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

Abstract

3002 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.