A phase I first-in-human clinical trial with PLZ4-coated paclitaxel-loaded micelles (PPM) in therapy-resistant non-muscle-invasive bladder cancer (NMIBC).

Abstract

806 Background: Approximately 75% of patients with non-muscle invasive bladder cancer (NMIBC) treated with transurethral resection (TUR) followed by intravesical Bacillus Calmette-Guérin (BCG) experience cancer recurrence. When BCG-unresponsive, most patients continue to have recurrences even with newly approved therapies and nearly 30% progress to invasive stages. We developed a first-in-class bladder cancer-specific nanotherapeutic, PPM, which is administered intravesically. Our preclinical data has demonstrated PPM can selectively target bladder cancer cells and deliver paclitaxel payload into these cancer cells following intravesical or intravenous administration. Methods: This is a 3+3 first-in-human dose escalation trial. Eligible patients must have pathologically confirmed NMIBC, be unresponsive to intravesical BCG therapy (with or without cytotoxic chemotherapy), possess adequate vital organ function, and consent to cystoscopy with TUR for response evaluation. PPM is administered via intravesical instillation once weekly for six weeks. The trial features three dose levels, with paclitaxel doses of 25 mg, 50 mg, and 75 mg. The primary endpoints include safety and the recommended Phase II dose; secondary endpoints encompass response rate, duration of response, systemic drug absorption, and molecular correlative studies. Patients will be followed at 3 month intervals for 2 years or until disease progression. Results: To date, three patients with pathologically confirmed NMIBC have completed a total of 18 treatments at the first dose level without any PPM-related adverse events: one patient was unresponsive to BCG and intravesical mitomycin therapy, while the other two had BCG-unresponsive disease. Two out of the three patients achieved ongoing complete remission for over six and nine months, respectively. The third patient demonstrated persistent disease, but no progression was noted. Enrollment for Dose Level 2 is currently open. Conclusions: PPM has demonstrated promising clinical activity without toxicity at the first dose level in patients with BCG-unresponsive NMIBC. Data at other dose levels will be presented at the meeting (ClinicalTrials.gov identifier: NCT05519241). Clinical trial information: NCT05519241 .