CT209 / 9 - A first-in-human phase 1 trial of IO-108, an antagonist antibody targeting LILRB2 (ILT4), as monotherapy and in combination with pembrolizumab in adult patients with advanced relapsed or refractory solid tumors (NCT05054348)
AACR American Association for Cancer Research: Annual Meeting 2022
oregon; portland; chiles
- Cancer immunotherapy has entered the mainstream with approval of T-cell checkpoint inhibitors. However, most patients with advanced solid tumors do not derive benefits, or relapse after T-cell checkpoint blockade. Myeloid checkpoint inhibition is a new approach to cancer immunotherapy. LILRB2 is primarily expressed by myeloid cells and its expression in tumors is associated with high macrophage infiltration. Several LILRB2 ligands (HLA-G, ANGPTL2, and SEMA4A) are known to contribute to the immune suppressive microenvironment of solid tumors. Blockade of the LILRB2 pathway has the potential to reactivate or enhance anti-tumor T cell immune responses. IO-108 is a IgG4 monoclonal antibody that specifically binds LILRB2 to block ligands interaction and activation of LILRB2. In vitro, IO-108 treatment of primary immune cells results increased pro‑inflammatory responses and an enhanced antigen presenting cell phenotypes. A Good Laboratory Practice repeat-dose, 15-day toxicology study in Cynomolgus monkeys at 0 (control), 1, 10, or 100 mg/kg/dose administered intravenously once weekly for a total of 3 doses showed that IO-108 was well-tolerated at all dose levels, with only non-statistically significant reduction of thyroid glands weight. No-observed-adverse-effect-level (NOAEL) of 100 mg/kg provides a sufficient safety margin for the IO-108 starting dose of 60 mg, which was derived using a MABEL (minimum anticipated biological effect level) approach. This clinical trial is a first-in-human, Phase 1, multicenter, open-label, dose-escalation, safety, pharmacokinetic (PK), and pharmacodynamic evaluation of intravenously administered IO-108, both as monotherapy and in combination with pembrolizumab, in adult patients with solid tumors that have failed standard of care therapies (NCT05054348). It is estimated that up to 36 patients will be enrolled in the study. IO-108 will be administered every 21 days, with a dose-limiting toxicity (DLT) evaluation period of 21 days. Patients will be enrolled into sequential cohorts and treated with increasing doses of IO-108 using mTPI (modified Toxicity Probability Interval) method. Safety, PK, and clinical activity will be evaluated on an ongoing basis. The primary objective of the study is to assess safety and tolerability at increasing dose levels of IO-108 in successive cohorts of adult patients (treated with or without with pembrolizumab) with advanced relapsed or refractory solid tumors, to estimate the maximal tolerated dose (MTD) or maximum administered dose (MAD) and select the recommended phase 2 dose (RP2D). Secondary objectives include characterizing PK, immunogenicity, and preliminary anti-tumor activity. Biomarker evaluation will include changes in myeloid cell markers and T-cells, LILRB2 expression level and receptor occupancy. Statistical analyses will be primarily descriptive in nature. Tabulations will be produced for appropriate disposition, demographic, baseline disease characteristics, safety, PK, pharmacodynamic, and clinical activity parameters. Response to treatment as assessed by RECIST v1.1 will be tabulated. To date, five patients have been dosed without DLT.
Earle A. Chiles Research Institute
Powderly, John; Taylor, Matthew H; and See full list of authors in comments, "CT209 / 9 - A first-in-human phase 1 trial of IO-108, an antagonist antibody targeting LILRB2 (ILT4), as monotherapy and in combination with pembrolizumab in adult patients with advanced relapsed or refractory solid tumors (NCT05054348)" (2022). Articles, Abstracts, and Reports. 6042.