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Zalifrelimab is an anti-cytotoxic T-lymphocyte antigen-4 (CTLA-4) antibody that neutralizes the inhibitory effects of CTLA-4 on the immune responses of tumor-specific T cells. While systemic anti-CTLA-4 therapy has demonstrated clinical efficacy in solid tumors, CTLA-4 inhibition has also been associated with toxicity due to immune activation. UGN-301 is an intravesical formulation of zalifrelimab prepared with reverse thermal hydrogel. Local administration into the bladder is expected to increase drug concentrations in the target organ without significant systemic exposure, potentially diminishing the systemic toxicity associated with CTLA-4 blockade. This master protocol comprises multiple treatment arms to evaluate the safety and determine the recommended phase 2 dose (RP2D) of UGN-301 as monotherapy and in combination with other agents in patients with recurrent NMIBC. Arm A will investigate UGN-301 monotherapy dose-escalation, Arm B will investigate UGN-301 dose-escalation + UGN-201 (imiquimod), a toll-like receptor 7 agonist with immune-stimulating anti-tumor effects and Arm C will investigate UGN-301 dose escalation + gemcitabine. Additional combinations are planned Each arm will enroll up to 30 patients (minimum 3 at each dose level and 6 at the RP2D) with recurrent NMIBC with high-grade Ta/T1 disease and/or carcinoma in situ (CIS) who failed at least 1 prior course of therapy. Arm A may also enroll patients with intermediate risk low-grade Ta/T1 disease. Patients will receive 6 once-weekly intravesical instillations as induction with optional maintenance at 6, 9, and 12 months for Ta/T1 patients without disease recurrence and CIS patients with complete response. After 2 monotherapy dose levels are cleared, combination arms may commence. Decision rules for dose-escalation, de-escalation, and expansion are based on a Bayesian Logistic Regression Model for pre-defined criteria related to toxicity, pharmacokinetics, and preliminary efficacy. The totality of accrued study data across all dose groups will be used to select the RP2D of UGN-301 as monotherapy and in combination with other agents. Both combinations arms have been initiated and the study is recruiting in the United States, Italy and Spain (NCT05375903). [ABSTRACT FROM AUTHOR]

Despite surgical and therapeutic advances, 15-30% of patients with high-grade (HG) NMIBC and over 50% of patients with intermediate risk disease experience recurrence or progression throughout their lifetime; therefore, improved treatment options are needed. Zalifrelimab is an anti-cytotoxic T-lymphocyte antigen-4 (CTLA-4) antibody that neutralizes the inhibitory effects of CTLA-4 on the immune responses of tumor-specific T cells. UGN-301 is an intravesical formulation of zalifrelimab prepared with reverse thermal hydrogel. Intravesical administration is expected to increase drug concentrations in the bladder without significant systemic exposure, potentially diminishing the toxicity associated with CTLA-4 blockade. A phase 1 study (UR001) was initiated to evaluate the safety and determine the recommended phase 2 dose (RP2D) of UGN-301 as monotherapy and in combination with other agents in patients with recurrent NMIBC. Arm A investigated escalating doses of UGN-301 monotherapy. The combination arms are investigating UGN-301 with intravesical UGN-201 [imiquimod, a toll-like receptor 7 agonist] (Arm B) or gemcitabine (Arm C). In Arm A, up to 30 patients (3-12 at each dose level and minimum 6 at RP2D) with recurrent NMIBC with intermediate risk low-grade Ta/T1 disease or HG Ta/T1 disease and/or carcinoma in situ (CIS) who failed at least 1 prior course of intravesical therapy were eligible. Patients received 6 once-weekly intravesical instillations as induction. Disease assessments occurred quarterly from 3-15 months after the start of treatment. Patients who remained disease free could receive an optional maintenance instillation at 6, 9, and 12 months. Patients with disease recurrence were released from the study after required safety monitoring. Dose escalation was guided by an adaptive Bayesian logistic regression model with pre-defined criteria related to toxicity, pharmacokinetics, and efficacy. Dose escalation continued until the maximum feasible dose (700 mg), maximum tolerated dose or RP2D was reached. The totality of data across all dose groups will be used to select the RP2D of UGN-301 as monotherapy and/or in combination with other agents. In Arm A, 20 patients received at least 1 dose of UGN-301 across 4 cohorts [100 mg (n=3), 300 mg (n=6), 500 mg (n=8) and 700 mg (n=3)]. All but 1 patient completed all 6 induction instillations. Dose escalation continued to the maximum feasible dose (MFD). Two serious adverse events of UTI requiring hospitalization occurred but were not treatment related. Treatment-emergent adverse events (TEAEs) were mild or moderate in severity except for 1 severe event, a urinary tract infection (UTI) considered related to procedure but not related to treatment (Table 1). No dose limiting toxicities and no TEAEs leading to treatment discontinuation were observed. Across all dose levels, the median duration of detectable UGN-301 in urine was at least 9.7 hours. Systemic exposure was detected at the MFD in a single patient at concentrations below those achieved with systemic administration. Among the evaluable CIS and Ta/T1 patients, 25% (1/4) and 50% (6/12), respectively, had a CR or were recurrence free (RF) at week 12 (Table 2). Local delivery of UGN-301 formulated in reverse thermal gel allowed sustained exposure of zalifrelimab in the bladder while limiting systemic exposure and thus mitigating the risk of systemic immune related toxicities associated with CTLA-4 inhibition. At all dose levels, including the MFD, UGN-301 was well tolerated and had a favorable safety profile. Together with the observed efficacy, continued evaluation of UGN-301 for the treatment of NMIBC is warranted. Evaluation of UGN-301 at dose levels of 300 mg and above in combination with UGN-201 (Arm B) and gemcitabine (Arm C) is ongoing in the US, Italy and Spain as part of the UR001 master protocol (NCT05375903). [ABSTRACT FROM AUTHOR]