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Agreed. Confirmation for entire tumor biomarking is building a strong foundation.
Long,
German expected enrollment commitment is down to 60 (according to the Germans) -- which I think they will meet with the clinics screening and enrolling this summer.
UK is at 24 (according to the Brits) : Which I think they met.
Meanwhile, I think the United States has been enrolling very quickly, and combined, all three countries may surpass the 240 (primary group) and 312 (both groups) prior to 110 events (or trial halt), and because of the German delay and perhaps increasing the Pseudo total enrollment for cushion, the total group is now listed as 348 by the Brits.
348 - 312 = 36.
This 11% overall enrollment increase is, interestingly, a “little bit.":)
John, I’m amazed as well. The most conservative estimates on enrollment by December 2013 were well above 150, with all the factors mentioned in my recent posts, even this low number would produce a much better result than ICT-107.
Note: Each quarter that passes us by means the rate NWBO needs to enroll at to reach full enrollment keeps decreasing. As of this quarter, we only needed to average 16 patients per quarter to reach full enrollment (240 in the primary group) by now.
Note: IMHO, yesterday’s investigation alerts are simply cover for a select group to buy more while keeping the “masses” at bay.
Yes, enrollment numbers are a bit elusive, but we had a few clues, and Pyrr seems convinced NWBO enrolled 192 patients around March of this year -- meaning around 180 in December 2013. Even if the numbers enrolled were only IMUC-like by December 10, 2014, we’d still have a 67 pfs DCVAX-L trial event to 103 pfs ict-107 event comparison.
(Plus the added benefit of more time elapsing for the 33.)
So one might say, "ok, 183% v. 60% over three years means 3x better improvement, right?”
Nope. DCVAX-L has more than a 3x improvement upon IMUC results, because as one reduces the % of total pfs events over a certain time, one necessarily increases the percentage progressing from the control group (decrease the % coming from the treatment group.). Plus, as always, the additional time from the 33 adds a further expected increase to treatment group pfs expectations. IMHO
One thing that may distract people from realizing how well the DCVAX-L trial appears to be going is that we are using event triggers where:
66 events = 60% of 110 eventual events.
88 events = 80% of 110 eventual events.
110 events = 100% of 110 eventual events.
But notice, there are really 240 eventual patients in the NWBO trial.
Now look at IMUC,
103 events = 83% of actual patients in the trial!
It’s hard to point out how significant the difference is.
Let me try.
Premise: If IMUC used the same ratio NWBO used; 110/240, for the 124 total patients in the IMUC trial, 100% of “eventual" events would be 56.
Think about that.
103 events = 183% of eventual events!!!
Do you see???
At 3 years plus (I reemphasize plus) DCVAX-L only had 60% of 110 “eventual" events.
At just 3 years, ICT-107 had 183% of 56 “eventual” events.
Correction:
IMUC actually had 103 pfs (not 95) events over approximately 3 years. With 124 (not 114) patients total, this means 83% already progressed 3 years from the time the IMUC trial started.
While NWBO had 67 pfs events in three years (plus time added for group of 33). Even with the extended time, with approximately 180 patients, only 37% progressed in 3+ years.
This correction does not change the (general) conclusions in my related post #15014.
The current phase III trial conversion gave up very little to become a pivotal trial. The FDA could not use the standard trial design pre-approval method for phase III because legislative regulations were not foresighted or broad enough to anticipate these scenarios. Nonetheless, NWBO worked closely with the FDA to achieve the phase upgrade.
The DCVAX-L phase III trial certainly qualifies for fast track, however, because DCVAX-L already has orphan status and is utilizing the accelerated approval process, it receives many overlapping benefits (compared to fast track). One missing benefit might be rolling reviews. Fast track status can remain unknown to investors during the trial. Fast track can be requested at any time. If the CRO and perhaps managing fire walled NWBO representative determine(d) this need, (say for instance) upon reviewing their size recalculation examination, they would likely apply for fast track (if it has not already been granted) in order to speed the accelerated approval process.
While the history of the trials for DCVAX-L is long and subtle, in reality the current trial is very simple. The planned primary group of 240 uses PFS as its primary endpoint. NWBO, for those of us new to the company, has an ethical advantage not normally afforded to long trials. That is the first 33 enrollees have been in the trial for a very long time. Normally the long tail effect hurts immunotherapy trials because the trial ends before the long term therapeutic effect can be adequately accounted for. If you take away the 33 long term mix of experimental patients in the DCVAX-L trial, you would have the same start date as the recent IMUC trial. That trial ended after approximately 36 months. This means many patients enrolled late in that trial had no chance to demonstrate long term effect. Thus, while the IMUC results seem disappointing, they are actually getting stronger as we speak.
On the other hand, NWBO’s primary trial group is at approximately 43 months since the first non carryover patients were dosed. This is already longer than IMUC had there trial out. This is a plus for NWBO. Now add the 33 patients that have been out approximately 6 years. We are looking at far more mature data than IMUC looked at if the trial was unblinded today. Now add to that the fact that both companies arrived at 67 events in the same time period, HOWEVER, IMUC was counting deaths while NWBO had only reached 67 progressions, MOREOVER, many of NWBO’s events probably came from the very old 2008 group, FINALLY, IMUC only had 114 ultimately enrolled when the event trigger was met WHEREAS, NWBO likely had somewhere near well over 150 (more like 175 to 185) when their event trigger occurred.
In other words, IMUC probably had somewhere near 95 PFS events in their 3 year trial with 114 patients gradually enrolled. NWBO had 67 PFS events with around 180 patients over a much longer time frame if you include the 33 carryovers.
The only way in which you can possibly question these remarkable results is:
1. Enrollment rate comparison -- i.e. how many patients were dosed early on in their respective trials. We don’t know this figure.
2. Enrollment requirements. NWBO did not take patients in the primary group who had true or false progression after initial chemoradiation.
Number 2 would be my only real concern (because IMUC definitely took a while to get to 114), HOWEVER Number 2 does not concern me because removing true and false progression patients from the primary group creates a wash effect. That is because pseudo-progression is actually a group that would have responded well to DCVAX-L and True-progression is a group that would normally not respond well to more chemo and/or DCVAX-L.
My conclusions are:
1. DCVAX-L is having significant effect on the treated (and likely crossover patients overall survival).
DCVAX-L’s PFS improvement likely exceeds IMUC’s results by a wide margin.
2. While the tertiary pseudo progression group is only 24 months old, pfs separation between treated and control arm patients is likely nearing or exceeding a 6 month spread at this point. I also base this second conclusion upon many large studies showing the best average results in various subgroups using the Stupp protocol, and many studies with dendritic therapy indicating significant responses in pseudo progression patients.
(While I highly respect the work done by alpha puppy, Pyrr and others in running KM analysis, I think the number of variables cannot account for some of the factors I mentioned above.)
There were originally two phase I/II trials to test safety, dose escalation and efficacy. These trials are now well over ten years old (some patients dosed almost 15 years ago), and they are usually referred to in one graph as 39 total patients. The long tail survival is astounding.
Another phase two trial was started before 2008, but it was “RESTARTED" (not “resumed") in 2008 (This was due to the fact that a placebo needed to be invented.) So the current phase III trial began as a phase II trial WITH A PLACEBO ARM in 2008. However, due to the economic crash, NWBO stopped enrolling new patients until early 2011. It is very important to note that we now know the 33 patients carried over from 2008 were from the Restart group, and thus they consisted of experimental and placebo patients. In 2011 the trial was RESUMED. The 33 patients carried over had been treated and/or on placebo during the three year interval. A smart poster named AVII helped clear up a misunderstanding I previously had about the 33 patients.
Anyway, as of early 2011, the RESUMED DCVAX-L trial planned to enroll 240 patients.
In approximately spring 2012, this phase II blinded trial was converted to a phase III blinded trial. 72 more patients are planned to be added to this phase III trial; however, they are to be separately analyzed from the group of 240. Only the eventual group of 240 will be used to determine the primary and secondary endpoints. The group of 72 will be used to determine a tertiary endpoint for patients who demonstrated “false progression” aka pseudo-progression after initial chemoradiation, but before treatment with DCVAX-L.
(Ultimately, the two groups will form a separate combined statistical result, that will be used for analytical and research purposes.)
Regarding use of Direct in Brain, it would be very interesting to know why only the breast cancer with brain metastases cases have limited enrollment in the Direct trial. Budzar politics? (He is a breast cancer chemo man). Competing trial enrollment at MDAnderson? It could also be that the recent historical changes to the Direct trial might provide insight -- aka: not needing to be a “treatment of last resort."
Anyway, as you know, there was much dissension regarding any and all Direct advantages sometime ago on this board:) Many of those advantages are being born out in the current phase I trial.
Ultimately, inoperable brain cancer will force the Direct-glioma proposition to a head.
Or perhaps what the Germans were told.
Manufacturing will still be required, but tumor preservation capacity demand could be reduced. If Kristen did not misinterpret what they were saying, and if the person she spoke to was not speculating, it would seem “soon” might still be a tad optimistic. Or is it?
Sentiment, John may know something about Dr. N.
On the other matter, Kristen's statement regarding imminent DCVAX treatment in Germany sans tumor requirement probably relates back to what the Germans perceive will occur with Direct. For other reasons, I am convinced the Germans reviewed Direct results through mid-March before granting the H.E. on DCVAX-L.
Migration by Blebbing: Video
http://www.scivee.tv/node/62194
How dendritic cells move from one place to another.
http://bloodjournal.hematologylibrary.org/content/113/23/5703.long?sso-checked=1
Interesting. Thanks for further history on Dr. Black.
Great point Long. When I first started studying biotech, the first thing that stood out was the phenomenon of longer trials for better drugs. The second thing that stood out was the statistical analysis acceptance of censoring and the consequent otherwise completely avoidable death watch for minimal event thresholds.
Modifications to trial design, such as the one you are highlighting would go a long way toward turning drug development right side up.
DCVAX product count update = 7.
1. DCVAX-L
2. DCVVAX-Prostate
3. DCVAX-Ovarian
4. DCVAX-Direct
5 and 6. UCLA (NWBO cosponsored) -- 2 new forms of DCVAX-L
7. DCVAX combined with prior irradiation of oxygen infused tumor.
I came to the same conclusions as you regarding the June Direct trial modifications.
Let me slightly clarify that. I’m very supportive of NWBO strategy thus far, and while I would like more questions answered, NWBO “tactics” seem logical and highly appropriate. IMHO.
Have a good weekend. I'll see you on Monday.
Last thought.
One day we may learn that within our autonomous immune system resides a level of sentience we never dreamed possible.
Thank You Sentiment and Evaluate for finding and emphasizing that video.
As many of the posters here know, I recently became slightly:) irate, repetitive and frustrated by the chemotherapy influence still pressed upon immunotherapy.
I honestly believe the "tsunami" of knowledge, advancements and results demonstrated by immunotherapy will drive us forward.
The researchers here are, believe it or not, the fortunate ones. They used the right science, but.... organic systems, in all their wisdom, only allowed a few (of all those who used the right theoretics) to demonstrate success. These very humble human beings even alluded to the scientists who are no longer in the field. They realized there by the grace of God.....
Wow. After watching that video, it is very difficult to understand any old guard (chemo/targeted) being opposed to the transitional but effective path offered by immunotherapy and specifically DCVAX-Direct.
I am restraining myself from reposting my list of advantages to patients, government, oncologists, surgeons and the rest.
Advancements in today's world are exponential, it would be foolish for anyone to argue against the benefits in this narrow window of time offered by Direct.
This means float just started decreasing, correct?
Hi Evaluate. UCLA is already conducting one of the trials referred to in the last sentence in your post. However it is using patients w/o gbm. It is sponsored by NWBO. Another trial with nwbo is waiting in the wings, and it will use oxygen enhanced tumors in coordination with radiation.
While phase III will likely get approval, the doctors and nwbo are also hoping to work towards a complete cure, moreover, new improvements on dcvax-l will create new patents.
I sent an email to Les. Tried to phone him, but no one answered..
DCVAX-L treatment requires a tumor sample about the size of a sugar cube. It cannot be preserved with paraffin wax. Those are 2 primary criteria.
Here is a good page (link) on reconstitution for the Russel 3000.
https://www.russell.com/indexes/americas/tools-resources/reconstitution/default.page
Reconstitution is official at close of U.S. markets today.
Unless someone beats me to it, I’ll look into that later today.
Also, for what it is worth, we may get some info on German price reimbursement negotiations on or before July 9, 2014, although I cannot confirm this, and I’m in a wait and see mode.
SmithonStocks thinks we will get an update on L relatively soon. (i.e. continue, continue plus expansion or otherwise) My thought is he is expecting it sometime before August. He all but completely rules out a futility DMC recommendation from the first review.
OK, from that perspective, I agree. GLTU and all longs.
Of course you’re trying to accomplish something. You do not want NWBO to give any more updates on Direct. You want investors to silence themselves and move on.
Look,
Vivek, the lead investigator, stated he was probably going to share data on May 30.
Vivek stated on June 1, 2014 that NWBO was free to share the Direct Data.
MDA and Budzar share data from ongoing phase I trials that are still enrolling.
Budzar hypocritically sabatoges NWBO.
Austin caves, and doesn’t want any more direct data shared until the trial is over.
Austin calls anyone with a different viewpoint on a "happy merry fantasy ride.”
Funny thing is most of us had moved on today, but you brought this back to front and center.
My opinion on your other questions:
1. L will complete enrollment for 240 primary group by September if Pyrr is right that we were at 192 enrollment a few months ago. He seems very confident in that fact.
2. Last dose for last patient enrolled in Direct phase I trial should be on or before January 31, 2015.
3. Long feels that another raise will be needed by 3rd quarter, but I think we will raise more money before then for inevitable Direct trial addition/expansion.
Austin, so now your distinction is physician dissemination would have been OK on MAY 30 but not company dissemination? Ironic then that Subbiah later stated at the conference that NWBO could share whatever they wanted to. Sorry, Austin, your argument “is not accomplishing anything.”
Agreed John. Also we talk a lot about PFS, but I noticed Astra Zenaca had a 3 month OS advantage, and that was with deadly side effects.
Frankly, I’m expecting better OS performance from DCVAX-L against highly reliable historical OS averages. It took IMUC 24 months to enroll 114 patients and they almost got to 3 month OS. In that 24 months they had 67 death events.
According to Pyrr, we almost enrolled 192 patients in 24-27 months, and yet we only had 67 PFS events. Granted we excluded some early progressors, but we also excluded some therapeutically receptive patients from the primary group as well, so it was likely a wash. Anyway with more patients enrolled, we clearly had no where near 67 death events in the same time frame as IMUC, because we only had 67 PFS events.
In other words, our trial enrolled far more patients than IMUC, but only had 67 progressions in the same time frame IMUC had 67 actual deaths. Thus the number of deaths in the DCVAX-L trial during that same time frame was likely a great deal lower. While we have a crossover arm, the comparison against highly reliable historical averages will be enlightening.
I noticed the FDA did indirectly look at historical averages in the Astra Zenaca trial, and they noted the control group performed below historical averages. The FDA did not think this helped Astra Zenaca’s cause. On the other hand, I think historical averages will be helpful for NWBO.
Great post Dok.
I still want to believe people value progress against cancer more than their station in life. I think Cramer and Feuerstein believe the opposite. I hope Subbiah and his staff stay strong. Orlando health, who is part of the Direct trial, disassociated themselves from MDAnderson on many different levels in December 2013 (wonder why). They still contract to share clinical trials.
If you go back to Coley’s Cocktail, yet WWII, Dendritic Cells, yet the 2008 crash, etc, one observes how a century could be wasted on war, internal squabbles, greed and intervening events. I see Adam Feuerstein as someone willing to sacrifice human progress for selfish gains -- power, greed and decent microbrews. Is it our grandchildren that will finally bring immunotherapy into complete fruition?
Quote:
Reuters
BY RANSDELL PIERSON
NEW YORK Wed Feb 26, 2014 1:00am EST
Dr. Vivek Subbiah, an oncologist at M.D. Anderson Cancer Center in Houston who is leading the DCVax-Direct trials, said he may present initial data at the annual meeting of the American Society of Clinical Oncology that begins May 30.
Subbiah and his colleagues test scores of experimental cancer drugs, many having new mechanisms of action.
"This is not a 'me-too' trial," Subbiah said. "It is one of the interesting technologies. Twenty years ago it was chemo, 10 years ago it was targeted therapies, and for this decade it will be drugs that boost the immune system."
This is what made Buzdar (Mr. Taxol) act irrationally.
Once and for all, Budzar, an employee unrelated to the NWBO trial, went out of his way to make hypocritical comments against NWBO, knowing full well he (Budzar) and MDAnderson frequently release ongoing phase I data while the trials are still enrolling. Budzar did this with national media to try and make the biggest impact possible. Barnstormer, quit worrying about investors trying to make their outrage over this ambush known to MDAnderson on MDA’s Facebook page. FaceBook page for goodness sake. Get over it.