(UroToday.com) The 2024 SUO annual meeting included a urothelial carcinoma session, featuring a presentation by Dr. Marco Maruzzo discussing a phase 1 dose-escalation study of UGN-301 (zalifrelimab) in patients with recurrent non muscle invasive bladder cancer (NMIBC). Bladder cancer is the 6th most common cancer in the US, with approximately 83,000 incident cases annually, and at diagnosis, 75% of patients present with NMIBC.
15-30% of patients with high grade disease and over 50% of patients with intermediate risk disease experience recurrence or progression and new therapies are needed. Zalifrelimab is an anti-CTLA4 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 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 recommended phase 2 dose) with recurrent NMIBC with intermediate risk low-grade Ta/T1 disease or high grade Ta/T1 disease and/or 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 recommended phase 2 dose was reached. The totality of data across all dose groups will be used to select the recommended phase 2 dose of UGN-301 as monotherapy and/or in combination with other agents.
In Arm A, 20 patients received at least one dose of UGN-301 across 4 cohorts [100 mg (n = 3), 300 mg (n = 6), 500 mg (n = 8,) and 700 mg (n = 3)], and 19 received all six doses as of the data cut off date of September 30, 2024:![In Arm A, 20 patients received at least one dose of UGN-301 across 4 cohorts [100 mg (n = 3), 300 mg (n = 6), 500 mg (n = 8) and 700 mg (n = 3)], and 19 received all six doses as of the data cut off date of September 30, 2024](/images/com-doc-importer/185-suo-2024/suo-2024-a-phase-1-dose-escalation-study-of-ugn-301-zalifrelimab-in-patients-with-recurrent-non-muscle-invasive-bladder-cancer/image-1.jpg)
Treatment-emergent adverse events 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. Two serious adverse events of UTI requiring hospitalization occurred but were not treatment related. No dose limiting toxicities and no treatment-emergent adverse events 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, with a maximal concentration in the urine plateauing at 500 mg:
One patient at 700 mg had 50-fold lower concentration than achieved with systemic administration and 2550-fold lower than the urine concentration. Among the evaluable patients with Ta/T1 and CIS +/- Ta/T1 disease, 46% (6 of 13) and 33% (2 of 6), respectively, were recurrence free or had a complete response at week 12. One patient with HG Ta treated with 100 mg remained recurrence free through 9 months, and 3 of 5 patients with Ta/T1 disease treated with 300 mg remained recurrence free at 15 month disease assessment (including 1 patient with HG T1 disease). In the 500 mg group, 1 of 4 patients with CIS disease and 1 of 3 patients with Ta/T1 disease remained disease free at 6 months and both remain in the study:
Dr. Maruzzo concluded his presentation discussing a phase 1 dose-escalation study of UGN-301 in patients with recurrent NMIBC with the following take home messages:
- 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 maximum feasible dose, 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
- This study is ongoing with patients receiving a combination therapy of UGN-301 with UGN-201 (Arm B) and gemcitabine (Arm C)
Presented by: Marco Maruzzo, MD, PhD, Instituto Oncologico Veneto, Padua, Italy
Written by: Zachary Klaassen, MD, MSc – Urologic Oncologist, Associate Professor of Urology, Georgia Cancer Center, Wellstar MCG Health, @zklaassen_md on Twitter during the 2024 Society of Urologic Oncology (SUO) Annual Meeting, Dallas, TX, Tues, Dec 3 – Fri, Dec 6, 2024.