SYST-07 WINDOW-OF-OPPORTUNITY STUDY OF ONC201 IN PEDIATRIC PATIENTS WITH DIFFUSE INTRINSIC PONTINE GLIOMA (DIPG) AND THALAMIC GLIOMA

BACKGROUND: H3 K27M-mutant diffuse midline glioma is a universally fatal malignancy primarily affecting children and young adults; no effective systemic therapy is available. ONC201, a first-in-class imipridone, is an oral, blood-brain barrier penetrating, selective small molecule antagonist of dopamine receptor D2/3 and agonist of the mitochondrial protease ClpP. ONC201 monotherapy demonstrated durable objective responses in adults with recurrent H3 K27M-mutant glioma. This phase 1 trial will evaluate ONC201±radiotherapy (RT) in pediatric patients with H3 K27M-mutant midline glioma DIPG. METHODS: This multicenter, open-label, dose escalation and expansion phase 1 study of ONC201 is comprised of eight arms that will evaluate the recommended phase 2 dose (RP2D) of ONC201, biomarkers, and pharmacokinetics (PK) of ONC201±RT in various treatment settings (NCT03416530). Arm G previously defined the RP2D for twice-weekly ONC201 on consecutive days. Arm H, for which enrollment is ongoing, will estimate the influence of tumor location and blood-brain barrier integrity on PK and intratumoral ONC201 exposure in biopsy-eligible pediatric tumors (DIPG or contrast-enhancing thalamic glioma). Patients eligible for Arm H will be aged 2-≤19 years, ≥2 weeks from last RT administration, and have a KPS/LPS ≥50; prior confirmation of H3 K27M mutation is not required. In Arm H, single-agent ONC201 administration will occur twice-weekly on consecutive days during each 21-day cycle at the RP2D defined in Arm G. Arm H has a planned enrollment of 27 patients (DIPG, n=15; thalamic glioma, n=12), with three patients undergoing a single biopsy at each of the following time points: 1-3 h post-first dose, 22-26 h post-second dose, 1-3 h post-first dose, 6-10 h post-second dose, and 22-26 h post-second dose. The 22-26 h post-first dose biopsy in thalamic glioma was previously collected and will not be assessed in this treatment arm. Plasma for PK analysis will be collected from all patients.