CTP-15. Dordaviprone (ONC201) in a pediatric patient with recurrent H3 K27M-mutant diffuse glioma and leptomeningeal disease

Abstract BACKGROUND H3 K27M-mutant diffuse midline glioma (DMG) is a molecularly and clinically distinct subtype of CNS WHO Grade 4 glioma with a median overall survival (mOS) of ~1 year from diagnosis. Leptomeningeal disease (LMD) has been reported in 10.5% and 52.9% of H3 K27M-mutant DMG cases across two retrospective analyses. Dordaviprone is a first-in-class, CNS-penetrant imipridone that demonstrated durable responses and tolerability in recurrent H3 K27M-mutant diffuse glioma patients. Patients with LMD were excluded from prior response analyses due to challenges with radiographic evaluation by standard response criteria. METHODS ONC028 (NCT04617002) is a US-based expanded access protocol to provide dordaviprone access to patients ineligible for clinical trials, including patients with LMD. RESULTS An 11-year-old female patient with progressive bithalamic H3 K27M-mutant DMG and extensive LMD, previously treated with craniospinal irradiation (36 Gy with 18 Gy focal boost to bithalamic tumor), concurrent and adjuvant temozolomide, and trametinib, was enrolled in ONC028. Dordaviprone was initiated at 500 mg weekly with grade 2 fatigue and episodic vomiting occurring over the course of therapy. No additional adverse events were reported. One month after dordaviprone initiation, the patient achieved an investigator-assessed radiographic response of the bithalamic tumor and near-complete resolution of LMD, both sustained for seven months. Clinical benefits included Karnofsky and Lansky Performance Status improvement from 50 to 80, and tapering of dexamethasone from 2 mg/day to discontinuation. Neurologic status improved from assisted ambulation, gastrostomy tube dependence, and fatigue/somnolence to unassisted ambulation, expressive speech, and resolution of focal neurological deficits. Dordaviprone was continued through progression, with a total therapy duration of 11 months. OS was 11 months from dordaviprone initiation, and 18 months from diagnosis. CONCLUSION This case report suggests a potential role for dordaviprone use in recurrent H3 K27M-mutant DMG with LMD.