Background: H3 K27M-mutant diffuse midline glioma is a universally fatal malignancy primarily affecting children and young adults; while radiotherapy (RT) provides transient benefit, no effective systemic therapy is currently 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. Previously, ONC201 monotherapy demonstrated durable objective responses in adults with recurrent H3 K27M-mutant glioma. This phase 1 trial was designed to evaluate ONC201±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. Arm G previously defined the RP2D for ONC201 administered twice weekly on consecutive days in patients with H3 K27M-mutant glioma who had completed radiotherapy. 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 Karnofsky/Lansky performance score ≥50; prior confirmation of H3 K27M mutation is not required. In Arm H, single-agent ONC201 administration will occur on two consecutive days each week during each 21-day cycle at the RP2D defined in Arm G. Evidence of disease progression is not required; as such, ONC201 may be administered in the maintenance setting or for recurrent disease. Arm H has a planned enrollment of 27 patients. Each patient will undergo biopsy at a single prespecified biopsy window, which will be assigned at enrollment (Table); plasma for PK analysis will be collected from all patients at all time points shown in the Table, with additional collection pre-dose and 0.5 h post first dose. Clinical trial information: NCT03416530.

^aPrior to second dose. ^bPreviously collected in another arm of the trial.