A Phase I Study To Evaluate The Safety And Tolerability Of Ab680 Combination Therapy In Participants With Gastrointestinal Malignancies

TPS788 Background: Metastatic pancreatic ductal adenocarcinoma (mPDAC) expresses very high levels of CD73 among tumor types, and CD73 expression level is a known poor prognostic factor in PDAC. Adenosine, a product of AMP breakdown by CD73, is highly immunosuppressive against effector T & NK cells in the tumor microenvironment. AB680 is the first clinical-stage small-molecule CD73 inhibitor, which is highly potent, pharmacodynamically active, and safe in healthy volunteer dose escalation studies. Targeting the adenosine pathway in combination with standard of care regimens may have a more profound effect on activating and inducing sustained anti-tumor immunity. Methods: This is a Phase 1/1b, open-label, dose-escalation, and dose-expansion study to evaluate the safety, tolerability, pharmacokinetics, pharmacodynamics, and clinical activity of AB680 in combination with AB122 (anti-PD-1 antibody) and standard chemotherapy (nab-paclitaxel [NP] and gemcitabine [Gem]) in participants with first line (1L) mPDAC. In the dose-escalation Ph1 portion, increasing dose levels of AB680 are administered every 2 weeks (Q2W) in combination with AB122 (240 mg Q2W) and NP/Gem (Gem 1000 mg/m2 + NP 125 mg/m2 IV on Days 1, 8, and 15 of each 28-day cycle). Up to 30 participants may be evaluated in Ph1 dose-escalation. In the dose-expansion Ph1b portion, AB680 will be administered at the recommended dose for expansion in combination with AB122 and NP/Gem in up to 40 participants. Adverse events will be graded according to NCI CTCAE 5.0 and antitumor activity assessed using RECIST v1.1. Conclusions: This Ph1/1b study will be the first to target the adenosine axis using a highly potent small-molecule inhibitor of CD73, AB680, in 1L mPDAC in combination with standard of care chemotherapy (NP/Gem) and a PD-1 antibody (AB122). Future results will be shared in upcoming scientific conferences. Clinical trial information: NCT04104672.