A phase I dose-escalation clinical trial with PLZ4-coated paclitaxel-loaded micelles (PPM) in patients with recurrent or refractory non-myoinvasive bladder cancer.

Abstract

TPS4615 Background: Bladder carcinoma is one of the top ten cancers in the US with approximately 75% of patients initially presenting with non-myoinvasive bladder cancer (NMIBC). The current standard of care for NMIBC is transurethral resection (TUR) followed by intravesical instillation, usually with Bacille Calmette-Guérin (BCG). Despite combination treatment, 20-80% of patients' disease recurs and 25% progress to invasive stages. The study drug, PLZ4-coated paclitaxel-loaded micelle (PPM), is a solvent-free injectable nanoscale micelle formulation of paclitaxel (PTX). Preclinical data on bladder cancer-specific targeting ligand named PLZ4 has shown potential to specifically deliver chemotherapeutic micelle into bladder cancer cells, both in vitro and in vivo (Zhang, Urol Oncol 2012). In a toxicokinetic study, female Sprague Dawley rats were given intravesicular injections of PPM once weekly for 6 consecutive weeks. No drug related mortality was reported, and no systematic exposure of PPM was observed in toxicokinetic analysis. The purpose of this phase I trial with PPM is to determine the toxicity and recommended Phase II dose. Methods: This is a single arm, open label, Phase I dose-escalation first-in-human trial with an expansion cohort for the treatment of recurrent or refractory NMIBC with PPM. Eligibility includes BCG unresponsive carcinoma in situ or Ta/T1 urothelial carcinoma. Treatment with pembrolizumab is not an inclusion or exclusion criteria as intravesical taxane has comparable efficacy as intravenous pembrolizumab. Up to 29 patients will be recruited at VA Boston Healthcare system. PPM will be given once weekly for six weeks, 50 ml of solution regardless of patient's size or weight will be administered as intravesical instillation. A 3 + 3 design is adopted for this Phase I trial. There are three dose levels at the dose escalation stage: Dose level I: PTX 25 mg or 0.5 mg/ml; Dose Level II: PTX 50 mg or 1.0 mg/ml; Dose Level III: PTX 75 mg or 1.5 mg/ml. At the expansion cohort, up to 12 patients will be treated with PPM at PTX dose of 50 mg or 1.0 mg/ml to determine the efficacy. The primary objective is to evaluate the safety and tolerability of PPM administered through intravesical instillation and determine the recommended Phase II dose of PPM. The secondary objectives are to evaluate the tumor response at 6 weeks after last treatment, determine systemic absorption within 6 hours after intravesical instillation of PPM and assess progression free survival. The efficacy will be determined by urine cytology and cystoscopy after finishing treatment. Molecular correlative studies will be performed. The toxicity will be assessed by Common Terminology Criteria for Adverse Events v5.0. Patients will be followed at 3 month intervals for 2 years or until disease recurrence or progression. This study is currently open for enrollment. NCT05519241. Clinical trial information: NCT05519241 .