PRIMO: Optimising the dose of duvelisib in patients with R/R peripheral T-cell lymphoma
Dr Steven Horwitz - Memorial Sloan Kettering Cancer Center, New York, USA
One of the presentations I had at this meeting was on duvelisib in peripheral T-cell lymphoma. Duvelisib is an oral PI3 kinase delta/gamma inhibitor and it’s now FDA approved for relapsed refractory follicular lymphoma in CLL, so low grade B-cell lymphomas. In the phase I study the optimal dose for low grade B-cell lymphomas was 25mg twice daily but the maximum tolerated dose, or the MTD, was 75mg twice daily and we had treated a cohort of T-cell lymphoma patients on that study that had about a 50% response rate. So we have been looking at extending that experience and trying to understand or better define the activity in peripheral T-cell lymphoma.
One question that we had was whether 75mg, or the higher dose, was needed for aggressive T-cell lymphomas, there is a little more toxicity at that dose level, or could we get away with a lower dose? The early data was a little bit conflicting. So what we presented here was the dose optimisation phase from the larger or more refined, the bigger phase II study. In the dose optimisation phase people were randomised to either 75mg twice daily or 25mg twice daily to see if there was a difference. It turned out it looks like there was. There was a group of people at the 25mg twice daily who had early progression so they didn’t get to their first evaluation and that didn’t happen at the 75mg dose. That did correlate with higher PK or early exposure to drug at the 75mg cohort so we think going forward you probably need that early, more reliable or higher drug exposure to capture a response in patients with aggressive disease.
So in the full PRIMO study, which will be another hundred patients or so, we’re going to treat everyone at 75mg twice daily and then they can dose reduce to 25mg twice daily to try to minimise some toxicity but try to make sure they get that early drug exposure which looks like it’s important, maybe not as important in the low grade B-cell lymphomas.
Did you observe any toxicities or adverse effects?
Yes, the toxicities were pretty much in line with what we’ve seen. There was a big phase I study looking at these doses so there is some transaminase elevation, there is some immunosuppression which we now prophylax for but there was no new or different safety signal in this study than what we’ve seen in the bigger registrational studies in other lymphomas.
What are the potential impacts of the study?
The end of the PRIMO study could lead to FDA approval and registration in T-cell lymphoma and then the drug would be available. It might need a different dosing strategy than we have for the low grade B-cell lymphomas where it’s already FDA approved. So that would just be another important tool for treating patients in the relapsed setting.
Long term what we’re really more interested in is having a bigger impact on the overall disease course. So we’re doing some combination studies where we combine it with other active agents and eventually maybe move it as part of front line treatment. We treat these patients with curative intent in the front line setting, usually with combination chemotherapy, so adding drugs to that, particularly if we have active drugs and if we can identify who is most likely to respond, we have a chance of making a better impact in the first line. So those are the steps that are coming and just nailing down the response rate in the relapsed setting is what this study is going to do.
