Gone for good.
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Sunstar, thanks I listened to it. Looks like this site has a lot of good stuff
http://cancergrace.org
Another outstanding person who is an investigator on the bavi phase 2 front-line pancreatic trial
is Tony Reid, MD, PhD. Here is the AACR pancreatic cancer conference poster.
http://www.peregrineinc.com/images/stories/pdfs/pancreatic_2012_aacr_poster.pdf
Dr. Reid is professor in the UC San Diego Department of Medicine, Division of Hematology/Oncology
Dr. Reid has published broadly on the use of a new agent for the treatment of these malignancies and conducts a variety of clinical trials that utilize correlative studies to translate between important clinical and basic science observations. He has focused most of his work on early phase therapeutic clinical trials using gene therapy strategies to enhance the immune response to these malignancies.
He received his medical degree from Stanford University, where he also received a Ph.D. in biochemistry. Dr. Reid's Ph.D. thesis focused on the use of interferon to treat cancer and identified pathways involved in the anticancer effects of interferon. These studies led to the recognition that many malignancies lacked pathways that block viral infections. These observations have formed the basis for subsequent research work and clinical trials exploiting the defects in antiviral pathways in tumors to treat tumors with gene therapy vectors.
He was the lead investigator on the original trials using Onyx-015 to treat colorectal cancer and has pioneered the use of adenoviral and vaccinia vectors to the treatment of cancer. Dr. Reid has received national recognition for his work including the awards from the Interferon Society, the International Society of Gene Therapy and the Society for Interventional Radiology.
Dr. Reid has been at the forefront of using interventional radiology to selectively deliver therapeutic directly to the tumor using the tumor's own vascular supply. Finally, Dr. Reid is on the review board of numerous prestigious journals including Nature Cancer Gene Therapy, Gene Therapy and Clinical Cancer Research.
There is a publication only abstract at the Chicago Symposium for the IST trial of bavi + carboplatin + pemetrexed
in front-line metastatic NSCLC. There was also a poster presented at the 2012 AACR meeting by the group doing
the trial at Univ of North Carolina and Univ of Pittsburgh.
http://www.peregrineinc.com/images/stories/pdfs/aacr_2012_nsclc_ist.pdf
I was checking out one of the investigators, Mark Socinski, MD. He was at UNC and was recently recruited to Pitt.
http://www.upci.upmc.edu/news/2011/072511_lung.cfm
[snip]
Dr. Socinski is an internationally renowned expert in the development of novel chemotherapy agents and treatment strategies for advanced non-small cell lung cancer and small cell lung cancer. He has played a leading role in developing aggressive and innovative combined-modality approaches to treat patients with locally advanced non-small cell lung cancer, and he is at the forefront of integrating novel targeted agents with cytoxic chemotherapy regimens. Most recently, his clinical research has focused on incorporating personalized medicine and the use of molecular biomarkers in the treatment of lung cancer.
[snip]
He completed his residency training in internal medicine at the Beth Israel Hospital, Harvard Medical School, and completed training in medical oncology at the Dana Farber Cancer Center, Harvard Medical School.
[snip]
Having someone of this caliber involved with one of the IST says a lot to me about the interest Bavi has generated.
Here is a video of him talking about lung cancer.
New info about the ESMO Annual Congress presentation. Note all three posters to be discussed are on NSCLC.
Session details.
NSCLC - Immunotherapy, SCLC and Mesothelioma
Moderators: M. O'Brien, Dr., J.F. Vansteenkiste, Dr
Session Info: Poster Discussion, [] NSCLC - Immunotherapy, SCLC and Mesothelioma
Day/Date: Saturday, September 29, 2012
Session Time: 12:40 PM - 2:00 PM
1237PD | Clinical activity and safety of anti-programmed death-1 (PD-1) (BMS-936558/MDX-1106/ONO-4538) in patients (pts) with advanced non-small cell lung cancer (NSCLC)
S. Gettinger1, L. Horn2, S.J. Antonia3, D.R. Spigel2, L. Gandhi4, L.V. Sequist4, J.M. Wigginton5, G. Kollia5, A. Gupta5, J.R. Brahmer6
1New Haven, CT/US, 2Nashville, TN/US, 3Tampa, FL/US, 4Boston, MA/US, 5Princeton, NJ/US, 6Baltimore, MD/US
1238PD | Active Specific Immunotherapy with Racotumomab in the Treatment of Advanced Non Small Cell Lung Cancer (NSCLC).
A. Macías1, S. Alfonso2, E. Santiesteban3, C. Viada1, I. Mendoza1, P.P. Guerra1, R.E. Gómez4, M.L. Ardigo4, A.M. Vázquez1, R. Pérez1
1Havana/CU, 2Las Villas/CU, 3Matanzas/CU, 4Buenos Aires/AR
LBA35 | Randomized, double-blind, placebo (P)-controlled phase 2 trial of Bavituximab (B) plus Docetaxel (D) in patients with previously treated locally advanced or metastatic non-squamous non-small-cell lung cancer
D.E. Gerber1, M. Joppert2, D.R. Spigel3, D. Singh4, D. Giorgadze5, M. Shtivelband6, O. Ponomarova7, J. Shan8, C.P. Belani9
1Dallas, TX/US, 2Ft. Meyers, FL/US, 3Nashville, TN/US, 4Jaipur/IN, 5Tbilisi/GE, 6Chandler, AZ/US, 7Kiev/UA, 8Tustin, CA/US, 9Hershey, PA/US
[12:40 PM] Invited Discussant, Abstracts 1237PD, 1238PD and LBA35
Speaker: J.F. Vansteenkiste
Leuven/BE
----------------------------------------------------------------------------------------------------
J.F. Vansteenkiste, MD, PhD
Respiratory Oncology Unit (Pulmonology) University Hospital Gasthuisberg, Leuven, Belgium
Here is a discussion he did at the ESMO meeting in 2010 of 5 posters.
https://www.webges.com/cslide/library/esmo/mylibrary/search/author/0/J.%20F.%20Vansteenkiste
My guess is that the presentation at the Stifel Nicolaus Healthcare Conference on Sept 5
will be a replay of the Wedbush presentation with the note that an interim analysis of the
second-line NSCLC trial will be presented on the 7th. There is also the late breaking poster
discussion at the end of Sept at the ESMO Annual Congress which might fill in some more
of the data from the trial.
Lets assume that MOS for the second-line NSCLC trial does reach statistical significance sometime in the future.
If the bavi + docetaxel arms have MOS > 2X docetaxel + placebo arm, then I would say move ahead with Priority Review, forget AA.
http://www.fda.gov/forconsumers/byaudience/forpatientadvocates/speedingaccesstoimportantnewtherapies/ucm128291.htm
Priority Review
Prior to approval, each drug marketed in the United States must go through a detailed FDA review process. In 1992, under the Prescription Drug User Act (PDUFA), FDA agreed to specific goals for improving the drug review time and created a two-tiered system of review times – Standard Review and Priority Review.
Standard Review is applied to a drug that offers at most, only minor improvement over existing marketed therapies. The 2002 amendments to PDUFA set a goal that a Standard Review of a new drug application be accomplished within a ten-month time frame.
A Priority Review designation is given to drugs that offer major advances in treatment, or provide a treatment where no adequate therapy exists. A Priority Review means that the time it takes FDA to review a new drug application is reduced. The goal for completing a Priority Review is six months.
Priority Review status can apply both to drugs that are used to treat serious diseases and to drugs for less serious illnesses. The FDA goal for reviewing a drug with Priority Review status is six months.
The distinction between priority and standard review times is that additional FDA attention and resources will be directed to drugs that have the potential to provide significant advances in treatment.
Such advances can be demonstrated by, for example:
evidence of increased effectiveness in treatment, prevention, or diagnosis of disease;
elimination or substantial reduction of a treatment-limiting drug reaction;
documented enhancement of patient willingness or ability to take the drug according to the required schedule and dose; or
evidence of safety and effectiveness in a new subpopulation, such as children.
A request for Priority Review must be made by the drug company. It does not affect the length of the clinical trial period. FDA determines within 45 days of the drug company’s request whether a Priority or Standard Review designation will be assigned. Designation of a drug as “Priority” does not alter the scientific/medical standard for approval or the quality of evidence necessary.
Thurly, here is a more recent (2011 vs 2004), but similar article, also in the JNCI.
Accelerated Approval of Oncology Products: The Food and Drug Administration Experience
http://jnci.oxfordjournals.org/content/103/8/636.abstract
Note the sentences in bold below. Does this mean that if AA were to be approved for Bavi in second-line NSCLC that the confirmatory trial could be done in first-line patients? Then Bavi could get approved for both first-line and second-line based on the one phase 3 trial??
....
Treatment of cancer patients is directed at prolonging their life (improved survival) and/or giving them a better life. All other endpoints used in cancer clinical trials must be surrogates for one or both of these. Surrogate endpoints to predict improved survival or a better quality of life or may either be established to do so or be reasonably likely to do so.
.....
The purpose of the accelerated approval regulation is to make drugs more rapidly available to cancer patients. The FDA has taken two policy initiatives to optimize the accelerated approval process and maximize the benefits of earlier availability of drugs to cancer patients. First, the accelerated approval regulations require that drugs that are granted accelerated approval be better than “available therapy.” This requirement greatly limits the number of drugs that are granted accelerated approval, especially for refractory indications, because once a drug is granted accelerated approval for an indication, that drug would block future accelerated approvals for that indication because it would be the “available
therapy.” The FDA policy initiative that removes this roadblock specifies that a drug that is granted accelerated approval cannot be considered “available therapy” because clinical benefit has not been confirmed. Thus, cancer patients need not be nonresponsive to drugs granted accelerated approval to be considered nonresponsive to “available therapy.” Second, postapproval trials to confirm clinical benefit for accelerated approvals need not be conducted in the same population as the trial that was considered for the accelerated approval and may be conducted in patients with a less advanced stage of the same cancer type. Otherwise, it may be difficult to accrue patients to a randomized confirmatory trial after the drug has already been shown to be reasonably likely to be better than available therapy.
The FDA considers “better than available therapy” to mean better efficacy. Although a drug with equal efficacy and less toxicity could possibly qualify as better than available therapy, the difference in toxicity must be substantial. Such a situation has not yet arisen.
...
Annual Shareholders Meeting. Just paid for my plane ticket.
See you there.
Yes, it could be true for virus-infected cells. There does seem to be something different in that trial.
It just suggests to me that this could be something to watch out for. I don't see any
problems with the trials so far. I don't think we can make a judgement until all
the data is in and analyzed.
If you remember this paper I posted in April.
Vascular Endothelial–Targeted Therapy Combined with Cytotoxic Chemotherapy Induces
Inflammatory Intratumoral Infiltrates and Inhibits Tumor Relapses after Surgery
http://www.neoplasia.com/abstract.php?msid=5083
by a group at UPenn, which used Bavi. There is today a new manuscript which has three of the same authors,
plus others, in Clinical Cancer Research.
Intraoperative Near-Infrared Imaging of Surgical Wounds after Tumor Resections Can Detect Residual Disease
http://clincancerres.aacrjournals.org/content/early/2012/08/29/1078-0432.CCR-12-1188.abstract
Very interesting use of Near Infrared Imaging (NIR). Remember that Peregrine has presented posters using
NIR-PGN650 imaging, and papers have been published.
http://www.peregrineinc.com/technology/ps-imaging/ps-imaging-data.html
From todays' paper:
Abstract
Background: Surgical resection remains the most effective therapy for solid tumors
worldwide. The most important prognostic indicator for cure following cancer surgery is
a complete resection with no residual disease. However, intraoperative detection of
retained cancer cells after surgery is challenging, and residual disease continues to be the
most common cause of local failure. We hypothesized visual enhancement of tumors
using near-infrared imaging could potentially identify tumor deposits in the wound after
resection.
Methods: A small animal model of surgery and retained disease was developed. Residual
tumor deposits in the wound were targeted using an FDA approved imaging agent,
indocyanine green (ICG), by the enhanced permeability and retention (EPR) effect. A novel
hand-held spectrometer was used to optically visualize retained disease after surgery.
Results: We found residual disease using near-infrared imaging during surgery that was
not visible to the naked eye or microCT. Furthermore, examination of tumor nodules was
remarkably precise in delineating margins from normal surrounding tissues. This
approach was most successful for tumors with increased neovasculature.
Conclusions: The results suggest that near-infrared examination of the surgical wound
after curative resection can potentially enable the surgeon to locate residual disease. The
data in this study is the basis of an ongoing Phase I/II clinical trial in patients who
undergo resection for lung and breast cancer.
Introduction
[snip]
ICG is avidly taken up in solid tumors that have “leaky capillaries” due to the enhanced
permeability and retention (EPR) effect (10). The EPR effect is a property by which
small molecules (ie. nanoparticles) accumulate in tumors due to the presence of defective
endothelial cells and wide fenestrations that characterize neovasculature in cancer tissues
(11). Although ICG is not tumor specific, for purposes of intraoperative diagnostic
imaging, the identification of any abnormal tissues is more important than specificity for cancer deposits.
[snip]
So this group has used Bavi, and NIR-PGN650 has been shown to be a good imaging agent
which is specific for tumors. This suggests to me that NIR-PGN650 could be used in the same way as in this paper.
Great. Here is another paper in the Journal of the NCI with some more detail by the same author Axel Hoos, MD, PhD.
FREE: http://jnci.oxfordjournals.org/content/102/18/1388.full.pdf+html
Thurly, I have it, I was just checking that everyone else could get it too. Thanks.
CJ put this in the intro and Jay Carlson told me it is the 18th.
Oct18 10amPDT: Annual S/H Meeting (Corp-HQs, Tustin) - def. proxy iss. 8-27-12 (Schd14A): http://tinyurl.com/8kltugd
Were you able to download the pdf of the whole article?
I agree with your sentiment.
Highly relevant article. The author is at BMS, Global Clinical Research.
Annals of Oncology, Volume 23, suppl 8, Sept 2012
Symposium on Advances in Immuno-oncology
http://annonc.oxfordjournals.org/content/23/suppl_8/viii47.full.pdf+html
Evolution of end points for cancer immunotherapy trials
A. Hoos
[snip]
overall survival
A delayed separation of Kaplan–Meier survival curves is
observed in almost all randomised immunotherapy trials, and
may occur months after the start of treatment. This is in
contrast to the Kaplan–Meier survival curves obtained in
clinical trials of chemotherapy, where early clinical effects are
achievable [4, 16]. The delayed separation of survival curves
associated with immunotherapy reduces the ability for
statistical power to differentiate between them [16, 17]. Clinical
trials that have a delayed response deviate from the standard
model used for randomised trials that assume a proportional
hazard, i.e. that no events occur before the separation of curves
and that the hazard is constant over time [18].
The delayed separation of curves has been reported in many
clinical trials of immunotherapeutic agents, including a
placebo-controlled phase III trial of the autologous active
cellular immunotherapy sipuleucel-T, where the
immunotherapeutic effect on survival was not evident for 8
months [19], and the first phase III trial of ipilimumab, where
separation of the survival curves for patients treated with
ipilimumab alone, ipilimumab plus gp100 vaccine or gp100
vaccine alone, was not observed until 4 months after the
initiation of treatment [20]. In both of these examples,
although immunotherapeutic activity occurred before the
separation of the Kaplan–Meier curves, it did not translate into
a survival difference between the curves or agents. As such, any
event that occurs before the separation of the curves is a ‘lost’
event in terms of the final analysis, as it does not contribute to
the effect that follows the separation of the curves.
It is clear that the delayed response, which is often
substantial, has a huge impact on the dynamics of the trial. To
describe the implications of the delayed separation of Kaplan–
Meier curves, a model scenario can be applied. The curves are
separated into two components: component 1 is no separation
of the curves (i.e. no difference), where the hazard ratio (HR) is
equal to 1, and component 2 is a separation of curves, which
requires a large delta value to power a statistically significant
difference between the two curves (Figure 4). The large delta
value is essential in the second component of the curve to
compensate for the lack of separation during the first
component of the curve. For example, consider a trial of 800
patients; if 200 events occur during the first component of the
curve (i.e. where HR: 1), then these are in effect lost events due
of the nature of the proportional hazard assumptions. This is
important because if, for example, 600 events were required for
the final analysis of survival, but only 400 events were
available, the final analysis would be under powered. In the
event that a treatment effect was observed, it may not be
statistically significant if the power of the study is only 50%.
This was not the case for the two phase III trials mentioned
earlier, as these had strong treatment effect responses that
overcame the delay in responses. Conversely, there are
examples where the treatment effect responses were not as
strong and the trial had a negative result as a consequence. In a
phase III trial of tremelimumab, for example, an early interim
analysis for survival showed no survival benefit, and as a result,
the study was terminated. An extended follow-up, however,
revealed an eventual separation of the survival curves [3].
Immunotherapeutic agents may differ with respect to the
presence and timing of delayed separation of the survival
curves. Therefore, exploiting our current knowledge to apply
adequate statistical modelling to describe HRs as a function of
time, and to differentiate them before and after the separation
of curves (ideally in randomised phase II trials), may improve
our ability to plan for pivotal phase III trials.
Yes, that is what I am saying. Of course, there will be more data coming out soon.
How fast regular approval is granted is another matter. In any case a phase 3 trial will be done.
Guidance for Industry Clinical Trial Endpoints for the Approval of Cancer Drugs and Biologics
U.S. Department of Health and Human Services
Food and Drug Administration
Center for Drug Evaluation and Research (CDER)
Center for Biologics Evaluation and Research (CBER)
May 2007
Clinical/Medical
http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/ucm071590.pdf
In the following discussion, the term regular approval denotes the longstanding route of drug
approval based on the demonstration of clinical benefit. That term is distinguished from accelerated
approval, which is associated with use of a surrogate endpoint that is reasonably likely to predict benefit.
My take on this: If the second-line NSCLC trial results in statistically significant increase in MOS,
and hence clinical benefit, then they could apply for regular approval. If the MOS is very strong, but not quite
statistically significant, then they could apply for accelerated approval.
I agree. If it has "clinical benefit" why would it not be approved for AA?
I don't think they have given up quite yet. I expect more too.
Peregrine's headquarters. Get it?
Annual shareholders meeting is on Oct 18th at the Falcon's nest.
I am probably going. Any of you longs going? Could be a great celebration.
I think Loofman should run a poll on this.
but I think many, probably the vast majority IMO, of holders would be tickled pink to take $20 a share
I think whether the ORR is significant or not is not relevant here. Survival is the
only thing that does matter. Even the survival might not be significant, but if the
survival data is very strong then continuing on to phase 3 is still very possible.
See my post # 88488 for how Avastin was not statistically significant for ORR or
survival in its phase 2 first-line NSCLC trial with C+P, but a phase 3 trial was
carried out and the survival data was statistically significant and Avastin was
approved for first-line NSCLC with C+P. We will see what happens.
Additionally, if the second-line NSCLC trial has very strong survival data filing
for advanced approval is not out of the question.
CJ, the reason I posted this is because I do not find it credible in any way that a
scientist of the caliber of Dr. Dvorak would agree to be a scientific advisor to Peregrine
if there was anything questionable about the science.
Total nonsense.
From the ClinicalTrials.gov website for the second-line NSCLC trial.
Doesn't sound like cross-over of patients is allowed. So why would the PI want to violate the protocol?
http://www.clinicaltrials.gov/ct2/show/NCT01138163?term=bavituximab&rank=6
All patients who complete the Combination Therapy Period (or discontinue for any reason other than disease progression or toxicity) will be eligible to enter the Monotherapy Period. Patients will continue to receive assigned blinded treatment (placebo or 1 or 3 mg/kg bavituximab) weekly until progression or toxicity.
Who is Harold F. Dvorak, MD?
Mallinckrodt Distinguished Professor of Pathology, Department of Pathology, Harvard Medical School
Chief, Pathology, Beth Israel Deaconess Medical Center
National Foundation for Cancer Research Fellow
2006 Albert Szent-Györgyi Prize winner
http://www.nfcr.org/research/197-harold-f-dvorak-md
Dr. Dvorak was awarded NFCR's Inaugural Annual Albert Szent- Györgyi Prize for Progress in Cancer Research for his groundbreaking discoveries of VEGF and its profound influence in the development of new anti-cancer therapies.
"Dr. Dvorak's breakthrough had a major influence on the research efforts of many other vascular scientists, and this has led to the development of anti-angiogenic drugs that target VEGF such as AvastinTM by the company GENENTECH. Avastin is the trade name for Bevacizumab and is a monoclonal antibody that recognizes all vascular endothelial growth factor isoforms and blocks angiogenesis. Bevacizumab was the first clinically available angiogenesis inhibitor in the United States."
Do a PubMed search and you will find 300 papers that he has authored or co-authored.
SCIENTIFIC ADVISOR PEREGRINE PHARMACEUTICALS
http://www.peregrineinc.com/about-us/medical-and-scientific-advisors.html
The onset is quick for the innate reaction, but it doesn't just stop, it is a continuing process.
There is plenty of information on bavi's MOA in the intro section. Thorpe has
done two posters, and the Barcelona and NYAS presentations, and papers, which
present the MOA. Obviously these people know nothing about immunology and are
too lazy to learn and yet want to argue about it. Bavi works through the immune
system so it is important to have some understanding of the basics. I am not
going to waste my time with them when it is clear they are willfully ignorant.
Yes, Avastin is approved for front-line NSCLC using C+P, based on the Sandler et al 2006 phase 3 trial.
http://www.avastin.com/patient/index.html
What Does Avastin Treat?
Avastin is approved for:
Metastatic colorectal cancer (mCRC) when started with the first or second intravenous 5-FU–based chemotherapy for metastatic cancer
Advanced nonsquamous non–small cell lung cancer (NSCLC) in combination with carboplatin and paclitaxel in people who have not received chemotherapy for their advanced disease
Metastatic kidney cancer (mRCC) when used with interferon alfa
Glioblastoma (GBM) in adult patients whose cancer has progressed after prior treatment. The effectiveness of Avastin in GBM is based on tumor response. Currently, no data have shown whether or not Avastin improves disease-related symptoms or survival in people previously treated for GBM
Check the NEJM paper I linked to, it is free.
Which statement are you referring to?
I will give you one example. Avastin + carboplatin+paclitaxel in front-line NSCLC.
The phase 3 trial is the Sandler et al. trial, NEJM, 2006.
http://www.nejm.org/doi/full/10.1056/NEJMoa061884
The phase 2 trial was Johnson et al, 2004, Journal of Clinical Oncology.
http://jco.ascopubs.org/content/22/11/2184.abstract
From the phase 3 NEJM paper:
"A randomized phase 2 study, involving patients
with advanced non–small-cell lung cancer who
had not previously received chemotherapy, compared
paclitaxel and carboplatin alone with paclitaxel
and carboplatin plus bevacizumab, with
bevacizumab at a dose of 7.5 mg or 15 mg per kilogram
of body weight intravenously every 3 weeks.15
In the group receiving the higher dose of bevacizumab,
as compared with the two other groups,
the median time to disease progression was significantly
longer. However, of the 66 patients who
received bevacizumab, life-threatening pulmonary
hemorrhage occurred in 6, including four fatal
events. Serious hemorrhagic events appeared to be
more common among patients with predominantly
squamous-cell carcinomas. These preliminary
results prompted the present phase 3 study, which
was designed to investigate whether the addition
of bevacizumab to paclitaxel and carboplatin improves
survival in patients with metastatic non–squamous-cell, non–small-cell lung cancer."
This is the subgroup analysis for the non-squamous patients in the phase 2 trial.
Note that although the TTP for the 15mg/kg dose group is significant,
for survival neither group is significant.
So this is an example of a phase 2 trial that is not significant for survival,
and yet the phase 3 trial was carried out. There are many examples of this.
My guess is that the HR and p-values will be released when the data have reached maturity. I don't know when that will be.
Statistical significance is not required prior to partnering or phase III design, it never has been.
Final blow to class of Hep C drugs? Does bavi still have a future in HepC?
Bristol-Myers Squibb Discontinues Development of BMS-986094, an Investigational NS5B Nucleotide for the Treatment of Hepatitis C
PRINCETON, N.J.--(BUSINESS WIRE)--Aug. 23, 2012-- Bristol-Myers Squibb Company (NYSE: BMY) announced today that the Company has discontinued development of BMS-986094 (formerly known as INX-189), a nucleotide polymerase (NS5B) inhibitor that was in Phase II development for the treatment of hepatitis C. This decision was made in the interest of patient safety, based on a rapid, thorough and ongoing assessment of patients in a Phase II study that the Company voluntarily suspended on August 1, 2012. The U.S. Food and Drug Administration (FDA) subsequently placed the compound on clinical hold.
The initial case of heart failure, which was the basis for halting the study, subsequently resulted in death. The Company is working in close collaboration with the FDA and clinical study investigators to conduct ongoing, comprehensive assessments and close follow-up of all BMS-986094 study patients. To date, nine patients have been hospitalized, including the initial patient; two patients remain hospitalized. While the cause of these unexpected events, which involve heart and kidney toxicity, has not been definitively established, the Company has determined that it is in the best interest of patients to halt development of BMS-986094.
The trial for advanced liver cancer (HCC) was started on Dec. 1, 2010 and has yet to complete enrollment (56 patients),
although Dec 2012 is listed as the estimated primary completion date. See my posts # 73683, 73697 and the poster
http://www.peregrineinc.com/images/stories/pdfs/aacr_hcc.pdf
I expect some interim data by the end of the year. I really think this could be an overlooked trial with huge potential.
Sorafenib is still the only approved therapy for HCC, and it only increased MOS by 35% over placebo.
This brings to mind the idea that perhaps it is a synergistic action of docetaxel
and bavituximab which could explain a bigger effect in the second-line trial.
It would be a lot easier to figure out if the first-line trial also used docetaxel.
This paper explored the immunomodulatory aspects of docetaxel.
A Novel Chemoimmunomodulating Property of Docetaxel:
Suppression of Myeloid-Derived Suppressor Cells in Tumor Bearers
Krithika N. Kodumudi, Karrune Woan, Danielle L. Gilvary, et al.
FREE: http://clincancerres.aacrjournals.org/content/16/18/4583.full.pdf+html
From the Discussion
....
These studies show the novel finding that docetaxel
directly modulates MDSC signaling and therefore phenotype
and function (i.e., cytokine) in vitro. Moreover, as
evidenced by the MDSC splenic leukocyte coculture,
MDSCs may be able to influence polarization of T cells
as well. The in vivo circumstances may be more complex,
but it can be inferred that docetaxel can directly induce an
M1-like polarization of MDSCs and contribute to an overall
shift toward M1/Th1 antitumor responses. However, it
does not rule out the possibility of paracrine contribution
of T cells and other leukocytes. Until now, in vivo docetaxel
treatment is thought to reduce tumor burden through direct
cytotoxicity (41); however, in this study, we show an
indirect immunomodulatory mechanism as well. As previously
mentioned, MDSC accumulation has been correlated
directly with tumor burden (8). Thus, there may be
synergism between multiple mechanisms of action of docetaxel
(i.e., direct cytotoxicity to tumors and a specific
subset of MDSCs and indirect antitumor responses via
immunomodulation).
Thanks. Could be a long time until we hear about the first-line MOS.
Look at post # 81841 for the treatment arms, and post # 81830 for the control arms.
There are 4 control arms with MOS > 10 months, and the mean is 9.8 months. It is not
clear to me if the MOS for the first-line trial has been triggered or not. The only important
data is how much bigger the MOS for the treatment arm is compared with the control arm.
It could be for that patient group control MOS is 11 months, then hopefully the treatment
arm MOS will be > 17 months.
Are you sure he was talking about the first-line trial and not the two treatment arms of the second-line trial?