Efficacy and safety of dordaviprone (ONC201) in prospective clinical trials of adult and pediatric recurrent H3 K27M-mutant diffuse glioma patients.

10017 Background: Dordaviprone (ONC201), a first in class imipridone, has demonstrated safety and efficacy in an integrated analysis of patients with recurrent H3 K27M-mutant diffuse midline glioma across clinical studies. Here, we report efficacy and safety findings from two prospectively defined clinical trial arms that evaluated single-agent dordaviprone response in recurrent H3 K27M-mutant glioma. Methods: Phase 2 trialONC013 (Arm B) and Phase 1 trial ONC014 (Arm F) were designed to evaluate the objective response rate (ORR) by RANO-HGG criteria of dordaviprone in adult and pediatric patients, respectively, with recurrent H3 K27M-mutant diffuse glioma. Open label dordaviprone was administered once weekly at 625 mg for adults and at a dose scaled by body weight for pediatrics. Responses were investigator-assessed by RANO criteria. Eligibility required measurable enhancing recurrence by RANO-HGG criteria, radiotherapy completed ≥90 days prior to dordaviprone unless unequivocal progression qualified per RANO, Karnofsky or Lansky performance status >60. DIPG, spinal tumors, leptomeningeal disease, and CSF dissemination were excluded. Results: ONC013 Arm B enrolled 30 patients (median age 32, range, 21-66 years) with the majority having a primary midline non-brainstem tumor (n = 19, 63.3%) and one prior recurrence (n = 22, 73.3%). The ORR was 16.7% (95% CI, 5.6-34.7) with 5 partial responses (PR). The median duration of response (DOR) and time to response (TTR) were 15.1 months (7.5-not reached) and 3.8 months (1.8-4.6), respectively. Three patients experienced a grade ≥3 treatment-related adverse events (TR-AE), none had treatment-related serious AEs (TR-SAEs), and 1 had TR-AE leading to dose reduction (ALT increase). ONC014 Arm F enrolled 11 patients (median age 14, range 11-19 years). Most had a primary midline non-brainstem tumor (n = 7, 63.6%) and 1 prior recurrence (n = 6, 65.6%). Two (18.2%) radiographic responses were reported, 1 response (9.1%) qualified by RANO criteria. One PR occurred with > 95% tumor regression and an 8.5-month DOR (1.9-month TTR). Another patient experienced a > 50% tumor regression (4.3-month TTR) that did not meet RANO PR criteria due to initiation of 2.5 mg dexamethasone post-baseline. 12-month PFS rate was not reached; 12-month OS rate was 27.3% (6.5, 53.9). One patient experienced a grade ≥3 TR-TEAE (9.1%); no TR-SAEs, treatment-related deaths, or TR-AE leading to treatment discontinuation occurred. Conclusions: In prospective clinical trials designed to evaluate ORR, single-agent dordaviprone response and safety in adult and pediatric recurrent H3 K27M-mutant diffuse glioma were similar to previously pooled analyses. Clinical trial information: NCT03295396 and NCT03416530 .