title: Pharmacokinetic, Pharmacodynamic, and Activity Evaluation of TMX-101 in a Multicenter Phase 1 Study in Patients With Papillary Non-Muscle-Invasive Bladder Cancer.
abstract: BACKGROUND
  Non-muscle-invasive bladder cancer (NMIBC) has a strong tendency to recur despite adjuvant instillations. TMX-101 is a new liquid form of imiquimod for intravesical instillation and has activity in vitro against urothelial carcinoma. The purpose was to analyze the activity of TMX-101 in low-grade NMIBC. Furthermore, pharmacokinetic and pharmacodynamic characteristics and adverse events were evaluated.
  
  
  METHODS
  A multicenter, prospective phase 1 trial in 7 patients with low-grade NMIBC was conducted. All patients underwent a marker lesion transurethral resection of the bladder tumor and 6 weekly instillations with TMX-101 0.2% or 0.4%. Cystoscopy 2 to 4 weeks after the last instillation evaluated the effect of TMX-101.
  
  
  RESULTS
  The effective biologic dose (EBD = complete response [CR] in > 2 patients) could not be defined because none of the patients experienced CR. Maximum plasma concentration was 75.1 ng/mL in the 0.4% dose group. No drug accumulation was observed. In the pharmacodynamic analysis, urinary interleukin 1 receptor agonist (IL-1ra) represents the most sensitive and uniform response after TMX-101 instillation. A total of 87.0% reported at least 1 adverse event. All events were of grade 2 severity or less (Common Terminology Criteria of Adverse Events version 4.02). No clinically significant changes in laboratory parameters or vital signs were observed during or after treatment.
  
  
  CONCLUSIONS
  Toll-like receptor 7 (TLR-7) agonists are effective in urothelial carcinoma in preclinical research. The EBD in this phase 1 study could not be determined because no patient experienced CR. IL-1ra could be valuable as a urinary biomarker in future developments. The safety of TMX-101 has been reconfirmed. New doses, other schedules, and NMIBC subgroups should be tested to define the EBD. A pilot study in carcinoma-in-situ patients is currently ongoing and results are expected shortly.
authors: Department of Urology, Radboud University Medical Center, Nijmegen, The Netherlands.
authors: Tom J H
authors: TJ
authors: Arends
authors: Department of Urology, Radboud University Medical Center, Nijmegen, The Netherlands.
authors: Rianne J M
authors: RJ
authors: Lammers
authors: Department of Urology, Radboud University Medical Center, Nijmegen, The Netherlands.
authors: Johannes
authors: J
authors: Falke
authors: Department of Urology, Radboud University Medical Center, Nijmegen, The Netherlands.
authors: Antoine G
authors: AG
authors: van der Heijden
authors: Telormedix SA, Bioggio, Switzerland.
authors: Irene
authors: I
authors: Rustighini
authors: Telormedix SA, Bioggio, Switzerland.
authors: Raffaella
authors: R
authors: Pozzi
authors: Pharma Integra Ltd, Wimbledon, London, England, UK.
authors: Miroslav
authors: M
authors: Ravic
authors: Pur/r Praxisklinik Urologie, Nordrhein-Westfalen, Germany.
authors: Andreas
authors: A
authors: Eisenhardt
authors: Department of Urology, Canisius-Wilhelmina Ziekenhuis, Nijmegen, The Netherlands.
authors: Henk
authors: H
authors: Vergunst
authors: Department of Urology, Radboud University Medical Center, Nijmegen, The Netherlands. Electronic address: Fred.witjes@radboudumc.nl.
authors: J Alfred
authors: JA
authors: Witjes
mesh_terms: D000283:Administration, Intravesical; D000634:Aminoquinolines / Q000008:administration & dosage* / Q000009:adverse effects / Q000493:pharmacokinetics; D000970:Antineoplastic Agents / Q000008:administration & dosage* / Q000009:adverse effects / Q000493:pharmacokinetics; D002292:Carcinoma, Renal Cell / Q000188:drug therapy* / Q000473:pathology / Q000601:surgery; D003558:Cystoscopy; D004305:Dose-Response Relationship, Drug; D005260:Female; D006801:Humans; D000077271:Imiquimod; D053590:Interleukin 1 Receptor Antagonist Protein / Q000652:urine; D007680:Kidney Neoplasms / Q000188:drug therapy* / Q000473:pathology / Q000601:surgery; D008297:Male; D008875:Middle Aged; D011446:Prospective Studies; D016896:Treatment Outcome
chemical_list: D000634:Aminoquinolines; D000970:Antineoplastic Agents; D053590:Interleukin 1 Receptor Antagonist Protein; D000077271:Imiquimod
keywords: Bladder cancer; Bladder instillation; Immunotherapy; Toll-like receptor 7; Treatment outcome