3 results on '"Sandrine Aspeslagh"'
Search Results
2. First-in-human phase I study of the OX40 agonist GSK3174998 with or without pembrolizumab in patients with selected advanced solid tumors (ENGAGE-1)
- Author
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Stephane Champiat, Aurélien Marabelle, Anna Spreafico, Mehmet Altan, Todd M Bauer, Osama Rahma, Karen A Autio, Neeta Somaiah, Meredith McKean, Aaron R Hansen, Jan H M Schellens, Willeke Ros, F Stephen Hodi, Jeffrey S Weber, John V Heymach, Herbert Struemper, Sandrine Aspeslagh, Daniel C Cho, Jennifer K Litton, Axel Hoos, Vincent K Lam, Emmett V Schmidt, Sophie Postel-Vinay, Frans L Opdam, Elaine M Paul, Christoph M Ahlers, Helen Zhou, Shelby A Gorman, Maura Watmuff, Kaitlin M Yablonski, Niranjan Yanamandra, and Michael J Chisamore
- Subjects
Neoplasms. Tumors. Oncology. Including cancer and carcinogens ,RC254-282 - Abstract
Background The phase I first-in-human study ENGAGE-1 evaluated the humanized IgG1 OX40 agonistic monoclonal antibody GSK3174998 alone (Part 1 (P1)) or in combination with pembrolizumab (Part 2 (P2)) in patients with advanced solid tumors.Methods GSK3174998 (0.003–10 mg/kg) ± pembrolizumab (200 mg) was administered intravenously every 3 weeks using a continuous reassessment method for dose escalation. Primary objectives were safety and tolerability; secondary objectives included pharmacokinetics, immunogenicity, pharmacodynamics, and clinical activity.Results 138 patients were enrolled (45 (P1) and 96 (P2, including 3 crossovers)). Treatment-related adverse events occurred in 51% (P1) and 64% (P2) of patients, fatigue being the most common (11% and 24%, respectively). No dose-toxicity relationship was observed, and maximum-tolerated dose was not reached. Dose-limiting toxicities (P2) included Grade 3 (G3) pleural effusion and G1 myocarditis with G3 increased troponin. GSK3174998 ≥0.3 mg/kg demonstrated pharmacokinetic linearity and >80% receptor occupancy on circulating T cells; 0.3 mg/kg was selected for further evaluation. Limited clinical activity was observed for GSK3174998 (P1: disease control rate (DCR) ≥24 weeks 9%) and was not greater than that expected for pembrolizumab alone (P2: overall response rate 8%, DCR ≥24 weeks 28%). Multiplexed immunofluorescence data from paired biopsies suggested that increased infiltration of natural killer (NK)/natural killer T (NKT) cells and decreased regulatory T cells (Tregs) in the tumor microenvironment may contribute to clinical responses: CD16+CD56–CD134+ NK /NKT cells and CD3+CD4+FOXP3+CD134+ Tregs exhibited the largest magnitude of change on treatment, whereas CD3+CD8+granzyme B+PD-1+CD134+ cytotoxic T cells were the least variable. Tumor gene expression profiling revealed an upregulation of inflammatory responses, T-cell proliferation, and NK cell function on treatment with some inflammatory cytokines upregulated in peripheral blood. However, target engagement, evidenced by pharmacologic activity in peripheral blood and tumor tissue, did not correlate with clinical efficacy. The low number of responses precluded identifying a robust biomarker signature predictive of response.Conclusions GSK3174998±pembrolizumab was well tolerated over the dose range tested and demonstrated target engagement. Limited clinical activity does not support further development of GSK3174998±pembrolizumab in advanced cancers.Trial registration number NCT02528357.
- Published
- 2023
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3. Worsening and newly diagnosed paraneoplastic syndromes following anti-PD-1 or anti-PD-L1 immunotherapies, a descriptive study
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Guillaume Manson, Alexandre Thibault Jacques Maria, Florence Poizeau, François-Xavier Danlos, Marie Kostine, Solenn Brosseau, Sandrine Aspeslagh, Pauline Du Rusquec, Maxime Roger, Maud Pallix-Guyot, Marc Ruivard, Léa Dousset, Laurianne Grignou, Dimitri Psimaras, Johan Pluvy, Gilles Quéré, Franck Grados, Fanny Duval, Frederic Bourdain, Gwenola Maigne, Julie Perrin, Benoit Godbert, Beatris Irina Taifas, Alexandra Forestier, Anne-Laure Voisin, Patricia Martin-Romano, Capucine Baldini, Aurélien Marabelle, Christophe Massard, Jérôme Honnorat, Olivier Lambotte, and Jean-Marie Michot
- Subjects
Neoplasms. Tumors. Oncology. Including cancer and carcinogens ,RC254-282 - Abstract
Abstract Background Paraneoplastic syndromes (PNS) are autoimmune disorders specifically associated with cancer. There are few data on anti-PD-1 or anti-PD-L1 immunotherapy in patients with a PNS. Our objective was to describe the outcome for patients with a pre-existing or newly diagnosed PNS following the initiation of anti-PD-1 or anti-PD-L1 immunotherapy. Methods We included all adult patients (aged ≥18) treated with anti-PD-1 or anti-PD-L1 immunotherapy for a solid tumor, diagnosed with a PNS, and registered in French pharmacovigilance databases. Patients were allocated to cohorts 1 and 2 if the PNS had been diagnosed before vs. after the initiation of immunotherapy, respectively. Findings Of the 1304 adult patients screened between June 27th, 2014, and January 2nd, 2019, 32 (2.45%) had a PNS and were allocated to either cohort 1 (n = 16) or cohort 2 (n = 16). The median (range) age was 64 (45–88). The tumor types were non-small-cell lung cancer (n = 15, 47%), melanoma (n = 6, 19%), renal carcinoma (n = 3, 9%), and other malignancies (n = 8, 25%). Eleven (34%) patients presented with a neurologic PNS, nine (28%) had a rheumatologic PNS, eight (25%) had a connective tissue PNS, and four (13%) had other types of PNS. The highest severity grade for the PNS was 1–2 in 10 patients (31%) and ≥ 3 in 22 patients (69%). Four patients (13%) died as a result of the progression of a neurologic PNS (encephalitis in three cases, and Lambert-Eaton syndrome in one case). Following the initiation of immunotherapy, the PNS symptoms worsened in eight (50%) of the 16 patients in cohort 1. Interpretation Our results show that PNSs tend to be worsened or revealed by anti-PD-1 or anti-PD-L1 immunotherapy. Cases of paraneoplastic encephalitis are of notable concern, in view of their severity. When initiating immunotherapy, physicians should carefully monitor patients with a pre-existing PNS.
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- 2019
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