So further development of duvaicit following the Primo trial is with a trial called the Turzo study, which is a randomized study. Now, I just want to pause there for a minute, we have a real dearth of randomized, uh, clinical trials in relapsed refractory. uh T cell lymphoma generally and certainly in subtypes specific. Uh, T cell lymphoma trials, uh, such as TFH, uh, derived, uh, T cell lymphomas. We do have one, which compared, uh, chemotherapy, uh, uh, it was an investigator choice control arm, uh, with an oral azocytidine, uh, which almost showed a benefit, but it was rather underpowered, so unfortunately that has not, uh, been developed further. Uh, but it's great that, uh, we're looking at duvalii in this, uh, properly designed randomized controlled trial. The other important thing about a randomized control trial, yes, it gives the best data, the best evidence that we have for benefit, and that obviously is crucial, particularly when you have a drug that has well-known toxicities, you know, we want to be able to justify exposing patients to a, a drug which has toxicities associated with it. And if we can show that there's not just an increased response rate, but an increased survival rate compared with standard of care, then absolutely that does justify uh using these uh agents. Uh, but we also need to show regulatory authorities and indeed funding bodies, uh, that, that, that this drug should be licensed and reimbursed. So I'll just give you my, um, experience in the UK is that the UK we will only be able to have a drug available in our nationalized healthcare system, uh, if there's a license, and that license from the MHRA, which is our regulatory authority, is, um. They very much want randomized trials, but that's not the end of the story. We also need to take it through our reimbursement agency, which is called NICE, and they need to show that it's cost effective. And again, a randomized phase 3 trial is really the best data, uh, for them to then chew the numbers as to whether this drug sort of adds up from a cost-effectiveness point of view. So it's really important to have data like this. So the Turzo study is taking patients with relapsed peripheral T cell lymphoma, um. They could, they must have had at least one prior line of treatment. They're particularly looking at the TFH uh cohort, and that's based on the primo data which suggests better overall responses and survival endpoints associated with that group of lymphomas. How do they define that? Well, they, they define that based on the presence of two or more of the immunohito chemical markers. So I say the ones that we tend to do are PD1, BCL-6, uh, um, there's, um. CD 10 is another commonly used one, but there are other CXCR 4 CXCR 13 IOS, for example. Uh, and if you have two of those or more of those markers as defined locally, uh, then that's one of the eligibility criteria. Now we are then sending in pathology to have a central review, but that is not actually part of the eligibility. Now there are also a number of other eligibility criteria which are relatively standard. Uh, for any clinical trials, so the um performance status has to be, uh, 0 to 2. They need measurable disease, uh, on a CT scan so that we can trace, uh, the activity of this, uh, agent and work out if a patient achieves a partial response or a complete response. Uh, the patient has to have reasonable hematological parameters, biochemical parameters, uh, etc. Now one key thing obviously with any clinical trial is safety, and I've already mentioned that there are some specific uh issues with PI3 kinase inhibitors. So we have to, for example, monitor for CMV reactivation, that is observed in some trials with PI3 kinase inhibitors. And if CMV is reactivated, we have to pause the drug, uh, although it can then be restarted once um the CMV titer falls. Obviously we clinically monitor the patients, so I've already mentioned things such as uh pneumonitis or colitis. Um, those are important things that we monitor for uh the liver function test, that was one of the main sort of safety findings in the Primot is derangement of LFT. And obviously there are protocol specified ways of managing these things, but they essentially involve, uh, particularly for the higher grade toxicities, halting the duvalii, waiting for resolution or treating, for example, with steroids, if it's a, uh, autoimmune pneumonitis or colitis. Um, it doesn't necessarily mean that we have to discontinue the juice it tends, depends a little bit on the grade of the, uh, of the adverse event and what that adverse event is. But when the juvelicid's restarted, there are protocol to find, uh, reductions in dose that can be applied in an attempt to keep patients on study and keep them benefiting. Now, the dose that's being used is the one that was determined by the primo trial, so it starts off with 75 5 mg twice a day orally for the first two cycles. Uh, there is then a protocol, a defined reduction in the dose to 25 mg uh BD and it's for up to then 3 years of treatment. Um, and that the reason they, they have that is they want to basically start at a higher dose in order to get tumor control. Um, however, they want to try and minimize the risk of the appearance of side effects, so therefore they reduce to the 25 mg from cycle 3, on, and there's good pharmacodynamic data to suggest that that 25 mg is a, is a reasonable dose to, to continue the patient on. Now, I mentioned that this is a randomized study, so it's a 11 randomization. Uh, the one arm is duvali, as I've mentioned, the other arm is either, uh, gem cytabine or bendamustine, so single agent, uh, chemotherapy. As I say, these are very much, uh, standard drugs, uh, used in Europe and the UK. Uh, we don't have access to, for example, HDA inhibitors that may be used elsewhere in the world or pralarexate. Uh, we really would be reaching for for gem cytopine or bendomastine. But this is investigators strict choice. So before the randomization happens, the investigator has to say. Which one they're gonna use, and then when the patient's randomized, if they're randomized to the standard of care, then you go for that drug. Now of course the the time on treatment, so the number of cycles of chemotherapy is gonna be significantly less than the patient is on treatment with duvaliib. And that's important because er when you look at uh adverse events that are related to treatment, you're gonna have a lot longer, uh, we hope, at least because hopefully that means patients will be benefiting, but you're gonna have patients on juvelicid potentially a lot longer than they were on the chemotherapy, uh, on the control arm. So we need to sort of be careful how we interpret safety data. We might expect to see a lot more adverse events on the juicive arm simply because patients are being treated for longer. Uh, so that's going to be a caveat when we, um, uh, sort of unlock the trial data and have a look at, um, uh, at the results. So I think it's going to be very interesting, uh, to see what this randomized data throws up, and I certainly hope that it's going to be good enough quality, uh, to end up, uh, if there's benefits, of course, uh, with a license for this agent.
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