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Thursday, June 24, 2021 1:06:13 PM

Re: Think1st post# 386184

Post# of 477832
Northwest has a product called DCVax that, when approved, offers a platform treatment for all solid tumors.

DCVax is a dendritic cell vaccine (hence the name DCVax) made up using a patient's own tumor (and no one else's) thus capturing all or most of the antigens that the vaccine will eventually target. The tumor is then mixed into a lysate using the patient's own white blood cells (obtained in a leukapheresis) from which the dendritic cells are grown and subsequently matured to a certain level (depending on which version of DCVax to be used - L or Direct).

The function of dendritic cells, often called the masters of the immune system, are to present antigens to the t-cells, which then know what to attack in the body and proceed to do so.

To produce this vaccine requires a certified GMP (Good Manufacturing Practice) manufacturing facility capable of producing these highly personalized autologous (made from one individual) vaccines, and the process takes about 8 days. In the end, the patient has hopefully enough vaccines to treat the tumor(s), and for now, the phase 3 trial is targeting glioblastoma (GBM), the worst of the worst brain cancer.

The trial began back in 2007 as a phase 2 trial, and evolved into a phase 3 trial. The primary end point was intended to be PFS (progression free survival) with the intention of using that endpoint to request accelerated approval (thus getting the treatment to patients more quickly), and the secondary endpoint of OS (overall survival) would serve as the confirmatory for AA. That is why the company thought the trial would have ended so much sooner.

Instead, they have discovered that DCVax-L causes pseudo-progression (psPD) whereby it appears that the tumor has returned, when instead, there is really just inflammation to indicate that a therapeutic reaction is taking place. Unfortunately, an MRI scan cannot differentiate psPD from tumor recurrence, and doubly unfortunate, the criteria for progression used in this particular trial (and for all diagnoses dating back to 2007 through 2014/15) meant that the patient had progressed (when they hadn't).

To add further, if you will, complications to the trial, upon progression (or false progression), all patients (fortunately for them, not so much for the trial), crossed over to known treatment with DCVax- L. This personalized vaccine is quite costly, and represents to the patient a chance to either live longer, or save their life, so naturally, it would be better to make it available to the patient upon progression (if they began as a control patient).

So if that wasn't enough to complicate this trial, around 2015, a screening halt was put on the trial by the FDA, that stopped enrollment into the trial. But it was called a screening halt as there were still patients for which the vaccine had been made, but had not entered the trial yet. These patients were allowed to continue through to randomization. By the way, any patients for whom the vaccine was made but were not able to ultimately enter the trial, they were given the opportunity to receive their vaccines.

Moving on... around 2016, they were able to determine that psPD was the culprit they were fighting. Now even though psPD was the primary endpoint, they had not made the mistake of allocating all the alpha to this endpoint as Dendreon had, in their earlier trial. So that meant that OS could still be used, but it also meant that OS would not have the full alpha either (if PFS were to fail). But this did mean that achieving statistical significance was going to be a higher hurtle for the trial.

Rather than leave that to chance (the trial is quadruple blinded), on the advice of their Scientific Advisory Board (SAB) and their Steering Committee, and various others (perhaps the regulatory agencies anxious for something that will actually help treat GBM), they have changed their endpoints, almost ensuring a stat sig reading in the end. I state "ensuring" because even the blended, blinded data beats the data they will be comparing this trial's data to. They have chosen to make their primary endpoint OS (instead of PFS), and they will use the CONTROL data from other recent historical GBM trials to compare the treatment arm of DCVax-L to. They will then use the patients in the control arm in the DCVax-L trial that have received DCVax-L (about 90%) and they will compare the OS data of those patients to the control arms of other recent historical RECURRENT GBM trials. And that will comprise the second endpoint for this trial.

There are other endpoints for this trial that have now been established, two of which will also compare the PFS for the randomized treatment and control arms of the actual trial, and the OS for the same.

Hopefully that better describes for you what the treatment is, what the trial is measuring, and why it's taken so damn long. No one is happy about how long the trial has taken to get to this point, nor is anyone pleased with how long it's taking to get the data read out. The company has indicated their intention is to release the data in a journal, and apparently releasing top line data (the brief synopsis of the data) is tied to the embargo conditions the publishing journal requires. The company believes that due to the change in endpoints, and the controversy of using those endpoints (using external control data in a randomized phase 3 trial is unusual), along with the problems with pseudo-progression and the confoundment of overall survival, publishing the results in a high-tier, well-respected journal is the best way to present the data. Most people with a brain should understand that.

That's not a bad synopsis as to the state of things.

Below is an extensive journal article where they presented their still blinded data (March 2017) from the trial while it was still on-going, that you can look over to learn more about how the entire data set (treatment and control) compared to standard of care (SOC) GBM data.
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