RT Journal Article
SR Electronic
T1 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
JF Journal for ImmunoTherapy of Cancer
JO J Immunother Cancer
FD BMJ Publishing Group Ltd
SP e004223
DO 10.1136/jitc-2021-004223
VO 10
IS 3
A1 Aung Naing
A1 John D Powderly
A1 John J Nemunaitis
A1 Jason J Luke
A1 Aaron S Mansfield
A1 Wells A Messersmith
A1 Solmaz Sahebjam
A1 Patricia M LoRusso
A1 Ignacio Garrido-Laguna
A1 Lance Leopold
A1 Ryan Geschwindt
A1 Kai Ding
A1 Michael Smith
A1 Jordan D Berlin
YR 2022
UL http://jitc.bmj.com/content/10/3/e004223.abstract
AB 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receiving itacitinib 300 mg once a day plus parsaclisib 10 mg once a day, which resolved when the study drugs were withdrawn.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.