Greengard E, Williams R, Moriarity B, Liu X, Minard CG, Reid JM, Fisher T, Evans E, Pastore DR, Zauderer M, Voss S, Fox E, Weigel BJ. 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). Pediatr Blood Cancer. 2024 Jun;71(6):e30938. doi: 10.1002/pbc.30938. Epub 2024 Mar 23. PMID: 38520670; PMCID: PMC11187758.
Publication Citation
Abstract
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. 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. 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. Pepinemab (20 mg/kg) is safe, well tolerated and resulted in adequate and sustained target saturation in pediatric patients. Encouraging disease control in 2 patients with osteosarcoma warrants further investigation with novel combination strategies to modulate the tumor microenvironment and anti-tumor immune response.