First-in-human phase 1 study of the ICOS agonist feladilimab on patients with advanced solid tumors
Background Inducible costimulator (ICOS) receptor belongs to the CD28/CTLA immunoglobulin super family, whose expression is restricted to T cells and is weakly expressed on resting TH17, follicular helper T cells, and regulatory T cells, but is highly induced on CD4+ and CD8+ T cells on activation b...
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| Language: | English |
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BMJ Publishing Group
2025-08-01
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| Series: | Journal for ImmunoTherapy of Cancer |
| Online Access: | https://jitc.bmj.com/content/13/8/e011475.full |
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| author | David Turner Antoine Italiano Victor Moreno Steven Hirschfeld Juan Martin-Liberal Michele Maio Todd M Bauer Christophe Le Tourneau Danny Rischin Catherine Ellis Eric Angevin Aaron Hansen Helen Zhou Ivan Diaz-Padilla Frans Opdam Sapna Yadavilli Marc Ballas |
| author_facet | David Turner Antoine Italiano Victor Moreno Steven Hirschfeld Juan Martin-Liberal Michele Maio Todd M Bauer Christophe Le Tourneau Danny Rischin Catherine Ellis Eric Angevin Aaron Hansen Helen Zhou Ivan Diaz-Padilla Frans Opdam Sapna Yadavilli Marc Ballas |
| author_sort | David Turner |
| collection | DOAJ |
| description | Background Inducible costimulator (ICOS) receptor belongs to the CD28/CTLA immunoglobulin super family, whose expression is restricted to T cells and is weakly expressed on resting TH17, follicular helper T cells, and regulatory T cells, but is highly induced on CD4+ and CD8+ T cells on activation by T-cell receptors. ICOS stimulation downstream effects include activation of conventional CD4+cells and cytotoxic CD8+cells, resulting in a durable antitumor response in preclinical models.Methods As part of a larger first-in-human study (GSK Study 204691), this study focused on 2 cohorts of 25 and 67 participants enrolled in a dose escalation and pharmacokinetic/pharmacodynamic (PK/PD) analysis of the ICOS agonist feladilimab (GSK3359609) as monotherapy. For these cohorts, the objectives were to determine the safety, tolerability, maximum tolerated dose (MTD) or maximum administered dose of feladilimab. Additional objectives included determining the recommended dose of feladilimab for further exploration, characterizing the PK properties, and immunogenicity.Results Feladilimab was examined over a range of 4 logs from 0.001 mg/kg to 10 mg/kg, and no MTD was established. Adverse events were manageable and consistent with those observed with other immunomodulatory treatments; fatigue, fever, and anemia were the most common events. PK showed a peak value 1 hour following infusion. Accumulation ratio ranged from 1.4 to 2.5 and was generally consistent with expected patterns of accumulation for a monoclonal antibody, and the drug showed linear dose proportionality. ICOS receptor occupancy was maximal at doses>0.1 mg/kg. Based on the collected data, doses of 0.3 and 1.0 mg/kg were selected for further exploration.Conclusions This study showed the feasibility of a modified Toxicity Proportion Interval design and PK/PD analysis to determine a recommended dose for a compound without a dose-limiting toxicity and a tolerable and manageable safety profile. |
| format | Article |
| id | doaj-art-9d80935786b0455493e95d1a70da966e |
| institution | Kabale University |
| issn | 2051-1426 |
| language | English |
| publishDate | 2025-08-01 |
| publisher | BMJ Publishing Group |
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| series | Journal for ImmunoTherapy of Cancer |
| spelling | doaj-art-9d80935786b0455493e95d1a70da966e2025-08-20T03:36:10ZengBMJ Publishing GroupJournal for ImmunoTherapy of Cancer2051-14262025-08-0113810.1136/jitc-2025-011475First-in-human phase 1 study of the ICOS agonist feladilimab on patients with advanced solid tumorsDavid Turner0Antoine Italiano1Victor Moreno2Steven Hirschfeld3Juan Martin-Liberal4Michele Maio5Todd M Bauer6Christophe Le Tourneau7Danny Rischin8Catherine Ellis9Eric Angevin10Aaron Hansen11Helen Zhou12Ivan Diaz-Padilla13Frans Opdam14Sapna Yadavilli15Marc Ballas1613 GSK, Stevenage, UK9 Department of Medicine, Institut Bergonié, Bordeaux, France3 START Madrid-FJD, Hospital Universitario Fundación Jiménez Díaz, Madrid, Spain12 GSK, Collegeville, Pennsylvania, USA4 Molecular Therapeutics Research Group, Vall d’Hebron Institute of Oncology (VHIO), Medical Oncology Department, Vall d’Hebron University Hospital, Barcelona, Spain1 University of Siena, Siena, Italy7 Greco-Hainsworth Centers for Research, Tennessee Oncology, Nashville, Tennessee, USA8 Institut Curie, Department of Drug Development and Innovation (D3i), Paris-Saclay University, Gif-sur-Yvette, France11 Department of Oncology, The University of Melbourne The Sir Peter MacCallum, Melbourne, Victoria, Australia12 GSK, Collegeville, Pennsylvania, USA15 Institut Gustave-Roussy, Villejuif, France6 Princess Margaret Hospital Cancer Centre, Toronto, Ontario, Canada12 GSK, Collegeville, Pennsylvania, USA14 GSK, Zug, Switzerland5 Netherlands Cancer Institute, Amsterdam, Netherlands12 GSK, Collegeville, Pennsylvania, USA12 GSK, Collegeville, Pennsylvania, USABackground Inducible costimulator (ICOS) receptor belongs to the CD28/CTLA immunoglobulin super family, whose expression is restricted to T cells and is weakly expressed on resting TH17, follicular helper T cells, and regulatory T cells, but is highly induced on CD4+ and CD8+ T cells on activation by T-cell receptors. ICOS stimulation downstream effects include activation of conventional CD4+cells and cytotoxic CD8+cells, resulting in a durable antitumor response in preclinical models.Methods As part of a larger first-in-human study (GSK Study 204691), this study focused on 2 cohorts of 25 and 67 participants enrolled in a dose escalation and pharmacokinetic/pharmacodynamic (PK/PD) analysis of the ICOS agonist feladilimab (GSK3359609) as monotherapy. For these cohorts, the objectives were to determine the safety, tolerability, maximum tolerated dose (MTD) or maximum administered dose of feladilimab. Additional objectives included determining the recommended dose of feladilimab for further exploration, characterizing the PK properties, and immunogenicity.Results Feladilimab was examined over a range of 4 logs from 0.001 mg/kg to 10 mg/kg, and no MTD was established. Adverse events were manageable and consistent with those observed with other immunomodulatory treatments; fatigue, fever, and anemia were the most common events. PK showed a peak value 1 hour following infusion. Accumulation ratio ranged from 1.4 to 2.5 and was generally consistent with expected patterns of accumulation for a monoclonal antibody, and the drug showed linear dose proportionality. ICOS receptor occupancy was maximal at doses>0.1 mg/kg. Based on the collected data, doses of 0.3 and 1.0 mg/kg were selected for further exploration.Conclusions This study showed the feasibility of a modified Toxicity Proportion Interval design and PK/PD analysis to determine a recommended dose for a compound without a dose-limiting toxicity and a tolerable and manageable safety profile.https://jitc.bmj.com/content/13/8/e011475.full |
| spellingShingle | David Turner Antoine Italiano Victor Moreno Steven Hirschfeld Juan Martin-Liberal Michele Maio Todd M Bauer Christophe Le Tourneau Danny Rischin Catherine Ellis Eric Angevin Aaron Hansen Helen Zhou Ivan Diaz-Padilla Frans Opdam Sapna Yadavilli Marc Ballas First-in-human phase 1 study of the ICOS agonist feladilimab on patients with advanced solid tumors Journal for ImmunoTherapy of Cancer |
| title | First-in-human phase 1 study of the ICOS agonist feladilimab on patients with advanced solid tumors |
| title_full | First-in-human phase 1 study of the ICOS agonist feladilimab on patients with advanced solid tumors |
| title_fullStr | First-in-human phase 1 study of the ICOS agonist feladilimab on patients with advanced solid tumors |
| title_full_unstemmed | First-in-human phase 1 study of the ICOS agonist feladilimab on patients with advanced solid tumors |
| title_short | First-in-human phase 1 study of the ICOS agonist feladilimab on patients with advanced solid tumors |
| title_sort | first in human phase 1 study of the icos agonist feladilimab on patients with advanced solid tumors |
| url | https://jitc.bmj.com/content/13/8/e011475.full |
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