Reference Detail

Ref Type

Abstract

PMID

Authors

Peter Meade Anderson, Janette Gortz

Title

Phase 2 study of DRD2 antagonist/ClpP agonist ONC201 in neuroendocrine tumors.

Journal	Vol	Issue	Date	Pages	Journal Short Title
Journal of Clinical Oncology	39	15_suppl	May 20, 2021

URL

https://ascopubs.org/doi/abs/10.1200/JCO.2021.39.15_suppl.3002

Abstract Text

Background: ONC201, an imipridone with specificity for the dopamine-like DRD2 receptor and the mitochondrial protease ClpP, imparts anti-cancer effects via up-regulation of TRAIL/DR5, dual AKT/ERK pathway inhibition, and promotion of an integrated stress response. Select neuroendocrine tumors are known to secrete dopamine and harbor elevated DRD2 expression, which is most pronounced in pheochromocytoma-paraganglioma (PC-PG). Methods: This investigator-initiated single center trial (NCT03034200) enrolled 10 patients with metastatic PC-PG to cohort A and 12 patients with other neuroendocrine tumors to cohort B. The primary endpoint was response using MRI or CT, PET-CT and/or PET-MRI imaging defined as CR + PR + SD > 3 months by RECIST criteria assessed by investigator. Secondary endpoints included progression-free survival, overall survival and safety. ONC201 was administered at 625 mg by oral capsules once each week. CT scans and tumor markers (plasma chromogranin and metanephrines) were followed at 6 weeks, 3 months and then every 3 months. Patients with clinical benefit could receive stereotactic body radiotherapy (SBRT) for non-indicator (e.g. bone) metastases. The data cutoff for this analysis is December 1, 2020. Results: In Arm A (n = 10; all paraganglioma) 5 patients exhibited a PR and 2 additional patients exhibited SD > 3 months. Median duration of therapy for patients was 9 months (range: 1.5-33) with 5 patients > 1 year. In Arm B (n = 12) there were 1 PR and 2 SD > 3 months. Median duration of therapy was 3 months (range: 1-33). The partial response occurred in a patient with desmoplastic small round cell tumor who remains on treatment for > 2 years. There was no instance of dose modification or discontinuation due to treatment-related adverse events. Conclusions: ONC201 is well tolerated at 625mg weekly in adults with advanced neuroendocrine tumors and is associated with clinical benefit that includes tumor response, particularly in paraganglioma patients. A more intense schedule of 2 daily doses each week is under evaluation, in addition to other neuroendocrine tumors. Clinical trial information: NCT03034200.

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Molecular Profile	Treatment Approach

Gene Name	Source	Synonyms	Protein Domains	Gene Description	Gene Role

Therapy Name	Drugs	Efficacy Evidence	Clinical Trials

Drug Name	Trade Name	Synonyms	Drug Classes	Drug Description

Gene	Variant	Impact	Protein Effect	Variant Description	Associated with drug Resistance

Molecular Profile	Indication/Tumor Type	Response Type	Therapy Name	Approval Status	Evidence Type	Efficacy Evidence	References