1075TiP - A phase I trial of ATG-101, an investigational PD-L1×4-1BB bispecific antibody, in patients with advanced solid tumors and mature B cell non-Hodgkin lymphomas: PROBE-CN

Background

ATG-101 is a novel bispecific antibody targeted to PD-L1 and 4-1BB. 4-1BB is an inducible costimulatory receptor expressed on activated T cells and other immune cell populations. The clinical development of 4-1BB agonist monoclonal antibodies has been hampered by limited efficacy and/or toxicity, notably hepatotoxicity. ATG-101 addresses these issues by enhancing the activity of 4-1BB agonism whilst reducing the potential of systemic toxicity through strategic engineering. First, the high affinity PD-L1 binder ensures preferential antibody distribution to the tumor microenvironment. In addition, conditional 4-1BB activation requiring trimer formation, reduces nonspecific activation. Finally, the absence of binding affinity toFcγR further mitigates the risk of effective nonspecific 4-1BB activation. ATG-101 demonstrated potent in vivo anti-tumor activities in various animal models and has been granted Orphan Drug Designation for the treatment of pancreatic cancer by the US FDA, providing rationale for PROBE-CN.

Trial design

PROBE-CN is a phase I, multi-center, open-label study in China to evaluate ATG-101 as a single agent in patients with advanced solid tumors and mature relapsed/refractory (RR) B-NHL. The study includes a dose escalation phase which enrolls patients with advanced solid tumors, and a dose expansion phase which enrolls selected cohorts of patients with advanced solid tumors or RR B-NHL to further evaluate safety and efficacy of ATG-101. The primary objective is to evaluate the safety and to determine MTD/RP2D and/or optimal biological dose of ATG-101. Patients must have advanced disease that has relapsed from or been refractory to standard therapies; measurable lesion per RECIST v1.1; ECOG PS ≤1. The starting dose for escalation is 0.014 mg/kg, and single-patient cohorts have been applied for the first two dose levels, with a BOIN design used in the following cohorts. The patients receive a dose intravenously once every 28 days (1 cycle), and the DLTs will be evaluated during the first cycle. As of 5 January 2024, four clinical sites in China are open to recruitment and 22 patients across eight dose levels have been enrolled.

Clinical trial identification

Editorial acknowledgement

Legal entity responsible for the study

Antengene (Hangzhou) Biologics Co., Ltd.

Funding

Antengene (Hangzhou) Biologics Co., Ltd.

Disclosure

J. Zhao: Financial Interests, Personal and Institutional, Full or part-time Employment: Antengene. Y. Guo: Financial Interests, Personal, Invited Speaker: Merck Serono, Roche, MSD, BMS, BeiGene. All other authors have declared no conflicts of interest.