Development of Ciclopirox Prodrug as a Novel Systemic Treatment for High-Risk Non-Muscle Invasive Bladder Cancer

Project Summary The American Cancer Society estimates ~80,470 patients will be diagnosed with bladder cancer (BCa) and ~17,670 will die of the disease in the US this year (www.cancer.org). BCa exists as two diseases, non-muscle invasive bladder cancer (NMIBC) and muscle invasive bladder cancer (MIBC). Approaches to treating NMIBC and MIBC, as well as treatment outcomes, are quite different. Despite endoscopic resection followed by intravesical administration of immunotherapy or chemotherapy agents, 60-70% of NMIBC will recur with 20-30% of patients progressing to MIBC, where the gold standard treatment is neoadjuvant cisplatin-based chemotherapy followed by radical cystectomy. CicloMed LLC is developing Ciclopirox Prodrug (CPX-POM) for the treatment of bladder cancer. CPX-POM is rapidly and completely metabolized to ciclopirox (CPX), the active metabolite and undergoes renal elimination resulting in urine concentrations that exceed in vitro IC50andapos;s several-fold following intravenous (IV) administration. In vitro activity of CPX was demonstrated in several high-grade human urothelial bladder cancer cell lines. In vivo preclinical proof of principle for CPX-POM has been thoroughly demonstrated in a validated, chemical carcinogen mouse model of bladder cancer. Following submission of an investigational new drug application to the US Food and Drug Administration (FDA), CicloMed LLC conducted a US multicenter, First-in-Human, Phase 1, open-label, dose escalation study in patients with advanced solid tumors (NCT03348514). Nineteen patients were enrolled in the Phase 1 trial. Based on safety and dose tolerance, the Recommended Phase 2 Dose (RP2D) for IV CPX-POM is defined as 900 mg/m2. The goals of this Direct to Phase II SBIR application are to characterize the clinical pharmacology of the IV CPX-POM RP2D in a window of opportunity study of 12 newly diagnosed or recurrent BCa patients undergoing transurethral resection (TURBT), and based pharmacologic activity demonstrated bladder tumor tissues obtained in these patients, interrogate urothelial cancer patient biospecimens for altered regulation of cell signaling pathways inhibited by CPX-POM administration. Single cell sequencing will be employed as an unbiased approach to characterizing pharmacologic activity and potential mechanisms of action in the window of opportunity study patients. Immunohistochemistry (IHC) analyses will determine effects of CPX-POM treatment on cell proliferation, Notch signaling pathway expression, and CD8+ tumor lymphocyte infiltration. Single cell sequencint will inform additional IHC analyses. The proposed window of opportunity trial in NMIBC patients and molecular/genetic interrogation of urothelial cancer biorepository are critical data needed to design and conduct the planned Phase 2 clinical proof of concept trial in 30-40 evaluable high-risk NMIBC patients.Project Narrative CicloMed LLC is developing Ciclopirox Prodrug for the treatment of bladder cancer (BCa). The ACS estimates that 80,470 patients in the US will be diagnosed with BCa this year and 17,670 will die of the disease. This SBIR project will characterize the clinical pharmacology of CPX-POM in a window of opportunity study in BCa patients undergoing transurethral resection and study BCa patient biospecimens to better characterize the mechanisms of drug action prior to designing a larger clinical trial.