RE:RE:RE:Dose escalation The other way to think about this is in regard to therapeutic window. You want your drug to have a wide therapeutic window. Simplistically the bottom end of the window is defined by the lowest dose where you have meaningful efficacy. The top of the window is defined by the dose where unacceptable toxicities begin. So if you get to dose 4 and you have your 1st meaningful clinical response and then you get to dose 7 and you still haven't had your first DLT (dose limiting toxicity) then essentially you've already identified a wide therapeutic window, you don't necessarily need to keep going higher and higher just for the sake of describing the full therapeutic window. That's just one example. In another if efficacy doesn't kick in until a later dose and you still don't have a DLT at dose 7 then in that example you have yet to describe a wide therapeutic window so you might keep going to higher doses to fully explore the therapeutic window. There are other weaker scenarios where you keep dosing higher or you are forced to stop at lower doses.
As I said lots of companies simply report they haven't reached MTD in their dose escalation, that must be because what they have explored gives them a big enough therapeutic window to play with without actually formally reaching the top end of it by describing where the MTD is.
Just one last point an earlier readout on this could signal strength or weakness in the data, a later readout is pretty much the same, it all depends whether efficacy or safety is triggering the timing. I think Q4 is probably the latest foreseeable outcome but there is plenty of opportunity for Paul to announce they've beat the deadline.
qwerty22 wrote:
They can stop at the final dose and just declare they haven't reached MTD. That's something that happens often enough to be normal in cancer dose escalation. You would do that if you have signs of efficacy. You might also use some of the rational JFM is talking about. Normal docetaxel is your guide here. While 100mg/m2 is the usual dose it still has efficacy at 60mg/m2 and this is the dose it can drop to if a patient has tolerability issues. So if you're just thinking about efficacy rather than MTD then you are talking about potential efficacy signal as early as May and that is without any potential extra concentrating effect from the active scavenging effect from Sortilin pulling more drug into the cell.
With efficacy kicking in at an earlier stage and using docetaxel as a guide I don't think they have to just keep going higher and higher just to prove the MTD.
Wino115 wrote:
In the pre clinical graphs at the webcast CM said they stopped some of the dosing because they proved their point, but that they could have continued dosing longer or higher. Do you think they can go beyond the 3x docetaxel? Do you think they will or will they max the dose at the 750ish level on your opinion?
jfm1330 wrote: I went back to the KOL presentation to determine at what dose Thera likely is right now in the dose escalation trial. Marsolais said it take three to four weeks for every cycle. It was annouced on March 23 that they injected the first patient of the trial at 30 mg/m2. So taking that date as the starting point it gives this assuming a full four weeks for every cycle, which is likely not the case, especially in the first two or three cycles. Anyways, it gives this
March 23: 30 mg/m2
April 20: 60 mg/m2
May 18: 120 mg/m2
June 15: 200.4 (on June 21, Marsolais said they were close to the MTD of docetaxel of 230 mg/m2. So this is in line with what he said then)
July 13: 300.6 mg/m2
So it gives July 13 for the first dose well above the MTD of free docetaxel. Again, Marsolais said three to four weeks per cycle, so more than three weeks, but in some cases, probably in the first cycles, with one patient, less than four weeks. So this dose of 300 mg/m2 has been likely given somewhere between July 5 and July 15. Likely in the middle of that interval. So it is easy to understand why Marsolais willing to say in the last CC that they will surely have a MTD of TH1902 that is higher than the MTD of free docetaxel. Also, he probably already had the dosing of free docetaxel over time in the blood after the injection of the 300 mg/m2 dose. So he knew the level of free docetaxel this dose was generating. If the number was as low as expected, it confirmed to him that toxicity at that dose was very unlikely.
The next step will be 420 mg/m2 on August 10. This will be close to two times the MTD of free docetaxel.
Then, if they get there, it would be 558.6 mg/m2 on September 7, and 742 mg/m2 on October 5. This would be a bit higherthan three times the MTD of free docetaxel, which is what they saw on rats in the preclinical.
So we are sure to have a significantly higher MTD of docetaxel with TH1902. At this stage the only question to answer is how much higher will it be. The higher it will be, obviously, the better it will bode for efficacy. This helps understanding why they are so confident with TH1902 anf the SORT1 approach in general. Why they hire people to coordonate preclinical and clinical work. It also allows to understand why they were willing to write in their last press release, and say through the CEO in their last CC that they believe that They have developed a targeted peptide-drug conjugate that may potentially transform the way cancer is treated. These are their words, not mine, and this is a very bold statement coming from them. I can't figure how they can be more positive than that without releassing real good results. After such a statement, coming out in a few months with negative results would be an absolute surprise. But again with this company at this time, it is a matter of credibility and they obviously don't have much with the market. So this statement went by like it was never made. Even here, I have been the only one underlining it. So we will have to wait for the real results. It will either be a shocker for many, or a big disapointment for me.