NWBO Company info 03/06/2016 02:51:02 $NWBO
Yeah, it was Germany. I spoke to NWBO way back then. They didn't elaborate on why but later I found out that they stopped in the rest of the sites because they didn't want to have any disadvantage/advantage to anyone being treated at any site. No further word on the details, but it was pretty clear that it started in Germany. I've put the pieces together from there. I think they're finding it easier to deal with the Sickness Funds with approval than through a yet untested thing like the HE. Just speculation from my conversations with NWBO management over the past several months. They're tight lipped, that's for sure, but that appears more out of trying to do the right thing, not something nefarious. That's my take.
Do we know that for sure? Maybe Germany was just quickest to update their site?
The screening hold was started in Germany, not the US. Everyone keeps claiming the FDA is the regulatory body involved. I don't believe it has anything to do with anything other than going for approval in Germany instead of wasting time and energy regarding the HE. I believe the negotiations with the German Sickness Funds may be better for the company if they receive approval than if they negotiate under the HE and then get approval. There's not a lot of information regarding how this works but I'm looking into it. I don't think futility is even a distant possibility.
You win! - the Post of Day
- loved it!
exwannabe,
It's not a "fairly serious allegation", it's a fairy serious strategy for those who might feel threatened. You want me to feel mad and greedy about being diluted and I want to feel like I am supporting a breakthrough technology that will help cancer patients and pay big dividends in the longer term. Please feel free to explain the biological importance of CXCR4 if you would like. I am very happy with my understanding of it how about you?
This is the problem as i see it:
How do you tell an egotistical know it all that he/she doesn't know it all........it is impossible to do. No matter what you say or how you say it the know it all will believe he/she knows it all. Coupled with the know it all's lack of transparency similar to how they describe their opponent leads to circular reasoning. BTW I also believe NWBO is nontransparent but that is another subject and one that I can see both sides equally albeit unhappily.
Just from following some of the studies you've cited, while you are not trying to predict what is going on behind the curtain, it seems you are highlighting the fact that upon trial success for immunotherapy companies, there is still much work to be done regarding manufacturing expansion from a clinical trial into a commercial endeavor -- particularly for a technology such as this -- and since this must be accomplished before approval (whether accelerated or regular approval), it is important for all of us to understand that even with trial success, there may be additional waiting.
Comparability is likely the biggest hurdle when ones goes from clinical scale to commercial scale with this technology. This may, not always, involve some preclinical work (thank goodness mice have quicker lifespans), cytokine analysis, purity consistency and alike. (Argos, who also makes a dendritic product, has stated emphatically they will have to go through that process to one extent or another if/when their phase three is successful)
Hypothetical:
So assuming NWBO will have to go through that process at some point (or is going through it), would they do it before alerting the public they already had trial success?
I'm thinking they would wait to share trial success despite the financial sacrifice this would take.
Why would they do that?
IMHO, they are absolutely assured another AF/ivillage/media/echo chamber/lame law firm attack in-between any trial success and approval. So unfortunately, if all this plays out, the bashers have likely made it a necessity to have it all done before NWBO announces -- under this scenario.
(Drummword stated Les gave the comparison of having to wait 6 months to learn the phase II was converted to a phase III, and that ended up being worth it, so, one way to read that is we are in the process of waiting 5 or 6 months to learn something good. If Drummond was accurate and Les was accurate, then one might assume this is how everything would have to go in a less then perfect world where AF gets the megaphone.)
So if you do not believe they are changing primary endpoints now, but you believe they will/have changed them, when are you assuming they have/will do that?
Complexity of radiographic worsening following immunotherapy
Given the recent marked increase in the application of immunotherapies for cancer indications, appreciation of the
complexity to accurately assess response has grown in parallel. On the one hand, radiographic improvement is felt to provide a straightforward indication of anti-tumor effect because immunotherapies do not decrease tumor vessel permeability leading to pseudoresponse as been observed following anti-angiogenic agents [26]. On the other hand, worsened radiographic findings following administration of an immunotherapeutic may be more challenging to interpret. Although MRI worsening may reflect underlying tumorprogression, at least for a subset of patients, early worsening of imaging findings may be followed by subsequent clinical benefit. For such patients, early discontinuation of immunotherapy treatment due to worsened imaging findings assumed to be due to progressive underlying tumor may result in premature termination of a potentially active therapeutic option. There are two possible explanations for a lack of correlation between progressive imaging findings and ultimate therapeutic benefit. First, unlike radiation therapy or chemotherapy which are expected to exert a direct and rapid cytotoxic effect, immunotherapies exert an indirect anti-tumor effect via induction of an anti-tumor immune cell infiltrate which may take time to mobilize. Importantly, the kinetics of such anti-tumor immune responses may vary between different types of immunotherapies. Nonetheless, in this situation, some patients may have bona fide tumor progression early in the course of their therapy prior to subsequently responding to an immunotherapeutic. Second, a subset of patients may have pseudoprogressive radiographic findings following administration of an immunotherapeutic agent (Fig. 1). Potent anti-tumor immune responses inherently elicit inflammatory changes in the tumor microenvironment, including the macroscopic as well as infiltrative microscopic tumor regions, which may result in increased tumor vessel permeability leading in turn to increased contrast uptake as well as associated edema. Precedent for pseudoprogressive radiographic changes has been established for neuro-oncology based on experience following administration of temozolomide chemoradiotherapy for newly diagnosed glioblastoma patients. In this setting, pseudoprogression typically peak within 3 months and occurs in 20–30 % of patients [27, 28]. Appreciation of temozolomide chemoradiation associated pseudoprogression was a key factor underlying the widespread adoption of the radiologic assessment in neuro-oncology (RANO) criteria [29]. A growing number of clinical trials evaluating a wide array of immunotherapeutics across a spectrum of cancer indications demonstrate that a subset of patients treated with immunocytokines, cancer vaccines, T cell therapies and immune checkpoint inhibitors will achieve a radiographic response, durable stable disease or enhanced survival despite worsening of early imaging findings [21–23, 30–38].
Immunotherapy response assessment in neuro-oncology
(iRANO) criteria
Although the principles underlying the irRC provide important response assessment guidance for ongoing immunotherapy efforts in general medical oncology, modification of these criteria appear warranted in order to optimally and safely apply such guidance for neuro-oncology patients. Similarly, although the RANO criteria were drafted to provide more effective assessment of response for neuro-oncology patients undergoing therapy in the modern era, RANO alone may not fully address relevant considerations for neuro-oncology patients undergoing immunotherapy treatment. Thus, a multi-disciplinary and multinational group of neuro-oncology experts is currently drafting guidance for response assessment of neurooncology patients undergoing immune-based therapies. The immunotherapy response assessment in neuro-oncology (iRANO) criteria will integrate key components of both irRC and RANO in order to take into account important nuances associated with neuro-oncology patients.
Conclusions
Immune-based therapies offer great hope for cancer patients based on their ability to treat existing tumors as well as generate tumor-specific memory immune responses capable of preventing future recurrence. Nonetheless, interpretation of early progressive radiographic findings has proven challenging in that at least a subset of such patients ultimately achieves meaningful anti-tumor benefit. The immuno-oncology community has recently drafted recommendations to guide treating clinicians when confronted with early radiographic worsening that includes continuation of immunotherapy pending confirmation of progression for clinically stable patients. The immunotherapy response assessment for neuro-oncology (iRANO) criteria are currently in development and will integrate key recommendations from RANO with those of irRC in order to help optimally evaluate the therapeutic potential of differentimmunotherapeutic approaches for neuro-oncology patients.
http://escholarship.org/uc/item/4f23c36s#page-1
This is my last post for tonight because frankly, I know you are wrong about both these points and i do have better things to do (maybe you do too, dunno)
This is from the paper you cite:
"Since mesenchymal signatures represent glioblastoma subgroups that are more resistant to conventional therapy, it can be speculated that DC vaccination somehow makes these tumors more susceptible to subsequent treatment"
Let me sum it up for you and everyone else. mesenchymal subtype is the least likely to respond to SOC. therefore the fact that this subgroup demonstrates pseudoprogression after dcvax is evidence that they DO respond to dcvax. period. end. fact.
Now to your point about that not meaning anything because they would be counted as an event in either case. This is from the original paper by the RANO group:
"We feel that our proposed method for marking suspicious areas of possible nonenhancing tumor progression and then retrospectively confirming them as areas of disease progression will help reduce the adjudication rate, but this remains to be determined."
This uncertainty is built in to all trial. patients are not labeled as progressors until SEVERAL scans show progression. its not that the second the patient leaves the MRI suite he/she is labeled as progressing vs. not progressing. the committee reviews multiple serial scans and then decides. the determination is made retrospectively.
good night
AVII, you already know the answer to that. The patient did not receive the Adjuvant until the booster shots began. No need to lead him down the garden path on that. I assume Reefrad is the radiologist he says he is, so no reason to keep those matters from him.
You would agree however that because they remove suspicious psPD and rPD at the 1st baseline, the trial converts to RANO's 12 week delay standard by default, because the second baseline is at 12 weeks post chemoradiation. (Giving many psPD a chance to calm down).
I'd note Reefrad's insistence regarding distinguishing between tumor and no tumor. If you have a signal that professional radiologists do not regard as a tumor, then you cannot have tumor increase by looking at that signal. I think therein lies one of the very important differences between a layman's analysis and a professional radiologists. In other words AVII, you may be right on size increase, but if it's not a tumor, it does not matter.
Interesting.
Dr. Liau describes this phenomena twice.
" the tumor or inflammation or whatever you see on the MRI scan gets worse before it gets better"
and
"One patient (patient 5) had near complete regression of residual tumor, which was seen on MRI 2 months after completion of peptide-pulsed dendritic cell vaccination and before any additional adjuvant treatment. Both the size of the areas of T2W hyperintensity and the contrast-enhancing tumor decreased in this patient (Fig. 2). Although this radiographic change is more likely related to a delayed response to radiation therapy, it is interesting to speculate that dendritic cell–based immunotherapy might have contributed to this clinical response,"
She speculates, but you sound pretty certain when you say
Quote:
We are talking about gbm patients who demonstrate a response to dcvax therapy.
Are you sure there's no bias sneaking into your assessment there?
Yeah, that's basically it. A couple comments in red.
1. You think the hold is for a safety/manufactuirng issue?
* You also think it may be to head off a safety issue that has not thus far resulted in harm to patients, and to do this, manufacturing would need to be fixed?
* You do not believe any such manufacturing issue might be related instead to modifying/expanding manufacturing for commercialization?
2. You think they reserved powering of .03 alpha for OS, that was previously "left on the table" at the last enhancement (back in 2014)? You don't think this is being done now. I'm not sure how much alpha they would reserve for OS. Others reserve more than 0.03. Look at AVAGLio and the RTOG trial.
3. You think if they are changing OS to the primary or coprimary endpoint, it would not result in a partial clinical hold, but for some reason you think that might be going on during this time?
No, I really don't think it is going on now.
4. You believe the following paragraph would only apply to an IND going from a phase I trial protocol to a phase II trial, and not from phase III to a confirmatory trial. You do not think review of phase III data plus setting protocol up for any possible confirmatory trial (perhaps using the current trial) would take considerable time, and certainly not take from August through March?
It could apply for a Ph2 going to a Ph 3 also. It might also apply for a Phase 1 continuing after the dose escalation stage.
Quote:
Partial Clinical Hold: A delay or suspension of only part of the clinical work requested under the IND (e.g., a specific protocol or part of a protocol [like screening patients] is not allowed to proceed; however, other protocols or parts of the protocol are allowed to proceed under the IND). If FDA requires that progress to the next study is contingent (1) on FDA review of additional data and (2) subsequent specific permission for the study to proceed, this represents a partial clinical hold. -- FDA
And btw, we are not talking about classic pseudoprogressors.
We are talking about gbm patients who demonstrate a response to dcvax therapy.
I disagree on one fundamental point, i believe they do confirm progression on follow up scans. That is, they do not diagnosis progression on 1 mri scan. It simply is not standard of care.
Mcdonald vs. RANO is irrelevant to this point.
Btw, neither prins nor LL are radiologists. That image does not look like tumor, it simply doesnt. Therefor that patient would not have counted as a progression event.
Quote:
Neither criteria have an allowance for the "transient" nature of the increase. (well RANO does but that is applied ONLY at the timepoint equivalent of Baseline 1; the first post treatment MRI)
too late to edit and correct an error.
RANO incorporates an allowance for the "transient" aspect by not calling a progression in the first 12 weeks, however, this element of RANO is not incorporated in the DCVax Ph3 nor is it an element of Macdonald criteria.
AVII.
while I don't judge your opinion below, I'm simply trying to see if I understand your position.
1. You think the hold is for a safety/manufactuirng issue?
* You also think it may be to head off a safety issue that has not thus far resulted in harm to patients, and to do this, manufacturing would need to be fixed?
* You do not believe any such manufacturing issue/delay might be related instead to modifying/expanding manufacturing for commercialization?
2. You think they reserved powering of .03 alpha for OS, that was previously "left on the table" before the last enhancement (back in 2014)? You don't think this is being done now.
3. You think if they are changing OS to the primary or coprimary endpoint, it would not result in a partial clinical hold, but for some reason you think that might be going on during this time?
4. You believe the paragraph below would only apply to an IND going from a phase I trial protocol to a phase II trial, and not from phase III to a confirmatory trial. You do not think review of phase III data plus setting protocol up for any possible confirmatory trial (perhaps using the current trial) would take considerable time, and certainly not take from August through March?
Quote:
Partial Clinical Hold: A delay or suspension of only part of the clinical work requested under the IND (e.g., a specific protocol or part of a protocol [like screening patients] is not allowed to proceed; however, other protocols or parts of the protocol are allowed to proceed under the IND). If FDA requires that progress to the next study is contingent (1) on FDA review of additional data and (2) subsequent specific permission for the study to proceed, this represents a partial clinical hold. -- FDA
Quote:
you asked for it.
Indeed I did, Thank you for your response (a bit snarky, but I understand)
Quote:
pray tell my friend, what ARE those criteria for defining progression by the committee? do you know?
Yes I do know,
They are using modified Macdonald.
They modified Macdonald such that it was similar to RANO (RANO criteria were only in development when this trial started.)
The parts of RANO they left out were the inclusion of steroid dosing changes in assessment and (importantly) the RANO caveat about not calling a progression event (under certain circumstances) in the first 12 weeks following chemorad.
I don't mean to be disrespectful when I remind you that RANO is stricter than Macdonald (it tends to identify progression events earlier).
This is because RANO also incorporates enhancement on T2/Flair.
Under RANO, a patient without enhancing disease on normal T1 Contrast but WITH enhancing disease on T2/FLAIR is considered a progression event. That tends to capture more events earlier.
Now please look again at that MRI from the paper.
And tell me if you agree with Dr. Prins and Dr. Liau when they describe it as displaying:
Quote:
Transient increase in MRI T2/FLAIR lesions (A) and contrast enhancement (
observed in a primary, newly diagnosed glioblastoma patient following DC vaccination (patient GBM5-4). Axial T2/FLAIR (A) and T1/contrast (
If what they say is correct, then it is a progression under Macdonald and under RANO.
Neither criteria have an allowance for the "transient" nature of the increase. (well RANO does but that is applied ONLY at the timepoint equivalent of Baseline 1; the first post treatment MRI)
Quote:
the very idea that NWBO knows about pseudoprogression of the mesenchymal subgroup since 2011 and failed to account for that in their phase 3 trial is LUDICROUS!
And how would you suggest they account for it?
Perhaps incorporate elements of iRANO (that was developed 4 years later)?
They did not.
One way to account for it would be to elevate OS to an endpoint with alpha reserved.
Quote:
I read scans of oncologic patients on immunotherapy on a daily basis, melanoma, squamous cell, bladder cancer etc. We see 'pseudoprogression' every day. We obviously dont know for sure what type of response is going on but with enough experience you just get the feel for it. in any event, the clinicians KNOW this and therefore they ALWAYS get additional follow up scans before diagnosing progression of disease.
Yes, I get that.
But I don't think you get that the assessment here is not done by the clinicians.
The assessment is done by the blinded independent assessment committee.
They will look at the scan, compare it with the post surgical MRI, and either grade it as a progression event or not.
And remember, this is entirely ethical. The patient receives SOC one way or the other. The only thing in the balance is the timing of x-over treatment availability. If the assessment committee comes back and says "progressed", the physician is free to continue temador if he wishes (and I bet most do if they have any questions about psPD), or they could switch to avastin, or repeat surgery, etc. Whatever the clinician thinks is best for the patient, but the patient will also have the option of definitely receiving DCVax.
Quote:
this is also built in to the phase III trial. patients have repeat MRIs.
Yes, they have them every 2 months.
But none are used for the purpose of confirming progression (except Baseline 2 for those being considered for the psPD arm when it was enrolling).
Quote:
btw, that image you reference DOES look like pseudoprogression. it does not look like tumor recurrence.
Yeah, I know. All the still living patients from the Phase 1 trials were likely psPD. That's my point. But NWBO says they lived as long as they do because of the DCVax treatment.
But regardless if it looks like psPD, the issue is: is there increased enhancement on T1 or T2/FLAIR. I think Dr. Liau says the answer is yes. Not yes to just one, but yes to both. And if even 1 is so, it is graded as a progression event under Macdonald criteria.
Current Report Filing (8-k) "Edgar (US Regulatory)" - 3/3/2016 2:48:01 PM
Prospectus Filed Pursuant to Rule 424(b)(5) (424b5) "Edgar (US Regulatory)" - 3/3/2016 8:51:07 AM
NW BIO Announces Registered Direct Offering Of Up To $27.6 Million With Existing Institutional Investors "PR Newswire (US)" - 2/29/2016 10:58:00 AM
Amended Statement of Ownership (sc 13g/a) "Edgar (US Regulatory)" - 1/27/2016 5:02:18 PM
NW Bio Announces Appointment Of Two New Independent Directors With Biotech/Pharma Expertise and Cybersecurity/Investigations ... "PR Newswire (US)" - 1/25/2016 9:30:00 AM
Prospectus Filed Pursuant to Rule 424(b)(3) (424b3) "Edgar (US Regulatory)" - 1/12/2016 5:07:45 PM
NW Bio Issues Statement on Adverse Market Conditions And NW Bio Stock Decline "PR Newswire (US)" - 1/8/2016 9:15:00 AM
Prospectus Filed Pursuant to Rule 424(b)(3) (424b3) "Edgar (US Regulatory)" - 12/30/2015 5:28:32 PM
Current Report Filing (8-k) "Edgar (US Regulatory)" - 12/29/2015 5:25:22 PM
NW Bio Announces Closing Of Registered Direct Offering of $12.6 Million "PR Newswire (US)" - 12/24/2015 4:29:00 PM
Current Report Filing (8-k) "Edgar (US Regulatory)" - 12/24/2015 12:23:22 PM
NW BIO ANNOUNCES A REGISTERED DIRECT OFFERING OF $12.6 MILLION "PR Newswire (US)" - 12/23/2015 9:00:00 AM
Notice of Effectiveness (effect) "Edgar (US Regulatory)" - 12/23/2015 6:01:43 AM
Robbins Arroyo LLP: Northwest Biotherapeutics, Inc. (NWBO) Misled Shareholders According to a Recently Filed Class Action "Business Wire" - 12/21/2015 4:07:00 PM
NW Bio Announces Annual Meeting Results, Re-Election of Directors "PR Newswire (US)" - 12/21/2015 1:05:00 PM
Securities Registration Statement (simplified Form) (s-3/a) "Edgar (US Regulatory)" - 12/14/2015 5:17:16 PM
Current Report Filing (8-k) "Edgar (US Regulatory)" - 12/14/2015 3:09:19 PM
NW Bio Announces Establishment of Special Committee And Law Firm To Conduct Independent Investigation of Recent Allegations "PR Newswire (US)" - 12/8/2015 8:15:00 AM
NW Bio Statement Regarding Appointments "PR Newswire (US)" - 12/8/2015 8:15:00 AM
NW Bio Announces Establishment of Special Committee And Law Firm To Conduct Independent Investigation of Recent Allegations "PR Newswire (US)" - 12/8/2015 2:30:00 AM
NW Bio Statement Regarding Appointments "PR Newswire (US)" - 12/8/2015 2:30:00 AM
NW Bio Plans to Expand Board, Welcomes Woodford's Call For Independent Investigation Of Allegations In Anonymous Internet Rep... "PR Newswire (US)" - 11/30/2015 7:15:00 AM
Amended Statement of Beneficial Ownership (sc 13d/a) "Edgar (US Regulatory)" - 11/24/2015 5:20:52 PM
Glancy, Prongay & Murray LLP Commences Investigation on Behalf of Northwest Biotherapeutics, Inc. Investors "Business Wire" - 11/23/2015 8:59:00 PM
3 Stocks I Would Avoid at All Costs "The Motley Fool" - 11/16/2015 7:01:05 PM
Yeah, it was Germany. I spoke to NWBO way back then. They didn't elaborate on why but later I found out that they stopped in the rest of the sites because they didn't want to have any disadvantage/advantage to anyone being treated at any site. No further word on the details, but it was pretty clear that it started in Germany. I've put the pieces together from there. I think they're finding it easier to deal with the Sickness Funds with approval than through a yet untested thing like the HE. Just speculation from my conversations with NWBO management over the past several months. They're tight lipped, that's for sure, but that appears more out of trying to do the right thing, not something nefarious. That's my take.
Do we know that for sure? Maybe Germany was just quickest to update their site?
The screening hold was started in Germany, not the US. Everyone keeps claiming the FDA is the regulatory body involved. I don't believe it has anything to do with anything other than going for approval in Germany instead of wasting time and energy regarding the HE. I believe the negotiations with the German Sickness Funds may be better for the company if they receive approval than if they negotiate under the HE and then get approval. There's not a lot of information regarding how this works but I'm looking into it. I don't think futility is even a distant possibility.
You win! - the Post of Day
- loved it!
exwannabe,
It's not a "fairly serious allegation", it's a fairy serious strategy for those who might feel threatened. You want me to feel mad and greedy about being diluted and I want to feel like I am supporting a breakthrough technology that will help cancer patients and pay big dividends in the longer term. Please feel free to explain the biological importance of CXCR4 if you would like. I am very happy with my understanding of it how about you?
This is the problem as i see it:
How do you tell an egotistical know it all that he/she doesn't know it all........it is impossible to do. No matter what you say or how you say it the know it all will believe he/she knows it all. Coupled with the know it all's lack of transparency similar to how they describe their opponent leads to circular reasoning. BTW I also believe NWBO is nontransparent but that is another subject and one that I can see both sides equally albeit unhappily.
Just from following some of the studies you've cited, while you are not trying to predict what is going on behind the curtain, it seems you are highlighting the fact that upon trial success for immunotherapy companies, there is still much work to be done regarding manufacturing expansion from a clinical trial into a commercial endeavor -- particularly for a technology such as this -- and since this must be accomplished before approval (whether accelerated or regular approval), it is important for all of us to understand that even with trial success, there may be additional waiting.
Comparability is likely the biggest hurdle when ones goes from clinical scale to commercial scale with this technology. This may, not always, involve some preclinical work (thank goodness mice have quicker lifespans), cytokine analysis, purity consistency and alike. (Argos, who also makes a dendritic product, has stated emphatically they will have to go through that process to one extent or another if/when their phase three is successful)
Hypothetical:
So assuming NWBO will have to go through that process at some point (or is going through it), would they do it before alerting the public they already had trial success?
I'm thinking they would wait to share trial success despite the financial sacrifice this would take.
Why would they do that?
IMHO, they are absolutely assured another AF/ivillage/media/echo chamber/lame law firm attack in-between any trial success and approval. So unfortunately, if all this plays out, the bashers have likely made it a necessity to have it all done before NWBO announces -- under this scenario.
(Drummword stated Les gave the comparison of having to wait 6 months to learn the phase II was converted to a phase III, and that ended up being worth it, so, one way to read that is we are in the process of waiting 5 or 6 months to learn something good. If Drummond was accurate and Les was accurate, then one might assume this is how everything would have to go in a less then perfect world where AF gets the megaphone.)
So if you do not believe they are changing primary endpoints now, but you believe they will/have changed them, when are you assuming they have/will do that?
Complexity of radiographic worsening following immunotherapy
Given the recent marked increase in the application of immunotherapies for cancer indications, appreciation of the
complexity to accurately assess response has grown in parallel. On the one hand, radiographic improvement is felt to provide a straightforward indication of anti-tumor effect because immunotherapies do not decrease tumor vessel permeability leading to pseudoresponse as been observed following anti-angiogenic agents [26]. On the other hand, worsened radiographic findings following administration of an immunotherapeutic may be more challenging to interpret. Although MRI worsening may reflect underlying tumorprogression, at least for a subset of patients, early worsening of imaging findings may be followed by subsequent clinical benefit. For such patients, early discontinuation of immunotherapy treatment due to worsened imaging findings assumed to be due to progressive underlying tumor may result in premature termination of a potentially active therapeutic option. There are two possible explanations for a lack of correlation between progressive imaging findings and ultimate therapeutic benefit. First, unlike radiation therapy or chemotherapy which are expected to exert a direct and rapid cytotoxic effect, immunotherapies exert an indirect anti-tumor effect via induction of an anti-tumor immune cell infiltrate which may take time to mobilize. Importantly, the kinetics of such anti-tumor immune responses may vary between different types of immunotherapies. Nonetheless, in this situation, some patients may have bona fide tumor progression early in the course of their therapy prior to subsequently responding to an immunotherapeutic. Second, a subset of patients may have pseudoprogressive radiographic findings following administration of an immunotherapeutic agent (Fig. 1). Potent anti-tumor immune responses inherently elicit inflammatory changes in the tumor microenvironment, including the macroscopic as well as infiltrative microscopic tumor regions, which may result in increased tumor vessel permeability leading in turn to increased contrast uptake as well as associated edema. Precedent for pseudoprogressive radiographic changes has been established for neuro-oncology based on experience following administration of temozolomide chemoradiotherapy for newly diagnosed glioblastoma patients. In this setting, pseudoprogression typically peak within 3 months and occurs in 20–30 % of patients [27, 28]. Appreciation of temozolomide chemoradiation associated pseudoprogression was a key factor underlying the widespread adoption of the radiologic assessment in neuro-oncology (RANO) criteria [29]. A growing number of clinical trials evaluating a wide array of immunotherapeutics across a spectrum of cancer indications demonstrate that a subset of patients treated with immunocytokines, cancer vaccines, T cell therapies and immune checkpoint inhibitors will achieve a radiographic response, durable stable disease or enhanced survival despite worsening of early imaging findings [21–23, 30–38].
Immunotherapy response assessment in neuro-oncology
(iRANO) criteria
Although the principles underlying the irRC provide important response assessment guidance for ongoing immunotherapy efforts in general medical oncology, modification of these criteria appear warranted in order to optimally and safely apply such guidance for neuro-oncology patients. Similarly, although the RANO criteria were drafted to provide more effective assessment of response for neuro-oncology patients undergoing therapy in the modern era, RANO alone may not fully address relevant considerations for neuro-oncology patients undergoing immunotherapy treatment. Thus, a multi-disciplinary and multinational group of neuro-oncology experts is currently drafting guidance for response assessment of neurooncology patients undergoing immune-based therapies. The immunotherapy response assessment in neuro-oncology (iRANO) criteria will integrate key components of both irRC and RANO in order to take into account important nuances associated with neuro-oncology patients.
Conclusions
Immune-based therapies offer great hope for cancer patients based on their ability to treat existing tumors as well as generate tumor-specific memory immune responses capable of preventing future recurrence. Nonetheless, interpretation of early progressive radiographic findings has proven challenging in that at least a subset of such patients ultimately achieves meaningful anti-tumor benefit. The immuno-oncology community has recently drafted recommendations to guide treating clinicians when confronted with early radiographic worsening that includes continuation of immunotherapy pending confirmation of progression for clinically stable patients. The immunotherapy response assessment for neuro-oncology (iRANO) criteria are currently in development and will integrate key recommendations from RANO with those of irRC in order to help optimally evaluate the therapeutic potential of differentimmunotherapeutic approaches for neuro-oncology patients.
http://escholarship.org/uc/item/4f23c36s#page-1
This is my last post for tonight because frankly, I know you are wrong about both these points and i do have better things to do (maybe you do too, dunno)
This is from the paper you cite:
"Since mesenchymal signatures represent glioblastoma subgroups that are more resistant to conventional therapy, it can be speculated that DC vaccination somehow makes these tumors more susceptible to subsequent treatment"
Let me sum it up for you and everyone else. mesenchymal subtype is the least likely to respond to SOC. therefore the fact that this subgroup demonstrates pseudoprogression after dcvax is evidence that they DO respond to dcvax. period. end. fact.
Now to your point about that not meaning anything because they would be counted as an event in either case. This is from the original paper by the RANO group:
"We feel that our proposed method for marking suspicious areas of possible nonenhancing tumor progression and then retrospectively confirming them as areas of disease progression will help reduce the adjudication rate, but this remains to be determined."
This uncertainty is built in to all trial. patients are not labeled as progressors until SEVERAL scans show progression. its not that the second the patient leaves the MRI suite he/she is labeled as progressing vs. not progressing. the committee reviews multiple serial scans and then decides. the determination is made retrospectively.
good night
AVII, you already know the answer to that. The patient did not receive the Adjuvant until the booster shots began. No need to lead him down the garden path on that. I assume Reefrad is the radiologist he says he is, so no reason to keep those matters from him.
You would agree however that because they remove suspicious psPD and rPD at the 1st baseline, the trial converts to RANO's 12 week delay standard by default, because the second baseline is at 12 weeks post chemoradiation. (Giving many psPD a chance to calm down).
I'd note Reefrad's insistence regarding distinguishing between tumor and no tumor. If you have a signal that professional radiologists do not regard as a tumor, then you cannot have tumor increase by looking at that signal. I think therein lies one of the very important differences between a layman's analysis and a professional radiologists. In other words AVII, you may be right on size increase, but if it's not a tumor, it does not matter.
Interesting.
Dr. Liau describes this phenomena twice.
" the tumor or inflammation or whatever you see on the MRI scan gets worse before it gets better"
and
"One patient (patient 5) had near complete regression of residual tumor, which was seen on MRI 2 months after completion of peptide-pulsed dendritic cell vaccination and before any additional adjuvant treatment. Both the size of the areas of T2W hyperintensity and the contrast-enhancing tumor decreased in this patient (Fig. 2). Although this radiographic change is more likely related to a delayed response to radiation therapy, it is interesting to speculate that dendritic cell–based immunotherapy might have contributed to this clinical response,"
She speculates, but you sound pretty certain when you say
Quote:
We are talking about gbm patients who demonstrate a response to dcvax therapy.
Are you sure there's no bias sneaking into your assessment there?
Yeah, that's basically it. A couple comments in red.
1. You think the hold is for a safety/manufactuirng issue?
* You also think it may be to head off a safety issue that has not thus far resulted in harm to patients, and to do this, manufacturing would need to be fixed?
* You do not believe any such manufacturing issue might be related instead to modifying/expanding manufacturing for commercialization?
2. You think they reserved powering of .03 alpha for OS, that was previously "left on the table" at the last enhancement (back in 2014)? You don't think this is being done now. I'm not sure how much alpha they would reserve for OS. Others reserve more than 0.03. Look at AVAGLio and the RTOG trial.
3. You think if they are changing OS to the primary or coprimary endpoint, it would not result in a partial clinical hold, but for some reason you think that might be going on during this time?
No, I really don't think it is going on now.
4. You believe the following paragraph would only apply to an IND going from a phase I trial protocol to a phase II trial, and not from phase III to a confirmatory trial. You do not think review of phase III data plus setting protocol up for any possible confirmatory trial (perhaps using the current trial) would take considerable time, and certainly not take from August through March?
It could apply for a Ph2 going to a Ph 3 also. It might also apply for a Phase 1 continuing after the dose escalation stage.
Quote:
Partial Clinical Hold: A delay or suspension of only part of the clinical work requested under the IND (e.g., a specific protocol or part of a protocol [like screening patients] is not allowed to proceed; however, other protocols or parts of the protocol are allowed to proceed under the IND). If FDA requires that progress to the next study is contingent (1) on FDA review of additional data and (2) subsequent specific permission for the study to proceed, this represents a partial clinical hold. -- FDA
And btw, we are not talking about classic pseudoprogressors.
We are talking about gbm patients who demonstrate a response to dcvax therapy.
I disagree on one fundamental point, i believe they do confirm progression on follow up scans. That is, they do not diagnosis progression on 1 mri scan. It simply is not standard of care.
Mcdonald vs. RANO is irrelevant to this point.
Btw, neither prins nor LL are radiologists. That image does not look like tumor, it simply doesnt. Therefor that patient would not have counted as a progression event.
Quote:
Neither criteria have an allowance for the "transient" nature of the increase. (well RANO does but that is applied ONLY at the timepoint equivalent of Baseline 1; the first post treatment MRI)
too late to edit and correct an error.
RANO incorporates an allowance for the "transient" aspect by not calling a progression in the first 12 weeks, however, this element of RANO is not incorporated in the DCVax Ph3 nor is it an element of Macdonald criteria.
AVII.
while I don't judge your opinion below, I'm simply trying to see if I understand your position.
1. You think the hold is for a safety/manufactuirng issue?
* You also think it may be to head off a safety issue that has not thus far resulted in harm to patients, and to do this, manufacturing would need to be fixed?
* You do not believe any such manufacturing issue/delay might be related instead to modifying/expanding manufacturing for commercialization?
2. You think they reserved powering of .03 alpha for OS, that was previously "left on the table" before the last enhancement (back in 2014)? You don't think this is being done now.
3. You think if they are changing OS to the primary or coprimary endpoint, it would not result in a partial clinical hold, but for some reason you think that might be going on during this time?
4. You believe the paragraph below would only apply to an IND going from a phase I trial protocol to a phase II trial, and not from phase III to a confirmatory trial. You do not think review of phase III data plus setting protocol up for any possible confirmatory trial (perhaps using the current trial) would take considerable time, and certainly not take from August through March?
Quote:
Partial Clinical Hold: A delay or suspension of only part of the clinical work requested under the IND (e.g., a specific protocol or part of a protocol [like screening patients] is not allowed to proceed; however, other protocols or parts of the protocol are allowed to proceed under the IND). If FDA requires that progress to the next study is contingent (1) on FDA review of additional data and (2) subsequent specific permission for the study to proceed, this represents a partial clinical hold. -- FDA
Quote:
you asked for it.
Indeed I did, Thank you for your response (a bit snarky, but I understand)
Quote:
pray tell my friend, what ARE those criteria for defining progression by the committee? do you know?
Yes I do know,
They are using modified Macdonald.
They modified Macdonald such that it was similar to RANO (RANO criteria were only in development when this trial started.)
The parts of RANO they left out were the inclusion of steroid dosing changes in assessment and (importantly) the RANO caveat about not calling a progression event (under certain circumstances) in the first 12 weeks following chemorad.
I don't mean to be disrespectful when I remind you that RANO is stricter than Macdonald (it tends to identify progression events earlier).
This is because RANO also incorporates enhancement on T2/Flair.
Under RANO, a patient without enhancing disease on normal T1 Contrast but WITH enhancing disease on T2/FLAIR is considered a progression event. That tends to capture more events earlier.
Now please look again at that MRI from the paper.
And tell me if you agree with Dr. Prins and Dr. Liau when they describe it as displaying:
Quote:
Transient increase in MRI T2/FLAIR lesions (A) and contrast enhancement (
observed in a primary, newly diagnosed glioblastoma patient following DC vaccination (patient GBM5-4). Axial T2/FLAIR (A) and T1/contrast ( If what they say is correct, then it is a progression under Macdonald and under RANO.
Neither criteria have an allowance for the "transient" nature of the increase. (well RANO does but that is applied ONLY at the timepoint equivalent of Baseline 1; the first post treatment MRI)
Quote:
the very idea that NWBO knows about pseudoprogression of the mesenchymal subgroup since 2011 and failed to account for that in their phase 3 trial is LUDICROUS!
And how would you suggest they account for it?
Perhaps incorporate elements of iRANO (that was developed 4 years later)?
They did not.
One way to account for it would be to elevate OS to an endpoint with alpha reserved.
Quote:
I read scans of oncologic patients on immunotherapy on a daily basis, melanoma, squamous cell, bladder cancer etc. We see 'pseudoprogression' every day. We obviously dont know for sure what type of response is going on but with enough experience you just get the feel for it. in any event, the clinicians KNOW this and therefore they ALWAYS get additional follow up scans before diagnosing progression of disease.
Yes, I get that.
But I don't think you get that the assessment here is not done by the clinicians.
The assessment is done by the blinded independent assessment committee.
They will look at the scan, compare it with the post surgical MRI, and either grade it as a progression event or not.
And remember, this is entirely ethical. The patient receives SOC one way or the other. The only thing in the balance is the timing of x-over treatment availability. If the assessment committee comes back and says "progressed", the physician is free to continue temador if he wishes (and I bet most do if they have any questions about psPD), or they could switch to avastin, or repeat surgery, etc. Whatever the clinician thinks is best for the patient, but the patient will also have the option of definitely receiving DCVax.
Quote:
this is also built in to the phase III trial. patients have repeat MRIs.
Yes, they have them every 2 months.
But none are used for the purpose of confirming progression (except Baseline 2 for those being considered for the psPD arm when it was enrolling).
Quote:
btw, that image you reference DOES look like pseudoprogression. it does not look like tumor recurrence.
Yeah, I know. All the still living patients from the Phase 1 trials were likely psPD. That's my point. But NWBO says they lived as long as they do because of the DCVax treatment.
But regardless if it looks like psPD, the issue is: is there increased enhancement on T1 or T2/FLAIR. I think Dr. Liau says the answer is yes. Not yes to just one, but yes to both. And if even 1 is so, it is graded as a progression event under Macdonald criteria.
Current Report Filing (8-k) "Edgar (US Regulatory)" - 3/3/2016 2:48:01 PM
Prospectus Filed Pursuant to Rule 424(b)(5) (424b5) "Edgar (US Regulatory)" - 3/3/2016 8:51:07 AM
NW BIO Announces Registered Direct Offering Of Up To $27.6 Million With Existing Institutional Investors "PR Newswire (US)" - 2/29/2016 10:58:00 AM
Amended Statement of Ownership (sc 13g/a) "Edgar (US Regulatory)" - 1/27/2016 5:02:18 PM
NW Bio Announces Appointment Of Two New Independent Directors With Biotech/Pharma Expertise and Cybersecurity/Investigations ... "PR Newswire (US)" - 1/25/2016 9:30:00 AM
Prospectus Filed Pursuant to Rule 424(b)(3) (424b3) "Edgar (US Regulatory)" - 1/12/2016 5:07:45 PM
NW Bio Issues Statement on Adverse Market Conditions And NW Bio Stock Decline "PR Newswire (US)" - 1/8/2016 9:15:00 AM
Prospectus Filed Pursuant to Rule 424(b)(3) (424b3) "Edgar (US Regulatory)" - 12/30/2015 5:28:32 PM
Current Report Filing (8-k) "Edgar (US Regulatory)" - 12/29/2015 5:25:22 PM
NW Bio Announces Closing Of Registered Direct Offering of $12.6 Million "PR Newswire (US)" - 12/24/2015 4:29:00 PM
Current Report Filing (8-k) "Edgar (US Regulatory)" - 12/24/2015 12:23:22 PM
NW BIO ANNOUNCES A REGISTERED DIRECT OFFERING OF $12.6 MILLION "PR Newswire (US)" - 12/23/2015 9:00:00 AM
Notice of Effectiveness (effect) "Edgar (US Regulatory)" - 12/23/2015 6:01:43 AM
Robbins Arroyo LLP: Northwest Biotherapeutics, Inc. (NWBO) Misled Shareholders According to a Recently Filed Class Action "Business Wire" - 12/21/2015 4:07:00 PM
NW Bio Announces Annual Meeting Results, Re-Election of Directors "PR Newswire (US)" - 12/21/2015 1:05:00 PM
Securities Registration Statement (simplified Form) (s-3/a) "Edgar (US Regulatory)" - 12/14/2015 5:17:16 PM
Current Report Filing (8-k) "Edgar (US Regulatory)" - 12/14/2015 3:09:19 PM
NW Bio Announces Establishment of Special Committee And Law Firm To Conduct Independent Investigation of Recent Allegations "PR Newswire (US)" - 12/8/2015 8:15:00 AM
NW Bio Statement Regarding Appointments "PR Newswire (US)" - 12/8/2015 8:15:00 AM
NW Bio Announces Establishment of Special Committee And Law Firm To Conduct Independent Investigation of Recent Allegations "PR Newswire (US)" - 12/8/2015 2:30:00 AM
NW Bio Statement Regarding Appointments "PR Newswire (US)" - 12/8/2015 2:30:00 AM
NW Bio Plans to Expand Board, Welcomes Woodford's Call For Independent Investigation Of Allegations In Anonymous Internet Rep... "PR Newswire (US)" - 11/30/2015 7:15:00 AM
Amended Statement of Beneficial Ownership (sc 13d/a) "Edgar (US Regulatory)" - 11/24/2015 5:20:52 PM
Glancy, Prongay & Murray LLP Commences Investigation on Behalf of Northwest Biotherapeutics, Inc. Investors "Business Wire" - 11/23/2015 8:59:00 PM
3 Stocks I Would Avoid at All Costs "The Motley Fool" - 11/16/2015 7:01:05 PM
