Replies to post #63744 on NorthWest Biotherapeutics Inc (NWBO)

[Pyrrhonian]

Protocol changes require only two things (in either order):

-Getting IRB approval of the changes, and
-Submitting proposed changes to FDA for review, then waiting 30 days before proceeding with said changes in the actual trial

Once you get both you're good to go. You don't need a response from FDA and usually don't get one. You can request dialogue but don't have to.

[Rkmatters]

longfellow,

Possible protocol changes?

Well, elevating OS to co-primary endpoint is a possible. I think maybe unlikely though. As we know, OS is somewhat compromised because of crossover, and even if median OS proves to be totally unprecedented, as I'm sure it will, it can only be measured against historical norms, due to absence of control, hence of limited statistical value. Plus the issue of possible use of other post-crossover therapies. And the OS data will take several years to mature...
You could not estimate trial ending Sept 2016, if this was your co-primary endpoint. --LF

I agree, it's going to take a while for OS data to come in, and that is one of the reasons why that I think that no matter what, they will want to add more patients to the trial, so that they have a big pool to derive OS events from. If the crossover is having placebo patients live longer than historical GTR norms, (21 - 24 months, which has psPD patients in it by the way) then they sort of might have to IMO.

Employment of immunotherapy imaging protocols?

More likely I would suggest.
From NWBO's point of view, they cannot allow the trial to fail on its primary endpoint, due to pseudo-progression being mistaken for disease progression. Use of iRano or irRC would ensure that that scenario does not happen. It's a tad unfortunate, that the original trial design goes back to a time when pseudo-progression had not been fully recognised, as a confounding factor. This would fit with the comment from Doc Bosch that the pseudo-progression issue was wreaking havoc with clinical trials.
Though quite how you go about retrospectively re-visiting progression decisions, using immunotherapy imaging criteria is not easy to see. -- LF

Immunotherapy PsPD patients were recognized in the prior study. They were watched.

"There were anecdotal cases of transient increased T2/FLAIR and enhancing lesions on MRI after DC vaccination, which may have suggested inflammatory responses post DC vaccination, particularly in the mesenchymal gene-clustered cohort of patients (Fig. 1). However, these MRI changes resolved in due course and did not require surgical intervention. The appearance and disappearance of such MRI findings, presumed to be related to vaccination and neuroinflammation, was noted in three of our patients (GBM 1–2, 1–3, and 5–4). These three patients were in the mesenchymal subgroup and are still alive over five years from the initial diagnosis of glioblastoma." - DCVax-L Phase I/II

Until the study ends, we won't know if these same three patients would have failed PFS. I pasted a portion of the Protocol today, and the PI knew that main arm psPD would be removed from the study; I truly believe they accounted for it, by way of ensuring that patients can depart from Stupp protocol the same way as Brad did; and crossover means immunotherapy continues.

I think Dr. Bosch comment meant studies that don't remove psPDs prior to enrollment. Too many psPD in a placebo arm would be destructive. That should not occur in this trial. They are removing the typical psPDs could skew the placebo arm positively. The only psPD who might show up in the main arm are those who are immunotherapy psPD patients - sort of late bloomers (if the inflammatory lesion is a new one or if the growth size meets PFS event standards).

All that said, I don't know if the trial is going to fail its primary endpoint, PFS. What I think is that it will be closer than what most folks think since we have never seen how a Stupp protocol patient would respond to the same patient selection criteria their prior DCVax-L trials were privy to. That Stupp landmark study recruited a mixed-resection bunch of patients (only 39% had GTR, and 17% had biopsy only) with KPS scores across the board, and it was able to get 7 mo PFS. This trial recruit healthy patients, who qualify for GTR, with only decent KPS scores, and so I imagine introducing Stupp chemotherapy protocol will mean much better PFS curve. Honestly, patients in both arms will do well, but we've already seen how well the DCVax-L will do. But there is a possibility that the treatment arm does worse in this study, as since they won't know which patients are on vaccine or not, they will not be able to assume any size growth is due to vaccine; they will need to determine the PFS at the time of the imaging (thought by central review). Maybe a few psPD will bring down treatment progression events a bit, but I don't necessarily agree that psPD are wreaking havoc on this study. If they are psPD, then the idea is they will go onto live a long time and make up for their false progression event on OS.

What they are finding now is that a successful surgery keeps local recurrence at bay, so SoC patients have a higher PFS, but the disease does return. Even the best surgery does not produce a cure in most patients. And so I'm obviously long as I think DCVax-L will do better on OS. Any patient who is alive longer than 2 years, well, they should do really well.

Subgroup identification?

Can they identify mesenchymal patients prior to commencement of L therapy? If so, how? What is the test? If they want approval for a subgroup, then there must be a routine test to identify a subtype prior to commencement of an approved therapy.

High TIL score? Same thing applies. Must be a simple test that can identify trial patients with this attribute, prior to commencement of therapy. -- LF

Yes. Very hard for me to explain, I'm not great on the lingo, but I'll try. By way of genomics sequencing, which King's College CTU is qualified to do, by the way. Prins recent speech covers it. And so as time has gone on, researchers have actually determined the exact targets in the individual patients. And if this study were a peptide only study, the peptide targets would not have been able to improve over time. If they used MAA, then they would need to continue to use MAA antigens. Not the case with lysate, the antigen targets may have changed as they learned more about HLA class 1 and 2 epitope targets. A patient that was recruited with the same gene profile in 2008, might have had different peptides in their vaccine than a patient say in May of last year. The beauty of Lysate.

This study is removing immune compromised patients. Prins speech covers how they want to target those patients with CI. So in review of the quote below, this study removes the folks who should live less than a year. And it keeps the ones who should live more than a year, and so TIL should show if the patients get over the hurdle for an immune response to show up.

"However, not all patient with an increased immune response were necessarily living longer. I think that one problem is that the tumor itself is fighting back. The tumor wants to survive and it secretes factors that is suppressing the immune response. And what we found is that this particular agent TGF-ß2 which is an immunosuppression agent that has been long documented to be secreted by brain tumors, seems to correlate with decreased survival. And another thing that we noticed is that patients who live longer, meaning over 2 years verses under 1 year, tended to have more T-cells, these immune cell enter their tumors. Theoretical these tumors are being attacked by the immune system, which is essentially what we want." -- Linda Liau in 2005

Quality of life is covered in their Tertiary endpoints, which they can use to support their primary endpoint.

• To compare decline in physical functioning, measured by KPS evaluation,
between patients in the treatment cohort and patients in the placebo cohort
for all randomized patients (i.e., patients either randomized at baseline with
no evidence of disease progression or patients with pseudoprogression at
baseline who are later randomized);
• To compare time to progression of disease (TTP; includes as events all
radiographic evidence of disease progression; all deaths are censored)
between patients in the treatment cohort and patients in the placebo cohort
for all randomized patients (i.e., patients either randomized at baseline with
no evidence of disease progression or patients with pseudoprogression at
baseline who are later randomized);
• To compare survival at 6, 12, 18, 24, 36 and 48 months between patients in
the treatment cohort and patients in the placebo cohort for all randomized
patients (i.e., patients either randomized at baseline with no evidence of
disease progression or patients with pseudoprogression at baseline who are
later randomized)