Replies to post #106053 on NorthWest Biotherapeutics Inc (NWBO)

[AVII77]

Your explanation of the placement of that first red dot is what I understood you to mean except that I was also trying to get clarification about why you believe PFS would be low to begin with.

The location of that "red dot" doesn't mean PFS is low per se. If it is above Z=0 it means DCVax is trending better then Placebo on PFS. If it is below Z=0 it means Placebo is trending better than DCvax on PFS.

This is why I interjected what I believed to be your past point about early apparent eventing being called progression due to potential faulty adjudication of pseudo progression.

OK, I think we're on the same page, but just to be clear we are talking about two different types of psPD.

The first "type" of psPD is due to chemorad treatment. Most of these patients will be removed at baseline. Any few who make it to be randomized should be balanced. They will not have any effect (perhaps a slight dilution, but negligible).

The second "type" of psPD may be due to inflammation from an immune response to DCVax. We know some patients in the P2 had exhibited signs of this but we don't know if it was the "first type" above (due to chemorad) or due to DCVax. It is this second type that, if it occurred, would only occur in the DCVax arm. And this is what RKMatters and I were arguing about.

I would like your explanation of why you think the red dot might be where you placed it if not because of pseudoprogression events being called progression especially in light of potential OS benefit from DCVax.

Remember, that plot is about PFS. The "red dot" is a hypothetical result at the interim for PFS (if the interim occurred in the summer of 2015 as planned).

I placed that "red dot" above the Z=0 line indicating results were trending positive for PFS, but below the futility line (indicating the trial is futile if continued. I wanted you and others to be able to easily see a situation where treatment could ethically be continued to be given (the results are trending positive) but at the same time where it is unethical to enroll additional patients (the trial is futile).

But, I also asked you to consider the situation of what would happen if that red dot was BELOW the Z=0 line. That suggests that placebo is trending better. However, given our knowledge about immunotherapies causing false progressions, such a finding might actually be expected for an effective immunotherapy. So, if the DSMB looked also at OS, and saw an OS trend in favor of DCVax (along with a negative trend for PFS), I think that would also be a situation where it is ethical to allow patients to continue to be treated (but still, no longer enroll new patients).

But the argument put forth by some that we know the trial isn't futile because they are allowing patients to remain on treatment is false. That argument doesn't dismiss the futility theory. Not at all.

However, for myself, if I knew the "red dot" was below that Z=0 line I would take that as a positive signal that DCVax "works". I say that because I don't think DCVax is harmful. It either has no effect or it is beneficial. So results below that Z=0 line would suggest to me biologic activity; the same biologic activity seen in the P2 (where we don't know if it was chemorad psPD or an immune response psPD.). And I would view that as a positive for DCVax's efficacy (not for the PFS endpoint, LOL, but for the treatment itself).

So yeah, I think it very likely the DSMB saw futility. Maybe they didn't communicate that to the sponsor and just said "stop enrolling, we can't tell you more", I dunno. Maybe they just reported to a steering committee who are keeping details from NWBO to protect trial integrity. Maybe NWBO knows and are keeping it quiet because they don't want to bias the OS data.

Just trying to connect the "dots" here.