Wino115 wrote: On that staining sample poster they presented, Prostate was one where there was a positive correlation with stage, however the overall average expression was lower than all the other cancers.
The H-Score Expression was:
Stage 1 - 4
Stage 2 -25
Stage 3 -80
Stage 4 -60
The ones considered "high" had scores in the 150+ level.
Given THTX has the same lead investigator as the Cybrexa CBX-12 program (their PDC uses the Enhertu and Trodelvy Warhead, Exatecan, and targets tumors via Ph levels, not a genetic expression), it's a useful one to look at. There's clearly a lot of differences so I'm not discounting the steep issues they need to figure out with the data.
The Cybrexa pre-clinical work looks very similar to what THTX was doing -- is it getting in to tumors, is it safe, etc... In fact, their website has the same language around showing that if it's more safe and tolerable, it opens up a huge therapeutic window. The preclinical used doses of 10mg and 5mg, and then they used 2.5mg and 5mg in their various "spider-charts" for colorectal and gastric cancers in mice. But they immediately went to the lower dosage taken 4 straight days, then off 3 days and then a second dose of 4 straight days. I'm just purely guessing but probably when they saw various safety signals were ok, they determined lower doses over consecutive multiple days was the way to proceed. It looks like they've just carried over the dosage they used in xenograph animal tests to the first in-human tests.
Here's the paper they published on it and you can see the dosing schdule on page 5, table 1. It's listed as daily for 4 days in a week and repeated for 3 weeks.
CBX-12 Peer Rev Paper Here's their poster presenting the data at a conference. You'll see the little blue arrows indicate when they dosed in the graphs.
Poster CBX-12 When it came to human trials they tried both a once a week over four weeks and the 3 days straight over 3 weeks. I guess they had better results with the 3 days straight. I suppose in hindsight instead of THTX just assuming all the safety signals and just trying to max one dose every 3 weeks they should have done something like that where there's a smaller dose but given in succession over multiple days, and then doing it the next week for 3-4 weeks and compare which is better for that therapeutic window of both safety and efficacy. They did not do that. Too bad MD Anderson didn't convince them of that CDX-12 regimin before they started. Clearly blasting in a huge dose every so often has had mixed results to say the least. They overly relied on the pre-clinical theory of MOA and safety, which was just as strong and very similar kinds of tests as the Cybrexa guys did. In fact, you'll see a lot of the same xenograph tests, plasma tests, uptake tests, etc.. where they compare plain old exatecan versus the PDC delivered exatecan. Just like what THTX was doing.
Anyway, that's probably the only thing we'll find supporting different type of PDC administrations but the caveat is exatecan is more powerful (THTX should have used that first!) and CBX-12 is not sort1 or any genetic overexpression dependant. It just uses the overall tumor environment as it's "target" via Ph levels. So there's plenty of differences. But hopefully their data tells them something useful around the issue. I think at worse, they could go back and do some fairly inexpensive testing in the labs first around lower doses over consecutive days to add to the data before resuming it. If that shows something, they could probably do what Cybrexa did which was to just pick out 2-3 specific cancer types and do that dosing regimin with a 3-4 patients in each. Then get your RECIST data and biopsy data and go from there. You could probably do that for $200k a patient or around $1.2-$2.5mil total. That would be it --either that data is telling you it's a viable path for a larger 1b or it's showing there's not much of a difference happening. You'd save yourself a lot of time and money and, if their data supports it, that's probably about what they'll recommend for a new protocol if I were to make a wild, uneducated guess. But that seems to be what the CBX-12 stuff would point to.
Joemare wrote: Pathology
2023 Feb;55(1):40-51. doi: 10.1016/j.pathol.2022.08.001. Epub 2022 Aug 20.
Aberrant protein expression of Appl1, Sortilin and Syndecan-1 during the biological progression of prostate cancer
https://pubmed.ncbi.nlm.nih.gov/36089417/ At least, you can have access to the sortilin antibodies............