NorthWest Biotherapeutics Inc (NWBO)

[Rkmatters]

Just catching up to speed here from an activity packed weekend and RK, you’re right in that what I stated had its origins in earlier discussions on this board as Flipper indicated and maybe the log kill discussion was someplace in my mind but what made me think of less tumor burden being beneficial to the P3 trial was actually one of the short arguments being used on DCVax-Direct i.e. there is too much tumor burden for Direct to be successful. So “the other side of the coin” that wasn’t being discussed in the current discussion was that, well, if there is less tumor burden there’s more DCVax-L to go around and should be beneficial to the P3 trial. I don’t partake in the great discussions on this board that help us all make learned decisions regarding all things NWBO but sometimes from the resultant discussions the black and white of it all becomes clearer to me and I thank everybody on this board for contributing to that. -- antihama

The problem with the "other side of the coin" theory, is that in the second Phase I/II DCVax-L study UCLA already was using the latest state of the arm equipment in both diagnostics and surgery, which they were privy to in 2005. Therefore, DCVax-L has already been introduced to patients who were benefactors of less tumor burden, and those results are within the current Ph I/II.

From UCLA's website on the InterOperative MRI:

MRI Suite (Intraoperative) MRI Scanner


Ronald Reagan UCLA Medical Center was one of the first hospitals in the world to install a dedicated operating room housing a powerful, 1.5 Tesla magnetic resonance imaging (MRI) scanner.

MRI Scanner - The MRI scanner allows UCLA neurosurgeons to obtain MRI images during surgery.

Detailed Imagery - Because the scanner is the same type used for advanced diagnostic tests, the images obtained during surgery can pinpoint small areas of residual tumor cells not visible using less powerful intraoperative MRI systems.

Technology Research - UCLA research confirms that the technology allows more complete removal of brain tumors and helps avoid complications.

Over 500 Surgeries (since 2005) - Neurosurgeons have performed more than 500 surgeries in the intraoperative MRI suite as of 2005.

The rest of the world however was not using the latest technologies. No clinical site was using it in 2000-2003 recruitment during the time of Stupp trial enrolled patients. So the Stupp landmark 2005 statistical findings that you often hear for GBM is based on sub par surgical resections. That study did not recruit patients based on extent of resection (EoR). This study recruits patients who qualify for a gross total resection (GTR). Of course not all will get it, but you can certainly bet the Placebo group results will beat out Stupp's 6.7 months of PFS and 14.7 months of OS. Why? Stupp Protocol patients were a mixed bunch of tumor burden patients (17% biopsy, 44% partial resection, 39% GTR (+95% qualifies for this definition)).

So where are we in terms of tumor load burden? The results seen in DCVax-L treated patients in Phase I/II are about as good as it can get on the GTR front. There is no way to improve an overall surgical resection that removed >98% of tumor burden. However, the same can not be said for the Placebo group. There was no true control comparison in that Ph I/II study, as no other site had the iMRI suite at the time, UCLA was among the first in the nation. No GBM study Placebo patient group has ever been in that kind of GTR "precision" surgical environment of a > 98% tumor burden removal. And for all intense purposes, for this Phase III the Placebo control group is the STUPP landmark study, but it is the STUPP on surgical steroids. And no one knows how good that will do but you can certainly bet it will not mimic Stupp clinical recruitment of high tumor burden load (61% of patients).

Even UCLA recognized GTR as a confounding factor when they wrote the following in their research on that Ph I/II trial.

"Therefore, it is possible that the extent of surgical resection may have been greater in our DC vaccinated patients compared to concurrent/historical controls, which could have influenced our survival results.” — DCVax-L Phase I/II

And they even covered the departure from STUPP protocol when they wrote this:

It is unclear whether the extended survival of our patients with mesenchymal gene expression signatures is a direct result of the vaccine effects, or good responses to follow-up therapies after failing the vaccine. Since mesenchymal signatures represent glioblastoma subgroups that are more resistant to conventional therapy, it can be speculated that DC vaccination somehow makes these tumors more susceptible to subsequent treatments (39) -- DCVax-L Phase I/II.

Now if AVII is correct, and late-blooming psPD who are enrolled into the main trial are classified as PFS, then it may mean an earlier recording of PFS for this trial verses the Ph I/II. But it also means that the Brad Silver's of the study get to depart the Stupp protocol treatment plan (same as he did), and get other drugs if necessary. The DCVax-L OS shouldn't change to the negative side. But, the psPD condition in the main arm could mean greater potential for failure on the PFS front, depending on how this trial marks progression.

While there is a risk that DCVax-L cohort PFS will worse for this trial than prior Ph I/II PFS, there is also potential that the crossover to open label can help the DCVax-L overall survival. The wild card that I see is that there is a restart of injection schedule for all vaccine patients. No one has ever seen what happens if a change is made in patients treatment plan of a DCVax-L patient. If the injection schedule reboot results in renewed vaccine's effect within the tumor suppression environment, then the DCVax-L treatment arm can potentially see better survival than the last Ph I/II study. I would hope that is the case. No one knows if the vaccine failure was due to the injections being spaced too far apart. And in the event that it was, then yes, this trial OS can be stronger for the vaccine group than any other study.

In my view, it is impossible to have a Placebo group that mimic's Stupp landmark study PFS results - given EoR criteria selection. And, so I'm actually anticipating that as a group, the Placebo cohort PFS will event later than most predict. My view I imagine is not surprising given my many post on the residual cell load/tumor burden subject. And, if I'm correct this tumor burden GTR factor can be the difference on the Overall Survival front as well, more than folks realize. Why? Well it may mean that the Placebo long-tail survivors will not be eligible to receive all their vaccine at the crossover to open label, given it's a 3 year study with a 3 year product shelf life (Evaluate found shelf-life within the German Label). If more DCVax-L product injections is better, which I believe is the case, then as a study, the DCVax-L cohort will get more of their personalized product than the placebo cohort. Tumor burden will have an effect on PFS events in both cohorts, and that same factor may result in one arm getting more of their vaccine treatment than the other at the crossover to open label (assuming the product works in the first place) due to the treatment length of the study (36 months); and that can make all the difference on the Overall Survival coming in significant.