Duvelisib plus romidepsin in relapsed/refractory T cell lymphomas: a phase 1b/2a trial.

Autor: Horwitz SM; Lymphoma Service, Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY, USA. horwitzs@mskcc.org.; New York Presbyterian Hospital-Weill Cornell Medical College, New York, NY, USA. horwitzs@mskcc.org., Nirmal AJ; Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA., Rahman J; Department of Biostatistics and Epidemiology, Memorial Sloan Kettering Cancer Center, New York, NY, USA., Xu R; Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA., Drill E; Department of Biostatistics and Epidemiology, Memorial Sloan Kettering Cancer Center, New York, NY, USA., Galasso N; Lymphoma Service, Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY, USA., Ganesan N; Lymphoma Service, Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY, USA., Davey T; Lymphoma Service, Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY, USA., Hancock H; Lymphoma Service, Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY, USA., Perez L; Lymphoma Service, Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY, USA., Maccaro C; Lymphoma Service, Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY, USA., Bahgat A; Lymphoma Service, Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY, USA., Marzouk E; Lymphoma Service, Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY, USA., Cathcart E; Lymphoma Service, Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY, USA., Moskowitz A; Lymphoma Service, Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY, USA., Noy A; Lymphoma Service, Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY, USA., Kumar A; Lymphoma Service, Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY, USA., Jacobsen E; Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA., Fisher DC; Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA., Mehta-Shah N; Department of Medicine, Division of Oncology, Washington University School of Medicine in St. Louis, St. Louis, MO, USA., Kim YH; Division of Oncology, Stanford University, Stanford, CA, USA.; Department of Dermatology, Stanford University, Stanford, CA, USA., Khodadoust M; Division of Oncology, Stanford University, Stanford, CA, USA.; Department of Dermatology, Stanford University, Stanford, CA, USA., Kotlov N; BostonGene Corporation, Boston, MA, USA., Nikitina A; BostonGene Corporation, Boston, MA, USA., Kudryashova O; BostonGene Corporation, Boston, MA, USA., Zubareva V; BostonGene Corporation, Boston, MA, USA., Zornikova K; BostonGene Corporation, Boston, MA, USA., Shin N; BostonGene Corporation, Boston, MA, USA., Sorokina M; BostonGene Corporation, Boston, MA, USA., Degryse S; BostonGene Corporation, Boston, MA, USA., Postovalova E; BostonGene Corporation, Boston, MA, USA., Bagaev A; BostonGene Corporation, Boston, MA, USA., Hosszu K; Department of Pediatrics and Immune Discovery & Modeling Service, Memorial Sloan Kettering Cancer Center, New York, NY, USA., McAvoy D; Department of Pediatrics and Immune Discovery & Modeling Service, Memorial Sloan Kettering Cancer Center, New York, NY, USA., Boelens JJ; Department of Pediatrics and Immune Discovery & Modeling Service, Memorial Sloan Kettering Cancer Center, New York, NY, USA.; Stem Cell Transplantation and Cellular Therapies, MSK Kids, Memorial Sloan Kettering Cancer Center, New York, NY, USA., Wu W; State Key Laboratory of Oncology in South China, Guangdong Provincial Clinical Research Center for Cancer, Sun Yat-sen University Cancer Center Collaborative Innovation Center for Cancer Medicine, Guangzhou, China., Ciantra Z; Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA., Appelt JW; Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA., Trevisani C; Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA., Amaka S; Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA., Weinstock DM; Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA.; Merck and Co., Rahway, NJ, USA., Vardhana SA; Lymphoma Service, Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY, USA. vardhans@mskcc.org.; New York Presbyterian Hospital-Weill Cornell Medical College, New York, NY, USA. vardhans@mskcc.org.; Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, NY, USA. vardhans@mskcc.org.
Jazyk: angličtina
Zdroj: Nature medicine [Nat Med] 2024 Sep; Vol. 30 (9), pp. 2517-2527. Date of Electronic Publication: 2024 Jun 17.
DOI: 10.1038/s41591-024-03076-6
Abstrakt: PI3K-δ inhibitors have shown impressive activity in lymphoid malignancies but have been hampered by autoimmune and infectious toxicities, leading to market withdrawals. We previously demonstrated activity of the PI3K-δγ inhibitor duvelisib in T cell lymphomas (TCLs) that was associated with inflammatory adverse events. As reported here, we conducted a phase 1b/2a study of duvelisib in combination with either romidepsin (n = 66) or bortezomib (n = 32) in patients with relapsed/refractory TCL and found that the addition of romidepsin, but not bortezomib, appeared to increase efficacy while attenuating PI3K inhibitor-driven toxicity. The primary endpoint of the study was to determine the safety and maximum tolerated dose of duvelisib, which was 75 mg twice daily when combined with romidepsin versus 25 mg twice daily when combined with bortezomib. The most common adverse events were neutropenia (42%, 25/59) and fatigue (37%, 22/59) in patients treated with duvelisib and romidepsin and diarrhea (48%, 11/23) and neutropenia (30%, 7/23) in patients treated with duvelisib and bortezomib. Duvelisib and romidepsin resulted in less grade 3/4 hepatotoxicity (14%, 8/59) compared to 40% (14/35) in our previous study with duvelisib monotherapy. This was associated with reductions in circulating inflammatory mediators and myeloid cell inflammatory gene expression. Secondary endpoints of overall and complete response rates were 55% (35/64) and 34% (22/64) for patients treated with duvelisib and romidepsin and 34% (11/32) and 13% (4/32) for patients treated with duvelisib and bortezomib. Among patients with peripheral T cell lymphomas (PTCLs), overall and complete response rates of duvelisib and romidepsin were 56% (27/48) and 44% (21/48), respectively, with exploratory analyses showing increased response rates in patients with a follicular helper T cell subtype. These findings support further development of combined PI3K and histone deacetylase (HDAC) inhibition in TCLs and suggest a unique strategy to enable PI3K inhibitor-based combinations for additional patient populations. ClinicalTrials.gov identifier: NCT02783625 .
(© 2024. The Author(s), under exclusive licence to Springer Nature America, Inc.)
Databáze: MEDLINE
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