CogDiss... regarding the crossover in the DCVax-L trial. I believe when they originally designed the trial, they based it on the OS of patients in the Phase 1 trials at UCLA. There were 8 recurrent GBM patients o DCVax demonstrated an average mOS of 18 months from original diagnosis. There were 15 ndGBM patients. Their mPFS (yes PFS) was 21 months, and their mOS was 35.83 months. So I think the thinking was that PFS was going to carry the day towards an accelerated approval, as there would be no confoundment issues there because the control arm would not begin their treatment until after they'd progressed. And even then, the trials had documented an mOS of 18 for recurrent (like control) and mOS of almost 36 months for newly diagnosed (like treatment). That kind of data looked to ensure a real winner... at the time.
The only major difference I can think of between the control arm in this trial and the recurrent patients in the older trials is that the vaccine was made from the original tumor for the control arm, and it was made from the recurrent tumor for the patients in the older trials. Whether that will make any difference I guess remains to be seen. It's just a detail I don't want to leave out.
By the way, it's interesting to note that according to my notes, there were three patients from that group of 15 ndGBM patients that exhibited an inflammation that was likely pseudo progression.
Below is the list of patients. The first number is the patient number (e.g. 10-5) and the next number is the number of days until they PFS evented. These numbers are from my old notes from a post I did on i-village quite some time back.
10-5: 173
5-5: 229
1-5: 237
5-1: 275
10-2: 391
1-1 394:
10-3: 416
1-9: 639 (639/30.42 = 21.01 median PFS
10-6: 791
10-4: 1483
1-6: 1496
1-2: 1781
5-3: 2104
5-4: 2138
1-3: 3107
Now according to my notes, Dr. Prins noted back in 2011 that patients 1-2, 5-4, and 1-3 all exhibited inflammation that could have been due to the vaccine. So that's about 20%. Now apparently these three initially had a different PFS then what is recorded on their data sheets. You'll notice that they are all three located on the other side of the median, so they didn't effect it. However, had they been diagnosed according to the trial criteria to have evented when all that had really happened was that they had exhibited an inflammation, that could very well cause problems with the PFS data from those trials, and correspondingly, the PFS data in this trial could be affected as well. And that would rule using AA out back at an earlier time in this trial based on the first endpoint of PFS. Now of course, if they can adjudicate the PFS data in a manner satisfactory to the FDA, then perhaps AA can still be an option.
Frankly, there are probably a variety of paths forward. Some that come to my mind are:
One... adjudicate PFS, and ask for AA based on it (I think **but don't know** it might hasten the approval process).
Two... adjudicate PFS simply for the data it provides for future trials, and ask for full approval based on OS. But that would take longer. If OS is stat sig, then I don't really see any problem, however, other than time. I think that some analysts, however, are unsure how a stat sig OS is to be determined. Some think that if PFS is not stat sig, there will be no alpha left to measure OS. That is what happens to Denreon in 2007. That would mean that no matter what OS exhibited, it would not be stat sig in this trial. So if that is the case, then analysts would definitely see a possibility that NWBO would have to go back to the drawing board, and would be hesitant to advise investing - until that detail is cleared up.
Another item to note... PFS is to be measured using an alpha of .02, which is pretty small. That should leave another spare .03 for use. Now the bears' argument for the missing .03 is that the company had it taken away, or some such nonsense, as a punishment or something weird like that.
And please note: Dr. Bosch has indicated on his presentation slides that the two endpoints are independently measured. I wish we could have gotten more detail on that, but that may be subject to any number of possibilities depending on what type of arrangements they've got with the regulatory agencies and how they approach the data in this trial. I'd frankly like to think that since the Dendreon debacle occurred back in 2007, then when NWBO set up the P3 trial in 2011, they made sure the error of not having enough alpha to measure OS was not repeated.
Three... they could also approach the FDA using the blinded data. Now how they would do that is open to interpretation (if they'd even do that - although I suspect it is on the table as a possibility). Maybe they could ask for AA based on blinded data, and then let OS finish out and then apply for full approval.
Four... they could approach the FDA using the blinded data and ask for full approval based on it.
I know longfellow doesn't like this approach - as it's somewhat like how Kite and Juno were approved (single arm data with no control - except their trials were P1s!). Still... I think it's another pathway of several, and probably even more, that I'm unaware of.
Anyway, I wanted to respond to your comment regarding crossovers as unethical. And I get what you're pointing out... most think of them as the ethical thing to provide the patients, but there is argument against that as well. I just wanted to use this an opportunity to bring some additional information relating to crossovers (and other things) for those who are soaking up everything NWBO right now.
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