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FDA grants fast track designation to a PARG inhibitor, ETX-19477, for the treatment of BRCA-mutated, platinum-resistant HGSOC.
The FDA has granted fast track designation to ETX-19477, a poly (ADP-ribose) glycohydrolase (PARG) inhibitor, for the treatment of patients with BRCA-mutated, platinum-resistant high-grade serous ovarian cancer (HGSOC).1
This novel small molecule was designed to inhibit PARG, a key enzyme involved in DNA damage repair and replication stress response. According to investigators, by disrupting PARG activity, ETX-19477 aims to exploit the inherent DNA repair deficiencies in BRCA-mutated tumors, leading to synthetic lethality and tumor cell death. The agent is currently being evaluated in the ongoing phase 1 ERADIC8 expansion study (NCT06395519), which is enrolling patients with BRCA-mutated solid tumors, including those with HGSOC.
“Patients with platinum-resistant ovarian cancer have a poor prognosis, and treatment options remain extremely limited, highlighting a substantial unmet need for new therapies,” Jeffrey Stafford, PhD, chief executive officer of 858 Therapeutics, shared in a news release. “We are pleased that the FDA has granted fast track designation to ETX-19477 and we are committed to working closely with the FDA to accelerate its development. This designation was based on preclinical data and emerging clinical data from our ongoing phase 1/2 trial of ETX-19477, including antitumor activity at tolerable doses.”
ERADIC8 is a 2-part, open-label, multicenter study evaluating ETX-19477 in a monotherapy dose-escalation and dose-expansion framework.2 The study uses a nonrandomized, sequential assignment design with no masking.
In the part 1 dose-escalation portion, participants are assigned to escalating dose levels of once-daily oral ETX-19477 to define dose-limiting toxicities (DLTs) and establish the maximum tolerated dose (MTD) and/or recommended phase 2 dose (RP2D). In the part 2 dose expansion portion, additional participants are enrolled at selected dose levels determined from part 1 to further characterize the safety profile and generate preliminary evidence of anti-tumor activity.
The primary objective is to characterize safety and tolerability, including DLTs, frequency and severity of adverse effects (AEs), clinically relevant ECG abnormalities, and serious AEs. Secondary objectives include characterization of pharmacokinetics, including maximum plasma concentration, maximum blood concentration, half-life, area under the blood concentration-time curve, clearance, and volume of distribution, alongside pharmacodynamics. Preliminary efficacy is assessed using RECIST 1.1 end points, including objective response rate, duration of response, and disease control rate.
Eligible participants are 18 years or older with histologically or cytologically confirmed, advanced solid tumors (recurrent incurable, unresectable, or metastatic) excluding primary central nervous system (CNS) tumors. Patients must also have radiographic or clinical progression on, after, or intolerance to their most recent systemic therapy, and, when available, should have received appropriate approved standard-of-care therapy in the recurrent/metastatic setting unless it was contraindicated, not tolerated, or declined.
The protocol notes preferential enrollment of patients with known loss-of-function BRCA mutations. Additional key inclusion criteria include an adequate washout from prior investigational therapy (≥ 3 weeks or 5 half-lives, whichever is shorter; minimum 2 weeks) and an estimated life expectancy of ≥ 3 months.
Key exclusions include: unstable or symptomatic CNS disease (untreated/progressing brain metastases or symptomatic/progressing leptomeningeal disease), recent radiotherapy (definitive within 6 weeks; palliative within 2 weeks), conditions likely to significantly alter oral absorption (including recent bowel obstruction), clinically significant cardiac risk (including prolonged QTcF > 470 ms on serial ECGs, recent myocardial infarction/unstable angina within 6 months, or uncontrolled arrhythmias/heart failure), and active uncontrolled infections (controlled HIV and “cured” hepatitis C on stable therapy are generally permitted). The study also restricts select concomitant medications that could affect ETX-19477 exposure, such as PPIs, strong CYP3A modulators, and strong P-gp inhibitors within protocol-defined washout windows, and excludes patients receiving therapeutic warfarin/coumarin anticoagulants.
