ONC201 in previously-irradiated pediatric H3 K27M-mutant glioma

10046 Background: ONC201 is the first DRD2 antagonist for clinical oncology. The recommended phase 2 dose (RP2D) of 625mg ONC201 orally once a week has been established in adult patients. ONC201 efficacy has been shown in high-grade glioma preclinical models and radiographic regressions with single agent ONC201 have been reported in adult recurrent H3 K27M-mutant glioma patients. We report results from the first Phase I pediatric clinical trial of ONC201. Methods: This multicenter, open-label, dose-escalation and dose-expansion clinical trial (NCT03416530) determined the RP2D of ONC201 in pediatric H3 K27M-mutant glioma patients as a single agent. ONC201 was orally administered once a week and scaled by body weight. Dose escalation was performed by a 3 + 3 design beginning with one 125mg capsule less than the adult RP2D equivalent. Three patients were treated at the starting dose and 19 were treated at the adult RP2D equivalent. Results: The primary endpoint was achieved by establishing the safety of the adult RP2D scaled by body weight to pediatric patients. Twenty-two patients with a median age of 9 (range 3-18) years old who received at least prior radiation have been treated with ONC201: 15 with diffuse intrinsic pontine glioma (DIPG) (4 recurrent; 11 not recurrent) and 7 with non-DIPG H3 K27M-mutant glioma (all not recurrent). As of February 5, 2019, patients have received a median of 18 ONC201 doses (range 3-41) without instance of dose-limiting toxicity. Pharmacokinetic profiles were comparable to those observed in adults (Cmax ~2.1ug/mL; AUC ~2.3hr*ug/mL) and exposure was similar across body weights. Nine of 22 patients remain on therapy, 13 have discontinued due to progression, and 4 off-study patients are alive with a median follow up of 5.8 months. Five of the 11 (45%) DIPG patients who initiated ONC201 following radiation, but prior to recurrence, remain on therapy (median 7.4 months; range 4.4-9.6): median PFS is 4.4 months from initiation of ONC201 and 9.7 months from diagnosis; 7 of 11 (64%) patients are alive with median follow up of 11.8 months from diagnosis. Conclusions: ONC201 was well tolerated and achieved therapeutic exposure in pediatric H3 K27M-mutant glioma patients at the adult RP2D scaled by body weight. Further investigation of first-line ONC201 to treat H3 K27M-mutant glioma and/or DIPG is ongoing. Clinical trial information: NCT03416530.