Abstract CT526: A Phase 1/2a Study of a PI3Kδγ dual inhibitor ZX-101A in patients with advanced solid tumors

Abstract

Abstract ZX-101A is a next-generation PI3Kδ/γ dual inhibitor, exerting synergistic effects on PI3Kδ and PI3Kγ-mediated processes through multifaceted mechanisms of actions. Phase 1/2a study, ZX-101A-101 (NCT04504708) is ongoing to assess safety, pharmacokinetics, pharmacodynamics, and preliminary efficacy in patients with advanced hematologic malignancies. Furthermore, recent preclinical studies of ZX-101A showed that dual inhibition of PI3Kδ and PI3Kγ restored the immune surveillance to inhibit solid tumor growth. ZX-101A-201 is a phase 1/2a open-label, multiple-dose ascending study to investigate the safety, pharmacokinetics, pharmacodynamics, and preliminary antitumor activity of once daily oral ZX-101A in 28-day cycles in patients with advanced solid tumors.ZX-101A had minimal effects on solid tumor-derived CT26, 4T1 and A20 cells in in vitro cell proliferation assay. In contrast, ZX-101A inhibited tumor growth when CT26 cells were grafted to wild-type syngeneic mice, while only showed a limited tumor growth inhibition when CT26 tumors grew on T-cell deficient nude mice. Thus, in vivo tumor growth inhibition in wild-type mice was attributed to the enhanced anti-tumor immunity by ZX-101A treatment. Flow cytometry analysis on ex vivo tumor tissues from syngeneic mouse demonstrated that ZX-101A decreased regulatory T cells and increased M1/M2 macrophage polarization in the tumor microenvironment. In A20 syngeneic model, ZX-101A in combination of anti-PD1 antibody achieved 99.7% TGI after 18 days of treatment, while anti-PD1 antibody alone only had TGI at 11.7%. Synergistic inhibitory effect of ZX-101A and anti-PD1 antibody was also observed in LLC, CT26 and humanized MC38 syngeneic mouse models. Safety assessment on the mouse spleen, thymus and colon organs indicated minimal side effects by the treatment of the ZX-101A alone and in combination with anti-PD1. These results suggested ZX-101A as a potential immunotherapeutic agent to treat appropriate solid tumor types. ZX-101A-201 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-101A monotherapy in patient with advanced solid tumors. Part 2 dose expansion will evaluate ZX-101A activity in up to three disease-specific cohorts. Inclusion of combination therapy is planned after obtaining the initial clinical assessment of ZX-101A on its safety, tolerability, pharmacokinetics, and pharmacodynamics in patients. Citation Format: Xiaoli Qin, Lori Luo, Li Ying-ying, Yin Wang, Shuaijun Sun, Xiaolin Hao, Jinfu Yang. A Phase 1/2a Study of a PI3Kδγ dual inhibitor ZX-101A 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 CT526.