So, um, the story of Duvolicid in peripheral T cell lymphomas is a little bit, um, serendipity and I would say a little bit of perseverance. So, um, there was an initial experience across all hematologic malignancies or many hematologic malignancies of studying Duvalicid in, in, um, in that study, to a bit to everybody's surprise, there were, um, just about a handful of patients with peripheral T cell lymphoma. And it turned out that their response rate was 50%. Now, at that time, the drug was being studied across hematologic malignancies. There was really much more of a push and an interest in more common B cell lymphomas like CLL and follicular lymphoma, and um the T cell lymphoma story was a bit, I would say was thought to be surprising. And so, but was quite exciting because most of the drugs that we have in peripheral T cell lymphoma have an overall response rate of 25% to 30% and so a drug that was orally available that had a response rate close to 50% seemed to be quite exciting. Um, and so at the time there was um less interest in studying, you know, these drugs in rare diseases in, in, in terms of a large study and so back in. 2000, um, you know, 13014 or so, um, at Memorial Sloan Kettering, we had developed an investigator initiated trial to further understand the utility of using Duvolleid based therapy in peripheral and and at that time cutaneous T cell lymphoma. So that study was a study where patients received um single agent Duvolleid. And um they were, they had the option of getting Duvolici plus Romodexin, the histone Diacetylase inhibitor, or Duvaliib with porttizumib um uh which was being studied at that time in T cell lymphoma and for patients, patients also had the option of joining an arm where they got. Duvaliab alone and after a month, if they had a complete remission at that time, they could stay on Duvolicab by itself. And that study again suggested that single agent Duvollei had a response rate of close to 50%, a complete remission rate of 25% to 30%, um, and also led to the data that led to the expansion of the Duvaliid plus Romopsin study, which again showed that the response rate of the combination was about 55-60%. And, um, specifically in the TFH phenotype lymphomas was higher and um Interestingly, the, um, the, you know, Duvalus had then got further developed in CLL and follicular lymphoma at a dose of 25 mg BID. But in peripheral T cell lymphoma, we had escalated the dose up to 75 mg BID, um, suggesting that the 75 mg dose had potentially was more effective. Um, but there were concerns about the toxicity of dulus of long term, uh, specifically their rates of transaminitis and, and infection. And what we saw, at least in our experience, was that the addition of um Romisin to Duvaliab at 75 mg BID had less um associated transiminitis than when Duvaliab was given alone at 25 mg BID, suggesting that whatever the immunosuppressive effects of giving a a concomitant Romisin seemed to um decrease the side effects. And, and now we know, we didn't know then, now we know that Duvali. Um, activates the microenvironment. There's a component macrophage activation. There's certainly a pro-inflammatory, um, milieu that Duvalii creates, which is probably what leads to the transominitis and the colitis and maybe even the rash that are seen with Duvalii and maybe giving some um. Uh, attenuated level of immune suppression with Duvaliab probably decreases the rate of toxicity, and we're hoping to see that in A051902 where we combine Duvaliab with um chap-based therapy as well. So that all of that data was occurring and I think there was a lot of enthusiasm and excitement amongst clinical investigators about using Duvolous and peripheral T cell lymphomas and specifically in TFH phenotype lymphomas where it seemed like the response rate was higher. And um and then that um then subsequently um reinvigorated interest in the development of the primo trial, which was the study of Duvaliib as a single agent, where it was found that the the dose that was ultimately used in the expansion was 75 mg BID for two cycles, um, and then dropped to 25 mg BID and given until progression or intolerance.
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