Phase 2 Study Explores Use of Fosciclopirox in Newly Diagnosed, Recurrent Bladder Cancer

John A. Taylor III, MD, MSc

Fosciclopirox (CPX-POM) will be investigated for the treatment of newly-diagnosed and recurrent bladder cancer in a phase 2 study, according to an announcement from the developer, CicloMed, LLC.¹

The National Cancer Institute (NCI) funded study (NCT04525131) is a window of opportunity analysis designed to determine the safety, dose tolerance, pharmacokinetics, and pharmacodynamics of CPX-POM in patients with newly diagnosed or recurrent bladder tumors with a target enrollment of 12 patients who will be given CPX-POM intravenously over 20 minutes once daily. The primary end point of the study include the number of patients with adverse events (AEs) or serious AEs, and dose-limiting toxicities. The incidence of treatment-related AEs is being explored as a secondary end point.

“In addition to supporting the phase 1B trial, the NCI SBIR grant enables us to study the relationships between targets modulated by fosciclopirox and treatment outcomes in patients receiving standard-of-care,” said John A. Taylor III, MD, MSc, director of urologic research, co-leader of the Drug Discovery, Delivery and Experimental Therapeutics Research Program, and founder and director of the Leo and Anne Albert Institute for Bladder Cancer Care and Research, in a statement. “We are reviewing our bladder cancer patient registry and biorepository comprising over 1,000 bladder tumor specimens from approximately 500 patients to identify patients who are more likely to benefit from fosciclopirox treatment.

Prior to the exploration of fosciclopirox showed that it was promising as treatment of patients with advanced solid tumors in a first-in-human trial (NCT03348514) for which data were presented during the 2020 American Society of Clinical Oncology Gastrointestinal Cancers Symposium. A total of 19 patients were included in the analysis and were dosed with 30 mg/m² fosciclopirox to start as a once-daily treatment on days 1-5 of each 21-day treatment cycle. Doses were escalated to 1200 mg/m² during the analysis to determine the maximum-tolerated dose of the agent.²

Investigators noticed that the number of treatment-related AEs had a tendency to increase as the dose of fosciclopirox increased, and they discovered that the MTD was 900 mg/m². The most common treatment-related AEs were nausea and vomiting. At the highest dose level, grade 3 confusion was observed in the study subjects, and at 600 and 900 mg/m2, some patients experienced grade 1 confusion. No QTc prolongation or other electrocardiogram abnormality was observed.

In terms of efficacy, 1 patient treated at the 240mg/m2 dose level achieved a partial response to fosciclopirox. The agent also demonstrated evidence of Notch and Want inhibition in the study subjects.

“Fosciclopirox inhibits the initiation and progression of bladder cancer in preclinical models, at least in part, by acting as a gamma-secretase complex inhibitor, resulting in inhibition of Notch and Wnt signaling pathways,” said Scott Weir, director of the Institute for Advancing Medical Innovation at the University of Kansas Medical Center and Acting chief scientific officer at CicloMed, in the press release.1 “By partnering with Taykor, we can explore relationships between Notch and Wnt signaling and response to immunotherapy and chemotherapy treatment. The initiation of this Phase 1B trial enables us to characterize the pharmacologic activity and mechanisms of fosciclopirox action following treatment in urothelial cancer patients.”

To further explore fosciclopirox in the newly-diagnosed and recurrent bladder cancer population, patients aged 18 years or older who have a cystoscopically confirmed bladder tumor and will be scheduled to undergo TURBT with an ECOG performance status of 0 or 1, a life expectancy of ≥3 months, and adequate bone marrow, renal, and hepatic function are eligible to enroll. These patients much not be pregnant or have heart disease or myocardial infarction within 6 months before the first dose of CPX-POM.

The study is actively enrolling at the University of Kansas Medical Center in Kansas City, Kansas with a target completion date of November 2021.

_References:

_{1. CicloMed announces initiation of phase 1B trial of fosciclopirox in newly diagnosed and recurrent urothelial cancer patients. News release. CicloMed CicloMed LLC. June 29, 2021. Accessed June 29, 2021. https://bit.ly/3AepEYj}

_{2. Patel MR, Ulahannan SV, Weir SJ, et al. Safety, dose tolerance, pharmacokinetics, and pharmacodynamics of fosciclopirox (CPX-POM) in patients with advanced solid tumors. J Clin Oncol. 2020;38(suppl 6):518. doi: 10.1200/JCO.2020.38.6_suppl.518}