Gone for good.
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RRdog, how about meeting me and some other retail investors at the annual shareholders meeting in Oct?
Entdoc, that would be fun but tomorrow is my last day here, back to Denver on Friday.
Maybe the annual shareholders meeting? I am seriously thinking of going this year.
You might want to brush up on antibodies. The part that is cut off is the constant
region which would bind to the Fc-gamma receptors on macrophages, dendritic cells.
The imaging agent, NIR, or I-124 is attached chemically to the F(ab')2 part.
So PGN650 has two Fab arms which are both specific for the epitope on domain 2 of
the beta2-GPI molecule which binds to PS. PGN650 does then mask PS and would have
immunomodulating properties, but it would not have the ability to bind to effector
immune cells. I also think the dose used for the imaging may be less than the
therapeutic dose used with bavi. Good night.
http://en.wikipedia.org/wiki/Antibody
http://en.wikipedia.org/wiki/Fab_region
Entdoc, hang tough. We all know Bavi is the real deal. You don't need me now.
I really am getting back to my vacation here in Sonoma.
Bungler, glad to see you had the same idea.
FTM
All I have to say is look at this from the Chicago Symposium in Thoracic Oncology,
then tell me that what will be presented is the same old stuff we have already seen.
In addition, the presentation was given a spot in a Plenary Session, not as
a Poster Discussion, nor as an Oral Abstract, nor just a Poster.
I am going back to my vacation now.
Late-breaking Abstract Guidelines
An abstract may be submitted as a late-breaking abstract if the abstract is an original abstract containing important late-breaking research results that were not available prior to the April 5, 2012, regular submission deadline.
Late-breaking abstract research should be limited to important new developments from Phase II and Phase III clinical research trials that will have an impact on practice or research and were not available prior to the regular abstract submission deadline of April 5, 2012.
Submissions that are an update from the April 5, 2012, submission deadline will not be considered for presentation.
Only those abstracts that are deemed to be of high scientific priority and which merit presentation will be accepted.
Late-breaking abstracts must not have been submitted, presented, accepted for presentation or published in any other scientific venue.
A special panel of peer reviewers will review the late-breaking abstracts and the corresponding author will be notified of the abstract status by late July 2012.
Not approved for stage 2. http://www.yervoy.com/patient.aspx
Indication
YERVOY (ipilimumab) is a prescription medicine used in adults to treat melanoma (a kind of skin cancer) that has spread (metastatic) or cannot be removed by surgery (unresectable).
Another reason is that sorafenib doesn't work all that well, but it is better than nothing, and the
only approved therapy for HCC, and works even less in Asian patients. See my post # 77582. So the hope
is that bavi + sorafenib will be a significant improvement. In addition, the rate of HCC is much, much higher
in Asia, due to infection with HBV, than in North America and Europe.
I am taking a hiatus from iHub until the Chicago symposium. Going on vacation for a
week and then just taking a break from it until the big news. Hold down the fort.
I thought the whole point of a phase II trial was to look for efficacy and safety.
Usually these trials are not powered to show statistical significance and
I don't ever remember Peregrine stating that as a goal. Now we see that regardless
of ORR or PFS that the survival will greatly exceed the control arm in a randomized,
double-blinded, placebo controlled trial. In a phase III trial for second-line NSCLC
median overall survival is the end-point which is the most important and trumps everything else.
I would say bavi is looking pretty good right now as a candidate for a phase III trial
with survival as the end-point. What exactly is wrong with that?
I am not trying to prove anything here. The whole point of the exercise is to look
at the mean of MOS from a population of phase III second-line NSCLC trials, all comparing
a treatment arm to a docetaxel control arm. I compute the mean of the MOS from
the 12 trials and compute the standard deviation of those. This is just to see what
kind of variability exists across many trials using various treatments. I wanted
to know the possible range of MOS out there. It is really quite simple. I think
you are trying to make it something it is not.
It says these are phase III at the top of the table.
The mean is correct, not the median. The whole point
here is to take a number of phase III trials and the
average of the MOS and see how the MOS varies. Of course
you can't compare trials directly, I am not, I was just
giving a number averaged over all the trials for a point
of comparison. See my post # 81830 for the control arms.
Thurly, I think Peregrine won't release any statistical results until much later, and hazard ratio is a statistical measure.
I find this to be quite useful for hazard ratios, no math involved. and FREE.
Biostatistics Primer What a Clinician Ought to Know: Hazard Ratios
Journal of Thoracic Oncology, June 2011.
http://journals.lww.com/jto/Fulltext/2011/06000/Biostatistics_Primer__What_a_Clinician_Ought_to.2.aspx
errata:
http://journals.lww.com/jto/Fulltext/2011/08000/Biostatistics_Primer__What_a_Clinician_Ought_to.29.aspx
Mojo, great find! I have been wondering about what is happening with the patients still alive. I have thought that
the primary tumors have become "stable" and metastasis has been stopped, as King alluded to in the last webcast,
and seen in several pre-clinical papers. The RECIST criteria for "stable disease" is everything that is not
"progressive disease", "partial response", or "complete response", which means less than 20% increase
and less than 30% decrease in tumor dimensions. That leaves a lot of room for the tumor to occupy. As seen
in the presentation you found those with "stable disease" live about as long as those with "partial response".
To me this just shows again how the end-points of ORR and PFS are not what to look at, overall survival is
the only truly relevant end-point, and always will be. This also shows that it might be possible to turn some cancer
into a manageable chronic disease.
Thanks for appreciating my artistic skill!
I listened to the NYAS talk yet again and came up with this. The minutes 22:30-25:30 tell
us about how the MOA has been updated to include exosomes. These very small vesicles are
released by the tumor and have PS on their surface. This PS is sensed by the macrophages and
dendritic cells which have PS receptors (TIM-3, TIM-4). This then causes an immunosuppresive
signal in those immune cells. When bavi is added it binds to the PS on the exosomes and the
Fc-gamma receptors on the immune effector cells. This send a immunostimulatory signal
to those immune cells. It is then the combination of the two signals which determines
what the immune response will be. The immunostimulatory signal over-rides the
immunosuppressive signal and the tumor microenvironment is changed to be immunostimulatory.
I drew this figure to show what is happening. This was the first time I have heard Thorpe
talk about exosomes in such detail. You can replace "exosome" with "tumor cell" also.
Two things that struck me, other than the obvious, was that King specifically mentioned
the liver cancer trial and how this would be a big deal for asia. The other was that the
first-line NSCLC MOS might not be known until Jan. That says to me again that they could
possibly go for AA in both first and second-line NSCLC at the same time.
FWIW, my guess is that MOS for the control arm was reached around the beginning of Feb and it was about 5.7 months.
Another late-breaking abstract for NSCLC on slide 16
http://www.esmo.org/events/vienna-2012-congress.html
This is a great picture showing the various ways the tumor microenvironment can manipulate immune cells.
The last pathway on the right is the newest and results in neutrophils with an N2 phenotype. See my post # 85862, 85863.
Coordinated regulation of myeloid cells by tumours
Dmitry I. Gabrilovich, Suzanne Ostrand-Rosenberg and Vincenzo Bronte
Nature Reviews Immunology Volume 112, April 2012, 253-268.
Figure 5 | Molecular mechanisms affecting the myeloid lineage in cancer. The tumour microenvironment
secretes many different cytokines and immune mediators that affect myeloid progenitors as well as mature myeloid
cells by regulating the activity of multiple transcription factors. These transcription factors, in turn, regulate the
synthesis of their protein targets, thereby affecting myeloid cell functions. ARG1, arginase 1; BCL-XL, B cell
lymphoma XL; C/EBPß, CCAAT/enhancer-binding protein-ß; DC, dendritic cell; G-CSF, granulocyte colony-stimulating
factor; GM-CSF, granulocyte–macrophage colony-stimulating factor; HSP70, heat-shock protein 70; IFN?, interferon-?;
IL, interleukin; iNOS, inducible nitric oxide synthase; MDSC, myeloid-derived suppressor cell; NF-?B, nuclear
factor-?B; NO, nitric oxide; NOX2, NADPH oxidase 2; PGE2, prostaglandin E2; PKCßII, protein kinase Cß isoform II;
ROS, reactive oxygen species; STAT, signal transducer and activator of transcription; TAM, tumour-associated
macrophage; TGFß, transforming growth factor-ß; TLR, Toll-like receptor; VEGF, vascular endothelial growth factor
I am with you. The science is fascinating, but the real goal is to cure people of their cancer,
or at least to make it a manageable chronic disease.
NHwild, I think it is a scam by iHub to get you to subscribe just so you can get more than 5 ignores!
Hatchet job 2....more to come?
Yes, indeed, who reeks of manipulation now?
Fools they are....latest hatchet job shows their ignorance.
http://www.fool.com/investing/general/2012/08/14/1-star-stocks-poised-to-plunge-peregrine-pharmace.aspx
Oh yes, hopefully they won't return, but there will always be new ones to take their place.
I have run out of ignores, 5 is just not enough! eom
Here is some more on the failed Amgen drug from Science Insider.
From this it sounds like the rationale wasn't very strong.
Amgen Pulls Cancer Drug
by Jennifer Couzin-Frankel on 10 August 2012, 3:50
The failure of a pancreatic cancer therapy, announced Wednesday by its maker Amgen, is yet another sign that a once-promising class of cancer treatments has failed to meet expectations. The latest therapy to flop, called ganitumab, is a monoclonal antibody that targets type 1 insulin-like growth factor receptor (IGF-1R). At Amgen, the drug made it all the way to a phase III clinical trial before the company pulled the plug partway through the trial after concluding that the therapy was unlikely to help patients live longer.
IGF-1R was deemed a promising target after researchers made a number of intriguing observations. Circulating levels of the hormone IGF-1 in a person’s blood were linked to a slightly higher risk of cancer. The receptor is often expressed on epithelial cells, the type of cells that turn cancerous, and it promotes cell survival. Finally, in cell cultures and animals, overexpressing the hormone could produce something that looks like cancer, and that would shrink when treated with an IGF-1R blocker.
But in patients, the drugs are “a serial failure,” says Vuk Stambolic, a cancer researcher at Princess Margaret Hospital and the Ontario Cancer Institute in Toronto, Canada. Other trials of this drug target in lung cancer have not worked, and the drugs’ effects in colorectal cancer are also questionable, Stambolic says.
The Achilles’ heel for many prospective cancer drugs is the biology. In short, it usually turns out to be more complicated than first thought. It may not be enough to go after IGF-1R alone, and the patients in these trials have very advanced disease and may be less likely to respond to narrowly targeted treatments. The work in animals and cells also may not fully mimic real life. “I think that the model is probably only partially representative of what happens in cancer,” Stambolic says.
Various companies are also testing a class of drugs that target both IGF-1R and the insulin receptor. The hope is that the double whammy will be more damaging to tumors.
Don't waste your time, he doesn't know the difference between PFS and MOS.
Thanks CJ. This should be the default post to go to for all questions about the MOA.
RRdog, Thanks. I will respond to questions, I just won't do it through a third party to someone on another
board. Anyone who is that interested in Peregrine can post on this board and get involved in the discussions.
If they want to post here on iHub and pose questions that is fine. I also wish people would do a little
homework and not make obviously incorrect statements when a few minutes with google, or reading
stuff on our intro section, will clear up their misunderstandings.
Yes, he doesn't really know much about bavi and how it works. He makes the mistake, that many do,
to lump bavi in with anti-angiogenics, like Avastin. While the result of treatment with Bavi is to destroy the
tumor vasculature, the MOA is not anti-angiogenic. Anti-angiogenic are usually mAbs that target the
receptors (VEGFR-1, VEGFR-2, VEGFR-3, FGFR) or their ligands (VEGF, FGF), that is the pathway involved
in the growth factor for vascular growth. Of course, these are upregulated in tumor growth, but they
are also part of normal growth, wound healing, etc. Bavi is a mAb that targets the PS upregulated
specifically, and uniquely, on the endothelial cells of the TUMOR vasculature. PS is not upregulated
on the vasculature of normal tissue. So Bavi is not involved in the angiogenic pathway at all.
The MOA for Bavi has at least three aspects to it and they are all connected, so you can't say
maybe some parts will work and others won't. I suggest looking at the post CJ put up yesterday
which is a concise overview of how Bavi works as previously presented by Thorpe.
See post # 86429, also see this http://en.wikipedia.org/wiki/Angiogenesis
After this I am not going to respond to what people say about Bavi on other websites.
That is a hole I am not going down.
Amgen, Citing Weak Results, Halts Study of a Cancer Drug
By KATIE THOMAS Aug 9, 2012
Amgen is halting a late-stage clinical trial of an experimental drug for pancreatic cancer after an outside monitoring panel concluded that the drug was unlikely to improve the survival of patients with an advanced form of the disease.
“These disappointing results underscore the difficulty of treating pancreatic cancer, which remains a major unmet medical need,” Dr. Sean E. Harper, executive vice president for research and development at Amgen, said in a statement released Wednesday. “We would like to thank the patients, caregivers and investigators for their participation and engagement in the study.”
The study was in Phase 3, the final stage of clinical trials before a drug maker applies for approval. Amgen said that no safety concerns were raised in the review of the trial — there simply was not enough evidence that it worked. A separate study of patients with locally advanced pancreatic cancer, which was in Phase 2, will also be stopped.
The drug, known as ganitumab and as AMG 479, targets a hormone called insulinlike growth factor 1, which has been linked to cancer. “If you asked me 10 years ago, I and many others would have said that’s one of the most interesting targets in oncology,” said Dr. Leonard Saltz, who is chief of the gastrointestinal oncology service at the Memorial Sloan-Kettering Cancer Center.
Dr. Saltz said he once counted 11 companies that had similar drugs in development. “They’ve all been disappointments. And so what it really turns out is that even though the science pointed very encouragingly in that direction, the clinical trials have not been successful.”
Still, any setback is a disappointment in the area of pancreatic cancer, Dr. Saltz said. “We desperately need a better treatment for pancreatic cancer,” he said. “It is one of the deadliest cancers that we know of.”
Because of the earlier failures of similar drugs, the news that Amgen’s version had also not succeeded is not expected to be a blow to the company, said C. Anthony Butler, a pharmaceutical analyst at Barclays Capital. “There are other programs that are more advanced,” he said, including a drug that fights cholesterol and ones that treat psoriasis and post-menopausal osteoporosis.
Amgen’s announcement comes as a handful of other drug makers have also canceled plans for experimental drugs. On Monday, Johnson & Johnson and Pfizer announced they were halting development of a closely watched Alzheimer’s drug after clinical trials failed to show it worked. On Wednesday, Merck cited business reasons in its decision to suspend development of a combination cholesterol drug. And last week, Bristol-Myers Squibb said it was suspending a study of a hepatitis C drug after a patient experienced heart failure. The patient’s condition was not disclosed.
Mr. Butler said the recent string of canceled trials highlights the risky nature of the drug business but is not evidence of more pervasive troubles in the industry.
I thought I would post this to put the bavi NSCLC results in context with what else is going on with NSCLC clinical trials.
Targeted drugs were supposed to be the next great thing, but in many cases they have been a bust.
From this you can see that there is much room for improvement in treatment of NSCLC.
---------------------------------------------------------------------------------------------------------------------------------------------
Journal of Clinical Oncology, August 10, 2012.
Multitargeted Tyrosine Kinase Inhibitors in Unselected Patients With Advanced Non–Small-Cell Lung Cancer (NSCLC):
Impressions From MONET (the Motesanib NSCLC Efficacy and Tolerability Study)
Daniel Morgensztern and Roy S. Herbst, Yale Comprehensive Cancer Center, Yale University School of Medicine, New
Haven, CT
---------------------------------------------------------------------------------------------------------------------------------------------
Angiogenesis is a complex and tightly regulated process that is
defined as the growth of new blood vessels, especially those that supply
oxygen and nutrients to cancerous tissue, from existing vasculature. 1
Because of the critical role of angiogenesis in the growth and
metastases from solid tumors, including non–small-cell lung cancer
(NSCLC), its inhibition represents a rational therapeutic strategy.
Vascular endothelial growth factor (VEGF) is a key ligand and
regulator of both physiologic and pathologic angiogenesis, including
that of tumors, with signaling occurring mainly through the
VEGF receptor 2 (VEGFR-2). 2
Bevacizumab, a humanized monoclonal antibody against circulating
VEGF, was the first antiangiogenesis drug to enter clinical practice
for NSCLC. Because of an increased risk of life-threatening
bleeding among patients with squamous cell carcinoma in the phase II
trial, 3 subsequent trials were limited to nonsquamous histology. The
addition of bevacizumab to chemotherapy was associated with improved
response rate (RR) and progression-free survival (PFS) in two
large randomized trials, Eastern Cooperative Oncology Group
(ECOG) 4599 4 and Avastin in Lung (AVAiL) ,5 although only ECOG
4599 was associated with improved overall survival (OS). Unfortunately,
the benefit from bevacizumab in patients with advanced
NSCLC is modest and transient, with essentially all responding patients
developing secondary resistance. One of the mechanisms that is
implicated in the development of resistance is the stimulation of
compensatory proangiogenic factors such as fibroblast growth factor
and platelet-derived growth factor(PDFGR) .6
Tyrosine kinase inhibitors (TKIs) compete with adenosine
triphosphate for the active site of the kinase domain. Because of the
well-conserved adenosine triphosphate binding sites of the kinases,
many TKIs (unlike bevacizumab, which exclusively targets the VEGF
ligand) inhibit multiple receptors. This ability to inhibit multiple angiogenesis
pathways offers the potential for increased efficacy and
decreased development of secondary resistance through redundant
pathways. Nevertheless, the decreased specificity may be associated
with increased toxicity. Given that single-agent TKIs directed against
similar targets such as sorafenib (VEGF-R2, VEGFR-3, PDGFR,
RAF-1, BRAF, c-KIT, FLT-3), 7 sunitinib (VEGFR-2, PDGFR, FLT-3,
c-KIT, RET), 8,9 and axitinib (VEGFR-1, VEGFR-2, VEGFR-3,
PDGFR, c-KIT) 10 have been well tolerated in NSCLC, the next step
would be to pursue their combination with chemotherapy or other
biologic agents.
Several randomized clinical trials comparing chemotherapy
alone or with the addition of TKIs have been conducted (Table 1).
In phase II studies, neither the addition of vandetanib 11 nor cediranib 12
improved the median PFS or OS compared with chemotherapy alone
using carboplatin and paclitaxel. Lack of OS improvement was also
observed in the two randomized phase III studies in the first-line
setting, the Evaluation of Sorafenib, Carboplatin, and Paclitaxel
Efficacy (ESCAPE) 13 and NSCLC Research Experience Utilizing
Sorafenib (NExUS), 14 as well as in previously treated patients. 15,16
Motesanib is a small-molecule targeted antagonist of VEGF receptors
1, 2, and 3, PDGFR, and KIT. In the phase IB study, five (17%)
of 29 patients who were treated with motesanib (50 mg per day, 125
mg per day, or 75 mg twice per day) in combination with carboplatin
and paclitaxel achieved partial response. Because of increased toxicity,
the twice-daily cohort was discontinued. The recommended motesanib
dose for subsequent studies was 125 mg once per day, which had
already been established as the maximum-tolerated dose for singleagent
therapy. 17 In the phase II study, 18 there were no significant
differences in outcomes between patients treated with carboplatin
plus paclitaxel and either bevacizumab or motesanib. In the article that
accompanies this editorial, Scagliotti et al 19 present the results of the
Motesanib NSCLC Efficacy and Tolerability (MONET1) trial, a multicenter,
randomized, double-blind phase III trial comparing carboplatin
and paclitaxel alone or in combination with motesanib 125 mg
per day as first-line therapy for NSCLC. The primary end point was
OS. All tumor types were initially included, but squamous cell carcinoma
was excluded after increasing gross hemoptysis and mortality
among the first 223 patients with this histology; this ultimately left
1,090 randomly assigned patients with nonsquamous histology for
evaluation. Although the overall RR was higher in the motesanib arm
(40% v 26%;P.001), the median PFS was only minimally improved
(5.6 v 5.4 months; P .001) and median OS was not significantly
improved (13 months v 11 months; hazard ratio, 0.90; P.14). In a
preplanned analysis, the 287 Asian patients were the only subset of
patients associated with improved survival from motesanib (hazard
ratio, 0.75; 95% CI, 0.59 to 0.97). Toxicity was significantly higher in
the motesanib arm, with incidence of serious adverse effects of 49%
compared with 34% in the chemotherapy alone arm. The motesanib
arm was associated with increased incidence of diarrhea, nausea, vomiting,
abdominal pain, hypertension, proteinuria, stomatitis, gallbladder
disorders, neutropenia, and thrombocytopenia. Levels of placental
growth factor, thought from previous studies to increase in response to
motesanib, were not associated with RR or survival. Therefore, MONET1
joins the growing list of studies that show no significant benefit from the
addition of multitargeted TKIs to chemotherapy.
Although the reason that TKIs failed to improve survival when
combined with chemotherapy is still unclear, this phenomenon has
been previously observed among patients treated with epidermal
growth factor receptor (EGFR) inhibitors; neither gefitinib 20,21 nor
erlotinib 22,23 showed survival improvement when added to chemotherapy.
However, the addition of the monoclonal antibody cetuximab
to chemotherapy produced mixed results, with improved
survival in the Cetuximab Plus Chemotherapy in Patients With Advanced
Non–Small-Cell Lung Cancer (FLEX) study 24 but not in the
Cetuximab and First-Line Taxane/Carboplatin Chemotherapy in Advanced
Non–Small-Cell Lung Cancer (BMS-099) study. 25
[snip]
In addition to the lack of survival benefit in NSCLC, multitargeted
antiangiogenic TKIs have been associated with significant
toxicity. Recent meta-analyses evaluating the adverse effects of the
two most commonly used TKIs, sorafenib and sunitinib, in multiple
malignancies showed that these drugs were associated with
increased risk of bleeding (relative risk, 2.0; P .015), 33 arterial
thrombotic events such as cardiac or cerebrovascular events (relative
risk, 3.03; P .015), 34 and treatment-related mortality (relative
risk, 2.23; P .023). 35 Therefore, TKIs to be used in
combination with chemotherapy should be carefully selected to
avoid major adverse effects.
[snip]
CJ, thanks for posting this.
I think a buyout for 2 billion would prompt a shareholder lawsuit. It would be criminal in my eyes.
Interim results from the pancreatic cancer trial could be reported here:
The 2012 Annual Meeting of the American Pancreatic Association (APA)
to be held jointly with the International Association of Pancreatology (IAP)
will take place at the Eden Roc Renaissance in Miami Beach FL from
Oct 31-Nov 3.
http://www.american-pancreatic-association.org/index.php?option=com_content&view=article&id=21&Itemid=22
The liver cancer trial is being run at UTSW. I expect that interim results from this trial will be presented
at a liver cancer meeting. The next meeting which might be a good place for this is here:
ILCA 2012
International Liver Cancer Association Sixth Annual Conference
14-16 September 2012
Berlin, Germany
http://www.ilca2012.org/programme.aspx
The ILCA 2012 Final Programme and Book of Abstracts will be published in August 2012.
After that the next would be this one:
The Liver Meeting 2012
The 63rd Annual Meeting of the American Association for the Study of Liver Diseases
9-13 Nov 2012
Boston, Massachusetts
http://www.aasld.org/lm2012/2012/Pages/default.aspx