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TPS5097 Background: Although immune checkpoint inhibitor (ICI) monotherapy has shown limited clinical benefit in patients with metastatic castration-resistant prostate cancer (mCRPC), better outcomes have been observed with combination anti-PD-1/CTLA-4 therapy. In addition, whereas response rates are low in unselected mCRPC populations, tumors with selected molecular characteristics, including those associated with aggressive variant disease, CDK12 inactivation, and microsatellite instability high (MSI-H) status, have shown increased sensitivity to ICIs. Finally, altering the tumor microenvironment to promote antitumor immunity by combining ICIs with chemotherapy or targeted agents also has potential to increase clinical benefit. Vudalimab (XmAb20717) is a humanized bispecific monoclonal antibody that simultaneously targets PD-1 and CTLA-4 and binds preferentially to PD-1/CTLA-4 dual-positive cells. In a Phase 1 study, vudalimab monotherapy was generally well-tolerated and associated with complete and partial responses in patients with multiple tumor types, including mCRPC. This Phase 2 study is designed to evaluate the safety and antitumor activity of vudalimab in combination with other anticancer agents or alone in subgroups of mCRPC patients with and without specific tumor molecular subtypes. Methods: This multicenter, open-label study is being conducted at approximately 20 sites in the United States. Patients with mCRPC that progressed following treatment with ≥ 2 prior lines of anticancer therapy are enrolled into the following parallel cohorts based on the presence or absence of molecular abnormalities from prior sequencing of metastatic tumor: aggressive variant (Cohort 1), homologous recombination deficient or CDK12 mutation positive PARP inhibitor progressor (Cohort 2) or PARP inhibitor naïve (Cohort 3), MSI-H or mismatch repair deficient (Cohort 4), and no targetable mutation (Cohort 5). All patients will receive vudalimab 10 mg/kg intravenously every 2 weeks. Cohorts 1, 2, and 5 (n = 20 each) also will receive carboplatin AUC 4 + cabazitaxel 20 mg/m2 (or docetaxel 60 mg/m2, if not received prior) every 3 weeks; Cohort 3 (n = 20) also will receive olaparib 300 mg 2x/day; and Cohort 4 (n = 5) will receive vudalimab monotherapy. The primary objective is to evaluate the safety/tolerability of treatment based on adverse events. Secondary objectives include evaluating objective response (RECIST 1.1, as modified by PCWG3), radiographic progression-free survival, and PSA response. Exploratory objectives include assessing pharmacodynamic activity in peripheral blood and tumor, and correlations of response with cohort-specific molecular tumor characteristics. Enrollment has been initiated. Clinical trial information: NCT05005728.

The variable impact of specific risk factors on survival outcomes based on pre-transplantation diagnosis was analyzed in adult liver transplant recipients reported to the Scientific Registry of Transplant Recipients: 778 with hepatitis B (HBV), 3463 with hepatitis C (HCV) and 7429 without viral hepatitis. Graft and patient survival for the HBV and no viral hepatitis groups did not differ significantly. The HCV group had significantly lower graft (p = 0.0019) and patient survival (p0.0001) than the no viral hepatitis group. Patient survival was significantly lower (p = 0.0011) for HCV compared to HBV patients; differences in graft survival approached significance (p = 0.0561). Donor age, which was not a risk factor in patients with HBV, was the strongest predictor of graft loss and death in patients with HCV, starting with donors40 years. Donor age60 years was the strongest predictor of graft loss and death in patients without viral hepatitis. The risks of graft loss and death were reduced for patients on tacrolimus-based immunosuppression with mycophenolate mofetil, regardless of disease etiology. There are clear differences in risk factors for poor outcomes based on underlying liver disease, particularly with regard to the impact of donor age.

Previous perfluorocarbon (PFC) emulsions have been associated with transient adverse events (i.e., platelet activation, decreased platelet count, febrile responses, changes in hemodynamic function). The Phase I studies described in this report were parallel, randomized, double-blinded, placebo-controlled studies conducted in 48 healthy volunteers (n = 24 per study) with perflubron emulsion (Oxygent; Alliance Pharmaceutical Corp., San Diego, CA). Because of the decreased platelet counts observed with previous PFC emulsions and the intended use of perflubron emulsion in surgical patients, these studies assessed postdosing coagulation responses and hemostasis. PFC pharmacokinetic variables were also evaluated. The primary endpoint for examination of coagulation effects was prospectively defined as bleeding time. Subjects received either saline (3 mL/kg) control, or perflubron emulsion at 1.2 g PFC/kg or 1.8 g PFC/kg, and were evaluated for a 14-day period. No postinfusion changes in bleeding time or differences in ex vivo agonist-induced platelet aggregation were observed. A 17% reduction in platelet count was observed 3 days after dosing in the 1.8-g PFC/kg group; levels recovered to baseline by Day 7. The intravascular half-life of perflubron for the first 24 h was dose dependent: 9.4+/-2.2 h and 6.1+/-1.9 h in the 1.8- and 1.2-g PFC/kg groups, respectively. Results indicate that this perflubron emulsion did not affect coagulation function in healthy volunteers.

Particle size distribution is a major determinant of particle clearance by the mononuclear phagocytic system and the potential for concomitant activation of resident macrophages. To test the safety of a second-generation perflubron-based emulsion (60% perfluorocarbon [PFC] wt/vol; Oxygent [Alliance Pharmaceutical Corp., San Diego, CA]) with a small mean particle size, two parallel, randomized, double-blinded, placebo-controlled studies were conducted in 48 healthy volunteers (n = 24 per study). The study described herein focuses on safety concerning immune function. The primary endpoint was defined prospectively as delayed hypersensitivity skin test responses with lymphocyte proliferative responses to mitogenic stimulation providing a secondary measure for changes in cell-mediated immunity. Subjects received either perflubron emulsion IV (1.2 g PFC/kg or 1.8 g PFC/kg) or saline (3 mL/kg) control. Perflubron emulsion had no effect on delayed hypersensitivity skin reactions, lymphocyte proliferative potential, circulating immunoglobulins, complement activation, or plasma levels of the inflammatory cytokines, tumor necrosis factor-alpha, interleukin-1 alpha, and interleukin-1 beta. Perflubron emulsion was generally well tolerated, although there was a dose-dependent increase in minor flu-like symptoms in the perflubron treatment groups at 24 h after dosing. Increased serum levels of interleukin-6 were observed in those subjects exhibiting febrile responses. The clinical safety profile of perflubron emulsion supports its continued investigation as a temporary oxygen carrier in surgical patients to reduce exposure to allogeneic blood transfusion.

To evaluate the impact of mycophenolate mofetil (MMF) on long-term outcomes of tacrolimus and corticosteroids, we analyzed data reported to the Scientific Registry of Transplant Recipients for 11,670 adult patients (3463 with hepatitis C [HCV]) who underwent primary, single-organ, liver transplantation between 1995 and 2001. Patients who were discharged from the hospital on tacrolimus-based immunosuppression with (n = 4466; n = 1323 HCV) or without MMF (n = 7204; n = 2140 HCV) were included in the analysis. Recipients treated at discharge with MMF, tacrolimus, and corticosteroids had significantly increased patient survival (81.0% vs. 77.0% at 4 years, P < 0.0001) and graft survival (76.4% vs. 72.9%, P < 0.0001), and lower rates of acute rejection (29.0% vs. 33.4%, P < 0.001) as compared to recipients treated at discharge with tacrolimus and corticosteroids alone. A trend toward lower rates of death from infection was observed (6.1% at 4 years for MMF vs. 7.1% at 4 years for tacrolimus and corticosteroids, P = 0.0508), but this result did not reach statistical significance. In multiple regression analyses, MMF triple therapy at discharge was associated with a reduced risk of death (hazard ratio [HR] = 0.77, P < 0.001), graft loss (HR = 0.81, P < 0.001), acute rejection (HR = 0.89, P = 0.002), and death from infectious complications (HR = 0.80, P = 0.007). Outcomes were similar for the cohort with HCV.In conclusion, the addition of MMF at discharge to tacrolimus-based immunosuppression is associated with improved long-term outcomes after liver transplantation in patients with and without HCV.