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

NCT06395519 · 858 Therapeutics, Inc.
In plain English

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About this study
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.
Eligibility criteria
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 design
Enrollment target: 120 participants
Allocation: non_randomized
Masking: none
Age groups: adult, older_adult
Timeline
Starts: 2024-05-13
Estimated completion: 2026-12
Last updated: 2026-03-27
Interventions
Drug: ETX-19477
Primary outcomes
  • To characterize the safety and tolerability of ETX-19477, the maximum tolerated dose (MTD) and/or RP2D of ETX-19477 (6 months)
Sponsor
858 Therapeutics, Inc. · industry
Contacts & investigators
Contact858 Therapeutics, Inc. · contact · dmccormick@8five8tx.com · (858) 987-8380
InvestigatorDaniel McCormick · study_director, 858 Therapeutics, Inc.
All locations (14)
Mayo ClinicRecruiting
Phoenix, Arizona, United States
Yale University, Yale Cancer CenterRecruiting
New Haven, Connecticut, United States
Mayo ClinicRecruiting
Jacksonville, Florida, United States
University of Chicago Medical CenterRecruiting
Chicago, Illinois, United States
Massachusetts General HospitalRecruiting
Boston, Massachusetts, United States
Mayo ClinicRecruiting
Rochester, Minnesota, United States
Laura & Isaac Perlmutter Cancer Center at NYU Langone HealthRecruiting
New York, New York, United States
Memorial Sloan Kettering Cancer CenterRecruiting
New York, New York, United States
Stefanie Spielman Comprehensive Breast CenterRecruiting
Columbus, Ohio, United States
Thomas Jefferson University, Sidney Kimmel Comprehensive Cancer CenterRecruiting
Philadelphia, Pennsylvania, United States
MD Anderson Cancer CenterRecruiting
Houston, Texas, United States
START Center for Cancer Care - Mountain RegionRecruiting
Salt Lake City, Utah, United States
Virginia Cancer SpecialistsRecruiting
Fairfax, Virginia, United States
Fred Hutchinson Cancer CenterRecruiting
Seattle, Washington, United States
A Study of PARG Inhibitor ETX-19477 in Patients With Advanced Solid Malignancies · TrialPath