So we had good data of single agent PI3 kinase, um, you know, I think it stands to reason we think that um combination therapy is probably the way to get higher CRs and as a bridge to cures. So we were looking at other potential combinations and uh started a study where we combined duvalii with either um uh Romodein, HDA inhibitor, or bortizumib, um. Um, uh, the bortizumib arm was was based on some genetic work out of Stanford that suggested that there were frequent mutations, particularly in CTCL, that might benefit from combination of PA3 kinase inhibition and uh uh bortizumib, and then, uh, in the Romodepsin, it was really combinatorial studies that showing additive or maybe even some uh. Synergy, but probably additive efficacy of Romopsin uh plus duvaicin. So we started, um, what were really parallel phase one designs with expansion cords of what we thought were the MTD and a couple of early things came out. One is that the responses in the Duvolicidromodepsin arm looked quite good, and that we could give full dose dulicip, so we escalated that to 75 mg twice a day, uh, with, um. Romipsin at 10 mg weekly, 3 out of 4 weeks, so we didn't go up to the full Romidpsin dose just to um for efficiency, uh, but we had no DLTs and could give those doses, full doses in combination. At the same time, we were looking at Duvalii plus porttizumib, and if you add duvaicid plusortizib, um, um, once we got above 25 mg twice a day in the Duvaliib, um, so that was cohort one, that was tolerated. Cohort two, once we uh escalated to 150 mg twice a day, we had. grade 3 transaminaseelivation in 3 out of 3 patients. Um, so that was the main side effect of, of single agent Duelli was transaminase elevation, and it was too small at that time to have a conclusion, but we could give full dose Duvalii 75 mg twice a day. With Romodpsin, we could not go above 25 mg twice a day with partizumab. Um, did some expansion cohorts and really it was clear to us that the Roma Depsin Duvali was the higher response rate arm with the majority of patients responding, lots of complete responses, a number of patients bridged allo transplant with curative intent. Uh, so we expanded that arm to statistically, um, uh, um, show that it was better than single agent Romodepsin. Uh, so that arm was expanded to over 50 patients. So what we saw in that expansion was what we had the clue from when the phase. One, which is that when you give Romodepsin plus duvaliib, the grade 3 or higher transaminasealivation is under 10% with with 75 mg twice a day of dubilisi. We knew from the phase one study that if you gave 75 mg twice a day of dubilisi, the grade 3 or higher transaminaseelivation was about 40%. Uh, so we really saw a significant reduction, uh, that we thought was real when we expanded that 50 patient cohort. Another interesting thing is we had a separate cohort on that study where you got one cycle of single agent duvaic specifically to get research biopsies, because in the phase one study that we had done, it was um the first time it was being looked at, we didn't do all the research biopsies. So we had a cohort of patients who got single agent duvalii, and if they, for one cycle got a research biopsy at the end of that cycle and if they did not have a CR they went on to the combination um uh uh arm with Romodopsin. And what we saw is that if you started with single agent Duvalii and then went on to Romodepsin, you had that same 40% risk of grade 3 to 4 transaminase elevation, and it was when you started combined with Romodpsin, that it seemed to reduce that risk. So that was super interesting to us, not expecting not. And that was just uh something we observed as we were treating patients. Um, so a translational colleague of mine, Sancho Vardana, uh, really worked a lot on that to try to understand what was going on here and was the HDAC inhibitor, was Romodpsin really providing a protective effect. And it looks like that, um, a lot of the, um, uh, inflammatory side effects, at least with transaminase elevation. Um, I'll talk about some of the other effects in a second. A lot of the inflammatory side effects are mediated by myeloid cells, and that Romodepsin really suppressed those cells. So in addition to potentially having some simulated activity against the T cell lymphoma, it suppressed one of the downstream side effects of PF 3 kinase inhibition and allowed us to give higher doses of Duvaliib longer, more safely. Um, and that's best shown with the reduction in the transaminaseelivation. We didn't see much colitis and we didn't see much pneumonitis. But the caveat there is that was a MSK multicenter study. It was an investigator initiated study, and the majority of patients who had CRs went to allo transplant, usually between 2 and 4 cycles, and the majority of patients without CRs, um, were not on therapy, you know, for many months. So the number of patients to get to 6 and 12 months. Of therapy to really where you might see that signal for colitis is very few, so we're not as confident that it truly reduces those effects, but pretty confident right now that at least with regard to the transam salvation or or one of the early acute toxicities that Romodpsin does blunt or, or reduce the the risk of that happening.
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