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Encouraging Early Data for Novel PI3K Inhibitors

Insights From:Jennifer R. Brown, MD, PhD, Harvard Medical School;Ian W. Flinn, MD, Sarah Cannon Center for Blood Cancer
Published: Tuesday, Jul 19, 2016


Transcript:

Jennifer R. Brown, MD, PhD:
The phase I trial of duvelisib in relapsed refractory CLL studied a dose of 25 mg b.i.d, which completely inhibits delta and inhibits gamma by about 50%. And this dose was selected from an initial dose escalation that went as high as 75 mg. The activity of the drug was quite good. The nodal response rate was about 83%, and the IWCLL (International Workshop Group on CLL) partial response rate was 58%. And this included the fact that half the patients had 17p deletion. Responses seemed to be as good in the patients with 17p deletion, as in those without, which is good. And the 2-year progression-free survival is 59%, which is quite good. So, the early phase I data were encouraging with duvelisib in CLL.

Ongoing trials with duvelisib include, in particular, the DUO trial, which is a registration trial randomizing patients to duvelisib versus ofatumumab in the relapsed refractory setting. The trial’s fully accrued and expected to read out later this year in 2016. So, we’ll hopefully get the results of that soon. There are a couple other trials.

Our institution is actually doing an investigator-initiated trial of FCR in combination with duvelisib, and we reported preliminary results of that at the ASH meeting in 2015. The combination has been reasonably well tolerated, and the rate of MRD negativity is significantly higher than historical comparison death CR alone. So, that’s encouraging, and that study is ongoing. There’s another study in which patients who’ve progressed on ibrutinib are being evaluated with duvelisib in combination with obinutuzumab, the SYNCHRONY study, which we are also participating in.

The other primary PI3 kinase inhibitor that’s moving forward in CLL is TGR-1202. This molecule is interesting. It’s billed as a next-generation PI3 kinase inhibitor because it has a somewhat different structure from idelalisib and duvelisib, and it was felt that it wouldn’t cause the transaminitis that can be seen with the other drugs. It has reported phase I data with a relatively limited number of patients, although nodal response rates appear to be high, and progression-free survival was about 2 years. Those data are going to be updated at this ASCO meeting, 2016, I believe.

The interesting thing about this drug is that there’s been less transaminitis and less colitis seen in the relapsed setting. And the reason for that is unclear since it’s thought that these toxicities are perhaps directly related to delta inhibition. So, it raises the question, is TGR as good a delta inhibitor or does it perhaps have some other activities against other targets that may mitigate the side effects that we have seen with delta inhibitors? I don’t think we know this yet, and the science is still relatively rudimentary in understanding these toxicities. It will be helpful for the further development of all the PI3 kinase inhibitors if we get a better understanding of how the immune system’s modulated by the different drugs, how this affects toxicity and efficacy, and then also how resistance occurs.

Transcript Edited for Clarity
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Transcript:

Jennifer R. Brown, MD, PhD:
The phase I trial of duvelisib in relapsed refractory CLL studied a dose of 25 mg b.i.d, which completely inhibits delta and inhibits gamma by about 50%. And this dose was selected from an initial dose escalation that went as high as 75 mg. The activity of the drug was quite good. The nodal response rate was about 83%, and the IWCLL (International Workshop Group on CLL) partial response rate was 58%. And this included the fact that half the patients had 17p deletion. Responses seemed to be as good in the patients with 17p deletion, as in those without, which is good. And the 2-year progression-free survival is 59%, which is quite good. So, the early phase I data were encouraging with duvelisib in CLL.

Ongoing trials with duvelisib include, in particular, the DUO trial, which is a registration trial randomizing patients to duvelisib versus ofatumumab in the relapsed refractory setting. The trial’s fully accrued and expected to read out later this year in 2016. So, we’ll hopefully get the results of that soon. There are a couple other trials.

Our institution is actually doing an investigator-initiated trial of FCR in combination with duvelisib, and we reported preliminary results of that at the ASH meeting in 2015. The combination has been reasonably well tolerated, and the rate of MRD negativity is significantly higher than historical comparison death CR alone. So, that’s encouraging, and that study is ongoing. There’s another study in which patients who’ve progressed on ibrutinib are being evaluated with duvelisib in combination with obinutuzumab, the SYNCHRONY study, which we are also participating in.

The other primary PI3 kinase inhibitor that’s moving forward in CLL is TGR-1202. This molecule is interesting. It’s billed as a next-generation PI3 kinase inhibitor because it has a somewhat different structure from idelalisib and duvelisib, and it was felt that it wouldn’t cause the transaminitis that can be seen with the other drugs. It has reported phase I data with a relatively limited number of patients, although nodal response rates appear to be high, and progression-free survival was about 2 years. Those data are going to be updated at this ASCO meeting, 2016, I believe.

The interesting thing about this drug is that there’s been less transaminitis and less colitis seen in the relapsed setting. And the reason for that is unclear since it’s thought that these toxicities are perhaps directly related to delta inhibition. So, it raises the question, is TGR as good a delta inhibitor or does it perhaps have some other activities against other targets that may mitigate the side effects that we have seen with delta inhibitors? I don’t think we know this yet, and the science is still relatively rudimentary in understanding these toxicities. It will be helpful for the further development of all the PI3 kinase inhibitors if we get a better understanding of how the immune system’s modulated by the different drugs, how this affects toxicity and efficacy, and then also how resistance occurs.

Transcript Edited for Clarity
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