Cancer Therapy : Clinical APhase IDose-FindingStudyof theNovel Toll-likeReceptor 8 Agonist VTX-2337 in Adult Subjects with Advanced Solid Tumors or Lymphoma

Purpose: This phase I, open-label, uncontrolled, ascending-dose study explored the safety, maximum tolerated dose (MTD), pharmacokinetics, and pharmacology of the TLR8 agonist VTX-2337 in subjects with advanced solid tumors or lymphoma. Experimental Design: VTX-2337 doses (0.1–3.9mg/m) were administered subcutaneously on days 1, 8, and 15 of each 28-day cycle. Safety/tolerability assessments included adverse events (AE); physical, ophthalmologic, and laboratory evaluations; and electrocardiograms. Dose-limiting toxicities (DLT) were evaluated during the first cycle. Pharmacokinetics were evaluated after the first dose. Plasma samples were quantitatively assessed for chemokines, cytokines, and other inflammatory mediators. Antitumor activity was assessed. Results: Thirty-three subjects were enrolled in 8 cohorts and received an average of 2 treatment cycles (range, 1–8 cycles). Most AEs were grades 1 to 2; the most common drug-related AEs were injection site reactions, chills, pyrexia, and influenza-like illness. One DLT was reported: grade 3 hypotension (3.9 mg/m). The MTD was considered the highest dose administered. Peak drug plasma levels and total systemic exposure were generally dose proportional. At doses 0.4 mg/m, increases above baseline levels were observed for plasma levels of G-CSF,monocyte chemoattractant protein-1, macrophage inflammatory protein-1b, and TNFa. Eight subjects (24.2%) had a best response of stable disease (median duration, 54.5