I did all the calculations one more time for confirmation.
First thing first though where is this number 100mg/kg in mice before p21 expression noted because I can not find it. I do see studies where they did 200/mg/kg mice and measuring the amount of P21 expression @ 6hr and 16hr. At 6hr the expression was 3x that of controls and at 16hr it was 5x that of controls. Likely because of some form of cascading pathway so what affect this may have at 24hr, etc.. is not yet known to us and we would need to consider clearance and half-life of the drug.
If we do use the 100mg/kg in mice as the first expression of p21 in the studies then I can agree with an equivalent in human. My calculation is 308 mg/m/m so thats spot on. I think I would like to see where that 100 number came from because p21 expression may actually be at a much lower dose.
For DLT comparisons:
NOAEL in mice was 90mg/kg or 277.5mg/m/m in human
NOAEL in dog was 5mg/kg (although symptoms were mild) which is 26.43mg/m/m in humans
With a caveat on these because the doses were given 5x weekly (clearance and half-life issues here!!) and the goal for this kind of study is just to find out the toxicity thats it. So they pumped um full of drugs to find that out.
Also and what everyone seems to be missing is p21 is not the only indicator of efficacy. They say it a PROBABLE that p21 expression means p53 activation.
They could also be seeing tumor reduction which is tested verses baseline at 2mo,4mo,6mo.
They are also testing at least 5 tumor markers for reduction in serum markers verses baseline at 1mo,2mo,3mo,4mo,5mo,6mo.
What I never understood was this idea that they just happened to do p21 biomarkers early when it specifically states in the protocol that the patients would be tested verses baseline at 7hr and 24 hr after EACH dose. A facility such as this has immediate access to qpcr equipment and the department costs are likely around $200 per test with a couple hour turn around if it is sent to another part of the facility but I would bet a couple pennies that there is a machine within five minute walk of their unit. There is not a cancer research facility in this country without one.
