The efficacy and safety of a selective PARP1 inhibitor ACE-86225106 in patients with advanced solid tumors: Preliminary results from a first-in-human phase 1/2 study.

3153 Background: ACE-86225106 is a highly selective PARP1 inhibitor, exhibiting high potency in enzymatic and DNA-trapping assays of PARP1, while maintaining significant selectivity over PARP2. Pre-clinical studies with ACE-86225106 have demonstrated strong anti-cancer activities in in vivo CDX models, with excellent tolerability. Here we report the preliminary clinical data of ACE-86225106 from the ongoing first-in-human study (NCT06380660). Methods: This is a multicenter, open-label, phase1/2 study of ACE-86225106 in adult patients with locally advanced (unresectable) or metastatic solid tumors. Phase 1 includes a typical “3+3” dose escalation and backfill module, followed by a dose expansion module in phase 2. The primary objective is to assess safety, tolerability, PK/PD profile, and pre-liminary efficacy of ACE-86225106 as a monotherapy. Results: As the data cut-off (23 Jan 2025), 10 patients received ACE-86225106 at a dose of 5mg, 10mg or 20mg QD, and 5 patients backfilled at a dose of 10mg QD. Median number of prior therapy lines was 3 (range 2-12). Two patients (squamous lung cancer and breast cancer each) did not complete the DLT evaluation period due to disease progression and were replaced. No DLTs were reported as of data cut-off. Among total fifteen patients (10 patients) who received at least one dose of ACE-86225106, no Grade 3 or higher treatment-related adverse events (TRAEs) were reported. There were no treatment discontinuations or dose reductions due to TRAE. The compound exhibited a relatively flat PK curve with mild accumulation after multiple dosing. The steady-state C trough was approximately 5 fold, 24 fold and 36 fold above target effective concentration at dose level of 5mg, 10mg, 20mg respectively. The PARylation inhibition was > 90% confirming target engagement. Of seven patients having post-treatment tumor assessment and being considered efficacy-evaluable, two patients (one fallopian tube cancer patient with BRCA mutation and one prostate cancer patient with BRCA wild type) achieved PR per RECIST1.1. Conclusions: Preliminary data indicate that ACE-86225106 is well tolerated and shows promising efficacy in heavily pre-treated advanced solid tumors. Clinical trial information: NCT06380660 .