RE:RE:RE:RE:RE:RE:RE:Best Case ScenarioTo me, it comes down to what I wrote the other day. I cannot see how the MTD would be lower than 420 mg/m2, unless they really enroll one patient at a time for the 21 days of the treatment cycle, then add another one at the same dose one month after. But that, to me, does not make sense. Also, remember this:
But the strange thing in the Credit Suisse presentation, is that Levesque says that they had "many patients", or "at least several patients" that have been dosed over 300 mg/m2 (300 mg/m2 is step 5 of the escalation process). So over 300 mg/m2 is 420 mg/m2. So back in November he said that they had "many, or at least several patients" that have been dosed above 300 mg/m2, so at 420 mg/m2. So probably, back then, the three added patients at step 6, which, again, is 420 mg/m2, were already injected. This presentation was held on November 11. So by now, the 420 mg/m2 should have been completed and cleared. Without any news at this point, it is likely that they are now at step 7, which is 560 mg/m2 or 2.43 times the MTD of docetaxel alone. jfm1330 wrote:
I agree there are many possibilities since they need at least six patients treated at a given dose with no more than one DLT event to qualify as a MTD. So they may need to come back to a lower dose they get that. Also, I don't know if they have six patients at every new dose level. That way would avoid the possible need to come back to a lower dose to confirm the MTD. In other words, let's say they did the 420 mg/m2 dose on six patients, with no more than one DLT, there would be no need to come back to that dose to validate it as a possible MTD, if they have two or more DLT events at 560 mg/m2. If they did six patients at 420 mg/m2 and failed at 560 mg/m2. They no longer need to test. They have the MTD. But if they clear the 560 mg/m2 dose on three patients, then it's the same problem. If they fail at 740 mg/m2, they would need to come back at 560 mg/m2 to treat three more patients. I don't know about the three or six patients cohort right away because the diagram in the Credit Suisse presentation is unclear about that. At 420 mg/m2 they show a cohort of one with a grade 2 toxicity + three, then at 560 mg/m2 it is three (one DLT) + six. Then at a possible 740 mg/m2, it is a cohort of six right away. So it is very confusing.
That being said, look back at this message of mine.
https://stockhouse.com/companies/bullboard?symbol=t.th&postid=34267553
Around december 10, I tought the 420 mg/m2 was cleared. So to me this is the baseline for a possible MTD, almost twice the MTD of docetaxel alone.
Then, during the last month, they were supposed to test the 560 mg/m2 dose, which is 2.43 times the MTD of docetaxel alone. Now the question is to know if they did this dose on a cohort of three or six patients. If they had two patients with DLT events, it is over, 420 mg/m2 will be the MTD and they should announce it in the coming days. If they did only three patients, it is complicated, will they do three more patients or six more as they show on the diagram in the Credit Suisse presentation. If so, it adds one more month and they would be doing it right now until the end of January. If they went right away with six patient a month ago, and there is no more than one DLT in these six patients, then they would be about to start the 740 mg/m2 dose and 560 mg/m2 would be the new baseline for MTD.
So, all that to say that I am quite sure that 420 mg/m2 is the lowest possible MTD they would come up with, but there is a good possibility that it could be 560 mg/m2, and a smaller possibility that it could be 740 mg/m2. At this point I would bet on 560 mg/m2 if they took patients with cancer types likely to overexpress sortilin and with more than minimal tumor burden, so not only a small tumor. But remember that every patients is tested at different times after injection to follow the level of free docetaxel in the bloodstream. They are not flying totally blind and maybe they were allowed by the FDA to adjust some parameters for the higher doses.
SPCEO1 wrote: All credit goes to Christian, who has impressed me in many ways over the years but most especially with his willingness to help people like you and your wife. Hopefully, some worthwhile treatment option will open up soon for your wife, assuming the Lord does not pull something off to heal her before that. We continue to pray daily for her!
Yours is the second report I have heard about the "enrolling one patient at a time" approach TH is apparently using. I am not sure that tells us much though. This trial was never going to have a lot of patients anyway and they could have added one patient a week since the company last shared they had only 5 patients through mid-October and that would only add up to an additional 12 patients or so. So, there just are not a lot of spots open in the first place. Also, it is entirely possible the trial has been altered in some way based on the early data, although that would likely mean something really noteworthy had been seen early on. Bottom line - we have no clue about where the trial is right now other than it must be somewhere near the end. The last we knew, theyhad stepped up to the 420 mg level and had a soewhat bad response, but not enough to stop the trial or even stop dosing people at the 420 mg level. But that was a long time ago. As we have speculated previously, TH could now be testing at a higher level or at a lower level in their search for the MTD. I suppose the upside scenario is they are now the roughly 3x level of normal docetaxel and the downside scenario is they encountered more problems at the 2x dosage level, hen moved down to the 1.5x dosage level and encountered more problems than they did with the one patient when the dosage level was still ascending.
The company remaining silent for so long does not seem to be an optimal capital markets strategy. I expect to see a new corporate presentation by at least Monday morning as they most likely will use one in their meetings with large shareholders early next week. If there is not much new info in this version, that will be pretty disappointing.
juniper88 wrote: As most on this board probably know my wife is battling Ovarian cancer. Through the help of Rusty who connected me to Christian Marsolais my wife was referred to 2 different clinical sites. Unfortunately, my will not be able to get onto the trial at this time because there is a waiting list to get on, so I was told. I was also told that they are still enrolling 1 patient at a time. It seems to me, and I'm just speculating, that patients are on a waiting list because doctors have seen some efficacy.
Wino115 wrote: Yes, I borrowed this from the science guys here -- Recommended Phase 2 Dose (RP2D), although I think this is a term they use in trials. In our case, it will also be for Phase 1b, although they may play around with some other dosage schedules around size and timing if they learned something over 1a that's intriguing.
juniper88 wrote: The dose to be used in the Phase II trial.
SPCEO1 wrote: I am likely going to say "Oh, of course!" but what is RP2D?
Wino115 wrote: Somewhat implied in your Best Case, but I would add a few signals around that final group of 6 patients that took the MTD to make it the RP2D:
--- All six are still on the drug and longest on the trial is at 4 months of progression free survival and ongoing.
--- Of those 6, at least 2 of 6 have had an objective response of some kind (recall, ORRs of 30% are considered huge in this class of patient. ORRs would be partial most likely, which is at least a 30% reduction in tumor).
SPCEO1 wrote: Here is how I would define it:
1.) Meaningful tumor regression in all sortilin overexpressing patients who survived long enough to get meaningful measurements in the phase 1a trial.
2.) MTD established at roughly three times the normal docetaxel dosage
3.) Minimal safety issues in the phase 1a. No worrying issues in the trial at all.
4.) FDA grants TH-1902 Breakthrough Therapy status
5.) US cancer analysts rush to pick up coverage of TH
6.) TH holds another cancer KOL presentation to update the market on the latest findings with Dr Rothenberg as one of the main speakers. The presentation includes not only more detail on the phase 1a but also addresses a now expanded phase 1b trial that will look at as many as 8 dfferent sortilin overexpressing tumor types and will also delve into where the Sort1+ platform goes from this initial start.
7.) These developments are all completed by the end of March
What am I missing?
Obviously, the reality of the situation is likely to be much more complicated. But sketching out a Best Case Scenario can help us judge how good the reality is when it finally becomes reality, which hopefully will be quite soon. Since I am an optimist, I will leave the Worst Case Scenario to anyone else who might want to out it together.