A Study of PARG Inhibitor ETX-19477 in Patients With Advanced Solid Malignancies
Summary
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.
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.
Arms & interventions
- DrugETX-19477
Oral medication taken daily
Outcome measures
Primary
To characterize the safety and tolerability of ETX-19477, the maximum tolerated dose (MTD) and/or RP2D of ETX-19477
Frequency of dose-limiting toxicities (DLTs), frequency and severity of AEs, including abnormal ECG parameters, and serious adverse events (SAEs)
Time frame: 6 months
Secondary
To characterize the pharmacokinetic (PK) profile of ETX-19477 by measuring maximum plasma concentration (Cmax)
Time frame: 3 months
To characterize the pharmacokinetic (PK) profile of ETX-19477 by measuring maximum blood concentration (tmax)
Time frame: 3 months
To characterize the pharmacokinetic (PK) profile of ETX-19477 by measuring elimination half-life (t1/2)
Time frame: 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
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
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
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
Eligibility criteria
Study locations (14)
Mayo Clinic
Phoenix, Arizona, 85054
Yale University, Yale Cancer Center
New Haven, Connecticut, 06510
Mayo Clinic
Jacksonville, Florida, 32224
University of Chicago Medical Center
Chicago, Illinois, 60637
Massachusetts General Hospital
Boston, Massachusetts, 02114
Mayo Clinic
Rochester, Minnesota, 55905
Laura & Isaac Perlmutter Cancer Center at NYU Langone Health
New York, New York, 10016
Memorial Sloan Kettering Cancer Center
New York, New York, 10065
Stefanie Spielman Comprehensive Breast Center
Columbus, Ohio, 43212
Thomas Jefferson University, Sidney Kimmel Comprehensive Cancer Center
Philadelphia, Pennsylvania, 19107
MD Anderson Cancer Center
Houston, Texas, 77030
START Center for Cancer Care - Mountain Region
Salt Lake City, Utah, 84112
Virginia Cancer Specialists
Fairfax, Virginia, 22031
Fred Hutchinson Cancer Center
Seattle, Washington, 98109