Phase II study of ONC201 in pheochromocytoma-paragangliomas (PC-PG), medullary thyroid carcinoma (MTC), and other neuroendocrine tumors.

Abstract

e16703 Background: ONC201 is an imipridone with specificity for the dopamine-like DRD2 receptor. Anti-cancer effects involve up-regulation of TRAIL/DR5, dual AKT/ERK pathway inhibition, and integrated stress response. Because TCGA analysis showed very high DRD2 expression in neuroendocrine tumors, especially pheochromocytoma-paragangliomas (PC-PG), an investigator initiated IND study of ONC201 in neuroendocrine tumors (CCF IRB17-808; CASE2716; IND132665; NCT03034200) was done. Methods: ONC201 dose was 625 mg po/wk. Metastatic PG-PG were enrolled in cohort A. Other neuroendocrine patients were entered in cohort B. Two additional patients had single patient IND. Because hypertension is an issue from catecholamine producing PC-PG, all PC-PG patients had combined alpha + beta blockade and bp was monitored in the clinical research unit after dose #1 ONC201. Additional data was obtained with daily home bp monitoring, often with a wireless cuff which connects into EPIC via MyChart. Labs, scans, and clinic visits were done at week 6, then every 3 months from initial ONC201 dose. Patients with clinical benefit remained on study and could get radiation for bone metastases. Results: Neuroendocrine tumors were treated with ONC201 included 10 PC-PG, 3 with MTC 13 with other varieties including sarcomas, adrenal cortical carcinoma (ACC), neuroblastoma, and GI neuroendocrine tumor (NET). ONC201 was exceptionally well tolerated. All patients were able to maintain or improve KPS while on study. No adverse effects on bp were seen. The only ONC201-related AE was temporary grade 1 neurocognitive dysfunction for ~36 hours after weekly ONC201 dosing in 2/10 PC-PG patients. 4/10 PC-PG patients remain on study at 28, 22, 22, and 4 month. 1 DSRCT patient achieved a PR at 3 months and has been treated 28 months. An ACC patient was initially responsive (PR), but rapidly progressed in liver; 1 GI NET patient had -10% reduction by RECIST at 3 months and remains on treatment. MTC may be responsive (1 no response, 2 stable and improving by RECIST at 3 months). Conclusions: ONC201 is very well tolerated with excellent quality of life and extended clinical benefit against neuroendocrine tumors. Although ONC201 has activity against neuroendocrine tumors, especially PC-PG, increased efficacy will likely require combination therapy. Clinical trial information: NCT03034200 . [Table: see text]