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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.

SUBMITTER: Chi AS

PROVIDER: S-EPMC7241441 | biostudies-literature | 2019 Oct

REPOSITORIES: biostudies-literature

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

Chi Andrew S AS Tarapore Rohinton S RS Hall Matthew D MD Shonka Nicole N Gardner Sharon S Umemura Yoshie Y Sumrall Ashley A Khatib Ziad Z Mueller Sabine S Kline Cassie C Zaky Wafik W Khatua Soumen S Weathers Shiao-Pei SP Odia Yazmin Y Niazi Toba N TN Daghistani Doured D Cherrick Irene I Korones David D Karajannis Matthias A MA Kong Xiao-Tang XT Minturn Jane J Waanders Angela A Arillaga-Romany Isabel I Batchelor Tracy T Wen Patrick Y PY Merdinger Krystal K Schalop Lee L Stogniew Martin M Allen Joshua E JE Oster Wolfgang W Mehta Minesh P MP

Journal of neuro-oncology 20190827 1

<h4>Background</h4>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.<h4>Methods</h4>Patients with H3 K27 ...[more]

PMID: 31456142

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Project description:Abstract H3 K27M-mutant gliomas often manifest as midline gliomas, have a dismal prognosis, and have no established or effective treatments at recurrence. ONC201 is the first clinical bitopic DRD2 antagonist/ClpP agonist and is under evaluation in Phase II trials for gliomas and other cancers. We previously reported in vitro studies suggesting dysregulated dopamine receptor expression and enhanced ONC201 sensitivity among H3 K27M-mutant gliomas. Following these observations, adults with midline H3 K27M-mutant glioma patients were enrolled to a dedicated Phase II clinical trial (NCT03295396), a multi-arm Phase II trial (NCT0252569), and expanded access protocols under the Sponsor’s IND. An integrated radiographic analysis with an objective response rate primary endpoint in patients who received ONC201 monotherapy with confirmed H3 K27M-mutant glioma (not primarily in the pons or spinal cord and without leptomeningeal spread) that was progressive and measurable disease by RANO criteria, >90 days from completion of prior radiation, and had KPS >60. As of December 15, 2018, 15 patients have received single agent ONC201 who meet these criteria (n=9 NCT03295396; n=5 NCT0252569; n=1 expanded access). ONC201 was orally administered at 625 mg weekly, except for one patient dosed once every 3 weeks. As midline gliomas can exhibit a mixture of contrast-enhancing and non-contrast-enhancing disease, objective response was assessed by blinded independent central review using RANO-HGG and RANO-LGG criteria for each patient. Best response to date by RANO-HGG criteria is at least 27%: 1 CR, 3 PR, 7 SD, and 4 PD; by RANO-LGG is at least 36%: 1 CR, 1 PR, 3 minor response (MR), 4 SD, 5 PD, 1 unevaluable. By RANO-HGG, median onset of response is 2.6 months (range 1.3–3.4); median duration of response has not been reached with a median follow-up of 7.7 months (range 1.8–29.8). Updated radiographic response, pharmacodynamics, safety, and other clinical outcomes will be reported.

Project description:H3 K27-altered diffuse midline glioma is a highly lethal pediatric-type tumor without efficacious treatments. Recent findings have highlighted the heterogeneity among diffuse midline gliomas with different locations and ages. Compared to tumors located in the brain stem and thalamus, the molecular and clinicopathological features of H3 K27-altered spinal cord glioma are still largely elusive, thus hindering the accurate management of patients. Here we aimed to characterize the clinicopathological and molecular features of H3 K27M-mutant spinal cord glioma in 77 consecutive cases. We found that the H3 K27M-mutant spinal cord glioma, with a median age of 35 years old, had a significantly better prognosis than H3 K27M-mutant brain tumors. We noticed a molecular heterogeneity of H3 K27M-mutant spinal cord astrocytoma via targeted sequencing with 34 cases. TP53 mutation which occurred in 58.8% of cases is mutually exclusive with PPM1D (26%) and NF1 (44%) mutations. The TP53-mutant cases had a significantly higher number of copy number variants (CNV) and a marginally higher proportion of pediatric patients (age at diagnosis <18 years old, p = 0.056). Cox regression and Kaplan-Meier curve analysis showed that the higher number of CNV events (≥3), chromosome (Chr) 9p deletion, Chr 10p deletion, ATRX mutation, CDK6 amplification, and retinoblastoma protein (RB) pathway alteration are associated with worse survival. Cox regression analysis with clinicopathological features showed that glioblastoma histological type and a high Ki-67 index (>10%) are associated with a worse prognosis. Interestingly, the histological type, an independent prognostic factor in multivariate Cox regression, can also stratify molecular features of H3 K27M-mutant spinal cord glioma, including the RB pathway, KRAS/PI3K pathway, and chromosome arms CNV. In conclusion, although all H3 K27M-mutant spinal cord diffuse glioma were diagnosed as WHO Grade 4, the histological type, molecular features representing chromatin instability, and molecular alterations associated with accelerated cell proliferative activity should not be ignored in clinical management.

Dataset Information

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

Publications

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

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