Exploring the safety, effect on the tumor microenvironment, and efficacy of itacitinib in combination with epacadostat or parsaclisib in advanced solid tumors: a phase I study.

Autor:	Naing A; Department of Investigational Cancer Therapeutics, MD Anderson Cancer Center, Houston, Texas, USA anaing@mdanderson.org., Powderly JD; Cancer Research Clinic, Carolina Biooncology Institute, Huntersville, North Carolina, USA., Nemunaitis JJ; University of Toledo College of Medicine, Toledo, Ohio, USA., Luke JJ; Division of Hematology/Oncology, University of Pittsburgh Medical Center, Pittsburgh, Pennsylvania, USA., Mansfield AS; Oncology, Mayo Clinic, Rochester, Minnesota, USA., Messersmith WA; School of Medicine, University of Colorado, Aurora, Colorado, USA., Sahebjam S; Clinical Research Unit, Moffitt Cancer Center, Tampa, Florida, USA., LoRusso PM; Yale School of Medicine, Yale Cancer Center, New Haven, Connecticut, USA., Garrido-Laguna I; University of Utah School of Medicine, Huntsman Cancer Institute, Salt Lake City, Utah, USA., Leopold L; Immuno-Oncology, Incyte Corporation, Wilmington, Delaware, USA., Geschwindt R; Immuno-Oncology, Incyte Corporation, Wilmington, Delaware, USA., Ding K; Biostatistics, Incyte Corporation, Wilmington, Delaware, USA., Smith M; Immuno-Oncology, Incyte Corporation, Wilmington, Delaware, USA., Berlin JD; Division of Hematology/Oncology, Vanderbilt University, Nashville, Tennessee, USA.
Jazyk:	angličtina
Zdroj:	Journal for immunotherapy of cancer [J Immunother Cancer] 2022 Mar; Vol. 10 (3).
DOI:	10.1136/jitc-2021-004223
Abstrakt:	Background: This phase I multicenter study was designed to evaluate the safety, tolerability, efficacy, and translational effects on the tumor microenvironment of itacitinib (Janus-associated kinase 1 (JAK1) inhibitor) in combination with epacadostat (indoleamine 2,3-dioxygenase 1 (IDO1) inhibitor) or parsaclisib (phosphatidylinositol 3-kinase δ (PI3Kδ) inhibitor). Methods: Patients with advanced or metastatic solid tumors were enrolled and received itacitinib (100-400 mg once a day) plus epacadostat (50-300 mg two times per day; group A), or itacitinib (100-400 mg once a day) plus parsaclisib or parsaclisib monotherapy (0.3-10 mg once a day; group B). Results: A total of 142 patients were enrolled in the study. The maximum tolerated dose was not reached for either the combination of itacitinib plus epacadostat (n=47) or itacitinib plus parsaclisib (n=90). One dose-limiting toxicity of serious, grade 3 aseptic meningitis was reported in a patient receiving itacitinib 300 mg once a day plus parsaclisib 10 mg once a day, which resolved when the study drugs were withdrawn. The most common treatment-related adverse events among patients treated with itacitinib plus epacadostat included fatigue, nausea, pyrexia, and vomiting, and for patients treated with itacitinib plus parsaclisib were fatigue, pyrexia, and diarrhea. In the itacitinib plus epacadostat group, no patient had an objective response. Among patients receiving itacitinib 100 mg once a day plus parsaclisib 0.3 mg once a day, three achieved partial response for an objective response rate (95% CI) of 7.1% (1.50 to 19.48). Treatment with itacitinib plus epacadostat demonstrated some increase in tumor CD8 + T cell infiltration and minor changes in six plasma proteins, whereas treatment with itacitinib plus high-dose parsaclisib resulted in downregulation of 20 plasma proteins mostly involved in immune cell function, with no observed change in intratumoral CD8 + T cell infiltration. Conclusion: Adverse events with JAK1 inhibition combined with either IDO1 or PI3Kδ inhibition were manageable, but the combinations demonstrated limited clinical activity or enhancement of immune activation in the tumor microenvironment. Trial Registration Number: NCT02559492. Competing Interests: Competing interests: AN reports research funding from Amplimmune, Arcus Biosciences, ARMO BioSciences, Atterocor/Millendo, Bristol Myers Squibb, Calithera Biosciences, CytomX Therapeutics, Eli Lilly, EMD Serono, Healios Oncology Nutrition, ImmuneOncia, Incyte, Karyopharm Therapeutics, Kymab, MedImmune, Merck, NCI, NeoimmuneTech, Neon Therapeutics, Novartis, Pfizer, PsiOxus, Regeneron, Surface Oncology, and TopAlliance Biosciences; advisory board of CytomX Therapeutics, Genome & Company, Kymab, Novartis, OncoSec KEYNOTE-695, and STCube Pharmaceuticals; and travel and accommodation expense from ARMO BioSciences. JDP reports clinical trial funding from AbbVie, Alkermes, AstraZeneca, BMS, Corvus, Curis, EMD Serono, Incyte, Macrogenics, MT Group, Precision for Medicine, RAPT Therapeutics, Sequenom, StemCell, Tempest, and Top Alliance BioSciences; advisory for AstraZeneca, Curis, and Merck; consultancy for AstraZeneca, BMS, and Curis; speakers’ bureau for BMS and Merck; laboratory contract research for Merck; and is founder and owner of BioCytics and Carolina BioOncology Institute. JJN reports board membership, employment, and stock ownership with Gradalis. JJL reports scientific advisory board (no stock) for 7 Hills, Spring Bank; scientific advisory board (stock) for Actym, Alphamab Oncology, Arch Oncology, Kanaph, Mavu, Onc.AI, Pyxis, and Tempest; consultancy with compensation from AbbVie, Alnylam, Array, Bayer, Bristol Myers Squibb, Checkmate, Cstone, Eisai, EMD Serono, Inzen Therapeutics, Janssen, KSQ, Macrogenics, Merck, Mersana, Nektar, Novartis, Pfizer, Regeneron, Ribon, Rubius, Silicon, Synlogic, TRex, Werewolf, Xencor, and Xilio; research support (all to institutions for clinical trials unless noted) from AbbVie, Agios (IIT), Array (IIT), Astellas, Bristol Myers Squibb (IIT and industry), Corvus, EMD Serono, Immatics, Incyte, Kadmon, Macrogenics, Merck, Moderna, Nektar, Numab, Replimune, Rubius, Spring Bank, Synlogic, Takeda, Tizona, Trishula, and Xencor; and patents (both provisional) serial #15/612,657 (Cancer Immunotherapy) and PCT/US18/36052 (Microbiome Biomarkers for Anti-PD-1/PD-L1 Responsiveness: Diagnostic, Prognostic and Therapeutic Uses Thereof). ASM reports honoraria to institution from AbbVie, AstraZeneca, Bristol Myers Squibb, Genentech/Roche, and Janssen; grant funding from Novartis and Verily Life Sciences; travel expenses from Roche; and is non-remunerated Director of Mesothelioma Applied Research Foundation. WAM reports institutional research funding (for this study) from Incyte. SS reports research support from Bristol Myers Squibb, Brooklyn ImmunoTherapeutics, and Merck; and advisory board for Boehringer Ingelheim and Merck. PML reports advisory board membership for AbbVie, ABL Bio, Agenus, Astellas, AstraZeneca, Bayer, Black Diamond, Cybrexa, CytomX, EMD Serono, Genentech, GenMab, GlaxoSmithKline, ImmunoMet, IQVIA, Kineta, Kyowa Kirin Pharmaceutical Development, MacroGenics, Molecular Templates, Pfizer, QED Therapeutics, Salarius, Shattuck, Silverback, STCube Pharmaceuticals, Takeda, TRIGR Therapeutics, and Zentalis Pharmaceuticals; advisory board and consultant for I-Mab; consultant for SK Life Science and Sotio; data safety monitoring board for Agios, Five Prime, Halozyme, and Tyme; and imCORE Alliance with Roche-Genentech. IG-L reports institutional research funding from Bayer, GSK, Incyte, Novartis, Pfizer, and Trishula; ad-hoc advisory board for Eisai and Pfizer; and data and safety monitoring committee for Sotio. LL, RG, KD, and MS report employment and stock ownership with Incyte. JDB reports nothing to disclose. (© Author(s) (or their employer(s)) 2022. Re-use permitted under CC BY. Published by BMJ.)
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