Abstract B005: Preliminary safety, PK and efficacy of a PARP1 selective inhibitor VB15010 in patients with advanced solid tumors in phase 1/2 study

Abstract Background: VB15010 is a next-generation, highly selective PARP1 inhibitor (Fang D. et al., AACR 2024, abstract 4537). Unlike first-generation PARP inhibitors (e.g., olaparib, niraparib), which inhibit both PARP1 and PARP2, VB15010 minimizes PARP2 inhibition, which is implicated in hematologic toxicities such as anemia, neutropenia, and thrombocytopenia. PARP1 selectivity is hypothesized to improve tolerability while preserving antitumor activity in homologous recombination repair (HRR) gene-mutated cancers. Methods: This multicenter, open-label, phase 1/2 trial (NCT06819215) evaluated the safety, pharmacokinetics (PK), pharmacodynamics (PD), and preliminary efficacy of oral VB15010 in patients with advanced solid tumors harboring HRR gene mutations. In the dose-escalation phase, VB15010 was administered once daily (QD) at 10, 30, 50, and 80 mg doses using a standard 3+3 design. The primary endpoints were safety, dose-limiting toxicities (DLTs), and recommended phase 2 dose (RP2D) determination. Secondary endpoints included PK, PD (PARylation inhibition), and efficacy assessed by RECIST v1.1. Results: As of July 1, 2025, 8 patients (2 males, 6 females; median age 58 [range 46–75]) were enrolled at 10, 30, and 50 mg QD dose levels. Tumor types included ovarian (n=4), breast (n=2), and prostate cancers (n=2). No DLTs were reported. The most frequent treatment-emergent adverse events (TEAEs; ≥2 patients) were decreased white blood cell count, anemia, neutropenia, nausea, and thrombocytopenia. Three cases of upper respiratory tract infection were deemed unrelated to study drug. Two serious adverse events (SAEs) of anemia resolved with treatment interruption and dose reduction. No TEAEs led to treatment discontinuation or death. PK analysis showed dose-proportional increases in exposure (Cmax and AUC) across 10–50 mg with a mean half-life of 8.5 hours, supporting QD dosing. VB15010 achieved ≥90% PARylation inhibition sustained over 72 hours at all dose levels. Among 7 evaluable patients, the objective response rate (ORR) was 42.8%, disease control rate (DCR) 57%, and median progression-free survival (PFS) 5.6 months (median follow-up: 3.9 months). Conclusions: VB15010 demonstrated favorable tolerability, promising PK/PD properties, and preliminary antitumor activity in advanced solid tumors with HRR gene mutations. These results support further clinical development in this patient population. Citation Format: Jinming Yu, Yuping Sun, Tiejun Yang, Li Wang, Ruifang An, Jin Yang, Yefeng Lu, Jia Song, Jing Han, Chenxi Li, Douglas Fang, Charles Z. Ding. Preliminary safety, PK and efficacy of a PARP1 selective inhibitor VB15010 in patients with advanced solid tumors in phase 1/2 study [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference on Molecular Targets and Cancer Therapeutics; 2025 Oct 22-26; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2025;24(10 Suppl):Abstract nr B005.