RE:RE:RE:RE:RE:RE:RE:RE:RE:RE:RE:RE:RE:Update pleaseOne thing to remember in this story is the fact that are not flying blind. Obviously they don't have full daylight and clear sky, but they have tools to guide them to some extent. The main one is the pharmacokinetic data that they gathered for each patient since the begining of the trial. They followed free docetaxel in the bloodstream after every injection at different time points, same for TH1902. They were able to correlate this data with the particular situation of every patient. Based on the type of cancer, they knew the probabilities for sortilin expression, they also knew tumor burden for every patient. All that to say that when they approached doses that could generate possible toxicities the choice of patient likely played a role. When I say choice of patient, I mean choice of cancer type. We know some advanced cancer types are very likely to overexpress sortilin.
I know the trial is in theory open to all comers, but in reality, I think it is clear that the oncologist of a patient with a cancer unlikely to express sortilin is unlikely to recommand this trial to his patient. So it is all comers, but there is still some kind of natural selection going on. It is likely that the higher the dose is, that patients willing to enroll must be patients with a cancer type likely to express sortilin.
I still think that the MTD of TH1902 cannot be the same for patients with very different sortilin expression and tumor burden. This is likely to make things a bit complicated when testing higher doses. This aspect of the trial was not explained by the company. They talked about the fact that the FDA requested all comers to see a difference in efficacy between high and low sortilin patients, but they did not talk about the fact that this would affect toxicity reproducibility from patient to patient. In other words, a given dose will be toxic for a patient without much sortilin expressing cells, or low level of sortilin expression, but it will not be toxic for a patient with a high number of sortilin expressing cells and high sortilin expression. This is very important and they did not say a word about that situation. So maybe the delay is due to a slower process because of that. To me, this all comers thing is very hard to apply if TH1902 is really quickly internalized by sortilin expressing cells. If TH1902 is not internalized, or very slowly internalized, then it would not make much difference. So enrollment of all comers is a good thing to demonstrate the role of sortilin in possible efficacy, but a source of problems when it comes to determine the MTD in patients expressing sortilin.
Wino115 wrote: I think you understand it correctly. The reason is that no company announces normal and expected SAEs they record in their trials. In fact, the trial is designed to push it to the point you see a bunch of sick patients, likely with neutropenia and other things which would clearly show you the limit was reached and you need to lower it back. It's part and parcel of a 1a dosage trial.
We only happened to hear of the initial one at the 1.5x level because they chose to update us where they stood during one of those healthcare conference webcasts. They've told us they are following the FDA dosage trial requirements to the "T" and we know that they can keep upping the dosage until they get a few dose limiting toxicity events at a particular level --more than just 1. Then they drop down one and do a full panel for a few cycles and end it.
In other words, for all we know there have been others at that level or near it. By definition there will be far more than one eventually. But nothing requires them to announce it unless they want to or wait to just review the whole thing and give us the answers -- dosage for next phase and here's what we learned. The only material event would be they have final results from the trial and need to release them. A second material event would be if they've changed what the 1b portion of the trial will be --either types of tumors, number of patients, or length of treatment. I suspect we may hear that, or a confirmation they are still with the initial FDA plan of 40 patients in 4 cancers, at the same time or soon after the 1b is discussed.
That's the reasons behind no PR around every toxicity, but you are right in thinking maybe they haven't hit it or, if we're really lucky, sortilin is present in most of the patients and it's attracted the majority of the PDC to get internalized so there isn't a lot of free chemo running around. Eventually it won't work and they end it. But we're not sure where they are until they decide to inform us. It's all guess work. I would assume that if there was something unbelievably bad going on, like patients having severe issues because of the treatment, they'd have to tell us. We know patients perishing is unfortunately part of this process to given the required state they are in. So it would have to be treatment related and we have not heard anything. So it's probably safe to say they've been dosing at high levels and there are no treatment related deaths. But there's likely other toxicity events and they are doing what the trial says they can or can't do around those. Once again, a clarification in the new year would sure be helpful!
PWIB123 wrote: Forgive my lack of knowledge in this space, but based on this suggestion, I would have expected to hear of several more Grade 4 (I think is what I read previously) events with neutropenia. Since we've only heard of the one, does that mean they were able to avoid disclosing the others somehow? I was thinking with "all comers" and a lack of a controlled target, that we would have heard of additional issues with toxicity, but we haven't. Why would that be?