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

Autor: Chi AS; NYU Langone Health and School of Medicine, New York, NY, USA., Tarapore RS; Oncoceutics, Philadelphia, PA, USA., Hall MD; Radiation Oncology, Miami Cancer Institute, 8900 N. Kendall Drive, Miami, FL, 33176, USA.; Nicklaus Children's Hospital, Miami, FL, USA., Shonka N; University of Nebraska Medical Center, Omaha, NE, USA., Gardner S; NYU Langone Health and School of Medicine, New York, NY, USA., Umemura Y; University of Michigan, Ann Arbor, MI, USA., Sumrall A; Levine Cancer Institute, Charlotte, NC, USA., Khatib Z; Nicklaus Children's Hospital, Miami, FL, USA., Mueller S; University of California, San Francisco, San Francisco, CA, USA., Kline C; University of California, San Francisco, San Francisco, CA, USA., Zaky W; M.D. Anderson Cancer Center, Houston, TX, USA., Khatua S; M.D. Anderson Cancer Center, Houston, TX, USA., Weathers SP; M.D. Anderson Cancer Center, Houston, TX, USA., Odia Y; Radiation Oncology, Miami Cancer Institute, 8900 N. Kendall Drive, Miami, FL, 33176, USA., Niazi TN; Nicklaus Children's Hospital, Miami, FL, USA., Daghistani D; Nicklaus Children's Hospital, Miami, FL, USA., Cherrick I; SUNY Upstate Medical University, Syracuse, NY, USA., Korones D; University of Rochester, Rochester, NY, USA., Karajannis MA; Memorial Sloan Kettering Cancer Center, New York City, NY, USA., Kong XT; University of California, Irvine, CA, USA., Minturn J; Childrens Hospital of Philadelphia, Philadelphia, PA, USA., Waanders A; Childrens Hospital of Philadelphia, Philadelphia, PA, USA., Arillaga-Romany I; Massachusetts General Hospital, Boston, MA, USA., Batchelor T; Massachusetts General Hospital, Boston, MA, USA., Wen PY; Dana-Farber/Brigham and Women's Cancer Center, Boston, MA, USA., Merdinger K; Oncoceutics, Philadelphia, PA, USA., Schalop L; Oncoceutics, Philadelphia, PA, USA., Stogniew M; Oncoceutics, Philadelphia, PA, USA., Allen JE; Oncoceutics, Philadelphia, PA, USA., Oster W; Oncoceutics, Philadelphia, PA, USA., Mehta MP; Oncoceutics, Philadelphia, PA, USA. MineshM@baptisthealth.net.; Radiation Oncology, Miami Cancer Institute, 8900 N. Kendall Drive, Miami, FL, 33176, USA. MineshM@baptisthealth.net.
Jazyk: angličtina
Zdroj: Journal of neuro-oncology [J Neurooncol] 2019 Oct; Vol. 145 (1), pp. 97-105. Date of Electronic Publication: 2019 Aug 27.
DOI: 10.1007/s11060-019-03271-3
Abstrakt: 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.
Databáze: MEDLINE
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