Replies to post #62951 on NorthWest Biotherapeutics Inc (NWBO)

[CaptainObvious]

Excellent post, RK

[Reefrad]

Your post is illogical:

1) iRANO is used to account for pseudoprogression vs. true progression.

2) iRANO cannot help if placebo patients are living longer.

3) Most of the trial sites do not have access to the newer surgical techniques you mention. They use Stupp and that's it.

[Doktornolittle]

Thanks RK. Lots of good stuff. I read it all but will have to read it all a couple more times to get the most out of it.

I posted too much yesterday and too long of posts, so trying to not do that today. But as I re-read your post here, one thing I will be trying to understand is why you worry that improved SOC may have benefited the control group more than the experimental group. Perhaps it is your explanation for a less than expected gap in SOC that LL references. I actually forgot she had said that.

Other questions before I re-read your post: You said...

"They may have not told us outright in 2014, but I believe they changed the lymphocyte count “inclusion” criteria after six weeks of chemoradition. Those blood cell counts can make a difference of 6 months in OS even before immunotherapy is introduced. And that kind of "inclusion" change will affect both arms before and after crossover. After crossover is where it will be seen most in immunotherapy. The less comprised and immunotherapy patient is going into an immunotherapy treatment, the better off they will do."

I thought they changed that WBC criterion also, but I can't remember why I thought that. Why do you think they changed it? I worry too that it might not benefit the experimental group more than the control group, even if they did not have crossover. An intact immune system is always a good thing, just a question of how much of a good thing. But I was very much in favor of having such a criterion because it seems unfair to test an immunotherapy on patients that no longer have a healthy immune system...

But again, I share your concern that it could help the controls also. Your point about crossover is based on the late point in SOC that the WBC criterion gets considered? Another angle of concern might be that since macrophages apparently provide early warning to raise PD-1 or L1(?) flags, introducing DC's into a stunned (but not dead) immune system might comprise a surprise attack that is more effective than if the immune system was healthy, at least in regards to macrophage activity. That is... if the stun state still allows DC migration and T-Cell activation and migration... while the macrophages remain dormant. Timing may be everything as the Italians stated, but the optimum timing may be even more complicated than their study indicated.

All could be tweeked down the road if DCVax-L passes, however, and hopefully reimbursement re-negotiated if efficacy increases in response to any such tweeks. But I don't know if it works that way. But even if not in the past, maybe this environment of tech moving so much faster than trials will allow such policies in the future.

[DoGood_DoWell]

RK,

I have known about 10 people with GBM over the past 10 years. Some of whom had the kind of resources that could buy the best care available. None lived beyond the established SOC range. Some were in the prime of their lives - so also had the advantage of age.

We also all know of several high profile cases, Kennedy, Biden, who also fit within the standard SOC survival times.

How many studies have achieved these longer survivals on SOC and have they been replicated? Many studies can't be replicated which is why I ask.

[Doktornolittle]

RK: One other point. If they did change the WBC criterion in 2014, then I would think that the addition of WBC as a covariate might allow them to massage the data to model the results that would be expected if the criterion had been implemented from the beginning. That's not much help if the new screening does not favor the experimental group, but it might, particularly in terms of PFS, if the pseudo's are properly identified.

I'm not talking from experience here. I am just going from what I read about covariates in a post that Senti's wrote yesterday.

I think it was Exwannabe that argued that covariates do not get used very much because the FDA recognizes that they can easily be abused. But that doc that Senti posted stated clear constraints that force covariates to be only of transparent utility and for the intent of their use to be stated up front. The utility of Methylation as a covariate would be straightforward, so I don't see how the FDA could have a problem with it. On the other hand, WBC would seem less clear. But I would hope that the WBC screening for an immunotherapy would at least be recognized as a very important factor and worthy of discussion in post analysis, even if the effect of that screening parameter is not 100% predictable. It would not be in the category of just adding a bunch of variables so you can pick out some random peak in the post analysis. The FDA would have to watch out for such, but it is a totally logical consideration and I believe the FDA would recognize that. In fact, the apparently did because if it was added to the trial then it was approved by the FDA... right?