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.

Abdominopelvic desmoplastic small round cell tumor with metastasis: A case report and literature review

“…Current clinical trials are exploring experimental treatments such as the receptor tyrosine kinase (RTK) inhibitor Pazopanib, dopamine-like receptor 2 antagonist ONC201, intraperitoneal radioimmunotherapy with 131I-omburtamab, and hyperthermic intraperitoneal chemotherapy. [11–14] DSRCT predominantly affects young males post-puberty, with androgens playing a role in its progression. [15] Salah-Eddine et al employed enzalutamide and androgen receptor-directed antisense oligonucleotides (AR-ASO) to inhibit DSRCT cell growth induced by 5α-dihydrotestosterone, significantly decreasing xenograft tumor burden and highlighting the efficacy of androgen-targeted therapies.…”

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 ].…”