title: 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: OBJECTIVE
  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.
  
  
  METHODS
  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)). 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(2), increases above baseline levels were observed for plasma levels of G-CSF, monocyte chemoattractant protein-1, macrophage inflammatory protein-1β, and TNFα. Eight subjects (24.2%) had a best response of stable disease (median duration, 54.5 days).
  
  
  CONCLUSIONS
  VTX-2337 is clinically well tolerated and biologically active with a predictable pharmacokinetic profile. Suitable doses for testing in combination studies were identified. Phase II placebo-controlled studies of VTX-2337 in combination with doxorubicin in ovarian cancer, and in combination with platinum chemotherapy, 5 FU, and cetuximab in head and neck cancer have been initiated (NCT #01666444 and NCT#01836029).
authors.affiliation: Authors' Affiliations: Mayo Clinic;
authors.forename: Donald W
authors.initials: DW
authors.lastname: Northfelt
authors.affiliation: Virginia G. Piper Cancer Center; The Translational Genomics Research Institute (TGen), Scottsdale, Arizona; and.
authors.forename: Ramesh K
authors.initials: RK
authors.lastname: Ramanathan
authors.affiliation: Authors' Affiliations: Mayo Clinic;
authors.forename: Peter A
authors.initials: PA
authors.lastname: Cohen
authors.affiliation: Authors' Affiliations: Mayo Clinic; Virginia G. Piper Cancer Center; The Translational Genomics Research Institute (TGen), Scottsdale, Arizona; and.
authors.forename: Daniel D
authors.initials: DD
authors.lastname: Von Hoff
authors.affiliation: Virginia G. Piper Cancer Center; The Translational Genomics Research Institute (TGen), Scottsdale, Arizona; and.
authors.forename: Glen J
authors.initials: GJ
authors.lastname: Weiss
authors.affiliation: VentiRx Pharmaceuticals Inc., Seattle, Washington.
authors.forename: Gregory N
authors.initials: GN
authors.lastname: Dietsch
authors.affiliation: VentiRx Pharmaceuticals Inc., Seattle, Washington.
authors.forename: Kristi L
authors.initials: KL
authors.lastname: Manjarrez
authors.affiliation: VentiRx Pharmaceuticals Inc., Seattle, Washington.
authors.forename: Tressa D
authors.initials: TD
authors.lastname: Randall
authors.affiliation: VentiRx Pharmaceuticals Inc., Seattle, Washington rhershberg@ventirx.com.
authors.forename: Robert M
authors.initials: RM
authors.lastname: Hershberg
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000970:Antineoplastic Agents / Q000493:pharmacokinetics / Q000627:therapeutic use* / Q000633:toxicity; D001552:Benzazepines / Q000493:pharmacokinetics / Q000627:therapeutic use* / Q000633:toxicity; D015179:Colorectal Neoplasms / Q000188:drug therapy* / Q000473:pathology; D005260:Female; D006801:Humans; D007279:Injections, Subcutaneous; D008223:Lymphoma / Q000188:drug therapy* / Q000473:pathology; D008297:Male; D020714:Maximum Tolerated Dose; D008875:Middle Aged; D009367:Neoplasm Staging; D051200:Toll-Like Receptor 8 / Q000819:agonists; D016896:Treatment Outcome
chemical_list: D000970:Antineoplastic Agents; D001552:Benzazepines; C495349:TLR8 protein, human; D051200:Toll-Like Receptor 8; C573973:VTX-2337