Lu, Guangrong

Abstract Background ONC201, a dopamine receptor D2 (DRD2) antagonist and caseinolytic protease P (ClpP) agonist, has induced durable tumor regressions in adults with recurrent H3 K27M-mutant glioma. We report results from the first phase I pediatric clinical trial of ONC201. Methods This open-label, multi-center clinical trial (NCT03416530) of ONC201 for pediatric H3 K27M-mutant diffuse midline glioma (DMG) or diffuse intrinsic pontine glioma (DIPG) employed a dose-escalation and dose-expansion design. The primary endpoint was the recommended phase II dose (RP2D). A standard 3 + 3 dose escalation design was implemented. The target dose was the previously established adult RP2D (625 mg), scaled by body weight. Twenty-two pediatric patients with DMG/DIPG were treated following radiation; prior lines of systemic therapy in addition to radiation were permitted providing sufficient time had elapsed prior to study treatment. Results The RP2D of orally administered ONC201 in this pediatric population was determined to be the adult RP2D (625 mg), scaled by body weight; no dose-limiting toxicities (DLT) occurred. The most frequent treatment-emergent Grade 1-2 AEs were headache, nausea, vomiting, dizziness and increase in alanine aminotransferase. Pharmacokinetics were determined following the first dose: T1/2, 8.4 h; Tmax, 2.1 h; Cmax, 2.3 µg/mL; AUC0-tlast, 16.4 hµg/mL. Median duration of treatment was 20.6 weeks (range 5.1-129). Five (22.7%) patients, all of whom initiated ONC201 following radiation and prior to recurrence, were alive at 2 years from diagnosis. Conclusions The adult 625 mg weekly RP2D of ONC201 scaled by body weight was well tolerated. Further investigation of ONC201 for DMG/DIPG is warranted.

Abstract ONC201, a bitopic DRD2 antagonist and allosteric ClpP agonist, has shown encouraging efficacy in H3 K27M-mutant glioma. Given that the thalamus has the highest extra-striatal expression of DRD2, we performed an integrated preclinical and clinical analysis of ONC201 in thalamic H3 K27M-mutant glioma. ONC201 was effective in mouse intra-uterine electroporation (IUE)-generated H3 K27M-mutant gliomas, with an in vitro IC50 of 500 nM and 50% prolongation of median survival in vivo (p=0.02, n=14). We analyzed thalamic H3 K27M-mutant glioma patients treated with ONC201 on active clinical trials as of 5/22/19 enrollment (n=19 recurrent and 10 post-radiation, non-recurrent; 5–70 years old). As of 12/18/2019, PFS6 and OS12 are 26.3% and 36.8%, respectively, in the recurrent group. For non-recurrent patients, with median follow up of 21.9 months (8.6–26.6) from diagnosis, median PFS or OS have not been reached. This surpasses historical OS of 13.5 months. Best response by RANO includes 1 CR, 3 PR, 4 SD, 8 PD for recurrent patients and 2 PR, 4 SD, 1 PD for non-recurrent patients (4 on-trial patients experienced regressions that are yet unconfirmed responses). Median duration of response for recurrent patients is 14.0 months (2.0–33.1). Furthermore, H3 K27M cell-free tumor DNA in plasma and CSF correlated with MRI response. In summary, single agent ONC201 administered at recurrence, or adjuvantly following radiation, demonstrates promising clinical efficacy in thalamic H3 K27M-mutant glioma patients who currently have no effective treatments following radiation. Investigations are ongoing to assess whether micro-environmental DRD2 expression explains the early exceptional responses in thalamic H3 K27M-mutant glioma.