RE:RE:RE:RE:Corporate Presentation AWOL Thank you for digging out all those details, that's very helpful.
So it appears we are in the right ballpark.. also, I just heard in the presentation that the dose doubling phase is indeed for the first 2 doses after the first (so: 30, 60, 120). That is just great!
Also, reading your linked article about Taxotere Ph1, I noticed the following in the dicussion section: "As a matter of fact patients could tolerate 115 mg/m2 (a dose which induces >80%grade IV neutropenia). "
My goodness! 80%+ Grade 4! That's hardly tolerable at all. Judging from that, the reference docetaxel MTD for our trial should definitely be lower than the 125 mg/m2 that I proposed. I'd say 100mg/m2 is already very tough, especially in our "end-of-the-rope" population.
To support that assumption, here is a paper that also states that 100 mg is "effective but not feasible" in a heavily pre-treated population:
https://ascopubs.org/doi/abs/10.1200/jco.1999.17.4.1127?journalCode=jco
So it definitely looks like the trial will go deep into therapeutic zone, and far past any equivalent docetaxel concentration.
Things are increasingly looking ideal, from my standpoint.
BTW, I'm really excited to know that the trial will be in the hands of an ADC specialist as per your other post. This can mean a lot in terms of motivation/dedication.
qwerty22 wrote:
FWIW I went chasing this issue.
I found an abstract that helps with the mol weight issue.
https://cancerres.aacrjournals.org/content/80/16_Supplement/2910.short
It says "TH1902 at 8.75 mg/kg/week (equivalent to docetaxel dose of 3.75 mg/kg/week)"
So my calculation starting dose at 30mg= docetaxel 12.9mg dose. You were pretty close.
I also found the Simon 1997 ref, what it says about starting dose is "In phase I trials of new drugs, the starting dose is usually one tenth of the LD10 (i.e., the dose that is lethal to 10% of animals) in the most sensitive animal species in which toxicology studies have been performed. "
https://linus.nci.nih.gov/techreport/accel_titr_des.pdf
So if you think it's low then it's because the LD10 was low in an animal toxicology test. Having said that I found this early docetaxel paper which shows Ph1 started dose escalation at 5mg/mm2 so TH-1902 is starting at 2.5x the docetaxel dose in Ph1 which roughly fits with what Paul said (did he say the drug was 3x less toxic than docetaxel in animal toxicology???). What I'm reading is dogs are particularly sensitive to docetaxel.
https://cancerres.aacrjournals.org/content/canres/53/5/1037.full.pdf
Going back to the Simon reference it also looks like there is only one doubling dose so your first set of numbers are maybe the correct ones. If that's true then the whole sequence of doses does look low. It essentially finishes just above the MTD for docetaxel (in terms of docetaxel equivalent doses). Potentially that means if the drug is less toxic then they don't reach the MTD. Maybe the intention is essentially to be using the drug at the MTD for docetaxel (equivalent dose) and checking for efficacy there in Ph2. You are right though one more doubling dose (your second set of numbers) does take the final TH-1902 dose to ~2.5x the equivalent dose of docetaxel which seems like the right place to stop. So maybe your 2nd set of numbers are the correct one. Either way they are in the therapeutic window based on what we've heard so far from the pre-clinical studies (that is, roughly speaking and not yet in humans, the drug is ~3x less toxic and maybe 4x-7x more efficacious)
Anyway I'm happy to leave it to them to get it right, I'm sure they know what they are doing, lol.
Spartrap wrote:
Yes, quite happy! It looks very straightforward, very well though out to me.
If I had any reservations, that would be about the grouping of Gynecological cancers in a single basket.. Ovarian, endothelial and endometrial.. do they share enough similarities? That looks a bit odd to me intuitively, but maybe it's the case.
Also, something I struggle to perfectly understand is the starting dose of 30 mg/m2 (then doubling to 60, then 100, 150, 210 and 280 according to fibonacci progression) . That seems a bit lowish, intuitively speaking again.
The reported MTD of docetaxel is not easy to find, but I gathered for heavily pretreated pts it's around 125 mg/m2. TH1902 is made of a peptide and of 2 molecules of docetaxel, so without knowing exactly the molecular weight of the peptide, I'd guess it represents more or less 50% of the weight of th1902.
So the starting dose would be equivalent to ~15 mg/m2 of Docetaxel, and subsequent doses be like 30, 50, 75 [the recommended Docetaxel dose], 105 and then 140 of equivalent docetaxel.
With pre-clinicals hinting at TH-1902's MTD being 3 times the Docetaxel MTD (IIRC), it seems to me we are on the lowish/safeish side and may probably not reach a DLT.
I'm not sure if this is a problem at this stage. Maybe also when they say "dose-doubling will be done for the first 2 dose levels", they mean the first two dose levels not including the starting dose. That would therefore imply a much wider span (30, 60, 120 for doubling, 200, 300, 420, 540 for Fibonacci) and would be perfect...
qwerty22 wrote:
You happy with the cancer protocol?
Spartrap wrote:
OK, it's rant time for me finally.. I guess I'm always a bit out of schedule:
What kind of company removes its Corporate Presentation, the essential tool for gathering first insights, right before and during a financing?! It's been AWOL and replaced by a placeholder since January 8 according to a Scarlet post.
Seriously, 8 days!
Where exactly, may I ask, are new investors supposed to gather informations about their new investment? That is completely unacceptable and amateurish!
And by the way, this resonates with the out-of-fashion, unattractive website, and e-mail alerts that only arrive one timeout of 3 (!!!). I agree with many here, to say that lots of changes are urgently needed in the communication department.