Preliminary results of a phase 1 study of Decoy20, an intravenous, killed, multiple immune receptor agonist bacterial product in patients with advanced solid tumors.
Authors: Waltzman Roger J. , Nieves Jeffery A. , Hanna Diana L. , Alistar Angela Tatiana , Al Hallak Mohammed Najeeb , Winer Ira Seth , Bhave Manali A. , Thomas Jacob Stephen , El-Khoueiry Anthony B. , Newman Michael J. 
Published: June 2024

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Background: Systemic activation of multiple immune receptors, such as Toll-like Receptor (TLR), Nucleotide oligomerization domain (NOD) like, and Stimulator of interferon genes (STING) may be required for efficient anti-tumor immune responses. Decoy20 is an attenuated, killed, non-pathogenic, bacterial product with ~90% reduction of lipopolysaccharide (LPS)-endotoxin activity to enhance intravenous (IV) safety, with retention of endogenous TLR1/2,2/6,8,9, NOD2 and STING agonist activity. Decoy20 produced pre-clinical single-agent and combination-mediated anti-tumor activity (colon, liver, pancreas, lymphoma), including innate/adaptive immune-mediated eradication of established tumors, involving combination with anti-PD-1, indomethacin, or cyclophosphamide. We hypothesized that, due to rapid clearance of systemic bacteria by the liver and spleen, Decoy20 may produce transient immune activation, suitable as monotherapy or in combination with approved agents (pulse-prime hypothesis). Methods: INDP-D101 (NCT05651022) is a single dose escalation and multi-dose expansion, Phase 1 trial of Decoy20 in patients with metastatic solid tumors refractory to standard therapy with a dose limiting toxicity (DLT) period of 28 days. Primary objectives: safety/tolerability. Secondary objectives: anti-drug immunogenicity, pharmacokinetics (PK) and preliminary efficacy. Exploratory objective: systemic immune activation via immune biomarkers. Results: As of January 2024, 11 patients (6F, 5M), mean age 56, with a relapsed solid tumor received a single dose of Decoy20 at 7x107 (n=4) or 3x107 (n=7) Killed Bacteria via 1-hour IV infusion and were evaluable for safety. Grade (G) 3 treatment related adverse events (AE’s) included lymphopenia (n=3), AST increase (n=3), IRR (n=1), bradycardia (n=1) and malaise (n=1); the only related G4 AE was lymphopenia (n=8). Bradycardia (n=1 at 7x107) and AST increase for greater than 72 hours (n=1 at 3x107) were DLTs. Lymphopenia resolved in 2-3 days, an expected PD outcome suggesting trafficking of lymphocytes to tissues. Biomarker analysis (n=11) demonstrated immune activation, with transient ≥3-fold induction of plasma analytes, including CD40L, G-CSF, IFN-γ, soluble IL-2 receptor, IL-2, 6, 8, 9,10, 12p70, 15, 18, 21, 27, 31, IP-10, I-TAC, MCP-1, MIG, MIP-1α/β, TNF-α/β and TRAIL. Decoy20 clearance occurred within 30-120 minutes of infusion. One patient with MSS-colon cancer has had stable disease for more than 6 months. Conclusions: Decoy20 generated transient AEs expected for LPS exposure. Broad systemic immune activation and preliminary evidence of stable disease were observed with only one infusion of Decoy20. These observations and PK data support our pulse-prime hypothesis and continued Decoy20 trial enrollment as a multi-dosed monotherapy and planned combinations. Clinical trial information: NCT05651022 .