Abstract 6240: A phase 1 study of selective PI3Kγ inhibitor ZX-4081 in patients with advanced solid tumors
Authors: Qin Xiaoli , Bautista Edgar , Li Ying-ying , Li Xiaomin , Peng Zhiyuan , Kong Deming , Yang Jinfu , Hao Xiaolin 
Published: June 2022

Abstract
ZX-4081 is a highly selective PI3Kγ inhibitor with an IC50 of 1.5 nM for PI3Kγ and 1000-fold selectivity over the other isoforms (α, β, and δ) in cell-based assays. PI3Kγ is predominantly expressed in leukocytes and plays a critical role in activation of myeloid cells at sites of inflammation and tumorigenesis, and in lymphocyte recruitment into tumor microenvironment. Previous studies reported that blockade of PI3Kγ-mediated signaling limits tumor growth and metastasis by activating CD8+ T cell and M1-like macrophage in the tumor milieu, and thereby overcome resistance to immune checkpoint inhibitors. ZX-4081-101 (NCT05118841) is a phase 1 first-in-human, open-label, multi-center, multiple-dose ascending study to investigate the safety, tolerability, pharmacokinetics, pharmacodynamics, and preliminary antitumor activity of twice daily oral ZX-4081 in 28-day cycles in patients with advanced solid tumors. The study consists of 2 parts, Dose Escalation and Dose Expansion. Part 1 dose escalation is designed to determine the safety, tolerability, and recommended phase 2 dose (RP2D) of ZX-4081. Part 2 dose expansion will evaluate ZX-4081 activity in a cohort of up to 40 patients with advanced solid tumors to obtain additional safety, tolerability, PK and PD at the RP2D dose. ZX-4081didn’t show significant inhibitory effects on solid tumor cell lines including 4T1 and CT-26 in in vitro cell proliferation assay. In contrast, in the 4T1 syngeneic mouse model, ZX-4081 treatment at 25 mg/kg BID, 50 mg/kg QD, and 50 mg/kg BID for 28 days reduced tumor growth by 34.6%, 21.2%, and 44.1% in size, respectively (p&lt; 0.0001). No body weight loss was observed in all treatment groups. The in vivo inhibitory effect of ZX-4081 on 4T1 tumor growth was attributed to its enhancement on the mouse anti-tumor immunity. In CT26 syngeneic mouse model, TGI of ZX-4081 at 5 mg/kg BID in combination with anti-PD1 antibody was 80.6% (p value &lt;0.01) in comparison with vehicle and anti-PD1 antibody alone groups. Flow Cytometry analysis illustrated that the combination of ZX-4081 and anti-PD1 treatment increased the ratio of CD8+ T cells to regulatory T cells relative to ZX-4081 alone and anti-PD1 alone treatment groups. Combination treatment also decreased M2-like macrophages (CD206+MHCII-) proportion in macrophages, consequently increased the ratio of M1-like to M2-like macrophages in comparison to ZX-4081 alone and anti-PD1 alone treatment groups. Overall, our studies suggest that ZX-4081 inhibits tumor growth by reprogramming tumor microenvironment via impairing PI3Kγ-AKT-mediated macrophage polarization to enhance anti-cancer immunity. Its absorption, distribution, metabolism, and excretion (ADME) and safety profile, through a series of in vitro and in vivo studies, support the clinical development of ZX-4081. Inclusion of combination therapy is planned after obtaining the initial clinical assessment of ZX-4081 on its safety, tolerability, pharmacokinetics, and pharmacodynamics.
Citation Format: Xiaoli Qin, Edgar Bautista, Ying-ying Li, Xiaomin Li, Zhiyuan Peng, Deming Kong, Jinfu Yang, Xiaolin Hao. A phase 1 study of selective PI3Kγ inhibitor ZX-4081 in patients with advanced solid tumors [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 6240.