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
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) o...
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BMJ Publishing Group
2022-03-01
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| Series: | Journal for ImmunoTherapy of Cancer |
| Online Access: | https://jitc.bmj.com/content/10/3/e004223.full |
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| author | Michael Smith Ignacio Garrido-Laguna Aung Naing Lance Leopold Jason J Luke Kai Ding Solmaz Sahebjam Ryan Geschwindt John D Powderly John J Nemunaitis Aaron S Mansfield Wells A Messersmith Patricia M LoRusso Jordan D Berlin |
| author_facet | Michael Smith Ignacio Garrido-Laguna Aung Naing Lance Leopold Jason J Luke Kai Ding Solmaz Sahebjam Ryan Geschwindt John D Powderly John J Nemunaitis Aaron S Mansfield Wells A Messersmith Patricia M LoRusso Jordan D Berlin |
| author_sort | Michael Smith |
| collection | DOAJ |
| description | 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receiving itacitinib 300 mg once a day plus parsaclisib 10 mg once a day, which resolved when the study drugs were withdrawn.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. |
| format | Article |
| id | doaj-art-5301f58ebe1d4437ac949bf2e4df972b |
| institution | DOAJ |
| issn | 2051-1426 |
| language | English |
| publishDate | 2022-03-01 |
| publisher | BMJ Publishing Group |
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| series | Journal for ImmunoTherapy of Cancer |
| spelling | doaj-art-5301f58ebe1d4437ac949bf2e4df972b2025-08-20T03:08:36ZengBMJ Publishing GroupJournal for ImmunoTherapy of Cancer2051-14262022-03-0110310.1136/jitc-2021-004223Exploring the safety, effect on the tumor microenvironment, and efficacy of itacitinib in combination with epacadostat or parsaclisib in advanced solid tumors: a phase I studyMichael Smith0Ignacio Garrido-Laguna1Aung Naing2Lance Leopold3Jason J Luke4Kai Ding5Solmaz Sahebjam6Ryan Geschwindt7John D Powderly8John J Nemunaitis9Aaron S Mansfield10Wells A Messersmith11Patricia M LoRusso12Jordan D Berlin13Incyte Corporation, Wilmington, Delaware, USA2 Medical Oncology, Huntsman Cancer Institute Cancer Hospital, Salt Lake City, Utah, USAThe University of Texas MD Anderson Cancer Centre, Houston, Texas, USAImmuno-Oncology, Incyte Corporation, Wilmington, Delaware, USA2 UPMC Hillman Cancer Center, University of Pittsburgh Medical Center, Pittsburgh, Pennsylvania, USA1Takeda Oncology, Cambridge, MA, USAClinical Research Unit, Moffitt Cancer Center, Tampa, Florida, USAImmuno-Oncology, Incyte Corporation, Wilmington, Delaware, USA1BioCytics, Huntersville, NC, USAUniversity of Toledo College of Medicine, Toledo, Ohio, USAOncology, Mayo Clinic, Rochester, Minnesota, USASchool of Medicine, University of Colorado, Aurora, Colorado, USAYale School of Medicine, Yale Cancer Center, New Haven, Connecticut, USADivision of Hematology/Oncology, Vanderbilt University, Nashville, Tennessee, USABackground 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.https://jitc.bmj.com/content/10/3/e004223.full |
| spellingShingle | Michael Smith Ignacio Garrido-Laguna Aung Naing Lance Leopold Jason J Luke Kai Ding Solmaz Sahebjam Ryan Geschwindt John D Powderly John J Nemunaitis Aaron S Mansfield Wells A Messersmith Patricia M LoRusso Jordan D Berlin 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 Journal for ImmunoTherapy of Cancer |
| title | 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 |
| title_full | 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 |
| title_fullStr | 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 |
| title_full_unstemmed | 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 |
| title_short | 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 |
| title_sort | 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 |
| url | https://jitc.bmj.com/content/10/3/e004223.full |
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