Abstract
Pediatric patients with advanced relapsed/refractory (R/R) solid (including central nervous system [CNS]) tumors have poor prognoses. KIT alterations are common in germ cell tumors and high-grade glioma (HGG); platelet-derived growth factor receptor alpha (PDGFRA) alterations are common in sarcoma and HGG. Diffuse midline gliomas with H3K27-altered (DMG-H3K27-altered) depend on PDGFRA signaling for tumor growth. However, no KIT-/PDGFRA-targeted therapies are currently approved for pediatric patients with R/R solid or CNS tumors, including DMG-H3K27-altered. The selective KIT and PDGFRA inhibitor avapritinib has demonstrated potent activity against KIT activation-loop (exon 17) and juxtamembrane (exon 11) mutants (IC(50)<2 nM), and PDGFRA activation-loop (D842V) mutants (IC(50)=0.24 nM). Cellular IC(50) of wild-type PDGFRA was 95 nM. CNS penetration in preclinical models (steady-state brain-to-plasma ratios from 0.74–1.00) indicates potential for CNS antitumor activity. Avapritinib is approved to treat adults with advanced systemic mastocytosis in the USA, and in Europe after ≥1 prior systemic therapy. Avapritinib is also approved for the treatment of adults with unresectable/metastatic gastrointestinal stromal tumors harboring PDGFRA exon 18 mutations (including D842V) in the USA, and PDGFRA D842V mutations in Europe. ROVER, a 2-part phase 1/2, multicenter, open-label study (NCT04773782), is investigating avapritinib in pediatric patients aged 2 to <18 years with R/R solid tumors dependent on KIT or PDGFRA signaling, including DMG-H3K27-altered. Objectives include safety, efficacy, and pharmacokinetics. Part 1 will enroll ≥12 patients; the primary endpoint is to determine the recommended Part 2 dose (RP2D). Part 2 will enroll ≥25 patients at the RP2D; the primary endpoint is objective response rate per RECIST v1.1 for solid tumors and Response Assessment in Neuro-Oncology for CNS tumors. Avapritinib once daily will be administered in continuous 28-day cycles. Study enrollment is planned at 26 sites in 9 countries, including North America, Europe, and Asia/Pacific.