NorthWest Biotherapeutics Inc (NWBO)

[sentiment_stocks]

Rapid Progressors show Double the progression from their Baseline MRI on the new Info Arm Poster


I posted the same heading on YMB last week sometime, and Diamond Jim recently pointed out to me that he didn't see that I’d posted the same point over here. I had, but it was buried in a previous post of mine when responding to Pyrr. And then when responding to Rational Thought (;) on YMB, I thought I’d go with Jim’s suggestion that I post it here on i-hub too.

The poster Dr. Bosch presented in Munich on the Info Arm patients had been updated on the poster presented at AACR. It was updated to show the criteria used to sort the info arm patients into their respective categories. Some might have missed this, assuming it to be the same as the poster shown in Munich. I’m sure many did notice this, but for those who didn’t, I had posted what the poster showed on YMB, obviously to point it out.

So I’ll point it out here again… and address some of the arguments cropping up (still) from the usual naysayers.

To explain the process of sorting to those interested, the GBM patient first had their tumor resected or removed. Within a few days after, the patient then had an MRI to show how much, if any, was left of the tumor. This is called a Post-Surgery MRI.

For the following six weeks, the patient undergoes intensive radiation therapy and chemotherapy. At the end of these six weeks, one would hope the patient’s GBM is gone, right? A new MRI is performed and this is called a Baseline MRI. For these patients, at the time, between 2011 and 2012, the results of this MRI determined whether you entered the trial or not.

If you showed on this Baseline MRI a progression of 25% or more tumor growth, OR one new lesion 1cm. or more in size, you could not enter the trial. If your MRI indicated either one of these, you were excluded from the trial and entered into the Information Arm.

It’s important to note here… this is the criteria used for this trial. It is based on both MacDonald and RANO criteria - both accepted criteria for determining progression in GBM. RANO goes further to define the size of any new lesion to be 10mm, which equals 1 cm. That means they went further than MacDonald criteria, which doesn’t define the size of the new lesion, and used the RANO criteria as well. And as noted on the poster, they used an Independent Medical Imaging company to read and classify the patients. The company nor the investigators determined the state of progression. The independent medical imaging group did.

Had you entered into the trial, showing no progression, you would have immediately begun treatment with DCVax-L. And because the information arm was set up to mirror the treatment plan of those in the trial, so too did the patients in the information arm begin to receive their DCVax-L treatment. There are two patient consent forms available on the internet… AVII found one, and I found another... and both reflect this.

This is very important. Why?

Because after the patients had been in this information arm and receiving DCVax-L, they were imaged again (according to the new poster) two months later, and this MRI served to sort these patients into their actual groups. These patients had received 3 treatments of DCVax-L by the time the Month 2 MRI was performed. If... as an investor, you think DCVax-L has any effect on GBM, you might believe that these patients might be improving at this point. We all know that this type of therapy takes time, but might some of these patients have started to stabilize due to the 3 vaccines they'd received prior to this sorting MRI? Answer: most likely.

Rapid Progressors
Well… apparently 20 of these patients had not. Because at this Month 2 MRI, these patients actually had doubled the progression of what had been shown at their Baseline MRI.

Now this progression is truly doubling. Let’s look at how that criteria might be grouped:

1.
Baseline MRI - 25% or more tumor growth;
Month 2 MRI - ADDITIONAL 25% or more tumor growth

This is not 25% more growth of the original 25% - as YMB poster Rational Thought argues on (whoever that is ;; - wink, wink). Had it been this, the AACR poster would have stated it.

It would have read 25% or more growth of the original 25% or more growth to equal 32.5 or greater%..

Let’s continue… the progression to be classified as a Rapid Progressor in the Info Arm after the Month 2 MRI could have also been this…

2.
Baseline MRI - 25% or more tumor growth;
Month 2 MRI - 1 new lesion of 1 cm. or greater

or

3.
Baseline MRI - 1 new lesion of 1 cm. or greater
Month 2 MRI - 1 ADDITIONAL new lesion of 1 cm or greater

or

4.
Baseline MRI - 1 new lesion of 1 cm. or greater
Month 2 MRI - 25% or greater tumor growth

Now these patients had also received 3 doses (according to the patient consent form and as I've already stated) of DCVax-L by this time, and had still doubled in one of the four scenarios listed above their progression -- according to the criteria set up by the investigators.

I don’t see how there can be any doubt that these 20 patients were not rapid progressors. One more time… they had doubled their progression.

For Rational Thought on YMB: One + One new lesion = Two. Double. How can it be 25% = progression at Baseline, and then 25% = of the Baseline progression? That would equal only 32.5%. That's not 25% plus 25% to equal 50%.

And on that note... was the one new ADDITIONAL lesion found at Month 2 MRI, when compared to the one new lesion found at Baseline, only 25% of the first new lesion found? Answer... No. There was a new lesion found at Baseline, and an entirely new lesion found at Month 2. Double.


Indeterminate Progressors
Now, we all know that some patients will respond better to DCVax-L than others, for any number of reasons. And two months later, after having been sorted into this Info Arm, 25 patients had. According to the criteria… these 25 patients had stable disease. That means that either they had not progressed ADDITIONALLY by enough to categorize them into the Rapid Progressor group. Or, they had begun to regress or stabilize (they'd received three doses of L, remember).


Now, some of these more staunch naysayers out there, who want to re-sort all these patients themselves, culling those who don’t do so well and adding them to the rapid progressor group; and then taking away a few of the longer living patients and adding them instead into the pseduo progressor group... well, you know it doesn’t work that way. The sorting has already been done. And I doubt very much the qualifications of those suggesting alternate sorting (like Adam, for that matter).


Pseudo-Progressors
Let’s note that from 2011 to 2012, there was no pseudo cohort in the trial. And we know now that there IS a pseudo cohort in the trial. The new poster tells us this. It states there is a Pseudo-Progressor arm in the trial that has 32 patients in it.


When did this arm begin? The company announced it began May 17, 2012, when they announced the trial had received its designation as a Phase III trial.

• Designation as a Phase III trial
• Expanded and enhanced statistical endpoint analyses
• Addition of another cohort of patients which can potentially expand the application
• of DCVax®-L, and which increases the trial to up to 300 patients
• Addition of interim analyses for efficacy

http://www.nwbio.com/northwest-bio-provides-update-on-dcvax-l-brain-cancer-trial-2/

Prior to May 2012, there was no pseudo cohort in the trial. So where did all those pseudo patients go that the naysayers are looking for? Well, they went into the Info Arm.

Had there been more pseudo patients in the Info Arm than just the one, what would that have offered those investigators who had this open label look at these patients?

Answer? It would have given them more than just one pseudo patient to measure their performance on DCVax-L. Instead, they got just one. One that is still alive.


Perhaps this is one of the reasons why the investigators decided to add a pseudo cohort to the trial.


As noted already, the revised poster shows only one patient is a “confirmed Pseudo-Progressor”. And we know this, as did the independent medical imaging company, because by their Month 2 MRI, this “confirmed” pseudo progressor patient had “ALL original 25% increase gone.”


That means that by the Month 2 MRI, only ONE patient demonstrated all their progression had gone. And by the criteria established for this group, that meant there was only one pseudo progressor.


Now other i-hub, YMB, and i-village posters on message boards, and Adam, a blogger, can bloviate all they want to that this is not acceptable; or look at sample scans and say a tumor looks twice as big at their 3 month scan as it did at 1 month so the Month 2 MRI should have been at Month 5, or 6 or 7, etc. But we know if we waited until Month 6 or 7, some of these patients would have already passed. Why bother with an MRI then. You could just do an autopsy.

And by the way, to my untrained eye (like yours AVII), the enhancement shown on those MRIs for 1 month and 3 months does not look double to me AT ALL); but none of us get to change the criteria established for this info arm anyway. The criteria is in place and it is what it is.


http://www.investorvillage.com/smbd.asp?mb=6543&mn=2008&pt=msg&mid=14886199


Unclassified
And finally, there are 5 patients that can’t be classified because of lack of images. If anyone on any message board was going to do any resorting… it might be with the ones that weren’t sorted. How about that? The others already were sorted. So we could hypothesize... as message board posters -- and not as radiologists, mind you... where we would sort these 5 patients. All the others were already sorted by people far more experienced at this than any of us... other than Reefrad. And while we’re at it, let’s not put any of them in the Indeterminate group because that sort of defeats the purpose.


In this group of 5, there are 3 who passed before 10 months. That sounds like the sickest of the sick… so if you sort these three patients into the rapid progressors, that changes the number of patients from 20 to 23. The median for that would be the 12 patient, right? A quick look at wikipedia shows that the median is the number separating the lower half of data from the higher half of data. So patient 12 represents the median.


If we start with 3 patients… then go to the chart and add on 9 more patients (to get us to 12), the 12th patient looks to have gotten to approximately 13.5 months. That’s still 3.5 months more than the highest median average of 10.8 months. And if someone’s going to state that now rapid progressors are living longer (looks like Rational is doing just that today), let's just remember the non-toxic side effects of L are infinitely preferable to the side effects of chemo or radiation, or the potentially fatal cytokine storms.


And if you take the remaining two patients from the 5 unclassified who lived much longer (one still alive), one might sort them into the pseudo group. Now you’d have three patients in this group. The middle patient lived for 30.1 months, so the median would still be 30.1 months for this group of 3. Nothing changed.


Of course, sorting these final 5 patients is really just an exercise in futility. The rapid progressors aren't even in the actual blinded DCVax-L trial. The Indeterminates are a mix of shorter and longer survivors - a possible view of how the main arm of the trial is performing - and we can see that from 25 of these patients, they have a median survival rate of 21.5 months. That’s 6.8 months longer than the14.7 median. Almost 7 months.


And finally, I’d like to address the argument that the criteria should have sorted the patients at an MRI later than the Month 2 MRI. “Just one more scan would have done it” according to Rational Thought on today’s YMB thread. Come on. If they’d done it like this… "some patients were sorted at Month 2 MRI, some more patients were sorted at Month 4 MRI, and then even more patients were sorted at Month 6 MRI"… the naysayers would say that the company was cherry picking the patients and sorting them to make the median come out how they wanted it to. Kind of like the naysayers are doing now. They established a criteria, and the independent medical imaging company followed it.


In closing, this info arm group offers investors a much closer look at how the actual patients in the blinded trial are performing on DCVax-L.

One can choose to accept the information as it has been presented,

or choose to do their own sorting of these patients,

or listen to those who have chosen to do their own sorting of these patients (none of which I’m sure will be the same).

[b[color=red]]It is evident that countries such as Germany, the UK and savvy investors such as Neil Woodford, have chosen to accept the information arm as it has been presented.[/color]