The safety, tolerability, pharmacokinetics, and pharmacodynamics of IDE161, a potent, selective, small-molecule inhibitor of PARG, is being evaluated in a phase 1 clinical trial for advanced solid tumors.
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Trial Name: A Study of PARG Inhibitor IDE161 in Participants With Advanced Solid Tumors
ClinicalTrials.gov Identifier: NCT05787587
Sponsor: IDEAYA Biosciences
Recruitment Contact: IDEAYA Clinical Trials, 650-278-8351 & IDEAYAClinicalTrials@ideayabio.com, Contact: Oktay Kirak, MD, PhD, okirak@ideayabio.com
Completion Date: September 2025
The first patient with an advanced solid tumor has been dosed in a phase 1 clinical trial evaluating IDE161 (NCT05787587), a potent, selective, small-molecule inhibitor of PARG with a mechanistically-differentiated target in the clinically-validated DNA damage repair pathway, according to IDEAYA Biosciences.1
In preclinical models, IDE161 showed activity in PARP inhibitor and platinum-resistant settings, as well as a favorable non-clinical safety profile.2 Additionally, preclinical efficacy and tolerability data showed that IDE161 elicited cellular activity in biomarker defined settings, strong synthetic lethal interactions with key DNA repair genes across multiple indications, and on-target cellular responses that were linked with homologous recombination deficiency (HRD) status.
These preclinical findings, which were presented at the American Association for Cancer Research (AACR) Annual Meeting 2023, support a phase 1 initial dose of IDE161 at 1-half of the predicted human efficacious dose.
"We are excited to clinically investigate IDE161 as a potential first-in-class synthetic lethality treatment for cancer patients with HRD.We believe IDE161 may be impactful for estrogen receptor [ER]-positive /HER2-negative breast cancer patients with HRD, as well as for patients having ovarian cancer and other solid tumors with HRD, for whom current treatment options are limited," said Darrin M. Beaupre, MD, PhD, chief medical officer of IDEAYA Biosciences, in a press release1."Based on its preclinical tolerability profile, IDE161 may also be suitable for evaluation with several distinct classes of combination agents, providing multiple paths to demonstrate patient benefit in these populations."
The phase 1 clinical trial aims to assess the safety, tolerability, pharmacokinetics, and pharmacodynamics of IDE161 as monotherapy, as well as its preliminary efficacy in patients who have tumors with HRD.3
The first part of the trial will utilize a dose-escalation method where patients will be assigned to a dose level and given oral IDE161 daily. Then, after a dose is decided in part 1, the dose-expansion portion of the study will be administered IDE161 at the determined dose level via oral administration once a day.
To be included in the study, patients must be aged 18 years or older with advanced or metastatic solid tumors excluding primary central nervous system (CNS) tumors. Patients are required to have documented evidence of genetic alterations conferring HRD and have progressed on at least 1 prior line of therapy in the advanced or metastatic setting that is considered an appropriate standard of care, or for which the participant has documented intolerance.
If patients have a known primary CNS malignancy GI function or GI disease impairment that may significantly alter the absorption of IDE161, active, uncontrolled infection, or clinically significant cardiac abnormalities, they will be excluded from the trial. Patients who have had major surgery within 4 weeks before enrollment, radiation therapy within 2 weeks before enrollment, systemic cytotoxic chemotherapy within 4 weeks prior to enrollment, radioimmunotherapy within 6 weeks of enrollment, been treated with a therapeutic antibody within 4 weeks prior to enrollment or have received treatment with an anti-cancer small molecule within 5 half-lives or 2 weeks, whichever is shorter, will also be excluded from the study.
In part A, primary end points are to characterize the safety and tolerability of IDE161, and secondary end points include evaluating the preliminary tumor activity, pharmacokinetics, and pharmacodynamics.
In the second part, investigators will further assess the safety and tolerability, and preliminary anti-tumor activity using duration or response and overall response as primary end points, along with secondary end points of pharmacokinetics and pharmacodynamics.
The trial is actively recruiting patients in Houston, Texas, and has an estimated study completion date of September 2025.
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