Phase II Study of ONC201 in Neuroendocrine Tumors including Pheochromocytoma-Paraganglioma and Desmoplastic Small Round Cell Tumor

Abstract

◥Purpose: Tumor dopamine-like DRD2 receptor expression is higher in pheochromocytoma-paraganglioma (PC-PG) compared with other cancers. ONC201 is a bitopic DRD2 antagonist with preclinical ONC201 activity in desmoplastic small round cell tumor (DSRCT).Patients and Methods: Patients (N ¼ 30) with neuroendocrine tumors were treated on this investigator-initiated trial (NCT03034200). ONC201 dose and schedule were 625 mg orally weekly in cohorts A (PC-PG) þ B (other neuroendocrine tumors) and 625 mg orally on 2 consecutive days each week in cohort C, which included 5 responding patients. The primary endpoint was radiographic response measured using RECIST. Secondary endpoints included progression-free survival, overall survival, and safety.Results: In arm A (n ¼ 10; all PC-PG), 50% (5/10) exhibited a partial response (PR) and 2 additional patients had stable disease (SD) >3 months. Median duration of therapy for arm A patients was 9 months (range: 1.5-33 months) with 5 patients treated >1 year. In arm B (n ¼ 12), there were 1 PR (DSRCT) and 2 SD (DSRCT; neuroblastoma) >3 months. Median duration of therapy in arm A was 18 months (range: 1-33 months) and arm B was 3 months (range: 1.5-33 months). Arm C PC-PG (N ¼ 8) showed 1 PR and 7 SD at 3 months, with median duration of therapy >10 months. There was no decline in Karnofsky performance status at week 12 for 28 of 30 patients and no dose modification due to treatment-related adverse events.Conclusions: Oral ONC201 was well tolerated in patients with metastatic neuroendocrine tumors and associated with clinical benefit, including tumor responses, particularly in some patients with DSRCT and the majority of patients with PC-PG.

Whole transcriptome analysis of canine pheochromocytoma and paraganglioma

“…According to TCGA data, human PPGLs have the highest DRD2 mRNA expression of all cancers. A phase II clinical trial of ONC201, a DRD2 antagonist, in human patients with metastatic neuroendocrine tumors including PPGL showed clinical benefit in the majority of patients with PPGL (5 partial responses, 7 stable diseases, 2 progressive diseases) ( 27 ). In our canine population, DRD2 was significantly overexpressed (36-fold).…”

The Management of Phaeochromocytomas and Paragangliomas in the Era of Precision Medicine: Where Are We Now? Evidence-Based Systemic Treatment Options and Future Cluster Oriented Perspectives

“…Recently, the promising results of a phase II trial (NCT03034200) evaluating an oral selective antagonist of the dopamine D2 receptor (ONC201) in neuroendocrine tumors and desmoplastic small round cell tumors (DSRCT) have been published, showing the greatest benefit especially in metastatic PPGLs. Of 10 patients with metastatic PPGLs enrolled, 50% (5/10; 3 SDHB-mutated) exhibited a PR and 2 patients (1 SDHB-mutated) had SD for more than 3 months, with good tolerability [ 113 ].…”

“…Despite the typical high expression of D2 receptors in PPGLs [ 114 ], discerning whether DRD2 antagonism, ClpP agonism or both contributed to responses in metastatic PPGLs is not easy in the absence of correlative studies on tissues [ 113 , 115 ].…”

Therapeutic targeting of TRAIL death receptors

“…ONC201 has shown preclinical activity as a single agent against a wide variety of solid and hematological [ 88 ] tumors, including lung [ 89 ], breast [ 90 ], pancreatic [ 91 ], ovarian [ 92 ], colorectal [ 81 ], prostate [ 81 ], hepatocellular [ 93 ], leukemia [ 94 ] and lymphoma [ 95 ]. Of note, ONC201 has shown efficacy against neuroendocrine tumors and brain tumors [ 96 , 97 ]. Such activity can be attributed to ONC201's ability to cross the blood-brain barrier as well as its ability to antagonize DRD2/3.…”

“…Such activity can be attributed to ONC201's ability to cross the blood-brain barrier as well as its ability to antagonize DRD2/3. Indeed, ONC201's activity against neuroendocrine tumors including pheochromocytomas and paragangliomas is correlated with their high expression of dopamine receptor type II [ 97 ]. Treatment with ONC201 reduced tumor growth in multiple glioma xenograft models, and a single dose doubled the overall survival of mice with an intracranial xenograft of human GBM [ 81 , 98 ].…”