Yi-Bin A. Chen, MD:Itacitinib is another oral JAK inhibitor that is made by Incyte [Corp]. Itacitinib, in contrast with ruxolitinib, has a bit more JAK1 selective inhibitory activity, whereas ruxolitinib is a JAK1/JAK2 inhibitor. These are 2 different receptor tyrosine kinases that have separate cell signaling pathways. JAK1 is thought to be much more inflammatory, and JAK2 is thought to conduct pathways that are thought to be much more important in hematopoiesis. That’s the rationale for using a JAK1 selective or a JAK1 tropic inhibitor such as itacitinib.
GRAVITAS-309 is a multicenter, phase III randomized trial testing itacitinib as up-front therapy for newly diagnosed chronic graft-vs-host disease. Patients, at the diagnosis of moderate to severe chronic graft-vs-host disease, are enrolled on the trial. There are 2 steps to the trial. The first phase helps define the dose of itacitinib for this population. It was a 20-patient run-in randomized trial to randomize patients to 1 of 2 doses of itacitinib in conjunction with systemic steroids for chronic graft-vs-host disease. The 2 doses were 200 mg and 300 mg. Actually, that phase of the trial has completed accrual. We await the results of the analysis, in terms of dose-limiting toxicities and pharmacokinetics, and a decision as to which dose we use moving forward.
The second phase of the trial is a much larger randomized portion, which will actually study steroids with placebo versus steroids plus itacitinib for the treatment of newly diagnosed chronic graft-vs-host disease. The primary end point of this trial is overall response rate at 6 months, with key secondary end points, as you would expect. We’re testing to see if adding itacitinib to steroids for up-front treatment of chronic graft-vs-host disease will have a benefit.
If itacitinib has a benefit in chronic graft-vs-host disease, we hope to see a few key results. Starting with the primary end point, we hope to see a higher proportion of patients have an overall response to up-front therapy. In addition to this, we also hope to see patients who receive itacitinib compared with placebo are able to decrease their systemic steroids much faster and have a higher quality of life. Looking for a difference in survival is a bit ambitious, given this is chronic graft-vs-host disease, and that with the short end points one would not expect to see a difference in survival yet based on how this trial is designed.
GRAVITAS-301 was a multicenter, international phase III trial that was studying the role of itacitinib in the treatment of patients with newly diagnosed acute graft-vs-host disease. Patients had to have grades 2 through 4 acute graft-vs-host disease that required systemic therapy. Upon enrollment, patients were then randomized to steroids plus placebo versus steroids plus 200 mg of itacitinib once a day. The primary end point of this trial was day 28 overall response rate, with key secondary end points such as 6-month nonrelapse mortality and overall survival. The hope would be that if itacitinib has a role and a benefit in acute graft-vs-host disease, we would hope to see that more patients at day 28 had an overall response. Hopefully, more patients had a complete response as well. And at 6 months, we hope that fewer patients had died of acute graft-vs-host disease. This study has finished accrual, and we look forward to the data in the upcoming year.
Transcript edited for clarity.