Replies to post #552530 on NorthWest Biotherapeutics Inc (NWBO)

[flipper44]

Dr. Van Der Bent was an author on the original 2005 Stupp protocol trial and the follow up data in 2009.

As some of us discussed on the board back in the day, Dr. V’s trial was never blinded. They knew how to test for Methylation status and idh-1 status back then, but a huge chunk of the patients in the trial were undetermined or not tested in the status log. In other words, by todays standards, many did not have GBM (and had a much more favorable prognosis) and a huge proportion may have been methylated mgmt (a more favorable prognosis)

It was the equivalent of a phase ii trial because it had so many flaws. Phase two unblinded trials often have great results. After 20 years of the Stupp protocol, we know from many trials and real world data that long term survival is nearly nonexistent. We know Temodar interferes with tumor cell repair in methylated patients but that this is not durable. We also know Temodar in standard doses unfortunately exhaust T-cells and these are two of many reasons why its usage does not stop the nearly universal fatal prognosis for GBM.

I recently glanced at Dr. V’s critique of the Phase iii DCVax-l results. My first impression is that his apparent demand for a second phase iii trial is irresponsible and illogical. This is an orphan designated indication where the FDA required a crossover because his Stupp protocol trial therapy as now implemented is an eventual death sentence by itself. The phase iii trial for DCVax-l, unlike his old trial, was blinded during randomization and thereafter. When it became obvious PFS could not be used as an accurate endpoint due to pseudo progression, the trial remained blinded but was converted to utilize a concurrent ECA. The blinded trial tested for idh1 and methylation status. Unlike his unblinded trial, the DCVax-l trial was not padded. The trial resulted in unprecedented actual long term survival — not extrapolated.

Anyway, I’ll look at his paper further to address his other thoughts, but right now it’s Christmas.

[meirluc]

Poorly selected external controls? The 131 unmethylated GBM treatment patients in the DCVax-L trial that encompassed 59% of that group's 221 treatment patients whose methylation status was known, had an mOS of 16.9 months which was very similar to the 16.6 months mOS of the unmethylated GBM patients in the external controls (ECAs). This strongly suggests that in the DCVax-L trial, the orthodox exclusion from the trial of the rapid progressors with the poor prognosis was matched by the exclusion of pseudo progressors whose prognosis was better than the average GBM patient. Bottom line, the difference between the exclusion criteria of the DCVax-L trial and the exclusion criteria of the ECAs was a wash because it still resulted in similar mOS results and the DCVax-L trial can therefore be legitimately compared to the mOS of the ECAs.

Please also note that 8 of the 131 unmethylated GBM patients (6.1%) in the DCVax-L trial survived more than 5 years and this strongly suggests that DCVax-L was most likely beneficial for many more unmethylated GBM patients It is quite possible that unmethylated GBM patients who succumbed at an earlier stage of the disease also received some benefits from DCVax-L and in the absence of DCVax-L treatment, the mOS of those unmethylated GBM patients could have been even lower than the 16.6 months mOS of the ECAs.

All of this points to the absence of cherry picking in the DCVax-L trial and that the results of that trial can therefore be legitimately compared to those of the ECAs.