(UroToday.com) The 23rd Annual Meeting of the Society of Urologic Oncology held in San Diego, CA was host to a bladder cancer abstract session. Dr. Caretha Creasy, PhD, Vice President of Early Development at UroGen® Pharma, presented the early protocol for a phase 1 dose-escalation study of UGN-301 (Zalifrelimab) as monotherapy and in combination with other agents in patients with recurrent non-muscle invasive bladder cancer.
Bladder cancer remains the sixth most common cancer in the United States, with approximately 84,000 new cases diagnosed and 17,000 bladder-cancer related deaths in 2021. At the time of diagnosis, 75% of patients present with non-muscle invasive disease. While standard treatment for high-grade non-muscle invasive bladder cancer remains transurethral resection of bladder tumor followed by adjuvant intravesical BCG, approximately a third of patients will not respond to BCG, and among those who demonstrate an initial response, more than half will experience recurrence or progression during long-term follow up. As such, radical cystectomy is strongly advocated in patients with BCG-unresponsive NMIBC due to the risk of invasive and metastatic disease, highlighting the need for further non-surgical treatment options for the treatment of patients with BCG failure.
Thus, there remains a large unmet clinical need in this disease space. Newer, effective intravesical therapy options are needed to improve bladder cancer-related mortality while limiting the treatment morbidity and burden of health care expenditures in patients with recurrent non-muscle invasive bladder cancer.
Zalifrelimab, an anti-cytotoxic T-lymphocyte antigen-4 (CTLA‑4) antibody, neutralizes the inhibitory effects of CTLA-4 on tumor-specific T-cell immune responses. While systemic anti-CTLA-4 therapy has proven clinical efficacy in solid tumors, this CTLA-4 inhibition has also been associated with toxicity secondary to this immune activation. As such, newer formulations that allow for site-directed therapy, while minimizing the systemic toxicity profile, are needed.
UGN-301 is an intravesical formulation of zalifrelimab prepared with reverse thermal hydrogel. This formulation allows for local intravesical instillation maximizing drug concentrations in the bladder, while minimizing significant systemic exposure and, thus, diminishing the systemic toxicity classically associated with CTLA-4 blockade. It is delivered in a cooled state as a liquid, which converts to a semi-solid gel deposit at body temperatures. It then slowly disintegrates and is excreted by normal urine flow. It provides sustained release of zalifrelimab over six to 12 hours.
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 the induction of tumor cell apoptosis. It is delivered at room temperature as a liquid and is subsequently drained after an hour. Phase 1 and 2 trials have demonstrated clinical activity and increased urinary cytokines in NMIBC patients treated with imiquimod.
This master protocol comprises two main treatment arms to evaluate the safety and determine the recommended phase 2 dose (RP2D) of UGN-301, both as monotherapy and in combination with other agents, in patients with recurrent non-muscle invasive bladder cancer:
- Arm A will investigate UGN-301 monotherapy dose‑escalation in patients with recurrent NMIBC with HG Ta disease and/or CIS or recurrent intermediate-risk LG Ta disease
- Arm B will investigate UGN-301 dose-escalation + UGN-201 in patients with recurrent NMIBC with HG Ta disease and/or CIS. Additional combinations are planned by UroGen®.
Each arm will enroll up to 30 patients (minimum of three at each dose level and six at each RP2D).
Patients with HG Ta disease and/or CIS must meet one of the following criteria:
- Have BCG-unresponsive disease and be unwilling or unfit to undergo radical cystectomy
- Have otherwise failed adequate BCG therapy
- Are BCG intolerant, defined as the inability to tolerate at least one full induction course of BCG
- Have HG Ta disease with tumors <= 3 cm and failed at least one previous course of therapy
- Have all papillary tumors visible by while light resected, and obvious areas of CIS fulgurated during screening or within 6 weeks before screening
- Absence of concomitant upper tract urothelial carcinoma or urothelial carcinoma within the prostatic urethra
Patients will receive six once-weekly intravesical instillations as induction therapy with optional maintenance at 6, 9, and 12 months for Ta patients without disease recurrence and mandatory maintenance for all CIS patients with complete responses. After two 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 combined 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.
The primary study objective is:
- To determine the biological effective dose (BED) and minimal tolerated dose (MTD) of UGN-301 as monotherapy and in combination with other agents in patients with recurrent NMIBC
- To determine the RP2D of UGN-301 as monotherapy and in combination with other agents in patients with recurrent NMIBC
Secondary objectives include:
- To evaluate the pharmacokinetics and immunogenicity of UGN-301 when administered as monotherapy and in combination with other agents
- To evaluate the pharmacokinetics of UGN-201 in combination with UGN-301 (Arm B only)
- To evaluate changes in PD biomarkers for UHN-301 when administered as monotherapy or in combination with other agents
- To identify markers of response or resistance to UGN-301 when administered as monotherapy or in combination with other agents
This study (NCT05375903) is actively recruiting as of the time of presentation.
Presented by: Caretha Creasy, Ph.D., UroGen® Pharma, Princeton, New Jersey
Written By: Rashid Sayyid, MD, MSc – Urology Chief Resident, Augusta University/Medical College of Georgia, @rksayyid on Twitter during the 23rd Annual Meeting of the Society of Urologic Oncology (SUO), Nov 30 – Dec 2, 2022. San Diego, CA