Pediatric and adult H3 K27M-mutant diffuse midline glioma treated with the selective DRD2 antagonist ONC201

Abstract

Background: H3 K27M-mutant diffuse midline glioma is a fatal malignancy with no proven medical therapies. The entity predominantly occurs in children and young adults. ONC201 is a small molecule selective antagonist of dopamine receptor D2/3 (DRD2/3) with an exceptional safety profile. Following up on a durable response in the first H3 K27M-mutant diffuse midline glioma patient who received ONC201 (NCT02525692), an expanded access program was initiated.

Methods: Patients with H3 K27M-mutant gliomas who received at least prior radiation were eligible. Patients with leptomeningeal spread were excluded. All patients received open-label ONC201 orally once every week. Safety, radiographic assessments, and overall survival were regularly assessed at least every 8 weeks by investigators. As of August 2018, a total of 18 patients with H3 K27M-mutant diffuse midline glioma or DIPG were enrolled to single patient expanded access ONC201 protocols. Among the 18 patients: seven adult (> 20 years old) and seven pediatric (< 20 years old) patients initiated ONC201 with recurrent disease and four pediatric patients initiated ONC201 following radiation, but prior to disease recurrence.

Findings: Among the 14 patients with recurrent disease prior to initiation of ONC201, median progression-free survival is 14 weeks and median overall survival is 17 weeks. Three adults among the 14 recurrent patients remain on treatment progression-free with a median follow up of 49.6 (range 41-76.1) weeks. Among the 4 pediatric patients who initiated adjuvant ONC201 following radiation, two DIPG patients remain progression-free for at least 53 and 81 weeks. Radiographic regressions, including a complete response, were reported by investigators in a subset of patients with thalamic and pontine gliomas, along with improvements in disease-associated neurological symptoms.

Interpretation: The clinical outcomes and radiographic responses in these patients provide the preliminary, and initial clinical proof-of-concept for targeting H3 K27M-mutant diffuse midline glioma with ONC201, regardless of age or location, providing rationale for robust clinical testing of the agent.

Keywords: Adult; DRD2 antagonist; Diffuse intrinsic pontine; Diffuse midline; Glioma; H3 K27M; ONC201; Pediatric; Radiation.

Conflict of interest statement

COI Disclosure:

RST, KM, LS, MS, JEA and WO have ownership/employment relationships with Oncoceutics that develops ONC201.

LS, MS, WO and MPM serves on the Board of Directors of Oncoceutics.

MPM has served as a consultant to Varian, Astra-Zeneca, Celgene, Tocagen, and Abbvie Research was funded in part through the NIH/NCI Cancer Center Support Grant P30 CA008748 to Memorial Sloan Kettering Cancer Center

MAK has served as a consultant (medical advisory board) to Bayer over the preceding 2 years.

Figures

Figure 1.

Swimmer’s plot of H3 K27M-mutant glioma patients treated with weekly ONC201. Adult patients are defined as >20 years of age and pediatric patients are defined as

Figure 2.

Gadolinium-enhanced MRI of adult recurrent H3 K27M-mutant glioma patient at (A) baseline and (B) 15.7 months after initiating ONC201 (625mg PO, weekly).

Figure 3.

Gadolinium-enhanced MRI of adult recurrent H3 K27M-mutant glioma patient at baseline (left) and one year (right) after initiating ONC201 (625mg PO, weekly). The on-treatment scan was taken 50 weeks after initiation of ONC201 and 22.5 weeks since the last dose of bevacizumab.

Figure 4.

MRI and cranial nerve palsy of H3 K27M-mutant DIPG patient. MRI at (A) diagnosis, (B) one month after radiation therapy, and (C) six months after beginning ONC201, (D) twelve months after beginning ONC201, and (E) eighteen months after beginning ONC201. Of note, the patient developed sites of tumor progression outside of the high dose region twelve months after beginning ONC201. Facial palsy at (F) diagnosis, (G) post-radiation, (H) four months after beginning ONC201, and (I) eight months after beginning ONC201, and (J) eighteen months after beginning ONC201.