4 research outputs found
Interim analysis:Open-label extension study of leniolisib for patients with APDS
Background: Activated phosphoinositide 3-kinase delta (PI3Kδ) syndrome (APDS; or p110δ-activating mutations causing senescent T cells, lymphadenopathy, and immunodeficiency) is an inborn error of immunity caused by PI3Kδ hyperactivity. Resultant immune deficiency and dysregulation lead to recurrent sinopulmonary infections, herpes viremia, autoimmunity, and lymphoproliferation. Objective: Leniolisib, a selective PI3Kδ inhibitor, demonstrated favorable impact on immune cell subsets and lymphoproliferation over placebo in patients with APDS over 12 weeks. Here, we report results from an interim analysis of an ongoing open-label, single-arm extension study. Methods: Patients with APDS aged 12 years or older who completed NCT02435173 or had previous exposure to PI3Kδ inhibitors were eligible. The primary end point was safety, assessed via investigator-reported adverse events (AEs) and clinical/laboratory evaluations. Secondary and exploratory end points included health-related quality of life, inflammatory markers, frequency of infections, and lymphoproliferation. Results: Between September 2016 and August 2021, 37 patients (median age, 20 years; 42.3% female) were enrolled. Of these 37 patients, 26, 9, and 2 patients had previously received leniolisib, placebo, or other PI3Kδ inhibitors, respectively. At the data cutoff date (December 13, 2021), median leniolisib exposure was 102 weeks. Overall, 32 patients (87%) experienced an AE. Most AEs were grades 1 to 3; none were grade 4. One patient with severe baseline comorbidities experienced a grade 5 AE, determined as unrelated to leniolisib treatment. While on leniolisib, patients had reduced annualized infection rates (P =.004), and reductions in immunoglobulin replacement therapy occurred in 10 of 27 patients. Other observations include reduced lymphadenopathy and splenomegaly, improved cytopenias, and normalized lymphocyte subsets. Conclusions: Leniolisib was well tolerated and maintained durable outcomes with up to 5 years of exposure in 37 patients with APDS. ClinicalTrials.gov identifier: NCT02859727.</p
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A Phase I Trial Using a Multitargeted Recombinant Adenovirus 5 (CEA/MUC1/Brachyury)-Based Immunotherapy Vaccine Regimen in Patients with Advanced Cancer
Lessons Learned
Concurrent ETBX-011, ETBX-051, and ETBX-061 can be safely administered to patients with advanced cancer. All patients developed CD4(+) and/or CD8(+) T-cell responses after vaccination to at least one tumor-associated antigen (TAA) encoded by the vaccine; 5/6 patients (83%) developed MUC1-specific T cells, 4/6 (67%) developed CEA-specific T cells, and 3/6 (50%) developed brachyury-specific T cells. The presence of adenovirus 5-neutralizing antibodies did not prevent the generation of TAA-specific T cells. Background A novel adenovirus-based vaccine targeting three human tumor-associated antigens-CEA, MUC1, and brachyury-has demonstrated antitumor cytolytic T-cell responses in preclinical animal models of cancer. Methods This open-label, phase I trial evaluated concurrent administration of three therapeutic vaccines (ETBX-011 = CEA, ETBX-051 = MUC1, and ETBX-061 = brachyury). All three vaccines used the same modified adenovirus 5 (Ad5) vector backbone and were administered at a single dose level (DL) of 5 x 10(11) viral particles (VP) per vector. The vaccine regimen consisting of all three vaccines was given every 3 weeks for three doses then every 8 weeks for up to 1 year. Clinical and immune responses were evaluated. Results Ten patients enrolled on trial (DL1 = 6 with 4 in the DL1 expansion cohort). All treatment-related adverse events were temporary, self-limiting, grade 1/2 and included injection site reactions and flu-like symptoms. Antigen-specific T cells to MUC1, CEA, and/or brachyury were generated in all patients. There was no evidence of antigenic competition. The administration of the vaccine regimen produced stable disease as the best clinical response. Conclusion Concurrent ETBX-011, ETBX-051, and ETBX-061 can be safely administered to patients with advanced cancer. Further studies of the vaccine regimen in combination with other agents, including immune checkpoint blockade, are planned