The conformation-selective PI3Kδ inhibitor roginolisib in patients with advanced or metastatic cancer, including metastatic uveal melanoma: first-in-human clinical trial.
СтатьяКлиническое исследование I фазыНазвание и аннотация: Перевод пока не подготовлен
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Di Giacomo Anna Maria, Simonelli Matteo, Losurdo Agnese, Spiliopoulou Pavlina, D'Alonzo Vincenzo, Amato Giovanni, Valente Monica, Barcenilla Hugo, Johnsson Anette, Gonzalez Laura, Tan Ziyang, Tadepally Lakshmikanth, Brodin Petter, Lahn Michael, Di Conza Giusy, Zorrilla Rebeca, van der Veen Lars, Bevilacqua Alessio, Kaur Paramjit, Hammett Tracey, Durini Marco, Corsi Andrea, Sindhwani Nikhil, Occhipinti Mariaelena, Snijder Robert, Abdul-Ahad Ayad, Meijer Aniko, Postiglione Umberto, Price Gregory, Hopton Gillian, Wood Emily, Vuaroqueaux Vincent, Peille Anne-Lise, Graham Jill, Poi Ming, Spetzler David, Carlo-Stella Carmelo, Santoro Armando, Evans Thomas R Jeffry, Maio Michele
Аннотация
Phosphatidylinositol 3-kinase delta (PI3Kδ) promotes tumour cell growth directly or indirectly by activating immune-suppressive cells. In contrast to previous PI3Kδ inhibitors, roginolisib is a selective, non-ATP competitive inhibitor, which locks PI3Kδ into an inactive state and causes an allosteric modulation. In a First-in-Human dose study, continuous daily dosing of roginolisib was investigated in patients with solid and haematologic malignancies. In Part A, 24 patients received escalating doses of roginolisib. In Part B, 20 mostly pre-treated metastatic uveal melanoma (mUM) patients received a dose associated with continuous PI3Kδ inhibition of >90%. The primary endpoint was safety, and secondary endpoints included pharmacokinetic (PK) and pharmacodynamic (PD) profile, clinical anti-tumour responses assessments. Exploratory endpoints included immunophenotyping, proteomics, genomics. No Dose Limiting Toxicity or drug related toxicities requiring dose modifications were observed ( ≥ Grade 3 toxicities: 3/44; 6.8%). In mUM, median Overall Survival (mOS) was 20.8 months (data-cut off December 2023) and 18.4 months (data-cut-off February 2026). mOS in mUM patients with Stable Disease at Week 16 ( = Cycle 5) was 28.5 months, while patients who progressed at Week 16 had a median OS of 12.3 months. Roginolisib was safe, had a predictable PK profile, T regulatory cell abundance was decreased while activated CD8+ T cells increased together with soluble plasma IL-15. ClinicalTrials.gov registration: NCT04328844.