Replies to post #104389 on NorthWest Biotherapeutics Inc (NWBO)

[Rkmatters]

I've tried to explain that to her before. A scan showing possible progression to treatment --even if the treatment is simple standard of care -- does not mean the patient progressed. Patients who do not progress are called pseudoprogression. Patients who are unclear but not yet crossed progression threshold but yet flagged for possible progression early on under immunotherapy are called Indeterminates, this term falls under RANO criteria for surgical resected patients.

Immunotherapy

Nonspecific imaging changes can also occur after immunotherapy. Inoculation of genetically engineered T cells in a murine model of glioblastoma multiforme has been shown to cause T1 gadolinium enhancement and T2 hyperintensity 24 hours after treatment, followed by decreased enhancement 2 to 3 days after treatment.61 Intratumoral administration of proinflammatory cytokines can cause prolonged increases in enhancement that can take up to 3 months after treatment to resolve.62,63Accordingly, new enhancement after immunotherapy should be confirmed on follow-up imaging, with the timing of the follow-up imaging possibly dependent on the type of immunotherapy.


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.

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


The CUA also makes it clear that suspected progression patients needed a follow-up scan, a requirement of MacDonald. Again from the 55 Compassionate Use Informational Arm abstract, what we know as fact that the first progression scan does not = confirmed progression. It by default removes Psuedoprogression response.

"Patients re-imaged at Month 2 after Baseline Visit to confirm either actual disease progression or pseudo-progression (patients categorized by independent medical imaging company)

 
Methods: Disease progression (recurrence) was determined through MRI imaging at the Baseline Visit and at Month 2 thereafter. All images were reviewed and analyzed by an independent specialized medical imaging company. Each image was reviewed separately by two independent reviewers, and any material differences were resolved by a third independent reviewer. Reviews were conducted using both RANO and McDonald criteria.
OS data is available for all 51 patients. Baseline and Month 2 images are available so far for 46 of the 51 patients.

Based on comparison of the Baseline and Month 2 images, the independent medical imaging company classified the 46 patients into the following 3 groups. The other 5 patients were unclassified, due to lack of available images.

* 20 Rapid-Progressor Patients: A new lesion ≥ 1 cm or tumor growth ≥25% at Baseline and at Month 2
* 25 Indeterminate Patients: Stable disease, modest progression and/or regression, or measurements still unclear
* 1 Pseudo-Progressor: Month 2 image showed resolution of most of the prior appearance of tumor growth"

http://www.nwbio.com/NWBT_ITOC_poster_3-25-15.pdf

[sentiment_stocks]

Hi antihama...

As your edit indicates, that 2nd portion from the protocol pertains only to those patients who, following temozolomide and radiation therapy **AND BEFORE RANDOMIZATION** show signs of progression. And of course, none of those patients that did show signs of unequivocal progression enter the main arm of the trial. Of course, there were 32 patients that came back 10 weeks later and were determined to be psPD and they entered their own arm of the trial.

I remember I thought similarly and brought that same passage from the protocol up to Avii... who quickly told me my error.

There is no passage like that in the protocol for those patients who are randomized and enter the main arm of the trial. And if they put that passage in to determine psPD before randomization, why didn't they put it in for those patients who might falsely progress after randomization? Well I think it's because they didn't realize that psPD could happen from DCVax... just TMZ and RT.

So unfortunately, I don't think those who wrote the protocol - which includes some of the finest physicians around - realized that the treatment itself could cause a pseudo progression - a false progression that some of the finest radiologists in the world might consider real progression. My guess is that with time, all those fine people started to realize it.

If LL was growing aware of it in 2012 when she told her tale of two tumors, then she may have been seeing it by 2011/2012 in the trial. But by then, there was a prior protocol that most likely delineated exactly how progression would be read, and as I went into some detail in post #102956, that there are no words in the April 2013 protocol about "waiting and seeing" and then doing another MRI in a couple of months. There is no baseline MRI AFTER you enter the trial that is written about in the protocol. RK believes that it is being done because MacDonald criteria does this. But that is NOT what is in the protocol. And so, IMO, it really doesn't matter what any other assessment criteria does or doesn't do. It's the protocol that calls the shots here.

So again, I don't think they initially realized that the treatment could ALSO cause a false progression. While some here don't think it does, it seems patients on blogs who are on the treatment do. In fact, three recently mentioned (Kay, Summer, Jefe) seem to think it's quite common. Is it common? Maybe not. But it's important to note that all of the immunotherapy assessment criteria are updating their formulas because they are finding that immunotherapies can cause a false progression.

And we know from the Information Arm, that enrolled in 2008, 2011 and 2012, had 25 patients that the very professional radiologists (the same ones used in the trial) couldn't determine what they were. So out of 55 patients, they couldn't tell with 25 patients if they were rapid or psPD? No. They couldn't. They had to wait and see.

Remember, LL also said back in December...

So those patients, in retrospect, were probably pseudo progressors, or people that were, you know, were read by radiologists as progression, but were probably pseudo progressors. And the issue with these multi-center trials is that, um, they’re all centrally reviewed… in terms of the radiology review… that’s to, you know, keep it unbiased. But because of the central radiology review, you don’t have the benefit of the clinical picture to decide if this is true progression or pseudo progression. So it’s all based on, you know, a certain percentage of increased mass on the MRI scan.

And she makes the point, and sort of underlines it, that with multi-center trials... UM... you don't have the benefit of that-there-whatcha-call "clinical picture" to decide if it's true progression or pseudo progression. It is just "a certain percentage of increased mass on the MRI scan." There really isn't any other way to read that, IMO.

So to reiterate, there is no mention in the protocol about performing a follow up MRI on a randomized patient if progression is suspected. To be really clear, this is AFTER the patients have already gone through the screening process to rule out rapid and psPD. It seems pretty cut and dried. If the progression reaches a certain size and the human radiologist that reads it deems that it is progression, it's progression. Even if it wasn't.

And if 3 out of 15 patients in the P1 trial (20%) - the best performing patients I believe - all showed false progression that would have deemed their response a progression event in this trial, well then, I'd suggest to Houston that we have a problem. But one might consider that if there were 20% of 220 patients on treatment that were falsely eventing in the first few months of treatment... and there was no wait and see and do another MRI if the progression was at or over the criteria specified - and clinical pictures did not figure in, well that seems lit would have presented a problem. To me, anyway.

Of course, I really believe that problem will be overcome... somehow. Survival is ultimately key here. If there are 20% of the treatment patients that falsely progressed, there are strong hints that these are also the patients that may very well become your long tail. These are the patients that really never did event... and hopefully they've gone on to just live and live and live. Hopefully, the FDA would see that and realize these patients really never evented. If that's what happened, of course.

And see, maybe the FDA, and those in the know, all took a look at that a while ago, and there was some initial confusion, suspicion, and maybe even some monkey-business where some conflicted people were being naughty and deserving of a spanking - and may have been trying to do a repeat of Dendreon's May 2007, and when that was all sorted through with perhaps the aid of our latest director CIA agent Cofer Black, then maybe by then, those good and righteous and non-conflicted persons remaining all agreed to just hold hands, sing kumbaya, and "wait and see" until about now. I mean, what if they thought it best wait it all out for that powered secondary endpoint, the one where everyone is living longer, and when 233 OS events were reached, do the data lock then, especially if that was what everyone who was good and righteous and not conflicted thought was the best thing for patients, investors, and the trial. I guess it's not really the median that is the super big deal here. It's the hazard ratio. And from what I understand, the longer that tail is for both PFS and OS, the better the hazard ratio is for both endpoints. And hey, isn't it nice that the screening halt is lifted by the FDA? They didn't have to do that. To me, that is another sign that there is love in the air amongst everyone who is anyone for this trial.

None of us on these boards know what the data will be when that unblind is done. Even poor Dr. Weller doesn't, even though he thinks he should. But what we will know is that there will be 98 of 331 patients that are still alive (30%). And if, as Flipper had suggested quite some time ago, if a strong percentage of them never even evented well past the median OS of 14.5 - well that is not a data point that can just be ignored.

And if only the best and non-conflicted people are Kumbabyaing together with LL, LP and the gang over DCVax-L.

Wouldn't that be nice if it worked like that? And you know what, despite those that think it won't, there's a pretty dang good chance, IMO, that it actually will. :)