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Fenix stated this:
John,
It is my opinion that if this patient's next MRI at 8 weeks shows diminishment or no further progression, he is accepted into the main body of the trial and then randomized. I don't think he is "analyzed separately" if this occurs.
Do you or anyone else have information regarding this?
Long, that is the Holy Grail I am searching for.
As you can see, I can get to that conclusion from different inferences and suppositions (even more than I placed in my post), but believe me, if I found that, my next post would not be rated S for supposition.
I will let you know. Please do the same for me.
Ou,
I agree, I do not use the word "important" other than to highlight what it means for the trial. As far as all subtypes, I wish they were cured today and we could invest in widgets.
"Actively Progressive" in that context meant progression within a very short window (0-4 weeks) after the initial round of chemo/radiation. This is sometimes different from "aggressive cancer."
If I understand you correctly, I think you hope that pro neural and neural subtypes also respond. I think, I hope and I pray that you'll see that with DCVAX-Direct.
(Sorry for the typos…for instance in the last portion I meant phase III not phase II.)
Anyway Ou, most of this has been in my head for some time, but I went back over many articles to retrace my thinking. There were a few key points when I originally worked this through that stood out to me, and I wanted to see if they still stood out after some time had passed. They did. I verbally highlighted those things in my post, so they are not hard to find.
Of course there are many other factors that caused me to invest in this company. Disclaimer to others….this is still biotech investing…stay within your means.
As far as the label issue; no, I do not believe they will restrict it. For two reasons. No safety issues. 2. The Proneural and neural groups are in an almost no win situation/choice….it wil be between them, their doctor and their insurance company…imho.
I'll speak to the other question after I get back.
I think its the other way around, but I could be wrong.
They bought during the fundraising spike on November 19/20. They bought approx. 3,214,000 shares at that time. They likely bought at $5.00 to $6.66 per share.
They decreased their position right before the new year to (likely) get a tax break at approximately $3.77 per share.
My guess is that they probably reinvested more after the first of the year once the 30 day tax rule had passed. Somewhere around January 31, 2014.
Pseudoprogression, True Progression and Four Subtypes:
This post is rated S for suppositions. Note: In the trial there are other additional steps that I have not included below. I've done this to focus on the matters I'm addressing as a layman.
Step 1. In the DCVAX-L trial, patients are given surgery and an initial round of chemotherapy and radiation that lasts about 6 weeks.
Step 2. The next step is deciding who gets enrolled in the main body of the study. This selection process must be completed within 4 weeks after Step 1 initial therapy is completed.
Step 2A. Within this 4 week selection window immediately after Step 1, patients with indistinguishable Pseudoprogression and/or true progression are not allowed into the main body of the study and will not be used for statistical purposes in order to request approval. Those with distinguishable true progression are excluded from the trial but may receive treatment on a compassionate basis. Those with indistinguishable pseudo/true progression are placed in a "side group" also known as the "extra arm (not the third arm)." They are outside the main body of the trial (not used for OS or PFS statistics in main body of Phase III trial). In those -- fence sitting -- patients where it can be ultimately determined they really do not have true progression, they will be selected and randomized into the trial.
All GBM patients fall into 1 of four subtypes. Classic, Neural, Proneural or Mesenchymal.
Subtype responses to Chemotherapy and Radiation.
Proneural patients typically are younger and live longer than the average of the group as a whole, but they do not respond very effectively to Chemotherapy and Radiation.
Classic patients respond fairly well to Aggressive Chemo and radiation.
Mesenchymal patients have the most aggressive cancer, but they surprisingly respond very well to Aggressive chemotherapy and radiation early on, but down the road they build up a resistance to chemotherapy treatment.
Neural patients do not respond very well to Aggressive chemotherapy, and unfortunately they do not live as long on average as the pro-neural group.
For a better understanding of the response to Aggressive chemotherapy plus radiation for these subtypes please see figure 5 in the following article. This is very important IMHO.
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2818769/
Subtype responses to additional therapy with DCVAX-L
Mesenchymal patients apparently have the best response to DCVAX-L treatment, and this response is synergistic to the response benefit they already received from aggressive chemotherapy and radiation. Proneural patients have little response to DCVAX-L.
It is unclear how the remaining subtypes respond to DCVAX-l additional therapy but I'll put forth some suppositions based upon prior information.
Background for suppositions:
*Dr. Linda Liau (and Dr.Kim) observed that DCVAX-L works better on patients that are stable when treatment with DCVAX-L is initiated. In other words, during that 4 week period after surgery/chemo/radiation, if there are no 'signs' of progression before DCVAX-L treatment is initiated, patients on average seem to do better.
"All patients that generated a systemic CTL response showed no MRI evidence of progressive disease at the time of vaccination [initiation]. Conversely, no patient with actively progressive disease developed statistically significant 'cytotoxicity. (which means being toxic to cancer cells)." This is really really important.
*The median time for pseudo-progression to appear after a 6 week round of radiation/chemo therapy is 4 weeks
* In a retrospective study, "early progression was confirmed in 42 patients (60%) according to Macdonald criteria and 15 patients (21%) according to RANO criteria. Pseudoprogression was identified in 10 (23.8%) or 2 (13.3%) patients in Macdonald and RANO groups, respectively. Cumulative survival of pseudoprogression group was higher than that of true progression group and not statistically different from the non-progressive disease group." This is also really really important.
Suppositions based on the above information.
I. If patients are excluded from the main body of the DCVAX-L trial that present signs of tumor progression/pseudoprogression within the first four weeks after the first round of chemo/radiation, most of those patients excluded from the trial will be those with true progression because:
A. They represent the larger percentage of patients in retrospective studies
B. Many pseudo progression patients will be included in the study anyway because the average time to pseudo progression takes a median average of 4 weeks.
2. If more pseudo-progression patients are left in the trial than real progression patients, the opportunity to demonstrate real treatment effect is significant because:
A. The real progression patients are likely to be pro-neural because:
1. The Kaplan-meier curves demonstrate those with no early response to chemotherapy and radiation are more likely to be pro-neural, and if mostly pro-neural patients are being excluded from the main body of the trial, and pro neural groups are longer lived than the group as a whole regardless of cemo/radiation/dcvax-l therapy, then the opportunity to show improvement in the remaining subgroups with less pro neural subtypes becomes more likely.
B. Remember, those with real progression at baseline in prior DCVAX-L studies had no systemic response to therapy.
What is the point here. Supposition
The point is that the inclusion/exclusion processes at the time for initiation of DCVAX treatment strongly points toward the fact that the majority of subtypes excluded were mostly in the pro-neural and neural category, and while some mesenchymal patients may have been excluded as well (because they tend to show inflammation that might be categorized as pseudo-progression), the majority of Mesenchymal patients will not demonstrate pseudo-progression at the time selection and treatment initiation starts. Moreover, those mesenchymal that do present pseudo progression are probably in the minority of their subtype.
Finally, the representation of subtypes is lore likely to appear in this order.
1. Classic -- should have the strongest representation in the actual body of the phase three DCVAX-L trial, and likely responds well to DCVAX-l.
2. Mesenchymal -- should have the second strongest representation in the actual body of the phase three trial and does respond very well to DCVAX-L.
3. Neural -- should have the third most representation (second to last) and likely does not respond as well to DCVAX-L as classic and mesenchymal. (nor does it respond as well to chemo radiation).
4. Proneural -- should have the least representation in the phase II DCVAX-L trial, and it does not respond near as well to dcvax-L (nor does it respond to chemo radiation).
Just my 2 cents….I'll explain my thinking more tomorrow, but research concludes the mesenchymal subgroup also responds well (not as well as it does to DCVAX) to "aggressive" chemo/radiation therapy. The key in the present DCVAX-L trial is that all tumors at baseline are stable due to trial design, and DCVAX-L has an overall more synergistic effect in this case. Regardless, IMHO, even if the trial design did not have the above feature, we'd still meet the endpoints.
Reef, thanks for your invaluable information on this issue,
I think that's a wrap!
FCB, I can turn that frown upside down:)
Data collection was at least 28 days later than you think for VTUS. In other words, they had to wait until at least Christmas 2013 for final data in order to start analyzing. That's because after the final enrollment and randomization, the last patients had to apply Butt cream for 28 days.
Also,
Primary Completion Date: December 2013 (Final data collection date for primary outcome measure) Clinical Trials.gov
Also,
Pain is a notoriously elusive outcome measure for any phase trial. Butt i digress….
Conclusion: The results after the final data was collected probably took exactly 6 weeks.
I believe they have to use more tools than just MRI and ultra sound, because there are some tumors that are too small to observe accurately with just ultra-sound. Dunno.
(In other words, some are too small to inject and some are even too small to initially see/observe even aided by ultrasound with any certainty.)
So ultimately, its tumor size. In metastatic patients or patients with multiple tumors, the reason not all tumors can be injected is because some are either too small to be seen (aka: 'occult') and/or too small to inject. If that is the case, then there will not be any ethics issues in this trial when systemic response is looked at in patients where not all tumors are injected. This is helpful.
Therefore, I am wondering how scientists will detect systemic response in these small tumors that are hard to see….I assume they will use various clinical means, including some types of chemical tracers?
I agree this goes to the heart of systemic treatment, and as a former cancer patient ( I was not metastatic) I can empathize with patients and doctors who would not want to be in the O.R. for a ridiculous amount of time trying to make certain every last tumor was injected….which they could not ever be sure of anyway.
Note: I'm writing as if I found the answer (by your lead), but I'm still "sleuthing" here….
In August of last year he had 3,248,000 and in February of this year he has 3,203,000 shares -- in aggregate. No noteworthy change.
I'd say keeping that many shares tied up in NWBO is extremely bullish.
I agree Ou,
and after chemo/radiation therapy weakens the immune system, studies demonstrate that dendritic cell therapy can restore and enhance the immune system.
Here is a great scientific review on dendritic therapy helping the immune system proliferate after chemo/radiation on GBM.
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3766324/#__ffn_sectitle
Gliadel Wafers continued….
Gliadel Wafers, which destroy the immune system,
passed the FDA for use in newly diagnosed GBM patients in 2003, but only increased overall survival by 9 weeks, and have all these side effects:
Side effects that have been reported in patients receiving Gliadel Wafer include seizures, intracranial infections, abnormal wound healing, and brain edema (swelling). Although these events may result as a consequence of brain surgery (craniotomy) without Gliadel Wafer, the above side effects are much more likely when Gliadel Wafer is used.
The rate of postcraniotomy surgical infection after Glidel wafer placement was reported to be as high as 28%. Extensive cerebral edema was also reported after Gliadel® placement, and led to severe neurologic compromise and death (Weber and Goebel 2005). Another cause of severe toxicity and death with Gliadel® wafers recently reported is obstructing hydrocephalus, and the authors of the case-report concluded that a large opening of the ventricle during surgery might be considered a contraindication for wafer placement (Gallego et al 2007).
Local treatment effects, such as pericavity necrosis are also commonly seen, affecting 11% of all patients, and 33% of the patients undergoing re-operation for radiological progression, which it makes difficult to differentiate between tumor recurrence and treatment effect based on non-invasive studies (Kleinberg et al 2004). Other observations following Gliadel® implantation include the formation of tumor bed cysts with new neurologic symptoms secondary to mass effect.
Gliadel Wafer is approved by the FDA for treatment of patients with newly-diagnosed high-grade malignant glioma as an adjunct to surgery and radiation. The 2003 FDA approval was based on clinical trial results showing the median survival of patients with high-grade malignant gliomas increased to 13.9 months from 11.6 months, and the median survival of patients with recurrent GBM increased to 6.4 months from 4.6 months.
Gliadel Wafers.
From a strategy perspective, Linda Powers is one of the smartest people I've ever observed. I also think she is compassionate. Those 2 personality traits are hard to balance. Obviously the face value point she made about Gliadel Wafers is extremely eye opening and demonstrative as to why the natural dendritic solution is preferable. My question is: why did she focus on the wafers here and now?
We know that's the idea, but his point was why take the chance? F3TT3F's point is the ethics side. I pointed out Triozzi already did it (skipped injecting some tumors in a patient) in a small study and I posited several scenarios that might explain why you might need to skip some tumors, but he has a fair question IMHO.
Since you're simply adding a note of caution, I'll restrain from establishing the differences in word context for the separate studies. Caution is always warranted in this field. I simply draw more inferences from the historical and scientific context related to Linda Power's use of the word "encouraged" in this case. Of course I look at everything I can get my hands on (as I'm sure you do as well), so there are a million and one reasons I am fully invested in this stock -- I am also diversified.
Note: I also looked into your question about why wouldn't NWBO inject all the tumors with Direct in the cases where a patient has multiple tumors.
First, in the seminal small human study related to intratumoral dendritic injection, Dr. Triozzi did not inject all the tumors. http://onlinelibrary.wiley.com/doi/10.1002/1097-0142(20001215)89:12%3C2646::AID-CNCR18%3E3.0.CO;2-A/abstract
Second, I ran across several informal cancer sites that inferred some tumors are simply too small to inject. I found a few studies on techniques, and scientists can inject very small tumors, so I'm still trying to find an answer. Perhaps in some cases there is not enough material to go around. Or there are just too many that are very very small.
That's as far as I got.
f3tt3f.
Is this the exchange and trial you were referring to?
Fair enough. I'll try to locate it.
Yes, the O'brien-Fleming interim sequential analysis hurdle gets lower (easier) each go around (view). Its always been counter-intuitive to me, but that's why I was not a math major and others here were.
Agreed. Someone else also made this point recently. I think it is likely true for L. And, as you know, Direct does not need any stinking chemo!
Sorry, I get a wild hare.
Super Squirrel.
Ou.
Your question:
Do the patients who get DCVax-L still get chemo on the same schedule as the control arm? Or is it dependent upon the patient's need for more chemo?
Answer IMHO: The same Schedule. 6 months of chemo. Source: ClinicalTrials.gov.
Tradingintheusa
ASCO treats completed trial related abstracts almost entirely different than they treat Trial in Progress abstracts. Go to my post 4315. See the sentences top to bottom that I placed in bold. I know you've looked into this some already, but when you scan the entire ASCO site, notice how ASCO wants data and results from normal abstracts but they prohibit data and results from 'Trials in Progress."
Thanks Ou,
This is actually the response I anticipated coming from my not so subtle challenge to f3tt3f. There is a big distinction. As you know, Cyclacel was talking after the trial results specifically about overall survival (I would have said the same thing where OS was observed (388 versus 218 days respectively). Cyclacel did not use the same description for PFS. Speaking for myself, this distinction separates the comparison of Cyclacel with the NWBO context irrevocably.
I also expected f3tt3f to give a reference to the "on track" comment from IMUC prior to their mediocre results -- which may rise from the ashes in time. At the time, I found IMUC's language potentially a little misleading (perhaps unintentionally or intentionally) and this proved to be accurate. (my suspicion arose when Larry Smith ( a very informed guy) gave a hint ahead of time that the IMUC results might not initially meet their lofty goals because of the trial design, and IMUC insiders started selling before trial results came in). Again with IMUC, there is a huge distinction from the specific context in which NWBO used the word "encouraged" (v. IMUC's "on track") for their trial. I won't go into all the context since I believe everyone here knows it.
Unrelated:
Ou, like you, I also found the reverse PFS-OS findings from Cylacel to IMUC interesting in their own right.
Be well.
Thanks for clarifying your position.
Back in June 2013, I too anticipated a few data sets would be publicly available by now on some patients. (There is some truth to the fact that Linda is still on a learning curve in some areas. I take this into consideration in synthesizing my personal analysis, but I must say that I personally gauge her as highly competent and very sincere despite a few bumps in the road). However, I believe the "glimpse" they gave us from their current observations is, to use her words, encouraging. I draw more inferences from this description than most people here. I have articulated my logic on why I feel confident in doing so over several posts covering a wide span of time.
between the lines said.
f3tt3f said.
You are entitled to your opinion.
Here is why I said, but for Linda Power's "glimpse" that they are "encouraged" by what they see in the phase I Direct trial, the ASCO submission would otherwise have little significance for me.
About ASCO
Ou.
Good Point. I think she used the word "glimpse" back then. That might be more accurate than 'result' or "update." She probably already knew she would not be allowed to give much. I have to admit, I put "encouraged" into the "glimpse" category -- maybe others would not.
In yesterday's conference she said she might be able to share a "bit" more before ASCO 'later this spring', but only if it would not compromise their presentation prospects at ASCO.
Future:
What might a "bit" be? It might simply be another comforting statement like, for instance, 'the trial(s) are beyond the slow period, we anticipate full enrollment by ____, and we continue to be encouraged by what we are seeing.' This future prospect might not seem like a glimpse, bit, result or an update; but I for one would still be very grateful, because without it, I feel the significance of the ASCO submission would be lost upon me.
Thanks.
You have a point. The only reason I added the fourth alternative is because Linda powers said the systemic response (aka: "the second stage of what [they] anticipate to see") is expected to be seen over a "much longer longer timeframe." That's why I think they are going to add the metastatic patients as the trial progresses -- in addition to the way it is listed on clinicaltrrials.gov -- which first lists local tumor then metastatic tumors.
Still Asco worthy? I think it could be, because scientists are now able to determine when a sustained immune response is detected in the lymphs and elsewhere. Plus, it would be pretty darned impressive to see an eradicated tumor in each patient (who otherwise likely had a very short time to live with no other options) plus indications of sustained immunity. Also, starting out simple (aka: individual tumor) may make more sense in "first in human" trials. Finally, DCVAX-L can't get lost in the shuffle, and so I believe the timing of Direct announcements is also critical.
Anyway, all our theories are positive and hopeful, and as you say….we shall see.
Bio and Long: 'Slow period'
Together you two came up with three possibilities. I think all of them are valid theories, and I'll add a fourth. Maybe the initial patients did not have multiple solid tumors. However, as the trial progresses, NWBO/MDAnderson plans to add 'multiple tumor' cancer patients into the trial as well.
This may be a very wise way to move through this trial. Especially when there is an initial slow period involving a minimal number of patients.
Case and Point: Look at clinical trials.gov….the first two types of cancers described are "[1.] Locally Advanced Tumor [2.] Metastatic Solid Tissue Tumors"
Nice to see your comprehensive thoughts on this board. Thanks and welcome.
I think you have some valid points, and they tie in nicely with the point someone else made that Linda did not mention that early 2015 is the expected end date for the L trial during this presentation. Instead she emphasized that their trial design was statistically cushioned by only needing to demonstrate 6 months PFS improvement….etc.
I would point out that when she states they are "encouraged" by the Direct phase 1 trial thus far, they are in fact following through with an early update. Even if we have to wait until ASCO for the next update, today's trial update would make their proposed timeline accurate from the last presentation -- that we would get an update soon, then in the spring, summer and fall.
Linda stated that NWBO and MDAnderson submitted the abstract "jointly."