Pharmacokinetic, Pharmacodynamic, and Activity Evaluation of TMX-101 in a Multicenter Phase 1 Study in Patients With Papillary Non-Muscle-Invasive Bladder Cancer.

Abstract

INTRODUCTION/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.

PATIENTS AND 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.

CONCLUSION:

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: Tom J H Arends, Rianne J M Lammers, Johannes Falke, Antoine G van der Heijden, Irene Rustighini, Raffaella Pozzi, Miroslav Ravic, Andreas Eisenhardt, Henk Vergunst, J Alfred Witjes
• Journal: Clinical genitourinary cancer (Clin Genitourin Cancer) Vol. 13 Issue 3 Pg. 204-9.e2 (Jun 2015) ISSN: 1938-0682 [Electronic] United States
• PMID: 25660383 (Publication Type: Clinical Trial, Phase I, Journal Article, Multicenter Study)
• Copyright: Copyright © 2015 Elsevier Inc. All rights reserved.

Chemical References

• Aminoquinolines
• Antineoplastic Agents
• Interleukin 1 Receptor Antagonist Protein
• Imiquimod

Topics

• Administration, Intravesical
• Aminoquinolines (administration & dosage, adverse effects, pharmacokinetics)
• Antineoplastic Agents (administration & dosage, adverse effects, pharmacokinetics)
• Carcinoma, Renal Cell (drug therapy, pathology, surgery)
• Cystoscopy
• Dose-Response Relationship, Drug
• Female
• Humans
• Imiquimod
• Interleukin 1 Receptor Antagonist Protein (urine)
• Kidney Neoplasms (drug therapy, pathology, surgery)
• Male
• Middle Aged
• Prospective Studies
• Treatment Outcome