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No. We were not told. Many if have disputed our theories on the halt. Mine is found in old posts.
As for pseudos, these would be the most responsive patients to therapy — a phony sign of progression where MRI changes means therapy is working well, but signs of MRI still mimic progression but is not progression at all. The pseudo that are pseudo progression due to standard of care treatments are removed from the trial at baseline and randomized 2:1 — separates from the main study. Their data will be reviewed as tertiary data. The only pseudos that make it into this trial will be the pseudos that were not evident at baseline (I.e., patients who present psuedoprogression after enrollment)
Hi Doc Logic,
We don’t have to use the confidential protocol to see that the study is 3 years after a patient is enrolled. All information proving that the study is 3 years can be found on public records.
The clinicaltrials.gov protocol reference the study directly as a 3 year study for patients, when considering in study participation and treatment schedule.
“This Phase III trial is designed to evaluate the impact on disease progression and survival time, as well as safety, in patients following treatment with DCVax(R)-L, an immunotherapy treatment for GBM.” — clinicaltrial.gov
If one accounts for the last patient in, also in clinicaltrials.gov, one can see the study is expected to go on several years, when including treatments and monitoring, for each and every patient (survival permitting).
“Two intradermal (i.d.) injections of DCVax-L(treatment cohort) or autologous PBMC (placebo cohort) per treatment. Treatments will be given at days 0, 10, 20, and at weeks 8, 16, 32, 48, 72, 96 and 120.”
The Phase III consent form also makes it vet clear that the active trial phase is 3 years.
“The clinical trial will consist of three phases: the initial evaluation phase (also known as the screening phase), the active treatment phase, and the follow-up phase. During the evaluation phase you will undergo some testing noted below to indicate whether you can participate. The next phase, the active treatment phase, is when patients are treated with DCVax-L or placebo. During this phase, which lasts up to 36 months, you will be asked to return to the clinic once every two months for MRIs and other tests as outlined below under Study Visits Procedures to determine how you are doing. During the follow-up phase, which starts after the 36 months is completed or after you leave the trial for any reason, you and/or a designated contact will be contacted every third month to collect medical history including data on long-term progression or re-growth of your brain cancer as well as survival data.. Please read the section titled Follow-Up Information.”
The SEC statements make it clear to that the study would be considered early termination if the last patient in did not receive their final dose.
"Prior to the last dose of the last patient enrolled in the Phase III trial for DCVax®-L or After the last dose of the last patient enrolled in the Phase III clinical trial for DCVax®-L but before any submission for product approval in any jurisdiction or after the submission of any application for market authorization but prior to receiving a marketing authorization approval: in any of these cases, the fee shall be $3 million." -- NW Bio 10Q
And the protocol also makes it clear that the company can stop the study — meaning not go the full duration of the patient treatment schedule — with this line:
“Treatment in this study must be discontinued for any of the following reasons:
• if the sponsor decides to stop the study” — protocol
“18. STOPPING THE STUDY
The sponsor may decide to stop the study at any point, for any reason.
APPENDIX A: SCHEDULE OF EVENTS
Visit 1 2 3 4 5/5a 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26
Surgery
Post-surgery MRI
Pre-leukapheresis
Leukapheresis
Radiation and
Chemotherapy
Baseline Visit (2) b,n
Enrollment
Immunizations
End of Treatment
Survival Follow-up
1 2 3 4 5 6 7 8 9 10
-1
wk
Time
0d
day
10
day
20
2
Mo
4
Mo
6
Mo
8
Mo
10
Mo
12
Mo
14
Mo
16
Mo
18
Mo
20
Mo
22
Mo
24
Mo
26
Mo
28
Mo
30
Mo
32
Mo
34
Mo
36
Mo
Ongoing”
So yeah, that too makes it clear the study is 3 years.
Discontinuing active treatment would be considered early stoppage of the study — anything less than the treatment schedule (reminder, any non-progressed patients switch over to placebo, in a blinded fashion, if DCVax-L study supply is exhausted)
“11. PATIENT DISCONTINUATION OF ACTIVE TREATMENT
An explanation for discontinuing treatment is recorded for each patient discontinuing
treatment on the appropriate eCRF. The Sponsor, or its designee, must be notified
immediately if a patient discontinues treatment. All patients, irrespective of treatment status,
will continue to be followed for survival. Treatment in this study must be discontinued for any
of the following reasons:
• if the sponsor decides to stop the study;
• at Investigator’s discretion;
• at the patient’s request;
• if the patient enrolls in a trial of another investigational agent for the treatment of GBM;
• Grade 4 or life-threatening toxicity (See Section 11, Adverse Events) attributable to
DCVax-L;
• injection site reactions of Grade 3 or higher, according to the grading in Appendix E” — protocol
It’s clear the original protocol intention was that the patient’s participation in the trial was scheduled to continued in a post hoc manner, after the primary end point and secondary endpoints were unblinded. No one will get an argument with me on that. Yes, that was their early plans. But the study itself, again was meant to be 3 years.
One, also needs to keep in mind that the protocol called for a shorter enrollment period, but that did not come to pass, as we all know.
“The study schedule anticipates an approximate active enrollment period of 12
months.“ — original protocol
Also note this from the protocol, 30 days after the patient exits from participation in the trial or last study treatment, (whichever comes later) tracking information on AE is still done.
All patients were meant to get 10 injections. All patients were meant to be in the study 3 years and survival followed, on-going. What’s unclear is the last patients follow-up period, that “on-going” period, but that one could reason need not include ever last patient data remain blinded for a definite period of time. Company doesn’t need more on-going follow up time imho. What clear to me is that the company can end the trial once the last patients completes 36 months of enrollment. My expectation is they plan to do the final data collection soon and report out once it’s complete.
One could argue that the company disclosed in their August 2014 press release that they planned to hold off “unblinding” until all patients completed their 36 commitment to the trial, with their words below “remain fully blinded until the trial is completed”. They also stated back then they didn’t intend to do the statistical analysis at the “the end of the trial”, but hey, others are welcome to perceive that they would follow the old protocol statistical analysis plan, but in retrospect it’s clear the timing of the plan changed, their protocol and their statistical analysis change. We were never told what it exactly became. But we were told they will analyze at the end of the trial. If you perceive the trial ends once the last enrolled patient consent is complete, then you agree the SAP should occur soon. Press release below.
“The Company has been blinded at all times, with no access to any data in the Phase III trial, and will remain fully blinded until the trial is completed. The changes relate to the statistical analyses that will be done at the end of the trial, and do not affect the treatment protocol, dosing, randomization of patients or other such aspects. The changes were driven solely by external factors — particularly research reports about a newly discovered variable which has been found to significantly affect GBM patients’ survival times, and which the Company recognized could significantly skew the clinical trial results if the trial’s statistical analyses did not control for it. The Company’s Phase III trial design and statistical analyses already controlled for key variables known at the time when the trial was designed, such as a particular genetic factor (referred to as MGMT methylation), the extent of tumor removal, and others.” — NW Bio August 2014
How much follow-up on-going would we need on the last patient? I perceive data collection period as enough!
I don’t know if they can afford to. I also can’t see allowing them to keep the data blinded beyond the studies consent period. Time will tell how long it takes to go through the final data lock period. Expecting we get news of some sort next month or December on trial status. We should all scream from the rooftops if we do not have the final unblinded data by March 2019.
Exactly, times change. If the blinded peep did reveal any flaw in the study’s protocol or endpoint design —which from Linda Liau’s 2017 speech, we know crossover causes some confounding- one way the company can potentially correct, is to get more long tail survival data.
Ps you may be upset to hear this but my opinion remains the same on that 2014 post of mine. They only shared the best view of the data. They didn’t tell us how many patients had failed to move onto later injects. You’ll have to read other 2014 posts to understand the context. But you probably won’t. Not here to educate you further on what you may have missed in prior pump press releases. Only, since you brought it up, very content to say my opinion on the facts remain the same. Best of luck to you on your debates.
I continue to believe that the company is misleading with their press releases. There is a difference with the truth and the whole truth. It is ultimately why I apologized to Adam Feurstein for giving him a difficult time. to It is also why I prefer to read their SEC statements. I know understand that it is the curse of the small biotech, as since their stock can be attached so viciously by the market, it’s best not to elaborate to skeptics content on the negatives of the study, particular if the positives outweigh the negative.
Also, you’re welcome to debate my opinions, but I should have been more clear for you, I do not mean ones from years ago. I frankly would need to review to understand how time and hindsightMay have changed my current viewpoints. Some of my opinions remain the same. But many do not, and that is common sense. Opinions shift when new SEC Facts become evident. Opinions shift with time. Opinions should not stay stagnant as you suggest. But I’m certain what I wrote in any of my prior posts, I adamantly perceived at the time — assuming the context is not misconstrued and mangled by you and others, of course. I still perceive many of my former opinions, including some from 2013, 2014, 2015, 2015, 2016, 2017 and 2018. Some choose to ignore company SEC statements, while others understand what it meant at the time and wait patiently for trial results.
Ps, it was my opinion well over a year ago that the company, through the 10Q, informed its shareholders that there was a likelihood that they would continue the controlled trial and not unblind the trial until after all patients completed their 3 year enrollment period. And as it turns out, what was my opinion has turned into fact. :)
The company will have at least 3 years of controlled data on each and every patient, post enrollment, sometime in November 2018. Data already exists on expected survival at 1, 2, 3 year marks, post surgery. Extended survival in this Phase III trial, once unblinded and revealed, can only be credited to standard of care or standard of care plus DCVax-L.
Obviously patients can be followed after a controlled trial ends. However, once a controlled trial is data locked all continued survival analysis after the data lock would be considered post hoc. Post hoc data is not the same as controlled data. You know this.
See prior post to understand why I was convinced a year ago that the company disclosed the trial was on-going. :)
Thanks Never left. Patiently waiting for the 3 years of the last enrolled patient in to cross. :)
Well well well, November 2018 is approaching. It seems I was correct on my read if the 2017 20Q, and that the company didn’t plan to unblind the study before every last patient crossed their 3 year commitment of being in the study.
How long will it take the company to gather final analysis and report out on a study that will end on every last patient? Time will soon tell.
Happy Fall/Happy Winter.
Well there is the January 2011 press release.
Pasted below.
Bethesda, MD, January 24, 2011 – Northwest Biotherapeutics (OTC Bulletin Board: NWBO) announced today that the Company is resuming enrollment of additional new patients into its ongoing 240-patient, double blind, randomized, placebo controlled Phase II clinical trial of DCVax® for Glioblastoma multiforme (“GBM”) brain cancer.
To date, this trial has been conducted at 13 clinical sites across the U.S., with 33 patients already having been enrolled. These patients have continued to be treated with the DCVax® regimen and follow-up during the last two years. The only aspect of the trial that stopped for a period of time was enrollment of additional new patients beyond the 33 patients who were already enrolled and receiving ongoing treatment. The Company is now resuming the process of accepting additional new patients to complete the trial.
You simply don’t have all the facts to conclude what the numbers were on the reported enrollment curve early on.
I perceive they gave us the double-blinded enrollment data mostly, as that enrollment timeline chart starts in June 2008, same as the double-blinded enrollment portion of the trial. I see that a good portion of the Vanguard period was left off the enrollment curve (the open label Vanguard portion was left off, not the double-blinded potion from June 2008) but I do know that this trial enrollment began earlier than then June 2008. From the recent scientific paper they stated this:
“We conducted this study at over 80 sites in 4 countries: the US, Canada, Germany, and the UK. Patient recruitment was initiated in 2007, and was paused from 2009 to 2011 for economic reasons. The midpoint of enrollment was reached in May of 2014, and the final patient was enrolled in November of 2015.” — JoTM May 2018
Why are you trying to draw conclusion from the lines on the enrollment curve that doesn’t include the true study start date? I have pointed out that you don’t have all the data. They have hardly given us the hard fact data on enrollment within those slide.
Anyway, hopefully you can see why I concluded early on, that enrollment curve was not perfect, and so I never regarded it as such. To be perfect, we would need it to start sometime in 2007, same as the Phase III trial 331 patient recruitment. The only percentages that are legally binding on that enrollment curves are the dates they revealed 50% and 100% enrollment marks. Investors eyeballing the chart and making conclusion leads to mistakes in assumptions imho. Treat the chart as informational only up until the 50 and 100% marks. Those are the only percentage that they specifically told us the EXACT dates.
Again providing the link for you to the enrollment curve.
https://www.nwbio.com/NWBio_ASCO_Update_On_Trials_6-5-17.pdf
The trial is double blinded. Once it’s unblinded we will possibly learn more about the different enrollment periods and why they made cuts to open enrollment period patients. Hope that helps.
No where did they state that those 3 patients were the only patients enrolled during that open enrollment period. That’s a night conclusion you have drawn. But it doesn’t work, as 2:1 enrollment means only 1 placebo patient. How do you reconcile that they referred to more than 1 placebo drop out after open enrollment? 1 is never a they. Hope you see that.
“Following up on these results, in 2007-2008, the Company designed and began a 140-patient randomized, controlled Phase II trial but without a placebo and without blinding (which can only be achieved with a placebo that is indistinguishable from the new treatment being tested), as no placebo then existed for a living cell product like DCVax. Unfortunately, without a placebo and blinding, patients who were randomized to the control group in the trial knew that this was the case – and, not surprisingly, they tended to drop out of the trial. As a result, that 140-patient Phase II trial had to be stopped and a placebo had to be developed to enable blinding, so that patients would not know whether they were receiving DCVax or a placebo.” — NWBIo 10K + 10Qs
I should add that I very much believe that the 3 randomized patients they refer to within the quote EX found refers to the removed 3 placebo patients who possibly enrolled and didn’t withdraw consent.
1 patient is never a “they”. But go ahead Ex and believe they only enrolled 3 patients in the open enrollment period. Company had never said that. They refer to many patients.
The Company used the following words about the open label placebo patients: “not surprisingly, THEY tended to drop out of the trial”. I’m suggesting that is where the 2:1 discretion lies — all open label placebo patients didn’t remain in the study, at all. And so the earliest enrolled patients were essentially all vaccine patients. Instead of ending with a 2:1 randomization, the trial ended up randomizing 22:0 (or whatever the count was at the time, from the 50 or so screened). None of the open placebo enrolled patients were followed until death as they all withdrew consent early on. They didn’t censor patients who dropped out at day zero randomization. They simply couldn’t get the placebo arm randomization done. And so they stopped openly randomizing patients openly as they couldn’t get a 2:1 randomization met. Since randomization failed, they worked with the FDA to designed the on-going Phase II study, as a double-blinded, placebo control, and created a placebo that was indistinguishable from DCVax-L. Now that said, this 2:1 open randomization period which failed to meet 2:1 randomization standard is still part of this Phase III trial and that’s why the numbers are off. They never discarded the vaccine data they accumulated.
More proof from company records about how impossible it was to maintain placebo enrollment:
“Following up on these results, in 2007-2008, the Company designed and began a 140-patient randomized, controlled Phase II trial but without a placebo and without blinding (which can only be achieved with a placebo that is indistinguishable from the new treatment being tested), as no placebo then existed for a living cell product like DCVax. Unfortunately, without a placebo and blinding, patients who were randomized to the control group in the trial knew that this was the case – and, not surprisingly, they tended to drop out of the trial. As a result, that 140-patient Phase II trial had to be stopped and a placebo had to be developed to enable blinding, so that patients would not know whether they were receiving DCVax or a placebo.” — NWBIo 10K + 10Qs
Thanks Tadasana.
Some who post here would like to believe that during the open enrollment period the company only enrolled 3 patients — 2 vaccine and 1 placebo! Talk about reading context into simply company SEC words! Hard to imagine how smart people would conclude that the company only enrolled 1 placebo patient during that open trial period. Clearly they enrolled many more than that as they redesigned the study to created an undistinguishable placebo. It wasn’t over 1 placebo enrolled patients that they did this. Clearly they don’t see that those placebo drop out patients are not 1 patients. But hey some want to believe 50 screened patients led to 3 enrolled patients, 1 placebo. Oh well. :)
Of course the randomization has always been 2:1. I’ve been arguing that all along! What you don’t seem to get is they failed to meet it perfectly during the open period. They informed as they had issues doing so, and you ignore it. They account for discrepancies in the SAP. How exactly they do so, we’ll eventually learn. They haven’t, as you like to believe “enrolled the last 31 patients to vaccine only”. That’s just wacky. They told us it’s a 2:1 randomization. They told us it wasn’t perfect early on. Again you choose to ignore clear SEC statements in favor of your own opinions.
How about you instead admit that you simply interpreted what I had written wrong. In fact my post that you don’t understand clearly states that the company they stopped enrolling the open label trial and redesigned the trial with a placebo control. I even used the words double blinded and 2008 in the same sentence.
“The company shared enrollment counts in 10Q when the trial began as a double blinded placebo controlled trial. And as of Sept 2008, count was at 11. “ — my post from earlier today
Never once did I state the blinded randomized trial started in 2011! Never once have I said they didn’t do 2:1 randomization. What I said is they failed to meet placebo enrollment in open trial portion of this same trial. Pretty clear on that.
Here are other sections within my post that clearly show the double blinded trial started in 2008.
Following up on these results, in 2007-2008, the Company designed and began a 140-patient randomized, controlled Phase II trial but without a placebo and without blinding (which can only be achieved with a placebo that is indistinguishable from the new treatment being tested), as no placebo then existed for a living cell product like DCVax. Unfortunately, without a placebo and blinding, patients who were randomized to the control group in the trial knew that this was the case – and, not surprisingly, they tended to drop out of the trial. As a result, that 140-patient Phase II trial had to be stopped and a placebo had to be developed to enable blinding, so that patients would not know whether they were receiving DCVax or a placebo.” — NWBIo 10K + 10Qs
“We obtained a new FDA clearance and re-approvals by all the clinical sites, and commenced the new Phase II trial in early 2008. Unfortunately, we had only been underway for a short period when the economic crisis hit. We were able to keep the trial open, and continue treating the patients already enrolled in the trial, but we had to suspend new enrollment of additional patients into the trial. This suspension continued through the end of 2010, solely due to the severe economic downturn and resulting resource constraints.”
June 2008 10Q (released on August 19, 2008): "to date only SIX patients have enrolled in the clinical trial, which is designed to include 240-patients. Given our lack of funding, it is unclear how quickly we will be able to increase enrollment, if at all. unsure if they could enroll more, financial constraints.”
Sept 2008 10Q (released on November 19, 2008): "to date only ELEVEN patients have enrolled in the clinical trial, which is designed to include 240-patients. Given our lack of funding, it is unclear how quickly we will be able to increase enrollment, if at all.”
You’re doing what you always do, adding unbelievable context to my post. Never ever did I state that the double blinded trial started in 2011. What I said is the 2011 is referred to as the restart period. And the 33 patients in the Vanguard period — which is a mix of both open and double-blinded patients, are only vaccine. They don’t use any 2:1 placebo data from that period because RANO started in 2011.
Stop twisting my posts. If you can’t understand them ask.
Recruitment started in May 2011. Enrollment is typically 3 months later. The protocol matches August 2011. You missed it.
This is fact.
NWBO May 2011 Enrollment PR: "To date, 33 patients have already been enrolled in this ongoing 240-patient GBM brain cancer trial and its information arm an have been proceeding through the treatment regimen and follow-up.”
And
“Efficacy will also be reviewed at the two interim analyses plus one final
analysis. Overall cohort (i.e., all data from the beginning of the study, followed by the “vanguard” cohort – i.e. those patients originally enrolled prior to the hold and followed up to the current time, and a “restart cohort”, i.e., those follow-up since the restart of the clinical trial (i.e., since August 2011). Although the primary view is towards all patients enrolled (i.e. overall cohort), a consistency of effect across subsets would be the primary intent of these additional cuts.”
Again, what is not clear for you is that they account for poor placebo enrollment into their statistical analysis. We know for a fact that they were at 33 patients by 2011, not 16 as you and others assert. You’re trying to present your interpretation as facts. And they are not. The enrollment curve he used simply told us that 1/2 the patients were enrolled by May 2015. And the other half by end of the enrollment period. I’m guessing that you and others are reading data lines on chart and making up number to fit some wacky theory. In fact, you have never given proof of where the number 16 prior to 2011 came from. You have none, as your information is not accurate.
Here’s the data he gave us with enrollment.
https://www.nwbio.com/NWBio_ASCO_Update_On_Trials_6-5-17.pdf
Your version of the facts has serious inconsistencies. Mine does not. The data remains blinded so i have always viewed his chart as an approximation. There are only a few things we can take away with seriousness from information they shared on the enrollment data, one of which was mid-point and the end of enrollment and the number 16 you fabricate is not one of them. But when the facts don’t align with your view you tend to view them as inaccurate.
His enrollment curve is that of the double blinded patients only. It’s not an exact representation of the overall cohort. Clearly you missed that. They were not at 16 patients in the overall cohort. They may have been at 16 in the double blinded. But they were not at 16 at 2011 restart.
The company informed us through legal documents that enrollment stood at 33 prior to August 2011 restart. You choose to ignore that fact. I, however, have not. That is the Vanguard numbers. The Vanguard period includes a portion of the double blinded trial. Whether that number was 11 or 16 doesn’t matter. What matters is 33 patients prior to 2011 restart will be included into the overall analysis. And we know for a fact that they had a extremely difficult time enrolling placebo patients early on. You’re trying to suggest that the Open label vaccine patients are not going to be included into the survival data somehow simply because Bosch’s double blinded enrollment chart does not include them. That we also know isn’t true.
I conclude that they didn’t keep placebo patients data from early on, regardless that they were a combination of open and double blinded, failed 2:1 perfect randomization. I conclude that they will not include the placebo patient data before RANO criteria. They need consistency with imaging criteria. The protocol confirms they may need to make cuts. My conclusion matches everything we have been told about those early on enrolled patients. Choose to believe what you want but you telling me how Bosch’s enrollment curve didn’t include open label data to me is irrelevant. The overall cohort includes those 33 patients.
Good day
Why is enrollment not exactly 2:1 randomization?
Short Answer: The 33 patients. These were vaccine patients who were enrolled during the Vanguard period.
331 overall patient trial
- 33 vaccine patients (vanguard period) =
298 patients (restart period “2011 onward)
298 patients randomized 2:1 =
199 vaccine
99 placebo
Longer answer, with further explanation, below. I’ll use company quotes “”, throughout my explanation of the facts.
NWBO May 2011 Enrollment PR: "To date, 33 patients have already been enrolled in this ongoing 240-patient GBM brain cancer trial and its information arm an have been proceeding through the treatment regimen and follow-up.”
The 2:1 randomization not being exactly 2:1 likely, in part, has to do with the different trial periods. The restart after the study pause which occurred in 2009 and 2010 enrollment study at 33 patients.
At one point this Phase III study was a Phase II 2:1 open label trial. Open label means patients knew whether or not they would receive their personalized vaccine. But after open randomization the placebo arm patients (no placebo at the time) would immediately drop out once the patients learned they were not going to get their vaccine. The Company used the following words about the open label placebo patients: “not surprisingly, they tended to drop out of the trial”. I’m suggesting that is where the 2:1 discretion lies — all open label placebo patients didn’t remain in the study, at all. And so the earliest enrolled patients were essentially all vaccine patients. Instead of ending with a 2:1 randomization, the trial ended up randomizing 22:0 (or whatever the count was at the time, from the 50 or so screened). None of the open placebo enrolled patients were followed until death as they all withdrew consent early on. They didn’t censor patients who dropped out at day zero randomization. They simply couldn’t get the placebo arm randomization done. And so they stopped randomizing patients openly as they couldn’t get a 2:1 randomization met. Since randomization failed, they worked with the FDA to designed the on-going Phase II study, as a double-blinded, placebo control, and created a placebo that was indistinguishable from DCVax-L. Now that said, this 2:1 open randomization period which failed to meet 2:1 randomization standard is still part of this Phase III trial and that’s why the numbers are off. They never discarded the vaccine data they accumulated.
More proof from company records about how impossible it was to maintain placebo enrollment:
“Following up on these results, in 2007-2008, the Company designed and began a 140-patient randomized, controlled Phase II trial but without a placebo and without blinding (which can only be achieved with a placebo that is indistinguishable from the new treatment being tested), as no placebo then existed for a living cell product like DCVax. Unfortunately, without a placebo and blinding, patients who were randomized to the control group in the trial knew that this was the case – and, not surprisingly, they tended to drop out of the trial. As a result, that 140-patient Phase II trial had to be stopped and a placebo had to be developed to enable blinding, so that patients would not know whether they were receiving DCVax or a placebo.” — NWBIo 10K + 10Qs
So far I accounted for 22 patients open label that we’re all vaccine. Pretty easy to understand my logic. Old interviews with lead investigators revealed that 22 patient count long ago. But what about the other 11 patients? The company shared enrollment counts in 10Q when the trial began as a double blinded placebo controlled trial. And as of Sept 2008, count was at 11.
“We obtained a new FDA clearance and re-approvals by all the clinical sites, and commenced the new Phase II trial in early 2008. Unfortunately, we had only been underway for a short period when the economic crisis hit. We were able to keep the trial open, and continue treating the patients already enrolled in the trial, but we had to suspend new enrollment of additional patients into the trial. This suspension continued through the end of 2010, solely due to the severe economic downturn and resulting resource constraints.”
June 2008 10Q (released on August 19, 2008): "to date only SIX patients have enrolled in the clinical trial, which is designed to include 240-patients. Given our lack of funding, it is unclear how quickly we will be able to increase enrollment, if at all. unsure if they could enroll more, financial constraints.”
Sept 2008 10Q (released on November 19, 2008): "to date only ELEVEN patients have enrolled in the clinical trial, which is designed to include 240-patients. Given our lack of funding, it is unclear how quickly we will be able to increase enrollment, if at all.”
Again, it was reported to us that 33 patients were in the trial before the trial resumed recruitment in 2011. I’m suggesting every last one of those patients that the trial continued to follow were vaccine only patients and the trial didn’t keep any data on placebo patients. Company had no funds and were going to potential fold. Once they had funds to resume it was almost two years later. That “Vanguard” data would be analyzed separately and as part of the main arm. They didn’t keep placebo data. It didn’t make sense to as the trial needed a controlled image criteria. When the trial resumed in 2011 it was to RANO criteria once patients were randomized.
“14. CRITERIA FOR ENDPOINT EVALUATIONS
Disease progression is assessed by MRI, including T1, T2 and FLAIR sequences, which can be supplemented with additional imaging modalities including (but not necessarily limited to) perfusion MR, perfusion CT, or other imaging modalities (conforming to local regulation). All images are subject to independent central review following a prospectively formulated review charter.” — NWBio protocol.
As a reminder, the protocol entailed reviewing the final analysis according to the enrollment period.
“Efficacy will also be reviewed at the two interim analyses plus one final
analysis. Overall cohort (i.e., all data from the beginning of the study, followed by the “vanguard” cohort – i.e. those patients originally enrolled prior to the hold and followed up to the current time, and a “restart cohort”, i.e., those follow-up since the restart of the clinical trial (i.e., since August 2011). Although the primary view is towards all patients enrolled (i.e. overall cohort), a consistency of effect across subsets would be the primary intent of these additional cuts.” — NWBio protocol
Prior to the trial restart, McDonald criteria was used. Upon the restart, RANO criteria was used. And thus, when the protocol mentions “ a consistence of effects” with regard to the primary endpoint, it’s clear to me the “ additional cuts” refer to Vanguard progression events. Because difference imaging criteria was used to determine progression, neither vaccine of placebo data progression events would needed for the endpoint analyses from the Vanguard period . And considering there was a) no open label placebo enrollment that stuck and b) low enrollment which used old imaging criteria — it made no sense to use the limited survival data they had on placebo. The survival data on vaccine patients, that, however, would be useful to exam effects across enrollment periods.
Again 298 were enrolled 2:1 after the restart. It’s accurate. Company has always enrolled 2:1. They just haven’t successfully kept early on placebo patients or placebo data simply became informational, but not trial worthy, as prior to 2011 patient progression events were not analyzed using RANO.
Hope that helps.
Hi Biosector investor,
I totally am. Hope you are too. :)
Patients were randomized 2:1. We know according to SEC documents that they lost placebo patients early on.
They have in the SAP plan on how to deal with those enrollment years. And yes, the blinded portion of the trial from 2011 on 2:1. We were already told exactly how many 2:1 they had from that period too. Even back then it was 2:1 randomization those years too. But suspect in the end they only had mostly vaccine since then didn’t have a viable undistinguishable vaccine. So in theory they did randomize the entire trial 2:1. Since it’s analyzed by site, each site has its own 2:1 randomization. If it’s not due to open label full enrolled vaccine cohort, but completely empty placebo cohort (again they notified us in SEC statements they had issues filling that cohort), then it’s a 80 site small difference.
DGDW,
The patients in the open label years were not blinded. They knew from the start that they were not getting placebo. And so they dropped out once they got their patient assignment. What would happen is patients would sign up for the trial and take their chances on 1:2 randomization. If they were put in the vaccine arm, they stayed. If they were put in the placebo arm, they dropped out. was impossible for NWBO to keep placebo patients when the trial opened in 2007. And so they lost the placebos that made up the 1 placebo : 2 vaccine randomization for those years. And that is why I predict the numbers at the end don’t match up 2:1 randomization. The open enrollment period ended up being probably 100% vaccine.
Totally agree on they wanted to try something else. I would have done the same thing. :)
Think I figured out why the 2:1 numbers don’t match. Short answer is the Vanguard “open label” trial period. It’s was still a 2:1 randomization, but the patients from that period, that were randomized to placebo group, prior to the trial being blinded or having a true “placebo”, tended to drop out. Only vaccine patients stayed in. But when the trial resumed in 2011, a new period began, blinded trial with a undistinguishable placebo. Forgot how many patients NWBO told us it ended up being exactly in that Vanguard, but it was close to 30 from what I can remember.
See SEC below:
“SEC 10K 2008 Statement: The study was not blinded because there was no available approach for making a placebo that was indistinguishable from the DCVax®-L. Almost 50 patients were screened at 4 clinical sites. However, patients were reluctant to enroll in the study when faced with a 33% chance of being randomized into the control arm of the study under which they will receive standard of care alone.
Following up on these results, in 2007-2008, the Company designed and began a 140-patient randomized, controlled Phase II trial but without a placebo and without blinding (which can only be achieved with a placebo that is indistinguishable from the new treatment being tested), as no placebo then existed for a living cell product like DCVax. Unfortunately, without a placebo and blinding, patients who were randomized to the control group in the trial knew that this was the case – and, not surprisingly, they tended to drop out of the trial. As a result, that 140-patient Phase II trial had to be stopped and a placebo had to be developed to enable blinding, so that patients would not know whether they were receiving DCVax or a placebo.?
We obtained a new FDA clearance and re-approvals by all the clinical sites, and commenced the new Phase II trial in early 2008. Unfortunately, we had only been underway for a short period when the economic crisis hit. We were able to keep the trial open, and continue treating the patients already enrolled in the trial, but we had to suspend new enrollment of additional patients into the trial. This suspension continued through the end of 2010, solely due to the severe economic downturn and resulting resource constraints.”
And the protocol does call for analyzing the periods together and then somewhat separately.
Overall cohort (i.e., all data from the beginning of the study, followed by the “vanguard” cohort – i.e. those patients originally enrolled prior to the hold and followed up to the current time, and a “restart cohort”, i.e., those follow-up since the restart of the clinical trial (i.e., since August 2011). Although the primary view is towards all patients enrolled (i.e. overall cohort), a consistency of effect across subsets would be the primary intent of these additional cuts. “ — protocol
Found the part about “protecting them from getting tumor reoccurrence” as interesting. Wondering how many patients will make up the long tail of no progression event.
From the link you posted:
“The researchers found that the average survival rate of those receiving the vaccine jumped to over 23 months. Another 30% of patients lived for more than 30 months and just under 25% survived for 36 months.
“What's particularly impressive about immunotherapy trials is that there seems to be a population of about 20 to 30% of patients who are living significantly longer than expected,” Liau said. “And those are the people in whom we think there may be a particularly strong immune response against their cancer that is protecting them from getting tumor reoccurrence.”
Last year, Linda Liau told us that many of then 10 survivors within the Compassionate Use Arm were without recurrence. And while yes, those indeterminate patients failed to make it into the main arm study due to suspicion of early progression, the next follow up MRI scan revealed no progression event. She could be adding those too.
From an old post, below. Note, I’m not sure if the links will still work, but what I wrote remains accurate.
—-
Consent form is for 36 months after enrollment. End of trial is considered 36 months for non-crossover patients.
"The duration of your participation in this study is approximately 36 months. Long-term follow-up may be beyond the 36 months of the clinical trial. Your participation in this study is entirely voluntary. You should read the information below, and ask questions about anything you do not understand, before deciding whether or not to participate. " -- consent form
http://neurosurgery.ucla.edu/Workfiles/Site-Neurosurgery/Brain_Tumor_Program/DCVax%20Consent.pdf
"All subjects who have undergone the leukapheresis will receive up to 10 injections of the study agent or placebo over the course of 3 years, except for those patients for whom it is determined that it is not safe for them to receive either treatment. All patients in the study will be followed for the collection of data related to progression or re-growth of brain cancer, and survival for a period of up to 36 months. In addition, long-term progression or re-growth of your brain cancer as well as survival, or overall survival will be followed beyond the 36 months of the clinical trial." -- consent form
http://neurosurgery.ucla.edu/Workfiles/Site-Neurosurgery/Brain_Tumor_Program/11-000686-%20Main%20ICF%2007Nov2012.pdf
See page 14 for treatment MRI visit up to 36 months post enrollment.
Trial protocol called for unblinding at sufficient PFS events (248 events); and alluded to OS (233 events) as well. They have surpassed both, so anything is possible. But the trial consent officially ends once the last patient is 36 months from randomization. I sincerely doubt that the FDA will allow them to go beyond data gathering of a few months. Also that would mean they would have approximately 2 more years of data to add to the long tail look of recently reported early first blended look. That look was when the last patient in was only 16 months in. No excuses then to not unblind IMHO. None.
That’s impressive. I’ll try to look through old research to see what I have.
Pretty sure Stupp second surgery was around 29% if memory serves.
Okay, back to work I go.
I forgot. That’s a much lower percentage than Stupp. Wasn’t Stupp about 29% resection.
Also think you have it incorrect, I think there is research out there which was previously posted that second resection upon progression only adds a couple of months.
Last, rate of Avastin use is good so far. My bet is it’s very synergistic with DCVax-L.
Off an old post of mine:
I personally believe they are seeing a synergistic combination with Bevacizumab (Avastin) after recurrence. Second surgery is not needed to use Avastin. Avastin was only approved for recurrent GBM in May 2009 and their studies started before then. Hypoxia significantly inhibits the infiltration of immune cells into tumor tissue. Bevacizumab is believed to normalize tumor vasculature and decrease tumor hypoxic area. Mesenchymal patients have varying degrees of Tumor infiltrating lymphocytes (TIL) before therapy. The vaccine is said to increase TIL afterwards. The combinations of these two therapies could be enhance immune response infiltrated into tumor. They already have historical data on how long patients survive with salvage therapies after progression.
Ahh, I wrote “unblinded” look. I hope folks know that I meant blended blinded look. Before anyone calls me out on it, correcting my own mistake.
If the company can unblind anytime they want it means it has been reached. We were waiting for one more death as of last July numbers. I posted older PRs, which were reported last year. Results they reported at ASCO were last year’s unblinded look. And with the death event rate they reported, no one should really think 233 deaths haven’t been crossed. It had most definitely been crossed. Best,
It’s possible this summer, since they are doing a data sweep now. But I perceive that as unlikely. See last post.
I don’t think they will end the trial before 36 months sweep is complete. As more patients die, the multi month sweep could take less time. Meaning if let’s say 35 of the 80 clinic sites have no more patients alive on this current round sweep, they wouldn’t need to revisit those sites to get an update, they’d already have final data on those sites.
Yes. Sometime in Nov makes the last patient enrolled for 36 months. There is still the multiple month process to data lock. I don’t think it will take 3 months again, but it could take us into the new year. Basing my opinion on NWBio statement from the Feb 2017 PR - which incidentally they alluded that the trial is going through a current data scrub now even in their most recent PR.
“There are 331 patients enrolled in the Trial. The Trial endpoints involve thresholds of 248 “events” for PFS and 233 “events” for OS. PFS events are primarily tumor progression (i.e., recurrence), although they can occasionally be patient deaths which occur without prior evidence of tumor recurrence. OS events are patient deaths. The PFS and OS events are continuing to accumulate as the Trial continues. The PFS events have surpassed the 248-event threshold, but the OS events have not yet reached the 233-event threshold. Based upon the pace of OS events during the last six to eight months, the Company’s current anticipation is that it will be several months until the Trial reaches 233 OS events.
Dr. Linda Liau, Principal Investigator of the DCVax®-L Trial commented: “It is gratifying to have the hold removed from the Trial and exciting to see this Trial now moving towards completion, although of course the longer it takes for PFS and OS events to accrue, the better the patients in the Trial are doing.”
The external parties managing the Trial are now moving forward with the process to reach data lock. In this process, all data from all of the treatment visits and follow up visits for all 331 patients in the Trial, must be subjected to quality control checking. The process involves in-person monitoring visits to all of the 80-plus sites in four countries to review the files onsite, as well as other documentary confirmation and checking of all MRI images. As such, it is a multi-month process. While this process is under way, OS and PFS events will continue to accumulate.
The Trial will reach data lock when the threshold events have been reached and the quality control checking has been completed for both the PFS and OS endpoints.
When data lock is reached, external statisticians and experts will make an independent analysis of the Trial data. The Company will remain blinded until data lock has been reached and the external data analysis has been completed.” — Portion of Feb 6, 2017 NWBio
And most recent press release confirms that they are going through an entire trial sweep right now. Sure they could data lock once it’s done. And if they seriously run out of a way to raise money without going to toxic spiral lenders, they might choose to unblind this summer, with the data aged another year. But I don’t think that will happen. I believe they will just report it, and then use that data to present another blinded blended data update in December 2018 at ANO Conference, as we early wait for the true unblinding to occur following the last patient in passing the 36 month / consent period end of the trial.
“The reported data are from the most recent prior full data collection in 2017. The Company is undertaking another full data collection, which is a multi-month process and will be continuing over the coming months.” — May 29, 2018 NWBio PR
They have lots of data that they could give us an post-hoc update on. For instance, it would be good to know how long and fat the tail for the PsPD in the compassionate use arm patient arm are soon.
Yes, on those warrants.
Yes, believe he signed it just the other day. :)
I think it could be a bit more patients than they currently process for compassionate use. Remember most hospitals allow for saving of the tumor. And while GBM is the only Phase III study open, they could in theory kick off their Phase II portion of their Phase I/II Direct. Patients will need to exhaust all clinical trial treatment options. With GBM that’s a bit more easier to do as there is a much shorter window to enter recurrent GBM trials. They’re going to need manpower to get these processed. But at this point there is less work to do for them with the clinical process. It’s just a waiting game for long tail. And so, I do think that it’s helpful the have legal backgrounds internally. They will know how to get this done. And they have quite of number of GBM doctors involved in this study so it may be that it just adds a bit more work to the clinicians desk. Really hopeful that terminally ill patients will gain access to Phase II/III clinical trial safety tested biological. Patients in the webcast went through the grueling process. Imagine patients here will too.
I’m not worried about dilution. Others may be, but I’m not. They have avoided true spiral debt so far. I think that will continue. I thought price action wasn’t bad. Someone is buying possibly, imho. I honestly think that they will make it to the end of the study, with the lights on. I also think that we will get more updates at other conferences. Good things ahead. :) But yes, I continue to believe that we have to wait until the trial 36 months go by before they consider unblinding. Anytime after last patient is 36 months out it could happen. But I don’t think they’ll ask for the 80 site sweep for final results until every last patient is 36 months out from treatment. And I don’t mean 36 months out from surgery. I mean they won’t do the Statistical analysis until they go through the lengthly process of finalizing each site imho. In the meantime, hope they make some money on RTT. And I do hope that they are able to get the price over where current warrants are.
Hope all is well.
Right To Try: Questions Answered Right To Try allows terminally ill Americans to try medicines that have passed Phase I of the FDA approval process and remain in clinical trials, but are not yet widely available. Right To Try could expand access to potentially life-saving treatments years before patients would normally be able to access them. In little over a year, Right To Try has become law in 33 states and counting: Alabama, Arizona, Arkansas, California, Colorado, Connecticut, Florida, Georgia, Idaho, Illinois, Indiana, Louisiana, Maine, Michigan, Minnesota, Mississippi, Missouri, Montana, Nevada, New Hampshire, North Carolina, North Dakota, Ohio, Oklahoma, Oregon, South Carolina, South Dakota, Tennessee, Texas, Utah, Virginia, West Virginia and Wyoming. It has passed with overwhelming bipartisan support in all 32 states. In fact, in most states, it has passed through the state legislature unanimously. This document answers the common questions about the impact of Right To Try. Question: What is the Right To Try Act? Answer: Right To Try is state legislation that allows terminally ill patients to work with their doctors and drug or device manufacturers to access investigational treatments that have passed the FDA’s safety testing phase (Phase I), but are not yet widely available. Question: Why was Right To Try developed? Answer: More than 1 million Americans die from a terminal illness every year. Many spend years searching for a potential cure, or struggle in vain to get accepted into a clinical trial. Unfortunately, FDA red tape and government regulations restrict access to promising new treatments, and sometimes for those who do get access, it’s too late. Fewer than 3 percent of terminally ill patients gain access to investigational treatments through clinical trials. Right To Try was designed to help the other 97 percent. Question: Right To Try advocates state that the FDA is the key obstacle to patients getting permission to try investigational treatments. In fact, the FDA approves 99% of requests it receives from physicians seeking to try investigational drugs on seriously or terminally ill patients. So why is Right To Try needed? Answer: Only about 1,000 people make it through the FDA’s “compassionate use” application process each year. The process is complicated, time-consuming, and expensive. The first step in the process requires a doctor to complete an application that
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try a medicine that has been shown to work on other people, they should have that right. Right To Try laws simply afford terminal patients, unable to participate in restrictive clinical trials, the same access to investigational medications that the FDA is already allowing for clinical trial patients enrolled in Phase II and III tests. Question: Right to try laws claim to give terminal patients access to unapproved treatments such as investigational drugs, biologics, and devices after these patients have exhausted all approved treatment options. In fact, there is no evidence that Right To Try laws have helped anyone. Why is that? Answer: While Right To Try laws have been passing swiftly nationwide, they are still new. The first law passed just over a year ago. As with any new policy that makes a significant change to the way things are currently done, it will take time for doctors, patients, and drug manufacturers to learn about Right To Try and what is and is not permissible. The Goldwater Institute has been working with doctors in a handful of Right To Try states to prepare for making treatments available under the law. Question: The FDA controls drug approval, and it trumps state law. How can states legally do this? Answer: It is well established that the U.S. Constitution was designed to provide a floor of protection for individual rights, not a ceiling. States may provide additional and greater protections of individual rights—and all of them do. For instance many states protect free speech rights to a greater extent than the U.S. Constitution, others provide greater privacy rights. While the Supreme Court has never addressed Right To Try specifically, it has held that states have great latitude in regulating health and safety, including medical standards, which are primarily and historically protected as a matter of local concern. The Supreme Court has recognized a state’s power to govern the practice of medicine involving terminal patients. For example, in Gonzales v. Oregon, the Court upheld the state’s “right to die” law, enacted by Oregon voters, over the objections of the U.S. Attorney General, who argued that federal law preempted the state law. Considering the Supreme Court deferred to a state’s authority to protect a person’s right to die, it would be consistent for the Court to protect a patient’s right to try to save his own life. In Abigail Alliance v. Von Eschenbach, a three judge panel found that the due process clause of the 5th Amendment guaranteed terminally ill patients’ access to investigational treatments that had passed FDA Phase I safety testing. However, upon a request by the FDA for a rehearing by the full court, that ruling was reversed. That decision is not binding on any other federal court outside the D.C. Circuit. Most important, it did not involve the same scenario presented by Right To Try, including the fact that no state law protecting access to investigational drugs was in place at the time.
Answer: Right To Try will not negatively impact the clinical trial process—it may even complement it. Investigational medicines that are available to terminal patients through Right To Try must be part of an on-going clinical trial. If a drug is removed from the clinical trial process, it will no longer be available to patients under Right To Try. Furthermore, in most states in order to be eligible for a drug under Right To Try the patient cannot be eligible for or able to enroll in a clinical trial. Only 3 percent of patients today are enrolled in clinical trials, and the trials often exclude the sickest people. Right To Try will not reduce the number of people participating in trials, but it will allow more patients to access drugs being tested, giving doctors and scientists even more information about safety and effectiveness.
http://righttotry.org/wp-content/uploads/2017/01/RTT-FAQ_QA.pdf