Replies to post #104379 on NorthWest Biotherapeutics Inc (NWBO)

[Rkmatters]

I meant to link this RANO about surgery.

Retrospective Assessments of Disease Progression Should Be Permitted in Clinical Trials

As discussed above, there are no validated imaging modalities that reliably distinguish treatment effects from tumor progression, and the clinical management often involves serial imaging studies to determine the persistence of the radiographic changes. In many patients, serial imaging evaluation will show that the extent of new enhancement has regressed without clinical intervention, and these patients are considered to exhibit “pseudoprogression.” 64,65 Others will show persistent progression of imaging changes and will be considered cases of true disease progression. Accordingly, an imaging-based response classification scheme must allow a retrospective categorization of a patient as having disease progression based on the results of serial radiographic imaging. When progression is suspected but treatment-related effects remain a valid possibility, the response should be called indeterminate. If subsequent evaluation proves that the changes reflect true progression, the time of progression should be retrospectively corrected to the first time at which an indeterminate response was noted.[/quote]

https://academic.oup.com/neurosurgery/article-lookup/doi/10.1227/NEU.0b013e318223f5a7


And Central Image review to do T2/FLAIR to find Psuedoprogression must be done retrospectively on the first scan after initiation treatment: 

Because blinded independent central review will be used to guide decision making in individual patients in real time, there will be a requirement for the technological ability of all sites to transfer images to central review without delay. Furthermore, there will need to be acceptance of the idea that participating investigators will cede final determination of a patient's status to the central review body and will allow retrospective identification of pseudoprogression as described above.

https://academic.oup.com/neurosurgery/article-lookup/doi/10.1227/NEU.0b013e318223f5a7

[AVII77]

Somehow he has convinced you that taking sporadic scan at various times to check for response is not acceptable. He has also convince you that Macdonald criteria does not adapt when measuring response. According to AVII, the first sign of any change from Post RT MRI, the patient is out. The way he imagines it, there is no time to measure response to and progression on a newly imposed treatment therapy. And he has you convinced and confused because the protocol does not tell you what counts as response.

I didn't "convince her".

It's really quite simple.

She read the protocol and understood it.

Anyone who reads the protocol and understands it realizes you are wrong. Again.

[sentiment_stocks]

AVII marks up Brad’s scan taking 2 weeks after initial treatment, and suggest that they are progression. - RK

Avii has never suggested that Brad progressed, at least that's not what I've read. He is suggesting that the MRI indicated it was progression. But because it was a P1 trial, and that the clinical picture, as LL calls it, could be applied in such an instance. But with the P3 trial, Avii is stating that if a patient falsely progresses, and the MRI indicates this to the radiologist, then there is no "waiting and seeing" as Linda Liau could do with Brad and the two others.

Somehow he has convinced you that taking sporadic scan at various times to check for response is not acceptable. - RK

Well he didn't have to try very hard because the protocol does not state that you can take sporadic scans to see if there is progression or not.

According to AVII, the first sign of any change from Post RT MRI, the patient is out.

Avii is not stating that with any change on the MRI, the patient is out. He is stating that if the MRI shows a progression as it is delineated in the protocol - and the protocol is very specific, then the patient crosses over.

With regards to the Phase III exclusion criteria, AVII ignores that response to RT/TMZ had not been measured yet. - RK

No, I don't believe he's ignoring that. But anyone showing either, according to the very specific protocol, does not enter the main arm of the trial. And I'm sure he would agree with me on that 100%.

Another scan was needed to confirm progression of those excluded patients. - RK

No argument there - as it pertains to the screening process before entering the trial. But these patients were most definitively excluded from the main arm. This scan either confirmed rapid or psPD. But of course, this has nothing to do with the Main arm of the trial.

And with regards to both Brad and the Phase III main enrollment, AVII ignored that DCVax-L therapy has not been measured yet. - RK

With Brad, LL "waited and saw". So it didn't matter if DCVax-L therapy had been measured or not. There is no reference to measuring response to the treatment in this manner. Unfortunately, as Avii has said 100 times, there is no base line measurement for DCVax in the protocol.

N-O-N-E.

You and me both would like there to be one there, but there is not.

The month 2 scan is the first scan in the trial to measure response. I have told him many times that response to therapy can not be measured before a patient is even on therapy. Even old MacDonald criteria wants to make sure the psuedoprogression patients are accounted for with regards to treatment response. And so, a subsequent scan would automatically be needed after Month 2. - RK

Well I think we'd all agree - Avii included - that a subsequent scan would be needed. Unfortunately, there is no such thing in the protocol. NO SUCH THING. I would very much like there to be such a scan, but there is not.

You can cite 5000 abstracts that state that waiting and seeing, performing sporadic scans, and any other such criteria assessment that all the other immunotherapy criteria in the world perform... and you can cite them from all the way from 1990 to 2017... but it will not change what is actually adhered to in this single P3 trial. This trial is a world unto its own. It has its own assessment criteria, and that is what it must abide by.

Unless the company has been able to change that, of course. Which I doubt. However, I wouldn't rule out the possibility of adjudicating those initial readings. The treatment patients crossed from treatment to treatment. That might be a winnable case, although there are many that might disagree with that. Still, why bother doing it, if there wasn't a good reason to do so? And the past 8-ks and PRs indicate that is happening.

But IMO, resolving this issue is very easy.

It all begins and ends with what the protocol states and nothing else.

And the 2010 assessment criteria regarding RANO is a mere footnote in the protocol, and pertains to only one section - the unequivocal progression of non-measurable disease. That means that if the progression was measurable and unequivocal, what that RANO paper stated had nothing to do with how the tumor was read.

And if the radiologist ruled progression, and then found out later (as they did with some of the 25 indeterminate patients) that they were WRONG, well you can't unring that bell.