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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]

Gemcitabine‐based therapy remains the mainstay of treatment for patients with biliary tract cancers (BTCs) with no second‐line treatment(s) established yet. Aberrant activation of the MAPK pathway in patients with BTC indicates its importance in BTC. Trametinib is a potent, highly selective, allosteric non‐competitive inhibitor of MEK1/MEK2. In this phase IIa open‐label, single‐arm study, we investigated the efficacy and safety of trametinib in Japanese patients with advanced BTC refractory to gemcitabine‐based therapy. All patients received oral trametinib 2 mg once daily until progressive disease (PD), death, or unacceptable toxicity. The primary objective was to determine the 12‐week non‐PD rate. Secondary assessments included safety, progression‐free survival (PFS), overall survival, and overall response rate. Targeted exome sequencing was used to identify biomarkers for sensitivity or resistance to trametinib monotherapy. Twenty patients (median age, 61.5 years) with carcinoma of gall bladder (40%), intrahepatic (25%) or extrahepatic (30%) bile duct, and ampulla of Vater (5%) were enrolled. The non‐PD rate at week 12 was 10% (95% confidence interval, 1.2‐31.7); it did not reach the threshold rate of 25%. Median PFS was 10.6 weeks (95% confidence interval, 4.6‐12.1) and 1‐year overall survival was 20.0%. Stable disease and PD were observed in 13 (65%) and seven (35%) patients, respectively. No new safety signals were reported. Although the primary end‐point was not met, prolonged PFS was observed in one patient having six somatic variants including synonymous NF1 exon 12 splice variant and a loss‐of‐function variant in ARID1A. Efforts to understand responsive mutations and sensitivity to targeted therapies are warranted. This trial was registered with ClinicalTrials.gov: NCT01943864. [ABSTRACT FROM AUTHOR]

The serine protease HtrA2/Omi is released from the mitochondrial intermembrane space following apoptotic stimuli. Once in the cytosol, HtrA2/Omi has been implicated in promoting cell death by binding to inhibitor of apoptosis proteins (IAPs) via its amino-terminal Reaper-related motif, thus inducing caspase activity, and also in mediating caspase-independent death through its own protease activity. We report here the phenotype of mice entirely lacking expression of HtrA2/Omi due to targeted deletion of its gene, Prss25. These animals, or cells derived from them, show no evidence of reduced rates of cell death but on the contrary suffer loss of a population of neurons in the striatum, resulting in a neurodegenerative disorder with a parkinsonian phenotype that leads to death of the mice around 30 days after birth. The phenotype of these mice suggests that it is the protease function of this protein and not its IAP binding motif that is critical. This conclusion is reinforced by the finding that simultaneous deletion of the other major IAP binding protein, Smac/DIABLO, does not obviously alter the phenotype of HtrA2/Omi knockout mice or cells derived from them. Mammalian HtrA2/Omi is therefore likely to function in vivo in a manner similar to that of its bacterial homologues DegS and DegP, which are involved in protection against cell stress, and not like the proapoptotic Reaper family proteins in Drosophila melanogaster. [ABSTRACT FROM AUTHOR]

Characterizes human HtrA2, a novel serine protease involved in the mammalian cellular stress response. Homology with Escherichia coli HtrA genes; Identification and cloning of HtrA2; Subcellular localization; Patterns of human HtrA2 protein expression; Influence of protease inhibitors on proteolytic activity of HtrA2.

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]