A Study of PARG Inhibitor ETX-19477 in Patients With Advanced Solid Malignancies (ERADIC8)

March 24, 2026 updated by: 858 Therapeutics, Inc.
This is a two-part, open-label, multicenter, dose escalation and dose expansion study designed to evaluate the safety, tolerability, pharmacokinetics (PK), pharmacodynamics (PDx), and anti- tumor activity of ETX-19477, a novel reversible small molecule inhibitor of PARG.

Study Overview

Status

Recruiting

Conditions

Intervention / Treatment

Detailed Description

A hallmark of many cancer cells is replication stress, which is characterized by the slowing or stalling of replication forks during the DNA replication process, leading to the accumulation of damaged DNA. The cellular response to replication stress is the activation of cell-cycle checkpoints and the DNA damage response (DDR) pathway to arrest the cell cycle and promote repair of the damaged DNA.

Poly (ADP) ribose glycohydrolase (PARG) plays a critical role in DDR with genetic depletion or inhibition by reference compounds resulting in increased numbers of single-strand breaks (SSBs) and double-strand breaks (DSBs) and reduced kinetics of break repair. In addition, under conditions of replication stress in cancer cells, PARG depletion or inhibition has been shown to inhibit proliferation and arrest cells in the S or G2 phase of the cell cycle and/or induce apoptosis alone or in combination with DNA damaging agents or replication stress inducers. The replication stress response represents a cancer-specific vulnerability, which can be targeted by PARG small molecule inhibition.

Study Type

Interventional

Enrollment (Estimated)

120

Phase

  • Phase 2
  • Phase 1

Contacts and Locations

This section provides the contact details for those conducting the study, and information on where this study is being conducted.

Study Contact

Study Locations

  • United States
    • Arizona
      • Phoenix, Arizona, United States, 85054
        • Recruiting
        • Mayo Clinic
        • Principal Investigator:
          • Felipe Batalini, MD
    • Connecticut
      • New Haven, Connecticut, United States, 06510
        • Recruiting
        • Yale University, Yale Cancer Center
        • Principal Investigator:
          • Michael Cecchini, MD
    • Florida
      • Jacksonville, Florida, United States, 32224
        • Recruiting
        • Mayo Clinic
        • Principal Investigator:
          • Pooja Advani, MD
    • Illinois
      • Chicago, Illinois, United States, 60637
        • Recruiting
        • University Of Chicago Medical Center
        • Principal Investigator:
          • Han Cun, MD
    • Massachusetts
      • Boston, Massachusetts, United States, 02114
        • Recruiting
        • Massachusetts General Hospital
        • Principal Investigator:
          • Richard T Penson, MD
    • Minnesota
      • Rochester, Minnesota, United States, 55905
        • Recruiting
        • Mayo Clinic
        • Principal Investigator:
          • Siddhartha Yadav, MD
    • New York
      • New York, New York, United States, 10065
        • Recruiting
        • Memorial Sloan Kettering Cancer Center
        • Principal Investigator:
          • Ezra Y Rosen, MD, PhD
      • New York, New York, United States, 10016
        • Recruiting
        • Laura & Isaac Perlmutter Cancer Center at NYU Langone Health
        • Principal Investigator:
          • Nancy Chan, MD
    • Ohio
      • Columbus, Ohio, United States, 43212
        • Recruiting
        • Stefanie Spielman Comprehensive Breast Center
        • Principal Investigator:
          • Sagar Sardesai, MBBS
    • Pennsylvania
      • Philadelphia, Pennsylvania, United States, 19107
        • Recruiting
        • Thomas Jefferson University, Sidney Kimmel Comprehensive Cancer Center
        • Principal Investigator:
          • Kevin Zarrabi, MD
    • Texas
      • Houston, Texas, United States, 77030
        • Recruiting
        • MD Anderson Cancer Center
        • Principal Investigator:
          • Timothy A Yap, MD, PhD
    • Utah
      • Salt Lake City, Utah, United States, 84112
        • Recruiting
        • START Center for Cancer Care - Mountain Region
        • Principal Investigator:
          • William B. McKean, Jr, MD
    • Virginia
      • Fairfax, Virginia, United States, 22031
        • Recruiting
        • Virginia Cancer Specialists
        • Principal Investigator:
          • Alexander I Spira, MD
    • Washington
      • Seattle, Washington, United States, 98109
        • Recruiting
        • Fred Hutchinson Cancer Center
        • Principal Investigator:
          • Kalyan Banda, MD

Participation Criteria

Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.

Eligibility Criteria

Ages Eligible for Study

  • Adult
  • Older Adult

Accepts Healthy Volunteers

No

Description

Inclusion Criteria:

  • Males and females of age ≥ 18 years at the time of signing the informed consent document.
  • Histologically or cytologically confirmed advanced (incurable recurrent, unresectable, or metastatic) solid cancer, excluding primary central nervous system (CNS) tumors.
  • Any solid tumor malignancy, excluding primary CNS tumors, with progression on or after or intolerance to most recent systemic therapy. Preferential enrollment consideration will be made for patients with known BRCA2 mutations resulting in loss of function.
  • Measurable disease per RECIST v1.1.
  • ECOG performance status 0-1.
  • Progression on or after or intolerance to most recent systemic therapy. Prior treatment in the recurrent/metastatic setting; patients must have received approved standard therapy that is available to the patient that is known to confer clinical benefit, unless this therapy is contraindicated, intolerable to the patient, or is declined by the patient.
  • No investigational agent within 3 weeks or 5 half-lives (whichever is shorter; minimum of 2 weeks) prior to first dose of study drug.
  • Life expectancy of at least 3 months.

Exclusion Criteria:

  • Receiving continuous corticosteroids at prednisone-equivalent dose of >10 mg/day. Chronic systemic corticosteroid therapy for physiologic replacement (≤10 mg/day of prednisone equivalents) and the use of non-systemic corticosteroids (e.g., inhaled, topical, intra-nasal, intra-articular, or ophthalmic) are permitted.
  • Definitive radiotherapy within 6 weeks and palliative radiation within 2 weeks prior to the first dose of study drug.
  • Symptomatic untreated or progressing brain metastases. Stable, treated brain metastases are allowed if no evidence of radiologic or clinical progression or increasing corticosteroid use for at least 4 weeks.
  • Impairment of gastrointestinal (GI) function or GI disease that may significantly alter the absorption of ETX-19477 and no history of bowel obstruction within 6 months and/or peritoneal fluid drainage within 8 weeks prior to the first dose of study drug.
  • Known symptomatic and radiologically progressing or leptomeningeal disease (LMD). If LMD has been reported radiographically on baseline magnetic resonance imaging (MRI), but is not suspected clinically by the Investigator, the patient must be free of neurological symptoms of LMD.
  • Resting ECG with QT interval calculated using the Fridericia's formula (QTcF) >470 msec on 2 or more timepoints within a 24-hour period, or history or family history of congenital long QT syndrome, or taking concomitant medications that are known to prolong the QT/QTc interval, or history of additional risk factors for torsades de pointes (Tdp).
  • History of myocardial infarction or unstable angina within 6 months prior to enrollment, or clinically significant cardiac disease, such as ventricular arrhythmia requiring therapy, uncontrolled hypertension, clinically significant uncontrolled arrhythmias, or any history of symptomatic congestive heart failure.
  • Known active or chronic infection (viral, bacterial, or fungal), including tuberculosis, hepatitis B, hepatitis C, or AIDS-related illness. Controlled infections, including HIV and "cured" hepatitis C (no active fever, no evidence of systemic inflammatory response syndrome) that are stable with undetectable viral load on antiviral treatment are not exclusionary.
  • Acute or chronic uncontrolled renal disease, pancreatitis, or liver disease (with exception of patients with Gilbert's Syndrome, asymptomatic gallstones, liver metastases, or stable chronic liver disease per Investigator assessment).
  • Known other previous/current malignancy requiring treatment within ≤2 years except for limited disease treated with curative intent, such as carcinoma in situ, squamous or basal cell skin carcinoma, or superficial bladder carcinoma and not requiring ongoing chemotherapy.
  • Patients receiving proton pump inhibitors (PPIs), strong cytochrome P450 (CYP)3A inhibitors and inducers, or P-glycoprotein (P-gp) inhibitors. Patients should not receive PPIs within 7 days prior to first dose of study drug. Strong CYP3A inducers or inhibitors or strong P-gp inhibitors should not be given within 6 half-lives prior to first dose of study drug.
  • Patients currently treated with therapeutic doses of warfarin sodium (Coumadin®) or any other coumarin-derivative anticoagulants

Study Plan

This section provides details of the study plan, including how the study is designed and what the study is measuring.

How is the study designed?

Design Details

  • Primary Purpose: Treatment
  • Allocation: Non-Randomized
  • Interventional Model: Sequential Assignment
  • Masking: None (Open Label)

Arms and Interventions

Participant Group / Arm
Intervention / Treatment
Experimental: Phase 1 Part 1: Monotherapy Dose Escalation
Participants will be assigned to a dose level.
Drug: ETX-19477
Oral medication taken daily
Experimental: Phase 1 Part 2: Monotherapy Dose Expansion
After a dose is decided in Part 1, participants entering part 2 will be assigned to a dose level.
Drug: ETX-19477
Oral medication taken daily

What is the study measuring?

Primary Outcome Measures

Outcome Measure
Measure Description
Time Frame
To characterize the safety and tolerability of ETX-19477, the maximum tolerated dose (MTD) and/or RP2D of ETX-19477
Time Frame: 6 months
Frequency of dose-limiting toxicities (DLTs), frequency and severity of AEs, including abnormal ECG parameters, and serious adverse events (SAEs)
6 months

Secondary Outcome Measures

Outcome Measure
Measure Description
Time Frame
To characterize the pharmacokinetic (PK) profile of ETX-19477 by measuring maximum plasma concentration (Cmax)
Time Frame: 3 months
Maximum Plasma Concentration [Cmax] for single (Cycle 1 Day 1) dose and at steady state (Cycle 2 Day 1) with trough levels at the beginning of the next cycle (Cycle 3 Day 1).
3 months
To characterize the pharmacokinetic (PK) profile of ETX-19477 by measuring maximum blood concentration (tmax)
Time Frame: 3 months
Time of Maximum Blood Concentration (tmax) for single dose and at steady state with trough levels at the beginning of the next cycle.
3 months
To characterize the pharmacokinetic (PK) profile of ETX-19477 by measuring elimination half-life (t1/2)
Time Frame: 3 months
Elimination half-life (t1/2) for single dose and at steady state with trough levels at the beginning of the next cycle.
3 months
To further characterize the pharmacokinetic (PK) profile of ETX-19477 by the Area Under the Blood Concentration-Time Curve (AUC0-t, AUC0-inf), Clearance (CL), Volume of Distribution (Vd)
Time Frame: 3 months
Area Under the Blood Concentration-Time Curve (AUC0-t, AUC0-inf), Clearance (CL), Volume of Distribution (Vd) of ETX-19477
3 months
To assess the preliminary anti-tumor activity of ETX-19477 in participants by measuring objective response rate (ORR) using RECIST v1.1
Time Frame: 2 years
Objective response rate (ORR) assessed using RECIST criteria v1.1
2 years
To assess the preliminary anti-tumor activity of ETX-19477 in participants by measuring duration of response (DOR) using RECIST v1.1
Time Frame: 2 years
Duration of response (DOR) assessed using RECIST criteria v1.1
2 years
To assess the preliminary anti-tumor activity of ETX-19477 in participants by measuring disease control rate (DCR) using RECIST v1.1
Time Frame: 2 years
Disease control rate (DCR) assessed using RECIST criteria v1.1
2 years

Collaborators and Investigators

This is where you will find people and organizations involved with this study.

Sponsor

858 Therapeutics, Inc.

Investigators

  • Study Director: Daniel McCormick, 858 Therapeutics, Inc.

Study record dates

These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.

Study Major Dates

Study Start (Actual)

May 13, 2024

Primary Completion (Estimated)

December 1, 2026

Study Completion (Estimated)

December 1, 2026

Study Registration Dates

First Submitted

April 24, 2024

First Submitted That Met QC Criteria

April 30, 2024

First Posted (Actual)

May 2, 2024

Study Record Updates

Last Update Posted (Actual)

March 27, 2026

Last Update Submitted That Met QC Criteria

March 24, 2026

Last Verified

March 1, 2026

More Information

Terms related to this study

Keywords

Additional Relevant MeSH Terms

Other Study ID Numbers

  • ETX-19477-101

Plan for Individual participant data (IPD)

Plan to Share Individual Participant Data (IPD)?

NO

Drug and device information, study documents

Studies a U.S. FDA-regulated drug product

Yes

Studies a U.S. FDA-regulated device product

No

This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.

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