Replies to post #63743 on NorthWest Biotherapeutics Inc (NWBO)

[Rkmatters]

Seriously Pyrr, you could debunk your own statement if you gave it some thought by a simple view of some data points.

The DMC may have recommended they halt the study for futility after seeing an excessive number of PFS events in DCVax-L group and/or ... Pyrr

You have NW Bio's 2013 old protocol assumptions for PFS and OS for this Phase III trial back when the trial was meant to be 240-patients. Let’s review:

ENDPOINT: Progression Free Survival (PFS): Time to objective demonstration of disease progression or death in either patients with no evidence of disease progression after external beam radiation therapy with concurrent temozolomide chemotherapy, or in patients who show pseudoprogression of disease.

They assumed median time to disease progression or death from enrollment (in patients with no evidence of disease progression after external beam radiation therapy with concurrent temozolomide chemotherapy) of 7 and 13.5 months among the placebo cohort and the treatment cohort, respectively.

ENDPOINT: Overall Survival (OS). In either patients with no evidence of disease progression after external beam radiation therapy with concurrent temozolomide.

The secondary endpoint will be time to death from enrollment (in patients with no evidence of disease progression after external beam radiation therapy with concurrent temozolomide chemotherapy) they assumed median survival times of 17 and 34 months among patients in the placebo and treatment cohorts.

During her October 2015 speech, Linda Liau stated that GTR median OS have risen to 22 - 24 month range. But she also made these two statements about the DCVax-L trial:

"The overall cohort has not yet reached its number of predetermined events. It seems like EVERYONE is living longer than we expected. Hopefully if patents didn't get anything the differences would be bigger." — Linda Liau in October 2015

"It seems like everyone is living longer than we would be expecting, so in reality what we are really comparing now is actually early DC vaccination verse later DC vaccinations” - Linda Liau in October 2015.

How do you reconcile your DMC finding futility with Linda Liau’s statement that EVERYONE is living longer? Do you spot the hole in your DMC “halt for futility” hypothesis yet? Would that not mean that AVII’s theory is accurate; and that the vaccine is very effective but the immunotherapy imaging standards do not match? Seriously, think about this:

The trial, as you know is randomized by 2:1; the Intent to Treat population is patients who qualify for Gross Total Resection (GTR). We also know that the best (pseudos) and the worst (rapids) immunotherapy patients are removed, and patients are randomized according to MGMT promoter status, meaning each arm will get their fair share of chemotherapy responders, as such following the old protocol 240-patient endpoint assumptions:

—1/3 of main arm (placebo cohort) is expected, after randomization, to have median event of 7 mo. PFS; 17 mos. OS.
—2/3 of the main arm (treatment cohort) is expected, after randomization, to have median event of 13.5 mo. PFS; 34 mos. OS.

For Linda Liau’s statements to be truthful, that means that the trial median needs to have a SIGNIFICANTLY high OS in both arms. Her statements suggest that they can not be falling short on their protocol assumptions. They can only be exceeding them. If this trial is removing pseudo progression patients prior to enrollment, and yet OS for a mixed MGMT promoter status is so high, where 80 of 240 patients are expected to >34 months OS, well that is some mighty strong acting placebo. Don’t you agree? If not, then show me one GTR SoC study, where the median OS surpasses 24 months (Linda confirmed this trial is surpassing) and yet the study has no pseudo patients within it. You won’t be able to do it. :)

[Doc logic]

Pyrrhonian,

I agree with you on this. To me it looks almost as if the company initiated the temporary hold, sent in data which FDA then reviewed and asked for continuing data as per Dr. Prins " still accruing patients" comment. This essentially leaves us with a rolling review of data up until the scheduled end of the trial unless there is or has been some sort of an ethicist intervention on behalf of pseudo/mesenchymal patients. If NWBO argues that these patients leave the main trial early and this leads to underrepresentation of this subgroup in the main arm, FDA might listen. Linda said they would not apply for AA until the end of the trial. To me this means FDA is actively trying to decipher data which is accruing very slowly while perhaps also working with the other regulator time lines and manufacturing prep so that approval can be expedited if received.