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.
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
Allocation
NON_RANDOMIZED
Purpose
TREATMENT
Masking
NONE
Enrollment
120
Oral medication taken daily
Mayo Clinic
Phoenix, Arizona, United States
RECRUITINGYale University, Yale Cancer Center
New Haven, Connecticut, United States
RECRUITINGMayo Clinic
Jacksonville, Florida, United States
RECRUITINGUniversity of Chicago Medical Center
Chicago, Illinois, United States
RECRUITINGMassachusetts General Hospital
Boston, Massachusetts, United States
RECRUITINGMayo Clinic
Rochester, Minnesota, United States
RECRUITINGLaura & Isaac Perlmutter Cancer Center at NYU Langone Health
New York, New York, United States
RECRUITINGMemorial Sloan Kettering Cancer Center
New York, New York, United States
RECRUITINGStefanie Spielman Comprehensive Breast Center
Columbus, Ohio, United States
RECRUITINGThomas Jefferson University, Sidney Kimmel Comprehensive Cancer Center
Philadelphia, Pennsylvania, United States
RECRUITING...and 4 more locations
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
To characterize the pharmacokinetic (PK) profile of ETX-19477 by measuring maximum plasma concentration (Cmax)
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).
Time frame: 3 months
To characterize the pharmacokinetic (PK) profile of ETX-19477 by measuring maximum blood concentration (tmax)
Time of Maximum Blood Concentration (tmax) for single dose and at steady state with trough levels at the beginning of the next cycle.
Time frame: 3 months
To characterize the pharmacokinetic (PK) profile of ETX-19477 by measuring elimination half-life (t1/2)
Elimination half-life (t1/2) for single dose and at steady state with trough levels at the beginning of the next cycle.
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)
Area Under the Blood Concentration-Time Curve (AUC0-t, AUC0-inf), Clearance (CL), Volume of Distribution (Vd) of ETX-19477
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
Objective response rate (ORR) assessed using RECIST criteria 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
Duration of response (DOR) assessed using RECIST criteria 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
Disease control rate (DCR) assessed using RECIST criteria v1.1
Time frame: 2 years
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