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Exploring the safety, effect on the tumor microenvironment, and efficacy of itacitinib in combination with
Aung Naing1, John D Powderly2, John J Nemunaitis3
1Department of Investigational Cancer Therapeutics, MD Anderson Cancer Center, Houston, Texas, USA anaing@mdanderson.org.
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receiving itacitinib 300 mg once a day plus parsaclisib 10 mg once a day, which resolved when the study drugs were withdrawn.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.
Insights
This study combined Janus-associated kinase 1 (JAK1) inhibition with either indoleamine 2,3-dioxygenase 1 (IDO1) or phosphatidylinositol 3-kinase δ (PI3Kδ) inhibition. The combinations were manageable but showed limited clinical activity and immune activation in the tumor microenvironment.
Area of Science:
- Oncology
- Immunology
- Pharmacology
Background:
- Phase I multicenter study evaluating itacitinib (JAK1 inhibitor) in combination with epacadostat (IDO1 inhibitor) or parsaclisib (PI3Kδ inhibitor).
- Investigated safety, tolerability, efficacy, and tumor microenvironment effects of dual-targeted therapy in advanced solid tumors.
Purpose of the Study:
- To assess the safety and efficacy of combining itacitinib with epacadostat or parsaclisib.
- To evaluate the translational effects of these combinations on the tumor microenvironment.
- To determine dose-limiting toxicities and maximum tolerated doses for the combination therapies.
Main Methods:
- 142 patients with advanced/metastatic solid tumors enrolled.
- Group A: Itacitinib + Epacadostat; Group B: Itacitinib + Parsaclisib or Parsaclisib monotherapy.
- Dose escalation to determine safety, tolerability, and preliminary efficacy.
Main Results:
- Maximum tolerated dose not reached; one dose-limiting toxicity (aseptic meningitis) observed.
- Common adverse events included fatigue, nausea, pyrexia, and diarrhea.
- Limited objective responses observed; itacitinib + epacadostat showed minor CD8+ T cell infiltration increase, while itacitinib + parsaclisib downregulated immune-related plasma proteins.
Conclusions:
- JAK1 inhibition combined with IDO1 or PI3Kδ inhibition demonstrated manageable adverse events.
- The combinations showed limited clinical activity and failed to significantly enhance immune activation within the tumor microenvironment.
- Further investigation may be needed to optimize combination strategies for solid tumors.
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