Phase I clinical trial of VTX-2337, a selective toll-like receptor 8 (TLR8) agonist, in patients with advanced solid tumors.

2537 Background: Toll-like receptors (TLRs) have emerged as attractive targets for anti-cancer immunotherapies. VTX-2337 is a novel, potent and selective small molecule (<500 MW) TLR8 agonist which activates myeloid dendritic cells, monocytes and NK cells to produce chemokines and Th1 polarizing cytokines, including TNFα, IL-12 and IFNγ. Such impacts induce innate and adaptive immune responses against tumor cells. VTX-2337 is the first selective TLR8 agonist studied in man. Methods: VTX-2337 was administered s.c. to 33 subjects with advanced solid tumors. weekly on Days 1, 8 and 15 of a 28d cycle. Using a modified Fibonacci dose escalation scheme, 8 cohorts of 3–8 patients received doses from 0.1 mg/m2 to 3.9 mg/m2. Pharmacokinetic (PK) and pharmacodynamic (PD)analyses were performed. Results: 19 males and 14 females with ECOG status 0-1 were enrolled. Median age was 65.0, and average time from diagnosis to study entry was 3.1 years. Common tumor types included colorectal (n=9), pancreatic (n=6) and melanoma (n=5). Grade 1 or 2 injection site reaction (85%), chills (58%), fever (42%) and flu-like symptoms (24%) were the most common drug-related adverse events, as expected from the pharmacology of the molecule. No drug-related hematologic or other laboratory toxicities were observed. The MTD was the highest dose tested (3.9 mg/m2), with one DLT of grade 3 hypotension in 1/6 evaluable subjects. Cmax values increased from 1.5 to 23.0 ng/mL and AUC0-∞ increased from 3.12 to 81.10 ng·hr/mL. Plasma levels of multiple immune mediators; including G-CSF, MCP-1, MIP1‐β and TNFα increased in a dose-dependent manner. PK and PD responses were accurately predicted from preclinical work in cynomolgus monkeys. There was no evidence of desensitization or augmentation of the PD response over multiple VTX-2337 doses. 25% of subjects experienced disease stabilization by RECIST at 8 weeks and received additional doses until progression. Conclusions: The TLR8 agonist VTX-2337 is safe and well tolerated, has a predictable PK profile and shows dose-dependent pharmacologic activity. Based on preclinical additive effects with various anticancer therapies, combination studies in multiple cancers are being initiated.