A Phase I Dose-Finding Study of the Novel Toll-like Receptor 8 Agonist VTX-2337 in Adult Subjects with Advanced Solid Tumors or Lymphoma

Abstract

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 (0.1-3.9 mg/m 2 ) 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 2

Late-Stage Cancer Patients Remain Highly Responsive to Immune Activation by the Selective TLR8 Agonist Motolimod (VTX-2337)

“…In this initial clinical study, the safety, MTD, PK, and PD activity of motolimod were assessed in a small number of subjects with advanced solid tumors. Although the study was not designed to demonstrate efficacy, multiple subjects had evidence of clinical benefit (10), and motolimod has been subsequently assessed for efficacy in multiple clinical studies, including ongoing phase II, randomized placebo controlled studies, in ovarian cancer and SCCHN.…”

“…Thirty-three subjects were evaluated in 8 successive cohorts using a dose-ascending protocol, where motolimod was administered weekly via s.c. injection, with weekly doses ranging from 0.1 to 3.9 mg/m 2 . Motolimod was well tolerated, with the predominant adverse events (AE) being transient grade 1 or 2 fever, chills, flu-like symptoms, and injection site reactions (10). The 3 highest motolimod dose levels; 2.0, 2.8, and 3.9 mg/m 2 (cohorts 6-8) administered weekly, were both active and tolerated.…”

Big opportunities for small molecules in immuno-oncology

“…Imiquimod (Aldara; Graceway Pharmaceuticals), a TLR7 and TLR8 agonist, has been approved as a topical monotherapy for the treatment of basal cell carcinoma 59 . Small-molecule agonists of TLR7 (852A) 60 and TLR8 (VTX-2337) 61 suitable for systemic administration are being evaluated as single agents in both solid and haematological malignancies. TLR9 agonists, such as IMO-2055, CPG 7909 and MGN1703, induce type l IFN secretion in dendritic cells, promoting a T H 1-type response of cytotoxic dendritic cells, natural killer cells and T cells as well as promoting M2 to M1 switching 133 ; all these effects contribute to tumour-specific immune responses and the reversal of immune suppression.…”

Targeting tumor tolerance: A new hope for pancreatic cancer therapy?

“…VTX-2337 is a synthetic TLR8 agonist that demonstrated effectiveness in preclinical models of head and neck cancer through innate immune modulation (Stephenson, et al, 2013). Subsequent phase I dose escalation studies demonstrated safety in patients with advanced cancer (Dietsch, et al, 2015;Northfelt, et al, 2014). However, clinical benefit of this strategy is currently unproven and concerns regarding off-target effects persist.…”