Gone for good.
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The 77% came from me. Improvement of the MOS of the 3 mg/kg arm over the mean of the 12 control arms:
percentage increase = 100*(13.1 - 7.4)/7.4 = 77%
http://investorshub.advfn.com/boards/read_msg.aspx?message_id=83132622
My estimate for the new "control" arm MOS is simply the average of the original control arm and the 1 mg/kg arm.
MOS = (5.6 + 11.1)/2 = 8.4 months.
Percentage increase = 100*(13.1 - 8.4)/8.4 = 56%
http://investorshub.advfn.com/boards/read_msg.aspx?message_id=83158600
Just a rough estimate, nothing more.
This is very good to see. I have been saying that all the attention which the anti-CTLA-4 and anti-PD-1
approaches have generated is good for the future of cancer immunotherapy. I note that the anti-PS approach
is further upstream in the immune response pathway and should work better.
http://www.bmsimmunooncology.com/bms-and-immuno-oncology.aspx
They also have a history page
http://www.bmsimmunooncology.com/immuno-oncology-history.aspx
"1891 William Coley uses bacterial infection with Coley toxin to treat cancer"
A picture of of William B Coley, the father of cancer immunotherapy, circa 1888
The corporate fact sheet says "Preliminary OS data" from the pancreatic trial during
the first quarter 2013, whereas it says "Median OS" from the first-line NSCLC trial.
This may mean that in the pancreatic trial control MOS has been reached and the
treatment arm MOS may not yet be reached by March. The distinction may be important.
Who knows.
Yes, I thought that was the confusion. The docetaxel was administered separately
from the placebo and bavituximab, so it wasn't possible not to receive docetaxel.
I don't follow you here. All arms were to receive docetaxel plus either placebo, or bavituximab.
When placebo was given the patients were also on docetaxel, which is the SOC.
In the original trial (Shepherd et al 2000) that tested docetaxel, the treatment arm got
docetaxel, and the control arm got nothing but best supportive care (BSC). In that trial the
MOS for docetaxel only was 7 months, and the control arm MOS was 4.6 months.
There were 6 cycles of treatment of 3 weeks, or 18 weeks, about 4 months. Patients weren't
receiving anything during weeks 26, and 52.
From what you say here it would seem that the placebo arm never got anything other
than placebo, so it was not affected at all.
Is there some reason you picked a 40% increase of MOS in pancreatic cancer, or just your guess?
I am curious about that too.
Yes, it is an assumption. It is just a theory based on what little we know.
I would say they have to use 3 mg/kg. Both the first-line NSCLC and pancreatic cancer trials are
using 3 mg/kg so the results from those might help.
This problem has several constraints which limit the possible ways in which the problem could have occurred.
1) How could the original Kaplan-Meier survival curve be so good if there was a mix up between the control arm and the 1 mg/kg arm?
2) The fact that they are making a new control arm combining the placebo arm and 1 mg/kg arm
tells me that there are too many patients in both arms affected to just throw them out. However, how can this be reconciled with the first statement above?
If the mix up had a big effect then the curves for the placebo and 1 mg/kg arms should be closer together.
3) That leaves the possibility that the mix up only caused a small effect, but it occurred with many patients.
My theory here is that many, maybe even all, of the patients in the placebo and 1 mg/kg arms received one incorrect dose. So all the placebo patients got 5 doses of placebo and one dose of
bavi at 1 mg/kg. I think this would cause hardly any change. Likewise, all patients in the 1 mg/kg arm got 5 doses of bavi and one dose of placebo. Again, this may have caused hardly any change. This might be especially true if the mix up occurred at the beginning or at the end of the 6 treatments. So the result is all the patients in these two arms were affected, but the mixed up doses didn't make any noticeable difference in the survival curves. You can see that correcting the data is not possible since there would be no one left. So the only thing to do is to combine them and make a new "control" arm. Alternatively, you can just recognize that the effect was small and not do anything. Luckily, the 3 mg/kg arm was not involved and so the question is what do you compare it with. I maintain that the comparison with the original placebo arm is still good enough if this happened the way I believe it did.
That is my theory. When Peregrine meets the FDA they will have all the data and know exactly what happened and when. If they can show the FDA the numbers I think it would be hard to not accept the fact that bavituximab works very well. There does not have to be statistical significance to be given the go ahead for a phase 3 trial, the FDA just has to believe bavi is safe and has a good chance of being effective for second-line NSCLC.
Hopefully, in the near future Peregrine will release a much more detailed explanation of the nature of the mix up.
Okay, my first wish is fulfilled, close enough anyway.
Mojojojo, I agree with you. The 13.1 months (or bigger) MOS for the 3 mg/kg arm stands on its own.
I think the "true" results are actually very close to the results presented in Chicago.
Correcting the placebo and 1 mg/kg arms would actually make the difference between
them bigger, not smaller. Onward and upwards.
Good question. How about the mix up occurred more or less randomly between the placebo arm and 1 mg/kg arms,
with a number of patients getting the wrong thing, but only once or twice during their treatment cycles.
So the number affected could be large, but the effect would be minor for each, however it would
be impossible to separate them out since there were a large number involved. I think that could explain it.
You make a good point. This leads be to think that it was a small number of patients involved, maybe
at only one clinical site. There is also the possibility that the mix up only occurred for part of the trial.
If some patients in the placebo arm got 1 mg/kg of bavi for only 2 cycles of treatment out of six
then it might have made very little difference. Similarly, if some of the patients in the 1 mg/kg arm got placebo
for 2 cycles and bavi for 4 cycles it also might not make much of a change in the MOS. All the more reason
to see the analysis with those patients dropped.
No idea.
True enough, but if Garnick agrees with this approach then I think it has a good chance.
The question is, what is the MOS for the new "control" arm? It will be greater than 5.6 months, maybe
about 8.3 months. I doubt that the 3 mg/kg will be statistically significant since it wasn't before (p = 0.07).
I hope that at some point Peregrine puts out an analysis in which they show the new combined control arm
along with the 3 mg/kg arm, and another analysis where the patients that had the mix up are just dropped from
what ever arm they were in and the resulting 3 arms are used.
I take it to mean that some of the 1 mg/kg arm got a placebo in addition to docetaxel and some in the
control arm got 1 mg/kg of bavi instead of placebo, and docetaxel. Everybody got the same dosage
of docetaxel. If they didn't get any docetaxel I think it would have been noticed.
mojojojo, can you repeat the exercise you just did yesterday and combine the placebo and 1 mg arms
as the new control arm, and plot the KM curves along with the 3 mg arm?
Thanks
Peregrine Pharmaceuticals Provides Update on the Internal Review of Its Phase II Second-Line Non-Small Cell Lung Cancer Trial
I think combining the placebo and 1 mg arms is a conservative thing to do, but may be necessary to allay concerns about the data.
I listened to the last quarterly conference call again, and read the transcript. I picked up something I hadn't
noticed before. Steve King said this as part of a response to one of the questions.
Yes, but neither poster has anything to do with the Peregrine trials.
Cotara uses an antibody that targets the histones released by necrotic cells at
the core of the tumor. The emissions from the Iodine-131 radioisotope then kill
surrounding cells. The core is a hypoxic region.
Bavi creates necrosis by destroying the tumor vasculature, which creates hypoxia,
and targets the PS on the vasculature. That PS exposure is increased in hypoxic regions.
So I think there may be too much overlap there. It might not gain you too much because
they both are centered in the tumor core region. I think the best results occur when
you combine two treatments with much different MOAs. Chemo is cytotoxic and creates
apoptotic tumor cells, and increases the PS on the tumor vasculature which Bavi can then target.
It might be worth testing in a preclinical model.
The amount of PS exposed on the tumor vascular endothelial cells to start with is not what is most important.
Rather, it is the amount of PS exposed when either chemo or radiation is used. That is why bavi will always
be used in combination. Preclinical studies have shown that bavi by itself is about equal to either chemo or
radiation alone, but the combination can be much better. In the pancreatic trial the standard chemo gemcitabine is used.
The preclinical study showed excellent results. For the prostate IST bavi is used with cabazitaxel, which is a taxane.
I wouldn't say that the prostate and/or pancreatic trials will necessarily do any better than the NSCLC trials.
We'll just have to wait for the data.
I doubt that they would wait until the annual ASCO meeting since it is in June. The rules for late-breaking abstracts
say that the data can not be released before the presentation at the meeting. I think we will know about all three
trials well before the beginning of June. Maybe some data from the ISTs could be presented at the annual ASCO meeting.
There are two different meetings. The one I just posted about is the 2013 Gastrointestinal Cancers
Symposium to be held from Jan 24-26, 2013, in San Francisco,
http://www.gicasym.org/
http://investorshub.advfn.com/boards/read_msg.aspx?message_id=83104601
The Annual ASCO meeting is to be held from May 31 - June 4, 2013 in Chicago,
http://chicago2013.asco.org/
Here is the ASCO meeting calendar
http://www.asco.org/ASCOv2/Meetings/Calendar+of+Events
The Annual AACR meeting is to be held April 6-10, 2013 in Washington, D.C.
http://www.aacr.org/home/scientists/meetings--workshops/aacr-annual-meeting-2013/aacrcentral.aspx
The AACR meeting calendar.
http://www.aacr.org/home/scientists/meetings--workshops/meetings--workshops-calendar.aspx
I don't think I ever said that first-line MOS would be 21 months, and I don't think it will be. My wish is for 20 months,
but that is probably stretching it a bit. I am thinking more like 17-19 months, with the control arm at 11-13 months.
I think if MOS for the treatment arm is 6 months longer than the control arm everything will be great.
Even though the text of the abstracts have not been released, the titles have been. The late breaking abstracts
are also included. You can search all the abstract titles at this website
https://iplanner.asco.org/gi2013/gi2013.aspx
I have seached for "bavituximab", "Thopre", "Peregrine", "phosphatidylserine" and found nothing.
You can also look at the detailed meeting program. Friday is the day for pancreatic cancer. You can see that
late breaking abstracts (LBA) are listed.
http://www.gicasym.org/meeting-program#Friday
Looks like no data will be presented at this meeting.
Of course, but this is just an exercise to see how bad the worse case scenario would be. Even then
the results are pretty good, so we can expect the corrected dataset to be even better.
I have not changed my "wish list" from when I posted it on Dec 10, 2012.
http://investorshub.advfn.com/boards/read_msg.aspx?message_id=82324652
I still hope for those results but don't expect them to all come true. Two out of three would be great.
Happy New Year.
I have read research that shows in the tissues normal apoptotic cells are removed within minutes by
macrophages. I think that is why you don't see any response from bavi. On the other hand tumors remain
for a relatively long time, as do sites of infection, long enough for the antibodies to arrive and bind to PS.
Try this post. It is the balance between the phagocytosis using the Fc-gamma receptors bound to bavi,
which is in turn bound to PS, and the TIM-4 PS receptors bound to PS.
http://investorshub.advfn.com/boards/read_msg.aspx?message_id=80729530
If anything the presence of bavi would increase the phagocytosis of apoptotic cells (efferocytosis) and so
should not be a problem. In the Q&A section of the NYAS talk by Thorpe someone asked the same
question and Thorpe gave the same answer.
http://en.wikipedia.org/wiki/Efferocytosis
CJ, I was confused at first because this description of Freeman's research appears to have little to do with
the title of the seminar he is to give at UTSW. The research description is from Freeman's lab website.
The seminar is about the TIM receptors for phosphatidylserine (PS), which were discovered about 5 years ago.
TIM receptors are involved in the regulation of T cells. TIM stands for "T-cell Immunoglobulin Mucin",
as in TIM-4 protein. TIM-4 is also the major PS receptor. I recently posted about a paper which showed how the Dengue
virus uses TIM-4 to gain entry to host cells. http://investorshub.advfn.com/boards/read_msg.aspx?message_id=81374675
Also, at the Society for ImmunoTherapy of Cancer in October a poster was presented by Bruce Freimark et al
which had this picture. When you see "PS receptor" think TIM-4.
http://investorshub.advfn.com/boards/read_msg.aspx?message_id=81011342
Here is a paper that Freeeman published in May 2010 in Immunological Reviews.
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2914464/
TIM genes: a family of cell surface phosphatidylserine receptors that regulate innate and adaptive immunity.
Freeman GJ, Casasnovas JM, Umetsu DT, DeKruyff RH.
Department of Medical Oncology, Dana-Farber Cancer Institute, and Department of Medicine, Harvard Medical School, Boston, MA, USA.
Abstract
The TIM (T cell/transmembrane, immunoglobulin, and mucin) gene family plays a critical role in regulating immune responses, including allergy, asthma, transplant tolerance, autoimmunity, and the response to viral infections. The unique structure of TIM immunoglobulin variable region domains allows highly specific recognition of phosphatidylserine (PtdSer), exposed on the surface of apoptotic cells. TIM-1, TIM-3, and TIM-4 all recognize PtdSer but differ in expression, suggesting that they have distinct functions in regulating immune responses. TIM-1, an important susceptibility gene for asthma and allergy, is preferentially expressed on T-helper 2 (Th2) cells and functions as a potent costimulatory molecule for T-cell activation. TIM-3 is preferentially expressed on Th1 and Tc1 cells, and generates an inhibitory signal resulting in apoptosis of Th1 and Tc1 cells. TIM-3 is also expressed on some dendritic cells and can mediate phagocytosis of apoptotic cells and cross-presentation of antigen. In contrast, TIM-4 is exclusively expressed on antigen-presenting cells, where it mediates phagocytosis of apoptotic cells and plays an important role in maintaining tolerance. TIM molecules thus provide a functional repertoire for recognition of apoptotic cells, which determines whether apoptotic cell recognition leads to immune activation or tolerance, depending on the TIM molecule engaged and the cell type on which it is expressed.
The correct word is not "efficiency", it is "efficacy".
-- "capacity for producing a desired result or effect; effectiveness."