Replies to post #99350 on NorthWest Biotherapeutics Inc (NWBO)

[Rkmatters]

The first Phase I reported the study as Time to Tumor Progression from Newly Diagnosed Surgery TTP.

“Time to tumor progression (TTP) was defined as the interval from surgical resection until the first observation of tumor progression.”

Clearly, TTP includes the wait time leading up to vaccine injections. But that isn’t exactly how they measure progression. Progression, they stated was measured from Baseline.

“Tumor response was monitored by clinical and MRI assessments at baseline (within 1 month before therapy), at day 56 post-therapy, and every 8 weeks thereafter as surrogate markers for clinical response and tumor status”

And because Baseline is used to MEASURE efficacy, but in terms of reporting TTP, they back date efficacy starting at SURGERY, that means includes the Time to Treatment (TTT) period from surgical period to BASELINE back in.

And so to REPORT TTP, one must need to know Time to Treatment (TTT):

“The median time between surgical resection and the initiation of dendritic cell vaccination was 18 weeks (range, 4-28 weeks). All patients had a baseline brain MRI scan within 1 month before starting the immunotherapy.

”

Surgery to Baseline to Vaccine is TTT, and that was listed as median of 18 weeks.
Baseline to Vaccine is less than 4 weeks (in most DCVax-L studies it is 1 week) = 1 week ( 7 Days)

“Clinical evaluations. Although this phase I clinical trial was not powered to detect clinical efficacy, tumor response was monitored by clinical and MRI assessments at baseline (within 1 month before therapy), at day 56 post-therapy, and every 8 weeks thereafter as surrogate markers for clinical response and tumor status.”

That leaves the Median time of Surgery to Baseline as - 17 weeks before Vaccine

Baseline to Vaccine is - 1 week to Vaccine (within a month).

And for example, when they reported the TTP, they ADDED the TTT (from surgery to vaccine) back in, and then they deducted the TTT (from Baseline to Vaccine) period back out, as part of Time to Treatment includes BASELINE to Vaccine. Baseline in current Phase III is -7 days before first Injection. And Baseline is where TUMOR measurements start.

So, if TTT is 18 week, then minus 1 week for Baseline to Vaccine = 17 weeks time from Surgery to Baseline. That Surgery to BASELINE is included in TTP. It is included in how they report data because they report data from the TIME OF SURGERY. However, the efficacy “or tumor response” to vaccine, was only measured from BASELINE.

BASELINE starts the TUMOR measurement clock. Baseline to Progression = PFS event (in days) in the N=8 chart.

In this Phase I, the first MRI is considered at day 56 after injection. That still falls around 8 weeks after vaccine (same as Phase I/II). Remember, Baseline to Vaccine is typically 7 days. So, then 56 days after the vaccine + 7 days for Baseline to Vaccine = 63 days+ is when patients can be removed for progression — if study removal is based off an MRI.

In the N=8, the first patient was removed at 64 days, and that means BASELINE to VACCINE period for that N=8 patient was 8 days. Again, in the Phase I/II, they described the first MRI as 8 weeks, which is equivalent to 56 days after first Injection, then include 8 days from BASELINE to vaccine, and that Patient rGBM10-1 had progression 64 days after BASELINE. That patients did not have progression 64 day after surgery, which is what AVII continues to allege.


http://www.aimath.org/WWN/tumorimmune/LiauDendriticCellVaccination.pdf

[AVII77]

RKMatters, I think I figured it out.

You may not believe it, but I try very hard to understand different points of view. I truly struggled to try to see why, something that is clear to me, is not recognized by you. Your last post gave me an important insight.

This is where I believe your thinking went astray:

You stress all this TTT (Time to Treatment) stuff. That was my clue.

What you don't appreciate is that for an autologous vaccine, surgery is an integral part of the "treatment".

That is why, uniformly, ALL autologous vaccine (single arm) trials measure efficacy from the time of surgery as their starting point.

So, for DCVax, surgery is an integral part of the treatment strategy (you must obtain tumor to make the vaccine).

If they measured the efficacy of this treatment strategy starting AFTER surgery, we would ignore the competing risk of death from the surgery itself.

That would not provide a meaningful estimate of the treatment strategy.

Take an extreme example, suppose 50% of rGBM patients died from surgery to obtain tumor but DCVax cured all of those who survived to receive treatment?

What is the REAL efficacy of the treatment strategy for a rGBM patient? Ignoring that surgery starting time point would grossly overestimate the benefit of the intervention in that extreme example (100% cured vs 50% cured).

And that is why they measured efficacy from surgery.