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

Mark N Stein1,2, Jyoti Malhotra2, Rohinton S Tarapore3

  • 1Division of Hematology/Oncology, Columbia University Medical Center, New York, NY, USA.

Journal for Immunotherapy of Cancer
|May 24, 2019
PubMed
Abstract

Insights

Weekly oral ONC201, a DRD2 antagonist, is safe and well-tolerated in advanced solid tumors. This dosing schedule enhances anti-tumor immune responses, showing promise for future cancer therapies.

Area of Science:

  • Oncology
  • Pharmacology
  • Immunology

Background:

  • ONC201 is a small molecule antagonist targeting DRD2, a receptor overexpressed in various cancers.
  • Preclinical studies demonstrated ONC201's antitumor efficacy and immunomodulatory effects.
  • Previous trials established a recommended Phase II dose (RP2D) of 625 mg every three weeks.

Purpose of the Study:

  • To evaluate the safety, pharmacokinetics (PK), and pharmacodynamics (PD) of weekly ONC201 administration.
  • To determine the RP2D for a weekly dosing schedule of ONC201 in patients with advanced solid tumors.
  • To assess the immunomodulatory effects of weekly ONC201 compared to every-three-week dosing.

Main Methods:

  • A Phase I dose-escalation study using a 3+3 design enrolled patients aged 18+ with advanced solid tumors refractory to standard treatments.
  • Dose levels ranged from 375 mg to 625 mg of ONC201, with a 21-day cycle and dose-limiting toxicity (DLT) window.
  • A dose expansion cohort of 11 patients confirmed the RP2D for weekly ONC201.

Main Results:

  • Twenty patients were enrolled; the RP2D was determined to be 625 mg weekly, with no DLTs, treatment discontinuations, or dose modifications due to toxicity.
  • PK profiles were consistent with established every-three-week dosing and remained stable between the first and fourth doses.
  • Weekly ONC201 induced serum prolactin, caspase-cleaved cytokeratin-18, integrated stress response, and Natural Killer cell infiltration; immune responses were heightened compared to every-three-week dosing.
  • Stable disease for over six months was observed in some prostate and endometrial cancer patients.

Conclusions:

  • Weekly oral administration of ONC201 is well-tolerated in patients with advanced solid tumors.
  • The weekly schedule enhances immunostimulatory activity compared to less frequent dosing.
  • These findings support further investigation of weekly ONC201 in clinical trials for cancer treatment.
Keywords:
CancerDopamineImmuno-oncologyImmunotherapyONC201Solid tumors

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