in pediatric patients with recurrent/refractory solid tumors, and activity in osteosarcoma. Experimental design: Pepinemab was administered intravenously on Days 1 and 15 of a 28-day cycle at 20 mg/kg, the adult RP2D. Part A (phase 1) used a Rolling 6 design; Part B (phase 2) used a Simon 2-stage design in patients with osteosarcoma. Pharmacokinetics and target saturation were evaluated in peripheral blood. Results: Pepinemab (20 mg/kg) was well tolerated and no dose-limiting toxicities were observed during Part A. There were no objective responses. Two patients with osteosarcoma achieved disease control and prolonged stable disease. Pepinemab pharmacokinetics were similar to adults. Conclusions: Pepinemab (20 mg/kg) is safe, well tolerated and resulted in adequate and sustained target saturation in pediatric patients. Encouraging disease control in two patients with osteosarcoma warrants further investigation with novel combination strategies to modulate the tumor microenvironment and antitumor immune response. Clinical trial registry: This trial is registered as NCT03320330 at Clinicaltrials.gov. Disclaimer: The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health.

Original languageEnglish (US)
Article numbere30938
JournalPediatric Blood and Cancer
Volume71
Issue number6
DOIs
StatePublished - Jun 2024

Bibliographical note

Publisher Copyright:
© 2024 The Authors. Pediatric Blood & Cancer published by Wiley Periodicals LLC.

Keywords

  • pepinemab
  • phase 1
  • solid tumors

PubMed: MeSH publication types

  • Clinical Trial, Phase I
  • Clinical Trial, Phase II
  • Journal Article
  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

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