Gone for good.
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CJ, when I try to download this I only get a little over 2 pages of the 7 pages.
It is at least 4 months now. Just more time for the data to "mature". Your guess
is as good as mine about any delay.
The trial was not powered to show any significance, or designed to do so, so why would you even discuss it?
I think it was just a shot in the dark. Knowing how bad pancreatic cancer is everyone would expect
the trial to show little effect. However, if by some miracle it worked, then wow! I don't think they lost
much in the process. The result is actually not bad (HR = 0.75) considering.
I don't think it was an oversight, or telling. I think it was simply a very small trial (70 patients) in a very nasty
disease. In all the trials that have been done in pancreatic cancer in the last 15 years only three have
shown a statistically significant increase in MOS. Nobody should have expected this small trial
to show such a result. It was obviously not designed to do so. There was a trial in 2007 that did
show statistical significance of a 0.33 month (10 days) increase in MOS. That was the Moore et al. trial
with Tarceva + gem vs. gem.
Erlotinib Plus Gemcitabine Compared With Gemcitabine Alone in Patients With Advanced Pancreatic Cancer:
A Phase III Trial of the National Cancer Institute of Canada Clinical Trials Group
Results
A total of 569 patients were randomly assigned. Overall survival based on an intent-to-treat
analysis was significantly prolonged on the erlotinib/gemcitabine arm with a hazard ratio (HR) of
0.82 (95% CI, 0.69 to 0.99; P .038, adjusted for stratification factors; median 6.24 months v 5.91 months).
One-year survival was also greater with erlotinib plus gemcitabine (23% v 17%; P .023). Progression-free
survival was significantly longer with erlotinib plus gemcitabine with an estimated HR of 0.77
(95% CI, 0.64 to 0.92; P .004). Objective response rates were not significantly different between the arms,
although more patients on erlotinib had disease stabilization. There was a higher incidence of some
adverse events with erlotinib plus gemcitabine, but most were grade 1 or 2.
Conclusion
To our knowledge, this randomized phase III trial is the first to demonstrate statistically
significantly improved survival in advanced pancreatic cancer by adding any agent to gemcitabine.
-----------------------------------------------------------------------------------------------
Here is the OS for the 100 mg cohort. For this group the increase in the MOS was 0.42 months with an HR = 0.81.
The other two trials were the FOLFIRINOX trial (342 patients) and the recent Abraxane trial (861 patients).
The FOLFIRINOX trial did not add the 4 chemo drugs to gem, rather it was those 4 drugs in the
treatment arm and gemcitabine in the control arm.
See the AACR poster. Note that the percentages for the GEM control arm don't add up to 100%, only 94%.
This was not the final number since the trial had not completed enrollment when the poster was made.
John, I would avoid any more trials for pancreatic cancer. Why risk it? They have good data on bavi's
effectiveness in breast cancer from the two earlier trials so I would pursue that. I think the current
investigator-sponsored trials (ISTs) might give some more clues on other indications. I hope
to see some data from the liver cancer trial this year, and prostate cancer. April 1 is, of course,
April Fools Day, which is why I chose it, because I think it is a fool's errand to predict stock prices,
or pretty much anything else! All I can say is that I still have a strong feeling about the science
behind the anti-PS approach to cancer immunotherapy.
So far the delayed response, in terms of survival, has only been a problem with the pancreatic trial.
If you look at the patient characteristics of the second-line NSCLC trial and the pancreatic trial, they
are not that different. Perhaps the PS score and metastasis is more of a determinant for
pancreatic cancer. Remember the MOS for the control arm of the second-line NSCLC trial (putting
aside the discrepancies) was 5.6 months, while for the pancreatic it was 5.2 months, again not
that different. Yet, the treatment arms were much different. I tend to think this has more to do with
the nature of pancreatic cancer and not the chemo drug used with bavi. So in answer, I guess
the thing to do is to avoid pancreatic cancer if you are a struggling biotech. It might work if you
could use bavi early on, but then again the nature of pancreatic cancer is that most of the patients
don't get diagnosed until they are in stage III/IV so it would be hard to find enough trial patients.
Maybe it is a problem with no solution, at least for now. I am not sure why they ran this trial, maybe
as a test of the limits of bavi's effectiveness?
It was a phase II trial, not a phase I/II trial
Official Title: A Randomized, Open-Label, Phase 2 Trial of Gemcitabine With or Without Bavituximab in Patients With Previously Untreated Stage IV Pancreatic Cancer
http://www.clinicaltrials.gov/ct2/show/NCT01272791?term=Bavituximab+OR+Peregrine&rank=1
This was the breakdown in the three trials
FOLFIRINOX
PS 0 = 38%
PS 1 = 62%
Abraxane
PS 0 = 60%
PS 1 = 40%
Baiv + gem ( from the AACR poster)
PS = 0 28%
PS = 1 56%
PS = 2 16%
FF, both the Abraxane study and the FOLFIRINOX study were done with only metastatic patients,
just as the Peregrine trial was done. FOLFIRINOX is a combination of 4 chemo drugs, and
Abraxane is albumin-bound paclitaxel. So the big difference was adding a monoclonal
antibody to gemcitabine, instead of more chemo drugs. I agree with your assessment that the
patients were dying faster than bavi could work. It will be interesting to see if
there was a subset that did better.
Sorry, I missed that.
New SEC form 13G/A filed
Looks like your timeline for when the pancreatic MOS was triggered was close, about mid-Nov?
Trying to put this in perspective. This paper was just published. It is a meta-analysis of randomized phase 2 and 3 pancreatic cancer trials.
http://www.ejcancer.info/article/S0959-8049(12)00681-8/abstract
Role of gemcitabine-based combination therapy in the management of advanced pancreatic cancer: A meta-analysis of randomised trials
This is a table which shows the HR for overall survival.
Also, note that the recent trial comparing Abraxane + gem vs. gem reported an HR of 0.72. The FOLFIRINOX trial reported an HR of 0.57.
Sounds plausible to me. Let us hope we see some of the data eventually.
No, but I would be lying if I didn't say I was less certain of the outcome.
For the time being, yes. There may be some insights that can be gleaned from the data. Maybe there
is something there that will allow them to try it again with different conditions. Practically speaking
though, with the limited resources they have I think this goes to the back of the queue.
Let us hope so. Looking at my tables for the control arms of pancreatic trials I see that the 5.2 months for
the control arm reported today is less than all the values in the table. This was a very sick group of patients.
It is good that the hazard ratio came in at 0.75.
Don't get me wrong. I still think Bavi will work well with other indications, just not pancreatic cancer.
This is not the end of it. To me it seems that the understanding of pancreatic cancer is lacking.
Bavi's MOA may be thwarted in some way in this cancer, or the patients were just too far gone
to give bavi a chance to help them. It will take more research. In the meantime Peregrine will have
to move on to more promising cancers, like breast cancer.
No, I still think the randomized, double-blinded, single-arm, 3 mg/kg arm will be very good. I still hope the
first-line is good too, but this just reduces the overall impact. The package won't look as good now. The reality
is that other drugs have failed against pancreatic cancer, like Avastin, but been approved for other indications.
WE WERE ALL WRONG!!!
Damn, what a disappointment. I was worried that pancreatic would be too hard to beat, but if we did it
would be fabulous. First-line NSCLC is the only hope now. Crap.
Connecting the dots: Thorpe, Gerber, Schiller --> Peregrine.
Meet Dr. Joan Schiller Oncologist and Lung Cancer Specialist
Andrea L. Simmons Distinguished Chair in Cancer Research
Dr. Schiller is Professor and Chief of the Division of Hematology-Oncology at UT Southwestern Medical Center
and Deputy Director of Simmons Cancer Center. She is founder and president of the National Lung Cancer Partnership.
http://profiles.utsouthwestern.edu/profile/81890/joan-schiller.html
Fellow of the American Society of Clinical Oncology
An award given for dedication and volunteer efforts in the field of medical oncology (2013)
American Thoracic Society's 2011 William J Marting II Distinguished Achievement award (2011)
Lung Cancer Medical Oncology Team
Jonathan Dowell, M.D.
David Gerber, M.D. <- gave the Chicago talk on Sept 7th
Randall Hughes, M.D.
If you do a pubmed search on her you get a list of 176 papers.
She is a major player in the clinical oncology of lung cancer. She is
very connected with all the big clinical oncologists in lung cancer.
One of the Associate Editors for the Journal of Clinical Oncology
http://jco.ascopubs.org/site/misc/edboard.xhtml
Both of these papers were just published online in Journal of Clincal Oncology, Feb 11, 2013
Maintenance Chemotherapy for Advanced Non–Small-Cell Lung Cancer: New Life for an Old Idea
David E. Gerber and Joan H. Schiller
Non–Small-Cell Lung Cancer: Then and Now
Joan H. Schiller, University of Texas Southwestern Medical Center, Dallas, TX
David R. Gandara, University of California, Davis, Comprehensive Cancer Center, Sacramento, CA
Glenwood D. Goss, The Ottawa Hospital Cancer Centre; University of Ottawa; and NCIC Clinical Trials Group, Ottawa,
Ontario, Canada
Everett E. Vokes, The University of Chicago Medical Center, Chicago, IL
AUTHORS’ DISCLOSURES OF POTENTIAL CONFLICTS OF INTEREST
Employment or Leadership Position: None Consultant or Advisory
Role: Joan H. Schiller, AdventRx Pharmaceuticals (C), Agennix (C),
ArQule (C), AVEO (C), Clovis Oncology (C), Daiichi Sankyo (C), EMD
Serono (C), Genentech (U), GlaxoSmithKline (C), Merck (C), Novartis
(C), Peregrine (C), Pfizer (C), Threshold Pharmaceuticals (C);
Lung Cancer Set to Overtake Breast Cancer as the Main Cause of Cancer Deaths Among European Women
http://www.sciencedaily.com/releases/2013/02/130212210039.htm
.....
Pancreatic cancer is the only cancer for which death rates are not predicted to decline in both sexes and, in fact, may rise in 2013. There will be a predicted 40,069 deaths (8 per 100,000) in men and 40,197 deaths (5.5 per 100,000) in women in 2013. These rates are higher than those recorded for 2009 of 7.9 per 100,000 in men and 5.4 per 100,000 in women.
For those of you so inclined there is a free software package for computing Kaplan-Meier analysis and making the plots.
It is called KMwin and you can get it here:
http://www.softpedia.com/get/Science-CAD/KMWin.shtml
To use KMwin you need to have the language R installed. It is also free and you can get it here:
http://www.softpedia.com/get/Programming/Coding-languages-Compilers/R-for-Windows.shtml
Here is the R project webpage:
http://www.r-project.org/
Here is free paper published on KMwin which has pictures of the user interface and an example of the kind of plots
you can make:
http://www.plosone.org/article/info%3Adoi%2F10.1371%2Fjournal.pone.0038960
I found it pretty easy to use. You do have to create a dataset for input which consists of events (deaths) or censoring.
Here is a plot I made of the original 3 arms of the second-line NSCLC trial. Note the p-values are computed using
the log-rank method since that is the only option.
Thanks for the complement. Although mojojojo's estimate for the 2nd-line NSCLC is lower than most
other estimates, even 11 months is quite good. This is especially true if you believe the original control
arm was not affected much by the discrepancies, which I do. What is your current estimate for
the 2nd-line NSCLC MOS?
FTM
I want to look at Mojojojo's result for pancreatic cancer in a different way. I am using pancreatic cancer because
the MOS values from the control arms of the phase 3 trials in my tables are fairly uniform. That is, there is not
too much variation in the results. This is probably because it is such a deadly disease that kills patients quickly
and the standard chemotherapy, gemcitabine, isn't very effective.
For each of the 13 clinical trails there is a group of patients which has certain characteristics. These include
the two most important, PS score, and disease extent, as well as others, such as CA 19-9 baseline values,
and other things such as age, gender, etc. There are also the unknowns, such as the individual's response to
gemcitabine, immune system condition, etc., things we think might influence the patient outcomes, but for which
we have no data. There are also the unknown unknowns. However, there are also constraints placed on what
patients are eligible, which are encoded in the inclusion, and exclusion, criteria for the trial. These criteria
are somewhat similar between the trials, so the patient groups have considerable overlap in
their characteristics, but also have their differences.
If we could take just one group of patients and run the same trial on them over, and over, we would get a
distribution of control arm MOS values about some mean. Obviously, that is not possible. But we do
have these 13 control arms from phase 3 trials. Each of them has a different input, that is group of patients,
which are somewhat different. Then they go through their trials and eventually the MOS values for the control
arms are computed. These values should also be distributed about some mean. We can think of the differences
in these control arm MOS values as due to noise which arises from the different inputs (patient groups).
See the figure below.
Let us now assume that the MOS for the treatment arm of the Peregrine pancreatic trial does come
out at 10.1 months, as Mojojojo has estimated. Let us make the hypothesis that Bavi is nothing but
a placebo, so the treatment arm can then be considered as a control arm receiving gemcitabine plus
placebo. If that is true, then what is the probability of a control arm producing a MOS value of 10.1 months?
I have tried to calculate that using the data I have and excel functions. I am no statistician, but I think I worked it out.
The value of 10.1 months is about 5 standard deviation units from the mean of the 13 control arms, as you
can see in the table below. That is an incredible difference. I am assuming that the control arm of the
Peregrine trial will turn out to be fairly similar to the mean of the 13 control arms I am using here. Since the
standard deviation of the those 13 MOS values is fairly small, it is probably a good assumption.
Of course, the only thing that is important to the FDA is the difference between the treatment arm and the
control arm of the same trial. I am just trying to get a measure of how different the bavi treatment arm might
be from the historic control arms. As an aside, the threshold of detection used by the physicists at CERN to
detect the Higgs boson was a 5-sigma event.
Thanks for reading,
FTM
There was very little response data presented in the pancreatic cancer poster. The only response information
was for less than half (32/70) of the eventually enrolled patients.
Mojojojo, I like the Big Picture here. Taking the means of your estimates we get
first-line NSCLC MOS = 17.9 months
second-line NSCLC MOS = 11.0 months
pancreatic cancer MOS = 10.1 months
These are great numbers! My guess is that all are > 50% improvement over their respective control arms.
Taken together this is an amazing result.
Yes, it is one of the site locations listed. Why is that weird?
Your friend is an idiot.
Why are you posting XML code? The webpage shows that nothing has been changed.
http://www.clinicaltrials.gov/ct2/show/NCT01272791?term=Bavituximab+OR+Peregrine&rank=1
PGN635 and Ebola
I was looking at the poster from the 2010 Biodefense meeting which looked at anti-PS antibodies and Ebola.
Targeting of Anionic Phospholipids Exposed on Infected Cells and Virions: Potential Broad-Spectrum Antiviral Therapy
I cut out part of an image and enlarged it. It shows PGN635 (green), anti-Ebola antibody (red) from sera, and cell nuclei (blue).
It is so spectacular I thought I would share it. It shows PGN635 bound to Ebola infected cells.
I have no idea. I am sure they will let us know if they submitted an abstract which was then accepted.
I think about March 1st the abstracts for the AACR meeting will come become available.
I tend to agree with what you have said. I think we are now waiting for the data to mature to the point
that the MOS can be reported with confidence that it is close to a "final" number. I think the numbers
for the first-line NSCLC won't be fully released until ASCO in June.
Joe Shan said this at the December conference call
There has never been a trial of Bavi at Mass General Hospital.
Check ClinicalTrials.gov.
From Nature Reviews Drug Discovery Feb 2013
Breakthrough drug programme debuts
Vertex receives the first 'breakthrough drug' designations, and application volume is on the rise.
The lowdown: With the introduction of the US Food and Drug Administration Safety and Innovation Act (FDASIA) last summer, the FDA was committed to creating a 'breakthrough drug' programme to expedite the development and review of drugs for serious or life-threatening diseases that may offer substantial improvement over existing therapies, based on preliminary clinical evidence. “The programme is to really highlight drugs that are game changers,” said John Jenkins, Director of the Office of New Drugs at the FDA's Center for Drug Evaluation and Research. Sponsors who are granted the designation are entitled to increased interaction with the FDA to ensure the drug development programme is streamlined and clinical trials are optimized for efficiency.
The first beneficiaries of the programme are Vertex's ivacaftor and its combination of VX-809 plus ivacaftor, the company disclosed at the J. P. Morgan meeting in San Francisco. Ivacaftor is already approved for cystic fibrosis in patients with at least one copy of the G551D mutation in the cystic fibrosis transmembrane conductance regulator (CFTR) gene, but the new designation could accelerate its approval into other patient groups as well.
As of mid-January, the agency had received a total of 16 applications for breakthrough drugs. Only the 2 from Vertex had been approved as Nature Reviews Drug Discovery went to press; 3 others had been rejected and 11 were still pending.
Draft guidance on the programme is due to be published by the end of 2013. But already, one key element is becoming clear: “[Companies] are really going to have to adjust their manufacturing plans,” says Jenkins. A company might hypothetically be able to complete the clinical trials needed to support an application in 1 year, he explained, but this is of little benefit if it does not plan to build a production plant for 3 years.
The idea is that Bavi causes an increase in the number of tumor infiltrating macrophages which makes
the tumor size increase. Thorpe has published data showing that there is an increase in macrophages.
The question is whether the tumor size in human patients does increase for a period of time and then
decreases as the tumor is destroyed.
The Stimuvax (L-BLP25) story. This is interesting. At first I couldn't figure out how the phase 3 trial could fail. From Dec 2012.
http://ir.oncothyreon.com/releasedetail.cfm?ReleaseID=727708
The updated phase 2b trial results were published in 2011 and showed good survival results. The trial enrolled both stage IIIB
and stage IV patients. Here are the survival curves. Top curve is all patients,
middle curve is stage IV, and bottom is stage IIIB.
Updated survival analysis in patients with stage IIIB or IV non-small-cell lung cancer receiving BLP25 liposome vaccine
(L-BLP25): phase IIB randomized, multicenter, open-label trial
J Cancer Res Clin Oncol (2011) 137:1337–1342
The phase 3 trial enrolled only stage IIIA and IIIB patients based on the phase 2b results. Seems like it should work fine.
Then I found this study.
A Multicenter Open-Label Study to Assess the Safety of a New Formulation of BLP25 Liposome
Vaccine in Patients With Unresectable Stage III Non–Small-Cell Lung Cancer
Clinical Lung Cancer November 2010
It turns out that the phase 3 study used a new formulation of the vaccine because changes were needed
for the scale up to manufacture the vaccine for phase 3. That is what I think doomed the phase 3 study.
So they ran a safety study on the new vaccine formulation and looked at survival too. However, it was
a single arm trial with 22 patients. Everything seemed okay. From the above paper: