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ORIGINAL REPORTS

Targeted Drug Therapy

Phase IIa Study of PLX2853 in Gynecologic Cancers With Known ARID1A Mutation and Phase Ib/IIa Study of PLX2853/Carboplatin in Platinum-Resistant Epithelial Ovarian Cancer

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Linda R. Duska , MD1
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Linda R. Duska
; Dmitriy Zamarin , MD2
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Dmitriy Zamarin
; Erica Hamilton , MD3
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Erica Hamilton
; Amit Oza , MD4
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Amit Oza
; Gini Fleming , MD5
x
Gini Fleming
; Alexander Spira , MD6
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Alexander Spira
; Oladapo O. Yeku , MD, PhD7
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Oladapo O. Yeku
; Debra L. Richardson , MD8
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Debra L. Richardson
; Jackie Walling, PhD, MBChB9
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Jackie Walling
; Kerry Inokuchi, MPA9
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Kerry Inokuchi
; Bernice Matusow, MS9
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Bernice Matusow
; Gideon Bollag, PhD9
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Gideon Bollag
; and Elizabeth M. Swisher, MD10
x
Elizabeth M. Swisher
 Show More
https://doi.org/10.1200/PO.23.00235

Abstract

PURPOSE

The Bromodomain and Extra-Terminal (BET) domain proteins facilitate the development of many human cancers via epigenetic regulation. BET inhibitors may be effective in reversing platinum resistance in ovarian cancer (OC) and may generate synthetic lethality with ARID1A loss. PLX2853 is an orally active, small-molecule inhibitor of BET bromodomain-mediated interactions that exhibits low nanomolar potency in blocking all four BET family members.

METHODS

We conducted a multicenter and open-label study with two parallel arms: a phase IIa study of PLX2853 monotherapy in patients with advanced gynecologic malignancies with an ARID1A mutation and a phase Ib/IIa combination study of PLX2853 plus carboplatin in women with platinum-resistant OC. The primary objectives were safety and tolerability for phase Ib and efficacy for both phase IIa portions. Thirty-four of 37 enrolled patients completed at least one post-baseline response assessment.

RESULTS

Of the 14 evaluable patients on the monotherapy arm, 1 (7.1%) achieved a best overall response of partial response (PR), 5 (35.7%) had stable disease (SD), and 8 (57.1%) had progressive disease (PD). Of the 20 evaluable patients on the combination arm, 1 (5.0%) had PR, 9 (45.0%) had SD, and 10 (50%) had PD.

CONCLUSION

This study confirmed the safety profile of PLX2853 and demonstrated the feasibility of combination with carboplatin. Although these results did not meet the prespecified response criteria, evidence of clinical activity highlights the rationale for further exploration of BET inhibitors in patients with ARID1A-mutated gynecologic malignancies, possibly in combination with agents targeting potential feedback mechanisms such as the PI3K pathway.

© 2023 by American Society of Clinical Oncology
CONTEXT

  • Key Objective

  • Novel agents are needed to treat platinum-resistant ovarian cancer. The current clinical trial hypothesized that Bromodomain and Extra-Terminal (BET) domain protein inhibitors may be effective in reversing platinum resistance and may generate synthetic lethality with ARID1A loss.

  • Knowledge Generated

  • PLX2853, an orally active, small-molecule inhibitor of BET, was tolerable both as a monotherapy and in combination with carboplatin. There was one partial response (PR) in each cohort, and an overall response rate (PR + stable disease) of 42.8% and 50%, respectively.

  • Relevance

  • Evidence of clinical activity in select patients supports the rationale for further exploration of BET inhibitors in patients with ARID1A-mutated gynecologic malignancies.

PRIOR PRESENTATION

Presented at the American Association for Cancer Research meeting, Orlando, FL, April 14-19, 2023.

SUPPORT

Supported by Plexxikon Inc, South San Francisco, CA.

DATA SHARING STATEMENT

A data sharing statement provided by the authors is available with this article at DOI https://doi.org/10.1200/PO.23.00235.

AUTHOR CONTRIBUTIONS

Conception and design: Dmitriy Zamarin, Erica Hamilton, Jackie Walling, Gideon Bollag, Elizabeth M. Swisher

Financial support: Alexander Spira, Elizabeth M. Swisher

Administrative support: Alexander Spira, Elizabeth M. Swisher

Provision of study materials or patients: Linda R. Duska, Erica Hamilton, Amit Oza, Gini Fleming, Alexander Spira, Oladapo O. Yeku, Elizabeth M. Swisher

Collection and assembly of data: Linda R. Duska, Dmitriy Zamarin, Erica Hamilton, Amit Oza, Gini Fleming, Alexander Spira, Oladapo O. Yeku, Jackie Walling, Elizabeth M. Swisher

Data analysis and interpretation: Linda R. Duska, Dmitriy Zamarin, Amit Oza, Gini Fleming, Alexander Spira, Oladapo O. Yeku, Debra L. Richardson, Jackie Walling, Bernice Matusow, Elizabeth M. Swisher

Manuscript writing: All authors

Final approval of manuscript: All authors

Accountable for all aspects of the work: All authors

AUTHORS' DISCLOSURES OF POTENTIAL CONFLICTS OF INTEREST

The following represents disclosure information provided by authors of this manuscript. All relationships are considered compensated unless otherwise noted. Relationships are self-held unless noted. I = Immediate Family Member, Inst = My Institution. Relationships may not relate to the subject matter of this manuscript. For more information about ASCO's conflict of interest policy, please refer to www.asco.org/rwc or ascopubs.org/po/author-center.

Open Payments is a public database containing information reported by companies about payments made to US-licensed physicians (Open Payments).

Linda R. Duska

Consulting or Advisory Role: Regeneron, Merck (Inst), Inovio Pharmaceuticals, Ellipses Pharma (Inst)

Research Funding: GlaxoSmithKline (Inst), Millennium (Inst), Bristol Myers Squibb (Inst), Aeterna Zentaris (Inst), Novartis (Inst), AbbVie (Inst), Tesaro (Inst), Cerulean Pharma (Inst), Aduro Biotech (Inst), Advaxis (Inst), Syndax (Inst), Pfizer (Inst), Merck (Inst), Genentech/Roche (Inst), Morab (Inst), Morphotek (Inst), Ludwig Institute for Cancer Research (Inst), Leap Therapeutics (Inst)

Patents, Royalties, Other Intellectual Property: UpToDate, Editor, British Journal of Ob/Gyn

Dmitriy Zamarin

Stock and Other Ownership Interests: ImmunOs Therapeutics, Calidi Biotherapeutics, Accurius

Consulting or Advisory Role: Genentech/Roche, Memgen, Celldex, AstraZeneca, Crown Bioscience, Synthekine, GlaxoSmithKline, Hookipa Biotech, Tessa Therapeutics, Xencor, Targovax

Research Funding: AstraZeneca/MedImmune (Inst), Genentech (Inst), Plexxikon (Inst), Bristol Myers Squibb (Inst), Synthekine (Inst), Merck (Inst)

Patents, Royalties, Other Intellectual Property: I hold a patent regarding the use of recombinant Newcastle Disease Virus (NDV) for cancer therapy (Inst)

Erica Hamilton

Consulting or Advisory Role: Pfizer (Inst), Genentech/Roche (Inst), Lilly (Inst), Daiichi Sankyo (Inst), Mersana (Inst), AstraZeneca (Inst), Novartis (Inst), Seagen (Inst), ITeos Therapeutics (Inst), Janssen (Inst), Loxo (Inst), Relay Therapeutics (Inst), Greenwich LifeSciences (Inst), Orum Therapeutics (Inst), Ellipses Pharma (Inst), Olema Pharmaceuticals (Inst), Stemline Therapeutics (Inst), Tubulis GmbH (Inst), Verascity Science (Inst), Theratechnologies (Inst)

Research Funding: AstraZeneca (Inst), Hutchison MediPharma (Inst), OncoMed (Inst), MedImmune (Inst), Stem CentRx (Inst), Genentech/Roche (Inst), Curis (Inst), Verastem (Inst), Zymeworks (Inst), Syndax (Inst), Lycera (Inst), Rgenix (Inst), Novartis (Inst), Mersana (Inst), Millennium (Inst), TapImmune Inc (Inst), Lilly (Inst), Pfizer (Inst), Tesaro (Inst), Boehringer Ingelheim (Inst), H3 Biomedicine (Inst), Radius Health (Inst), Acerta Pharma (Inst), Macrogenics (Inst), AbbVie (Inst), Immunomedics (Inst), Fujifilm (Inst), eFFECTOR Therapeutics (Inst), Merus (Inst), Nucana (Inst), Regeneron (Inst), Leap Therapeutics (Inst), Taiho Pharmaceutical (Inst), EMD Serono (Inst), Daiichi Sankyo (Inst), ArQule (Inst), Syros Pharmaceuticals (Inst), Clovis Oncology (Inst), CytomX Therapeutics (Inst), InventisBio (Inst), Deciphera (Inst), Sermonix Pharmaceuticals (Inst), Sutro Biopharma (Inst), Zenith Epigenetics (Inst), Arvinas (Inst), Harpoon (Inst), Black Diamond Therapeutics (Inst), Orinove (Inst), Molecular Templates (Inst), Seagen (Inst), Compugen (Inst), G1 Therapeutics (Inst), Karyopharm Therapeutics (Inst), Dana Farber Cancer Hospital (Inst), Onconova Therapeutics (Inst), Shattuck Labs (Inst), PharmaMar (Inst), Olema Pharmaceuticals (Inst), Immunogen (Inst), Plexxikon (Inst), Amgen (Inst), Akeso Biopharma (Inst), ADC Therapeutics (Inst), AtlasMedx (Inst), Aravive (Inst), Ellipses Pharma (Inst), Incyte (Inst), MabSpace Biosciences (Inst), ORIC Pharmaceuticals (Inst), Pieris Pharmaceuticals (Inst), Pionyr (Inst), Repertoire Immune Medicines (Inst), Treadwell Therapeutics (Inst), Jacobio (Inst), Accutar Biotech (Inst), Artios (Inst), Bliss Biopharmaceutical (Inst), Cascadian Therapeutics (Inst), Dantari (Inst), Duality Biologics (Inst), Elucida Oncology (Inst), Infinity Pharmaceuticals (Inst), Relay Therapeutics (Inst), Tolmar (Inst), Torque (Inst), BeiGene (Inst), Context Therapeutics (Inst), K-Group Beta (Inst), Kind Pharmaceuticals (Inst), Loxo (Inst), Oncothyreon (Inst), Orum Therapeutics (Inst), Prelude Therapeutics (Inst), ProfoundBio (Inst), Cullinan Oncology (Inst)

Amit Oza

Consulting or Advisory Role: MorphoSys, AstraZeneca

Research Funding: AstraZeneca (Inst), GlaxoSmithKline (Inst), Merck (Inst)

Uncompensated Relationships: Ozmosis Research

Gini Fleming

Honoraria: Physicans' Education Resource

Research Funding: Corcept Therapeutics (Inst), AbbVie (Inst), Iovance Biotherapeutics (Inst), Syros Pharmaceuticals (Inst), Sermonix Pharmaceuticals (Inst), Compugen (Inst), Plexxikon (Inst), Roche (Inst), GlaxoSmithKline (Inst), Celldex (Inst), AstraZeneca (Inst), Molecular Templates (Inst), CytomX Therapeutics (Inst), Astellas Pharma (Inst), K-Group Beta (Inst), Pfizer (Inst), Merck (Inst), Incyte (Inst)

Other Relationship: DSI (Inst), Merck (Inst), Caris Life Sciences (Inst), Eisai (Inst), AstraZeneca (Inst)

Uncompensated Relationships: AbbVie

Alexander Spira

Leadership: Next Oncology (Inst)

Stock and Other Ownership Interests: Lilly

Honoraria: CytomX Therapeutics, AstraZeneca/MedImmune, Merck, Takeda, Amgen, Janssen Oncology, Novartis, Bristol Myers Squibb, Bayer

Consulting or Advisory Role: Array BioPharma (Inst), Incyte, Amgen, Novartis, AstraZeneca/MedImmune (Inst), Mirati Therapeutics, Gritstone Bio, Jazz Pharmaceuticals, Merck (Inst), Bristol Myers Squibb (Inst), Takeda, Janssen Research & Development, Mersana, Blueprint Medicines (Inst), Daiichi Sankyo/Astra Zeneca, Regeneron, Lilly, Black Diamond Therapeutics, Sanofi

Research Funding: Roche (Inst), AstraZeneca (Inst), Boehringer Ingelheim (Inst), Astellas Pharma (Inst), MedImmune (Inst), Novartis (Inst), Newlink Genetics (Inst), Incyte (Inst), AbbVie (Inst), Ignyta (Inst), LAM Therapeutics (Inst), Trovagene (Inst), Takeda (Inst), Macrogenics (Inst), CytomX Therapeutics (Inst), LAM Therapeutics, Astex Pharmaceuticals (Inst), Bristol Myers Squibb (Inst), Loxo (Inst), Arch Therapeutics (Inst), Gritstone Bio (Inst), Plexxikon (Inst), Amgen (Inst), Daiichi Sankyo (Inst), ADC Therapeutics (Inst), Janssen Oncology (Inst), Mirati Therapeutics (Inst), Rubius Therapeutics (Inst), Synthekine (Inst), Mersana (Inst), Blueprint Medicines (Inst), Regeneron, Alkermes (Inst), Revolution Medicines (Inst), Medikine (Inst), Black Diamond Therapeutics (Inst), BluPrint Oncology (Inst), Nalo Therapeutics (Inst)

Oladapo O. Yeku

Stock and Other Ownership Interests: hC Bioscience

Honoraria: Medscape

Consulting or Advisory Role: Gimv, TigaTx, hC Bioscience

Patents, Royalties, Other Intellectual Property: Dr Yeku has a patent for MUC16 Directed Antibodies for therapeutic applications pending and a patent for Human Artificial Chromosomes for therapeutic applications pending

Debra L. Richardson

Consulting or Advisory Role: AstraZeneca, Mersana, GlaxoSmithKline, Immunogen, Eisai, ProfoundBio

Research Funding: Genentech (Inst), AstraZeneca (Inst), Syros Pharmaceuticals (Inst), Innovent Biologics (Inst), Deciphera (Inst), ArQule (Inst), Roche (Inst), Tesaro (Inst), Merck (Inst), Karyopharm Therapeutics (Inst), Aravive (Inst), Mersana (Inst), Harpoon therapeutics (Inst), Hookipa Biotech (Inst), Five Prime Therapeutics (Inst), Fujifilm (Inst), Clovis Oncology (Inst), Arch Oncology (Inst), Plexxikon (Inst), GlaxoSmithKline (Inst), Lilly (Inst), Celsion (Inst), Shattuck Labs (Inst)

Jackie Walling

Leadership: Plexxikon, Entos AI, Opna, Orbus Therapeutics, Propella Therapeutics

Stock and Other Ownership Interests: Amgen

Consulting or Advisory Role: Harpoon Therapeutics, Myovant Sciences, Nurix, Plexxikon, Aminex, Rhizen Pharmaceuticals, Flag Therapeutics, Propella Therapeutics, Nuvation Bio, Oryzon Genomics, Janux Therapeutics, Ambagon Therapeutics, Lyell Immunopharma, Rgenta, Entos AI, Black Diamond Therapeutics, Cumulus Oncology, Storm Therapeutics, Orbus Therapeutics, Opna Bio

Kerry Inokuchi

Employment: Opna Bio, Plexxikon

Stock and Other Ownership Interests: Opna Bio, Daiichi Sankyo/UCB Japan

Travel, Accommodations, Expenses: Opna Bio, Plexxikon

Bernice Matusow

Employment: Plexxikon, Opna Bio, LLC

Stock and Other Ownership Interests: Daiichi Sankyo/UCB Japan, Opna Bio, LLC

Travel, Accommodations, Expenses: Opna Bio, LLC

Gideon Bollag

Employment: Plexxikon, Opna Bio

Leadership: Plexxikon, Opna Bio

Stock and Other Ownership Interests: Many

Consulting or Advisory Role: Goldman Sachs, Reactive Biosciences, Ambagon Therapeutics

Patents, Royalties, Other Intellectual Property: Multiple patents (Inst)

Elizabeth M. Swisher

Leadership: IDEAYA Biosciences

Other Relationship: Novartis

No other potential conflicts of interest were reported.

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ARTICLE CITATION

DOI: 10.1200/PO.23.00235 JCO Precision Oncology no. 7 (2023) e2300235. Published online October 5, 2023.

PMID: 37797273

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