Search

Introduction & Objectives Atopic dermatitis (AD) is a chronic, relapsing inflammatory skin disorder. Dysfunction of regulatory T cells (Treg) may play a role in AD immunopathogenesis.1 Rezpegaldesleukin (REZPEG: NKTR-358) is a polyethylene glycol (PEG)-conjugated recombinant human interleukin 2 (rhIL-2) with the ability to selectively promote the activation and up-to 12-fold expansion of Tregs, while having relatively minimal effect on conventional T cells (Tcons).2 It represents a potential novel therapeutic approach for patients with moderate-to- severe AD. A Phase 1b study of REZPEG for patients with moderate-to-severe AD demonstrated a rapid time to response (2-4 weeks) during induction therapy and a prolonged durability of response, i.e. throughout the 36- week follow-up after cessation of therapy.3 These results support further development of REZPEG for patients with AD. Objective Evaluate the efficacy and safety of REZPEG in patients with moderate-to-severe AD. Materials & Methods This Phase 2b, randomized, double-blinded, placebo-controlled, international, multicenter study of REZPEG vs placebo enrolls biologic and JAK-inhibitor (JAKi) naïve adults with moderate-to-severe AD, defined by a baseline Eczema Area and Severity Index (EASI) score of ≥16, an Investigator's Global Assessment (IGA) AD score of ≥3, affected total body surface area (BSA) of ≥10%, and chronic AD history of at least one year. Patients are randomized in a 3:3:3:2 ratio to three different REZPEG dosing regimens or placebo, administered subcutaneously during the induction phase. Responders achieving EASI50 post-induction are re-randomized to maintenance dosing every 4 or 12 weeks. Non-responders or those experiencing acute exacerbations are transferred to an open-label rescue arm receiving REZPEG. The primary outcome is the least squares mean percentage reduction in EASI from baseline at the end of induction. Secondary and exploratory endpoints include proportions achieving IGA 0/1 with a ≥2 point reduction, EASI75, EASI90, EASI50, itch relief (≥4 point improvement on the Numerical Rating Scale), % BSA improvement, safety, tolerability, patient-reported outcomes (PROs), pharmacokinetics, and pharmacodynamics. Results Trial ongoing (NCT06136741). Conclusion REZPEG represents an innovative approach to stimulate regulatory T cells, potentially offering lasting benefits for patients with moderate-to-severe AD. This Phase 2b trial seeks to define the optimal dosing schedule and further establish the efficacy and safety profile of REZPEG in a population new to biologic and JAK inhibitor therapies. [ABSTRACT FROM AUTHOR]

Cabozantinib inhibits multiple receptor tyrosine kinases, including the TAM kinase family, and may enhance response to immune checkpoint inhibitors. One cohort of the ongoing phase Ib COSMIC-021 study (NCT03170960) evaluating cabozantinib plus the PD-L1 inhibitor atezolizumab in men with metastatic castration-resistant prostate cancer (mCRPC) that has progressed in soft tissue on/after enzalutamide and/or abiraterone treatment for metastatic disease has shown promising efficacy. Here, we describe the rationale and design of a phase III trial of cabozantinib plus atezolizumab versus a second novel hormone therapy (NHT) in patients who have previously received an NHT for mCRPC, metastatic castration-sensitive PC or nonmetastatic CRPC and have measurable visceral disease and/or extrapelvic adenopathy - a population with a significant unmet need for treatment options. Trial Registration Clinical Trial Registration: NCT04446117 (ClinicalTrials.gov) Registered on 24 June 2020. [ABSTRACT FROM AUTHOR]

Introduction: Focal segmental glomerulosclerosis (FSGS) is characterized by proteinuria and a histologic pattern of glomerular lesions of diverse etiology that share features including glomerular scarring and podocyte foot process effacement. Roundabout guidance receptor 2 (ROBO2)/slit guidance ligand 2 (SLIT2) signaling destabilizes the slit diaphragm and reduces podocyte adhesion to the glomerular basement membrane (GBM). Preclinical studies suggest that inhibition of glomerular ROBO2/SLIT2 signaling can stabilize podocyte adhesion and reduce proteinuria. This clinical trial evaluates the preliminary efficacy and safety of ROBO2/SLIT2 inhibition with the ROBO2 fusion protein PF-06730512 in patients with FSGS. Methods: The Study to Evaluate PF-06730512 in Adults With FSGS (PODO; ClinicalTrials.gov identifier NCT03448692), an open-label, phase 2a, multicenter trial in adults with FSGS, will enroll patients into 2 cohorts (n = 22 per cohort) to receive either high- or low-dose PF-06730512 (intravenous) every 2 weeks for 12 weeks. Key inclusion criteria include a confirmed biopsy diagnosis of FSGS, an estimated glomerular filtration rate (eGFR) ≥45 ml/min/1.73 m2 based on the Chronic Kidney Disease Epidemiology Collaboration formula (30–45 with a recent biopsy), and urinary protein-to-creatinine ratio (UPCR) >1.5 g/g. Key exclusion criteria include collapsing FSGS, serious/active infection, ≥50% tubulointerstitial fibrosis on biopsy, and organ transplantation. The primary endpoint is change from baseline to week 13 in UPCR; secondary endpoints include safety, changes in eGFR, and PF-06730512 serum concentration. Results: This ongoing trial will report the efficacy, safety, pharmacokinetics, and biomarker results of PF-06730512 for patients with FSGS. Conclusion: Findings from this proof-of-concept study may support further development and evaluation of PF-06730512 to treat FSGS and warrant assessment in phase 3 clinical trials.

Patients with refractory or relapsed acute myeloid leukemia (R/R AML) have a poor prognosis, with a high unmet medical need. Idasanutlin is a small-molecule inhibitor of MDM2, a negative regulator of tumor suppressor p53. By preventing the p53-MDM2 interaction, idasanutlin allows for p53 activation, particularly in patients with TP53 wild-type (WT) status. MIRROS (NCT02545283) is a randomized Phase III trial evaluating idasanutlin + cytarabine versus placebo + cytarabine in R/R AML. The primary end point is overall survival in the TP53-WT population. Secondary end points include complete remission rate (cycle 1), overall remission rate (cycle 1) and event-free survival in the TP53-WT population. MIRROS has an innovative design that integrates a stringent interim analysis for futility; continuation criteria were met in mid-2017 and accrual is ongoing. Trial registration number: NCT02545283. [ABSTRACT FROM AUTHOR]

Treatment for relapsed/refractory multiple myeloma (RRMM) remains an unmet need. Isatuximab, an anti-CD38 monoclonal antibody has shown efficacy and tolerability as a monotherapy and combination therapy in Phase I/II studies in RRMM. Here, we describe the design of the Phase III ICARIA-MM study (NCT02990338) which will evaluate isatuximab in combination with pomalidomide (Pom) and low-dose dexamethasone (dex) (Pom/dex) versus Pom/dex alone in RRMM. Patients will be randomized in a 1:1 ratio. The primary endpoint is progression-free survival. Response will be determined by an independent response review committee using IMWG criteria (2016) and safety will be assessed throughout. Approximately 300 patients (150 in each arm) are expected to enroll. The first patient was recruited in January 2017 and accrual is ongoing. [ABSTRACT FROM AUTHOR]

Introduction: Focal segmental glomerulosclerosis (FSGS) is characterized by proteinuria and a histologic pattern of glomerular lesions of diverse etiology that share features including glomerular scarring and podocyte foot process effacement. Roundabout guidance receptor 2 (ROBO2)/slit guidance ligand 2 (SLIT2) signaling destabilizes the slit diaphragm and reduces podocyte adhesion to the glomerular basement membrane (GBM). Preclinical studies suggest that inhibition of glomerular ROBO2/SLIT2 signaling can stabilize podocyte adhesion and reduce proteinuria. This clinical trial evaluates the preliminary efficacy and safety of ROBO2/SLIT2 inhibition with the ROBO2 fusion protein PF-06730512 in patients with FSGS., Methods: The Study to Evaluate PF-06730512 in Adults With FSGS (PODO; ClinicalTrials.gov identifier NCT03448692), an open-label, phase 2a, multicenter trial in adults with FSGS, will enroll patients into 2 cohorts (n = 22 per cohort) to receive either high- or low-dose PF-06730512 (intravenous) every 2 weeks for 12 weeks. Key inclusion criteria include a confirmed biopsy diagnosis of FSGS, an estimated glomerular filtration rate (eGFR) ≥45 ml/min/1.73 m 2 based on the Chronic Kidney Disease Epidemiology Collaboration formula (30-45 with a recent biopsy), and urinary protein-to-creatinine ratio (UPCR) >1.5 g/g. Key exclusion criteria include collapsing FSGS, serious/active infection, ≥50% tubulointerstitial fibrosis on biopsy, and organ transplantation. The primary endpoint is change from baseline to week 13 in UPCR; secondary endpoints include safety, changes in eGFR, and PF-06730512 serum concentration., Results: This ongoing trial will report the efficacy, safety, pharmacokinetics, and biomarker results of PF-06730512 for patients with FSGS., Conclusion: Findings from this proof-of-concept study may support further development and evaluation of PF-06730512 to treat FSGS and warrant assessment in phase 3 clinical trials., (© 2021 International Society of Nephrology. Published by Elsevier Inc.)