First-in-human study of ZG0895, a TLR8 selective agonist, as monotherapy in patients with advanced solid tumors.

e15103 Background: ZG0895 is a potent and novel Toll-like receptor (TLR) agonist that shows a highly selective activation of TLR8. It inhibits tumor growth by launching TLR8 downstream signal cascades, thus activating both innate and adaptive immune systems. We report preliminary results from a phase I, first-in-human, dose escalation study evaluating the safety, pharmacokinetics (PK) and antitumor activity of ZG0895 in patients with advanced solid tumors. Methods: Eligible patients previously treated with or intolerant to available standard systemic therapy(ies), received subcutaneous (s.c.) injection of ZG0895 weekly. If tolerated during the first treatment cycle (21 days per cycle), patients would continue weekly s.c. administrations of ZG0895 until disease progression, loss of clinical benefit, or development of unacceptable toxicity. Dose escalation scheme for ZG0895 was planned with eight dose levels (0.06, 0.18, 0.37, 0.75, 1.50, 2.25, 3.00, 3.75 mg/m 2 ) according to an accelerated titration in the first two dose levels and the standard “3+3” design in the rest dose levels. Primary end points are the safety, tolerability, and recommended phase 2 dose (RP2D) of ZG0895. Secondary endpoints include overall response rate (ORR), disease control rate (DCR) and progression free survival (PFS) per the Response Evaluation Criteria in Solid Tumors version 1.1, as well as pharmacokinetics. Results: At data cut-off (December 25, 2023), 7 patients (5 males and 2 females), with the median age of 59 (range: 38-74) years old, received weekly s.c. injections of ZG0895 at the dose levels from 0.06 mg/m 2 to 0.75 mg/m 2 and completed the DLT observation period. Of the 7 patients, 4 (57.1%) received at least 3 lines of prior antineoplastic therapies, and 3 (42.9%) had exposed to PD-(L)1 inhibitors previously. No dose limiting toxicity events were reported. Five patients (71.4%) experienced grade 1 or 2 treatment-related adverse event (TRAE), and the most frequent events were injection site pain, hypertriglyceridaemia and proteinuria. None of patients experienced ≥grade 3 TRAE. Two patients experienced SAEs (intestinal obstruction and tumour haemorrhage), and both events were not related to ZG0895. The C max and AUC increased from 0.06 to 0.18 mg/m 2 approximately in dose proportion. Conclusions: During the first 4 dose groups, ZG0895 was well tolerated in patients with advanced solid tumors. Phase I dose escalation of ZG0895 are underway in higher doses. Clinical trial information: NCT05877664 .