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Phase IIa Study of PLX2853 in Gynecologic Cancers With Known ARID1A Mutation and Phase Ib/IIa Study of

Linda R Duska1, Dmitriy Zamarin2, Erica Hamilton3

  • 1University of Virginia School of Medicine, Charlottesville, VA.

JCO Precision Oncology
|October 5, 2023
PubMed
Abstract

Insights

This study investigated PLX2853, a BET inhibitor, in gynecologic cancers with ARID1A mutations. While not meeting primary efficacy endpoints, PLX2853 showed a favorable safety profile and warrants further research in this patient population.

Area of Science:

  • Oncology
  • Epigenetics
  • Pharmacology

Background:

  • Bromodomain and Extra-Terminal (BET) domain proteins are implicated in human cancer development through epigenetic regulation.
  • BET inhibitors show potential in overcoming platinum resistance in ovarian cancer (OC) and may induce synthetic lethality in tumors with ARID1A loss.
  • PLX2853 is a potent, orally active small-molecule inhibitor targeting all four BET family members.

Purpose of the Study:

  • To evaluate the safety and tolerability of PLX2853 monotherapy in patients with advanced gynecologic malignancies harboring an ARID1A mutation.
  • To assess the efficacy of PLX2853 in combination with carboplatin in women with platinum-resistant OC.
  • To explore the clinical activity of BET inhibition in ARID1A-mutated gynecologic cancers.

Main Methods:

  • A multicenter, open-label study with two parallel arms: Phase IIa for PLX2853 monotherapy and Phase Ib/IIa for PLX2853 plus carboplatin.
  • Primary objectives included safety, tolerability, and efficacy assessments.
  • Thirty-seven patients were enrolled, with 34 completing at least one post-baseline response assessment.

Main Results:

  • In the monotherapy arm (14 evaluable patients), one patient (7.1%) achieved a partial response (PR), and five (35.7%) had stable disease (SD).
  • In the combination arm (20 evaluable patients), one patient (5.0%) achieved PR, and nine (45.0%) had SD.
  • Overall response rates did not meet prespecified criteria, with 57.1% and 50% experiencing progressive disease (PD) in the monotherapy and combination arms, respectively.

Conclusions:

  • PLX2853 demonstrated a confirmed safety profile and feasibility when combined with carboplatin.
  • Despite not meeting primary response criteria, the study provides evidence of clinical activity for BET inhibitors in ARID1A-mutated gynecologic malignancies.
  • Further investigation of BET inhibitors, potentially combined with agents targeting feedback mechanisms like the PI3K pathway, is warranted.

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