A Phase I dose-escalation study is underway to evaluate the safety and determine the recommended Phase II dose (RP2D) of UGN-301 (zalifrelimab) as monotherapy and in combination with other agents in patients with recurrent non-muscle invasive bladder cancer (NMIBC). The trial, presented at the 2024 Society of Urologic Oncology (SUO) annual meeting, addresses the unmet need for new therapies in NMIBC, a disease with high recurrence rates.
Background and Rationale
Bladder cancer is the sixth most common cancer in the USA, with approximately 75% of cases being non-muscle invasive. However, 15-30% of patients with high-grade NMIBC and over 50% of those with intermediate-risk disease experience recurrence or progression. Zalifrelimab, an anti-cytotoxic T-lymphocyte antigen-4 (CTLA-4) monoclonal antibody, neutralizes the inhibitory effects of CTLA-4. UGN-301 is an intravesical formulation of zalifrelimab prepared with reverse thermal hydrogel (RTgel), designed to increase drug concentrations in the bladder while minimizing systemic exposure and associated toxicities.
Study Design and Objectives
The multi-part Phase I study includes up to 30 patients per arm and utilizes a Bayesian logistic regression model to determine the biologically effective dose and maximum feasible dose of UGN-301. Patients with recurrent NMIBC are randomized to one of three arms:
- Arm A: UGN-301 monotherapy
- Arm B: UGN-301 + UGN-201 (imiquimod formulation)
- Arm C: UGN-301 + gemcitabine
Key inclusion criteria include patients with high-grade Ta/T1 disease and/or CIS who meet specific criteria, such as BCG-unresponsive disease, failure of adequate BCG therapy, BCG intolerance, or high-grade Ta disease with tumors ≤3 cm that have failed at least one previous course of therapy. All papillary tumors must be resected, and obvious areas of CIS fulgurated before screening.
The primary study objectives are to determine the biologically effective and maximum tolerated doses of UGN-301 as monotherapy and in combination with other agents, as well as the recommended Phase II dose. Endpoints include the incidence of treatment-emergent adverse events and dose-limiting toxicities, concentration of UGN-301 in blood and urine, complete response rate at 3 months (for CIS patients), and recurrence-free survival rate at 3 months (for Ta/T1 patients).
UGN-201: TLR7 Agonist
UGN-201 is a proprietary formulation of Imiquimod, a toll-like receptor 7 (TLR7) agonist. TLR7 dependent activation of the immune system causes a profound tumor-targeted cellular cytotoxic immune response and induces tumor cell apoptosis. It is delivered at room temperature as a liquid and is subsequently drained after an hour. Phase I and II trials have demonstrated clinical activity and increased urinary cytokines in NMIBC patients treated with imiquimod.
Ongoing Recruitment
Study recruitment is currently ongoing. The trial's findings are expected to provide valuable insights into the potential of UGN-301, alone and in combination, for the treatment of recurrent NMIBC.
