You know, so after we had this early signal from the phase one in T-cell lymphoma against a small number of patients, but a but a 50% response rate in PTCL, that really stood out different towards other available agents. So at that time, approved agents were things like pralatrexate, Romodepsin that in their pivotal studies had response rates less than 30%. So, uh, a follow-on study done primo, which was a proper phase two, of um of Duvaliib, uh, as a single agent in relapse or fracctory T cell lymphoma was started. At that time though, we didn't know what the right dose was because the FDA approved dose was 25 mg twice a day, but in the phase one study, um, almost no or no patient with T cell lymphoma had that dose. So because the patients with low grade B cell lymphoma took up all the early slots, all the T cell lymphoma patients were treated at, at, um, mostly at 75 mg twice a day if you had 50, a few at 100. So the response rate was there, but we didn't know whether it mattered the dose, um. We had some internal data from a separate study we're doing that our best guess in a small number of patients was the dose probably wouldn't matter and probably 25 would be as effective as 75. Um. The PK or the PD difference in 25 versus 75 is that 25 mg twice a day, you get very good inhibition of PI 3 kinase delta, but not as much PI3 kinase gamma, and you really need to go up to the higher doses to get more significant inhibition of PA3 kinase gamma. didn't know at the time or still don't know for sure that that's really important or critical. But so the beginning of the Primo study started with the randomization of patients getting 75 mg twice a day or 25 mg twice a day. I predicted that it wouldn't matter, but actually we saw better responses at 75 mg twice a day, in the sense that um uh more patients at 25 twice a day had early progression. And what we saw in the um in the PK data is it may take a cycle or so to get up to good levels. And our hypothesis from that was that in aggressive diseases, unlike follicular um um lymphoma or CLL in aggressive diseases, if you really don't get the PK up quickly, some patients may escape and some patients with aggressive T cell lymphoma will have early progression. So what we learned was that 75 mg twice a day seemed to be important early on to capture control of disease. Um, we also knew that 75 twice a day had more toxicity in terms of um transambinase elevations and probably later, uh, inflammatory side effects. So looking at that, the decision was made to modify the expansion part or the really the the efficacy portion of Primo study to give patients 75 mg twice a day to try to establish disease control, and then patients who didn't progress, so stable disease or better, were then uh. escalated to 25 mg twice a day to try to maintain long-term remission because we really want long term progression free and of course overall survival, um, with a lower um chance of some of these late toxicities that can complicate long-term treatment with PI 3 kinase inhibitor. So that's how it was done. Um, and the results, you know, were good. Um, so the response rate was just under 50%. It was great for us to see because our phase one had a 50% response rate and to see that that was done in a more than 100 patient phase two cohort, really confirming that. And then we started to understand some differences in subtypes. So one thing we didn't know going in, but we now know, know now is anaplastic large cell lymphoma is much less likely to respond to single agent PI3 kinase inhibition. Uh, so those patients, particularly positive, but L positive out negative, had about a 15% response rate. The response rate in peripheral T cell lymphoma NOS was about 50%, and then really high response in angiooblastic T cell lymphoma, where over 60% of patients responded and uh more than 50% of those had complete responses. So that time was sort of the first observation um that was made that that subtype AITL and. The helper T cell lymphoma seemed to be the group that most benefited from PI3 kinase inhibition, at least delta gamma inhibition in this study, um, both in terms of response rate, CR rate, and progression free survival. Um, so that seemed to be the group that really benefits still reasonable responses in PTCL NOS and probably not a great single agent for anaplastic large cell lymphoma.
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