ZX-101A is a next-generation PI3Kδ/γ inhibitor, without the purine motif in the first generation marketed drug duvelisib. It is not an inhibitor or substrate of major CYP enzymes and potentially avoids the drug-drug interaction limitation of duvelisib in combination therapies or with concomitant medications. Preclinical studies suggested an improved therapeutic window compared to duvelisib. Its absorption, distribution, metabolism, and excretion (ADME) and safety profile, through a series of in vitro and in vivo studies, supports the clinical development of ZX-101A in hematologic malignancies. Dual inhibition of PI3Kδ and PI3Kγ by ZX-101A as treatment of hematologic malignancies may exert synergistic effects through inhibiting PI3K signaling in malignant lymphocytes and cytokine/chemokine signaling from the tumor microenvironment as well as enhancing anti-tumor immunity. In vitro cell proliferation assay demonstrated ZX-101A potently inhibited cell proliferation of B- and T-cell lymphoma cell lines, but without effect on cells derived from solid tumors. In vivo tumor growth inhibition was observed in B-cell lymphoma CDX mouse model and multiple syngeneic animal models including A20, 4T1 and CT26, supporting a multifaceted anti-tumor effect of ZX-101A. Both in vitro and in vivo studies demonstrated that ZX-101A decreases regulatory T cell differentiation from naïve CD4+ cells and optimizes M1/M2 macrophage polarization. Additionally, in A20 syngeneic mouse model, ZX-101A in combination with anti-PD1 antibody achieved 99.7% tumor growth inhibition (TGI) after 18-days of treatment, while TGI was only 11.7% with anti-PD1 antibody alone. ZX-101A-101 is an ongoing Phase 1/2a, first-in-human, open-label, multicenter, multiple-dose ascending study to investigate the safety, tolerability, pharmacokinetics, pharmacodynamics, and preliminary antitumor activity of once daily oral ZX-101A in 28-day cycles in patients with relapsed/resistant/refractory advanced hematologic malignancies (ClinicalTrials.gov Identifier: NCT04504708). 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-101A. Part 2 dose expansion will evaluate ZX-101A activity in up to three disease-specific cohorts (CLL/SLL, indolent NHL, and based on emerging data from Part 1, Peripheral T-cell lymphoma may be included). Inclusion of a cohort of combination therapy is planned.

Citation Format: Xiaoli (Shelley) Qin, Edgar Bautista, April Teitelbaum, Xiaolin Hao, Jinfu Yang. A phase 1/2a, dose-escalation and dose-expansion study of ZX-101A in patients with relapsed/resistant or refractory advanced hematologic malignancies [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr CT202.