Safety and enhanced immunostimulatory activity of the DRD2 antagonist ONC201 in advanced solid tumor patients with weekly oral administration

Mark N. Stein, Jyoti Malhotra, Rohinton S. Tarapore, Usha Malhotra, Ann W. Silk, Nancy Chan, Lorna Rodriguez, Joseph Aisner, Robert D. Aiken, Tina Mayer, Bruce G. Haffty, Jenna H. Newman, Salvatore M. Aspromonte, Praveen K. Bommareddy, Ricardo Estupinian, Charles B. Chesson, Evita T. Sadimin, Shengguo Li, Daniel J. Medina, Tracie SaundersMelissa Frankel, Aparna Kareddula, Sherrie Damare, Elayne Wesolowsky, Christian Gabel, Wafik S. El-Deiry, Varun V. Prabhu, Joshua E. Allen, Martin Stogniew, Wolfgang Oster, Joseph R. Bertino, Steven K. Libutti, Janice M. Mehnert, Andrew Zloza

Research output: Contribution to journalArticlepeer-review

12 Scopus citations


Background: ONC201 is a small molecule antagonist of DRD2, a G protein-coupled receptor overexpressed in several malignancies, that has prolonged antitumor efficacy and immunomodulatory properties in preclinical models. The first-in-human trial of ONC201 previously established a recommended phase II dose (RP2D) of 625 mg once every three weeks. Here, we report the results of a phase I study that evaluated the safety, pharmacokinetics (PK), and pharmacodynamics (PD) of weekly ONC201. Methods: Patients ≥ 18 years old with an advanced solid tumor refractory to standard treatment were enrolled. Dose escalation proceeded with a 3 + 3 design from 375 mg to 625 mg of ONC201. One cycle, also the dose-limiting toxicity (DLT) window, was 21 days. The primary endpoint was to determine the RP2D of weekly ONC201, which was confirmed in an 11-patient dose expansion cohort. Results: Twenty patients were enrolled: three at 375 mg and 17 at 625 mg of ONC201. The RP2D was defined as 625 mg with no DLT, treatment discontinuation, or dose modifications due to drug-related toxicity. PK profiles were consistent with every-three-week dosing and similar between the first and fourth dose. Serum prolactin and caspase-cleaved cytokeratin-18 induction were detected, along with intratumoral integrated stress response activation and infiltration of granzyme B+ Natural Killer cells. Induction of immune cytokines and effectors was higher in patients who received ONC201 once weekly versus once every three weeks. Stable disease of > 6 months was observed in several prostate and endometrial cancer patients. Conclusions: Weekly, oral ONC201 is well-tolerated and results in enhanced immunostimulatory activity that warrants further investigation. Trial registration: NCT02250781 (Oral ONC201 in Treating Patients With Advanced Solid Tumors), NCT02324621 (Continuation of Oral ONC201 in Treating Patients With Advanced Solid Tumors).

Original languageEnglish (US)
Article number136
JournalJournal for ImmunoTherapy of Cancer
Issue number1
StatePublished - May 22 2019

All Science Journal Classification (ASJC) codes

  • Immunology and Allergy
  • Immunology
  • Molecular Medicine
  • Oncology
  • Pharmacology
  • Cancer Research


  • Cancer
  • Dopamine
  • Immuno-oncology
  • Immunotherapy
  • ONC201
  • Solid tumors

Fingerprint Dive into the research topics of 'Safety and enhanced immunostimulatory activity of the DRD2 antagonist ONC201 in advanced solid tumor patients with weekly oral administration'. Together they form a unique fingerprint.

Cite this