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Sorry if this interview with Linda Liau (Dec. 2017) has been posted earlier.
Future Outlook on Glioblastomas.
Martand Bhagavatula/ Dec.2017
" With just a 10% three-year survival rate and 90% recurrence rate, glioblastomas are among the deadliest tumors. Most prevalent in adults, the tumor increases in frequency with age and gender, striking men more than women [1]. I recently spoke with Dr. Linda M. Liau, MD, PhD, MBA, a professor, director of the brain tumor program, and chair of the neurosurgical department at the University of California, Los Angeles about her work concerning glioblastomas. She currently works in the field of advances in glioblastoma treatments, and took the time to answer questions regarding the approaches of modern treatments and what the future holds."
https://youthneuro.org/journal/article/150/
beartrap12,
Watch this (Dec.2016):
We were LIVE on Facebook with Charles Cobbs, MD, Director of the Ben and Catherine Ivy Center for Advanced Brain Tumor Treatment and Linda Liau, MD, Director, Brain Tumor Program, UCLA School of Medicine taking all of your questions about brain tumor treatments & advancements.
LIVE Q&A - Brain Tumor Treatments & Advancements
Min. 22, 54s
maverick_1,
Thanks!
DC as well!
The reason why I am still alive is because in 2011 my sister and my mom hooked me up with an experimental trial of the Dendritic Vaccine. That particular study had started in the US at Duke university, and the Italians were the first to follow that trial here in Rome and the rest of Europe followed two years later. The fact that I am still alive does somehow makes them very excited, it seems to work… once in a while… for particular people with particular types of bodies. There are now quite a few trials about this all over Europe.
http://thefinchinmybrain.com/index.php/2019/04/11/blog-14/
PCORI HEALTH CARE HORIZON SCANNING SYSTEM.
HIGH POTENTIAL DISRUPTION REPORT • MAY 2019
P.5
Table 1 lists 4 topics selected for inclusion during the High Potential Disruption Report decision meeting. Included topics are those that a majority of the voting team agreed had high potential for disruption, based on stakeholder ratings and comments and available data. Topics are listed alphabetically by Topic Title. The report below follows the same organization.
Table 1. Included Topics for Priority Area: Cancer
Topic Title
-DCVax-L for Treating Glioblastoma Multiforme (Adjuvant Setting).
-Pembrolizumab (Keytruda) for Treating Recurrent or Metastatic Head and Neck Squamous Cell Carcinoma (First-Line Setting).
-Pexidartinib for Treating Tenosynovial Giant Cell Tumors.
-Sodium Thiosulfate (Pedmark) for Preventing Cisplatin-Mediated Ototoxicity.
P.6
DCVax-L for Treating Newly Diagnosed Glioblastoma Multiforme.
Highlights: https://www.pcori.org/sites/default/files/PCORI-Health-Care-Horizon-Scanning-System-High-Potential-Disruption-Report-May-2019.pdf
Kristyn Power ( see testimony ASCO 2018:
My Dad has been treated with DCVax-L. He received the treatment at his second recurrence and has received only the vaccine since 2015. He continues to thrive and will have his 5 year anniversary next month.
— Kristyn Power, CFA (@KristynPower) June 2, 2019
Doc logic,
IMO we know what happened to the original 12 (or 11) LTFU patients.
See presentation Linda Liau SNO Nov. 2018.
unfortunately by December 2016 we already had the 331 patients with 232 treatment and 99 placebos set in stone.
Dr. Liau knew that the randomization of 2.3:1 was permanent.
Remember Dr. Liau's presentation way back during December 2016 when she stated that about 86% of the trial had at some point received the vaccine and therefore about 14% did not. Her statement may have been based on data collected months prior to December 2016 and implied at the time that 46 of the 99 placebos had not yet crossed over.
However, the JTM publication that was based on the data collected during March 2017 (only 3 months after LL's presentation) stated that about 90% of the trial had received DCVax-L at some point and implied that 10% of the trial or only about 33 patients had not yet crossed over.
NWBO initiated the hold in Germany and has maintained that hold there to this day. I believe the Germans would have divulged the reason(s) for the hold if NWBO did not initiate it voluntarily and, in my opinion, NWBO had business reasons, ie Mr. Neil Woodford and or others, for not wanting reasons for the hold being divulged. Best wishes.
Some blogs and social media comments have noted that the EudraCT trials database in Europe states that there is a “Temporary Halt” of the trial in Germany. In actuality, the trial status in Germany is that the trial is ongoing as noted above, and the Company has only undertaken a temporary suspension of new screening.
The Company has sought to have the EudraCT listing corrected, but the database includes only certain pre-specified categories and there is no category that corresponds to a temporary suspension of new screening only, while a trial is ongoing.”
XenaLives,
Thank you for the information! Unfortunately the Wayback Machine doesn't have that page archived.
In the meantime i found additional information about the issue.
Nothing new, but anyone else notice they finally posted the June 4th press release on https://nwbio.com/press-releases/ ? I use a tool to track changes on web pages and got an alert, which is how I noticed.
So if Germany put the brakes on, and Les mentions to diver that they don't want to have any other patients being treated unfairly (something like that)... that might add up to the company then deciding make the halt trial wide.
SpursFan08,
here is the PR June 10, 2019:
Cognate BioServices, Inc. (Memphis, TN) receives Statement of Compliance to EU Good Manufacturing Practice for manufacture of Advanced Therapeutic Medicinal Products.
https://www.prnewswire.com/news-releases/cognate-bioservices-inc-memphis-tn-receives-statement-of-compliance-to-eu-good-manufacturing-practice-for-manufacture-of-advanced-therapeutic-medicinal-products-300864397.html
I don't have any axe to grind here, but it seems to me that some DCVaxL manufacture for the trial likely did occur in the UK at Kings, between 2013 and 2015.
Fraunhofer IZI Annual Report 2013 Page 23
a real highlight of 2013 was when we started to manufacture and conduct quality controls for investigational medicinal products with regard to two of our key projects: CVac™ on behalf of Prima BioMed Ltd. and DCVax®-L for Northwest Biotherapeutics Inc./Cognate BioServices Inc.
https://www.izi.fraunhofer.de/content/dam/izi/en/documents/Publications/Annual_Report_IZI_2013.pdf
Page 34 - Fraunhofer IZI Annual Report 2015.
Furthermore, applications to conduct respective clinical trials were submitted to the responsible authorities in the United Kingdom and Germany and initially authorized in the UK. Consequently, in June 2013, production commenced for the treatment of patients there. Authorization of the trial in Germany the following year then also gave the green light for the production of batches for German patients, which has been ongoing since August 2014.
https://www.izi.fraunhofer.de/content/dam/izi/en/documents/Publications/Annual_Report_IZI_2015.pdf
Longfellow95,
Thank you for the information!!!
Shame they are not telling us what was the nature of the amendments..
The other thing that comes to mind for a substantial amendment, is change of UK manufacturing site. Around this time, UK DCVaxL manufacture switched from Kings in S.London to CCGTT at the Royal Free in N.London.
We've never known why this switch of manufacturing site occurred, but it may account for one of the listed amendments.
Both the study treatment (DCVax-L) and placebo (PBMC) were prepared by Cognate BioServices, Inc. for all patients in the US and Canada, and by Cognate and the Fraunhofer Institute for Cell Therapy together for patients in Europe,
during the chemoradiotherapy period before the baseline visit. The production of DCVax-L involved processing the resected tumor tissue into a lysate, and then collection, purification, differentiation, activation and loading of the autologous DCs. In general, approximately 2 g of tumor tissue was needed to produce the full ten doses for the 36-month treatment and follow-up schedule. The vaccine was aliquoted in individual doses and cryopreserved at?<?150 °C [22]. The doses were stored centrally, and shipped individually to the clinical trial sites.
The very precise study duration is presumably the period in the UK when the study was active. Like elsewhere, the active phase of the trial has been completed for some months, with follow up now restricted to logging ongoing patient event dates.
NHS
Amending an approval
Last updated on 14 May 2019
https://www.hra.nhs.uk/approvals-amendments/amending-approval/
Maybe the Germans are less discerning about value for money.
DC Vax-Brain Phase III trial for GBM- Current
Research type
Research Study
Full title
Protocol 020221: A Phase III Clinical Trial Evaluating DCVax®-L Brain, Autologous Dendritic Cells Pulsed with Tumor Lysate Antigen for the Treatment of Glioblastoma Multiforme
IRAS ID
131576
Contact name
Keyoumars Ashkan
Contact email
k.ashkan@nhs.net
Sponsor organisation
Northwest Biotherapeutics Inc
Eudract number
2011-001977-13
Clinicaltrials.gov Identifier
NCT00045968
Duration of Study in the UK
4 years, 6 months, 31 days
Research summary
The purpose of the study is to determine the safety and efficacy of an investigational therapy called DCVax(R)-Brain in patients with newly diagnosed GBM for whom surgery is indicated. Patient must enter screening at a participating site prior to surgical resection of the tumor. Patients will receive standard of care, including radiation and chemotherapy (including temozolomide) and two out of three will additionally receive DCVax-Brain and the remaining one third will receive placebo. Patients randomized to placebo will have the option to receive DCVax-Brain in a crossover arm upon documented disease progression.
REC name
London - Chelsea Research Ethics Committee
REC reference
11/LO/0957
Date of REC Opinion
5 Oct 2011
REC opinion
Further Information Favourable Opinion
London REC annual reports: April 2014 – March 2015
https://www.hra.nhs.uk/documents/630/ar-lon-chelsea-14-15.pdf
RES Committee London-Chelsea Annual Report 01 April 2014- 31 March 2015.
P.27
Table 10.2: Breakdown of current status of all modified amendments reviewed within the reporting period.
Favourable opinion timeline
Amendment REC Reference:11/LO/0957/AM08/1
Title: DC Vax-Brain Phase III trial for GBM
Version: Substantial Amendment 7
Date: 30/04/2014
Number of Days on clock: 5
London REC annual reports: April 2015 – March 2016
https://www.hra.nhs.uk/documents/702/ar-lon-chelsea-15-16.pdf
RES Committee London-Chelsea Annual Report 01 April 2015- 31 March 2016
P.22 and page 23
Table 10.1: Breakdown of current status of all substantial amendments reviewed within the reporting period.
Amendment REC Reference: 11/LO/0957/AM14
Title: DC Vax-Brain Phase III trial for GBM-Current
Version: Substantial Amendment 9
Date: 21/04/2015
Number of Days on clock: 6
Amendment REC Reference: 11/LO/0957/AM15
Title: DC Vax-Brain Phase III trial for GBM-Current
Version: Substantial Amendment 06
Date: 06/05/2015
Number of Days on clock: 11
Amendment REC Reference: 11/LO/0957/AM16
Title:DC Vax-Brain Phase III trial for GBM-Current
Version: Substantial Amendment 10
Date: 22/07/2015 19
Number of Days on clock: 19
Amendment REC Reference: 11/LO/0957/AM17
Title: DC Vax-Brain Phase III trial for GBM- Current
Version: Substantial Amendment 11
Dated: 12/08/2015
Number of Days on clock: 16
JR111,
I have a question for you. Why didn't the Germans finish enrolling their placebo patients into the trial and why might this be related to NWBO's still in force voluntary hold on the trial portion in Germany when the screening hold was lifted by FDA? I always love to see what the bears try to come up with. Best wishes.
Novocure's recent announcement was for Germany, not the EU. They think they might get some kind of reimbursement from Germany for GBM in October 2020 -- if it's any calculation like France and the UK gave, it's fools gold.
Marzan,
About the UCLA DCVax-L (brain) trials:
See min.3.45:Northwest Biotherapeutics Inc Oppenheimer Healthcare Conf Dec 10th 2013
Artificial intelligence helps to better assess treatment response of brain tumors
No. 21 | 03/04/2019 | by Koh
A team from Heidelberg University Hospital and the German Cancer Research Centre has developed a new method for the automated image analysis of brain tumors. In their recent publication, the authors show that machine learning methods carefully trained on standard magnetic resonance imaging (MRI) are more reliable and precise than established radiological methods in the treatment of brain tumors. Thus, they make a valuable contribution to the individualized treatment of tumors. In addition, the validated method is an important first step towards the automated high-throughput analysis of medical image data of brain tumors.
https://www.dkfz.de/en/presse/pressemitteilungen/2019/dkfz-pm-19-21-Artificial-intelligence-helps-to-better-assess-treatment-response-of-brain-tumors.php
https://www.thelancet.com/journals/lanonc/article/PIIS1470-2045(19)30098-1/fulltext
Definition of codswallop
British
: NONSENSE
Synonyms for codswallop
applesauce [slang], balderdash, baloney (also boloney), beans, bilge, blah (also blah-blah), blarney, blather, blatherskite, blither, bosh, bull [slang], bunk, bunkum (orbuncombe), claptrap, crapola [slang], crock, drivel, drool, fiddle, fiddle-faddle,fiddlesticks, flannel [British], flapdoodle, folderol (also falderal), folly, foolishness,fudge, garbage, guff, hogwash, hokeypokey, hokum, hoodoo, hooey, horsefeathers[slang], humbug, humbuggery, jazz, malarkey (also malarky), moonshine, muck, nerts[slang], nonsense, nuts, piffle, poppycock, punk, rot, rubbish, senselessness,silliness, slush, stupidity, taradiddle (or tarradiddle), tommyrot, tosh, trash,trumpery, twaddle
https://www.merriam-webster.com/dictionary/codswallop
Min. 8 Linda Liau comment about the extended survival in DC-vaccinated patients with mesenchymal gene expression signatures = group of 9 patients (Phase 1)
...half of them continued to live beyond 5 years at the time this was reported and Brad is actually in this group and 4 of this 5 are actually still alive today.....
Rather, since this trial used Macdonald Criteria, there is no confirmatory scan required for progression events. The blinded MRI team look at the MRI and decide progression or not. If progression: the patient is allowed to cross (as he/she was promised when agreeing to participate in the trial)
The initial protocol was written on Macdonald Criteria....... in 2010 we went to RANO and iRANO....
The statement in the trial protocol only says that if a patient does this, they are off trial as far as the primary PFS goes. They would still be followed for OS.
Have you considered the likelihood of DCVax trial patients enrolling in the TOCA rGBM trial upon progression? (AVII77)
All patients were allowed to receive DCVax-L following tumor progression/recurrence, as well as other approved treatments per local practice.
AVII has been exactly on regarding two points he argued.
1. What the median OS would be for the blended ITT, and
2. That DCVax-L can cause significant psPD.
He made these claims long before these were settled matters.
listen at the 20 minute mark. She indicates that with the first iteration of the trial, the “vanguard group” (she doesn’t call it that, but we have referred to that group of 38 as that), those enrolled from 2007/08 to 2010, had very few placebo patients. LL indicates that when the trial rebooted around 2010, and eventually became a P3 trial, it was at this time forward that the trial was fully randomized. At least that’s how I heard it.
"The Company is clarifying that the 32 patients in the Pseudo-Progressor Arm are in addition to the 331 patients enrolled in the Main Arm of the Trial and are not included in the 331. The Company notes that there are 90 patients in other separate arms of the Trial in addition to the 331 patients in the Main Arm, making a total of 421 patients. The 90 patients include the 32 patients in the Pseudo-Progressor Arm, 55 patients in the Information Arm, and 3 patients who were enrolled at the very beginning of the Trial when it was randomized but not yet blinded. The Trial was blinded after those initial patients were enrolled.
In addition to these 421 patients, the Company has treated a substantial number of patients on a compassionate basis under an Expanded Access Protocol."
In December 2006, we commenced recruiting patients with newly diagnosed GBM in a 141 patient Phase II DCVax ® -Brain clinical trial. We planned to carry out the study at 12 to 15 clinical sites. The study was designed as a randomized study in which patients received either DCVax ® -Brain in addition to standard of care or standard of care alone. To date, almost 50 patients have been screened at 4 clinical sites. However, patients have been 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. In order to address this issue we redesigned the study as a randomized, placebo controlled, double blinded study with a cross-over arm allowing control patients to be treated with DCVax ® -Brain in the event that their cancer progresses.
The study size has been increased from 141 to 240 patients and is designed to enable us to petition the FDA for accelerated approval if the study generates results similar to those achieved in earlier Phase I studies. In order to enable rapid enrollment, we are in the process of enrolling 45 to 50 additional clinical sites for this trial. As of April 9, 2008, seven sites are active and a further 31 sites are at various stages of thestart-up process. We are engaged in discussions with the FDA concerning the study design and end points. Depending on trial results, we plan to seek product approval in both the U.S. and the European Union.
We plan to rely on our current DCVax ® -Brain Phase II clinical trial as a single study in support of regulatory approval. However, to date, only eleven patients have enrolled in the clinical trial,
which is designed to include 240 patients. Given our current lack of funding, it is unclear how quickly we will be able to increase enrollment, if at all.
UW Medicine Neurological Surgery Grand Rounds 4.24.19
Linda M Liau, MD, PhD, MBA - Perspectives on Glioblastoma (1994-2019)
Australian Government- National Health and Medical Research Council.
"How clinical trials work."
If the individuals in the group being given the new intervention show a significant improvement, without any serious side-effects, over the control group, then the researchers may end the clinical trial early and seek to change the nature of the clinical trial to afford more patients the opportunity to receive the new intervention.
2015: NWBO did their first data collection! (blinded)
Why would you do a first interim analysis for efficacy in the summer of 2015 when you did a first blinded data collection in 2015? (and they have done it once for the last four years)
Sunday, 01/21/18 05:00:05 PM
Linda Powers:
I can't spell out a formula for you. We do periodic data collections. When we do a data collection, it's about a 3 month process to collect an update. The independent CRO sends physical staff to all of the sites. We have some 80 sites in this trial. A breathing, human person looks at the files at each hospital and looks at the numbers and compares them to the central database. The central database is kept by an independent data company that's separate from the CRO. And, by the way, the company (NWBO) doesn't do any of this. That process generates what are called queries. Anything where a piece of data is missing or inconsistent, is a query. A data collection process can generate several thousand queries. All of them have to be resolved. Only then do you have a clean data set from the collection. Once you have a clean collection, then it goes to the independent statisticians who then tabulate it. So you have the CRO making the in person visits, you have the queries getting resolved and the independent data company holding the clean data set, and you have the independent statisticians tabulating it. It takes about three months to do that process.
We have done it once each for the last three years.
We have not made any announcements about the spring of this year, but, it would be a, uh, reasonable thought that there might be a similar cycle in the spring of this year. And it would be the same process, would take three months or so. As we reported in ASCO last year, a huge number of patients, way more than expected, were still alive. We have to weigh that... how much of an additional home run would we get if we continue vs. going with what we have now.
That 66th event efficacy interim was never conducted. Rather, they resized the trial such that the first efficacy interim would occur at 149 events (still 60% but now 60% of the resized target of 248 PFS events).
It is that 149th event IA, mentioned by NWBO numerous times in early 2015 (yes, 2015, not 2013) where I believe a futility finding was observed. (AVII)
SNO 2018
The top 100 patients – 30% of all patients in the trial – have a Kaplan Meier median survival of 58.4 months.
That means that 50 patients will live 58.4 months or longer.
June 2019 ASCO
Marnix Bosch may be telegraphing that 20% of the ITT group of 331 patients will live 60 months or more.
50/66= 32% improvement.
So you see, I'd argue that all of the indeterminate group were NOT pseudo progression patients (no matter what LL says). And coming from that position, and that I can agree that it's likely 11 were psPD, then the percentages, as I see them, were more like this.
3/11 lived to 7 years - so 27% lived 7 years
5/11 lived to 5 years - so 45% lived to 5 years
mOS of that group of 11 - looks to be about 60 vs. Gunjur (whoever that is) saw 27.4.
Her research interests include translational experimental therapeutics of cell-based immunotherapy for brain tumors
and the characterization of biomarkers of response to immune-based therapies.
She is internationally recognized for her achievements in understanding the immunology of malignant brain tumors and pioneering the use of dendritic cell-based vaccines for glioblastoma. Clinically, she has developed novel ways to map brain function during awake brain tumor surgeries, and specializes in surgery for brain tumors in eloquent areas.
But in reality, when you treat patients, if you give them the option, you tell them if you can live three more months with this therapy, versus, you have a twenty to thirty-five percent chance of living five more years, most patients would actually opt for
that thirty percent chance of living five more years than okay,
I’ll do this and I’ll give you three more months.
And then also I think, as with any treatment, there’s going to be a subset of patients that benefit, and some that do not. Cause obviously with these immunotherapy trials, twenty-five,thirty percent have that long tail.
So in conclusion, brain tumor vaccines are feasible and safe, and can potentially lead to a significant subgroup of long-term, meaning greater than five year survivor, progression-free survivors.
So this is just not being alive, it’s being alive without progression.
And I think, you know, for patients, that is meaningful. Granted, it’s not everybody, like I said, it’s about twenty-five percent,
but if we could identify who those 25% of patients are to get on these trials, that may be meaningful.
Advent Bioservices has a new Chief Operating Officer (since April '19) by the name of Mike Scott.
About Mark Lowdell:
Also involved with several other bio start-ups.
Co-director of Novacure with LP.
Your logic is sound, but, for instance, the info arm does not match up with blended phase three at three years.
Flipper44,
Linda LIau's December 15, 2016 Presentation at Seattle Science.
But in reality, when you treat patients, if you give them the option, you tell them if you can live three more months with this therapy, versus, you have a twenty to thirty-five percent chance of living five more years, most patients would actually opt for that thirty percent chance of living five more years than okay, I’ll do this and I’ll give you three more months.
exwannabe,
My post 231363
Dave Innes
Follow-up survival data from the Information Arm patients who did not qualify for the Phase III trial are encouraging and appear consistent with the blinded interim data from the trial.
In the group of 25 Information Arm patients
who had actual or apparent early tumor recurrence, the follow-up data showed that 40% of the patients lived for 3 years or more, 20% of the patients lived for 5 years or more, and 12% of the patients are still alive at 7 years.
This Information Arm survival data is especially encouraging since this group included patients who already had actual tumor recurrence as well as others who had the appearance of tumor recurrence but who could not be definitely determined.
rogers5729,
Look at slide 33: https://nwbio.com/wp-content/uploads/ASCO-2019-Presentation-FINAL.pdf
7 patients lived for 3 years or more.
3 patients died between 35 and 36 months.
7/25= 28%
IMO 28% (from the Information Arm) appear consistent with the blinded interim data from the trial.
SNO data 2018:
Survival of the whole ITT population at 3 years: 28.2%
Marnix Bosch min.1.50s
Dave Innes
Vice President, Investor Relations
NW Bio?
Highlights Of NW Bio’s Program Update
In The Industry Expert Theater Presentation At ASCO
For immediate release on Tuesday, June 4, 2019
Follow-up survival data from the Information Arm patients who did not qualify for the Phase III trial are encouraging and appear consistent with the blinded interim data from the trial.
In the group of 25 Information Arm patients who had actual or apparent early tumor recurrence, the follow-up data showed that 40% of the patients lived for 3 years or more, 20% of the patients lived for 5 years or more, and 12% of the patients are still alive at 7 years.
This Information Arm survival data is especially encouraging since this group included patients who already had actual tumor recurrence as well as others who had the appearance of tumor recurrence but who could not be definitely determined.
The top 100 patients – 30% of all patients in the trial – have a Kaplan Meier median survival of 58.4 months.