Gone for good.
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Exactly when has Peregrine failed with the FDA in the last 10 years? They haven't had a phase III trial yet. The only thing I remember is a success to move Cotara to phase III. They have moved through the sequence of clinical trials with bavituximab from phase I, IIa, IIb as they should. Next stop phase III. I don't see any failure there. The phase I trial with bavituximab began in June 2005. Going from phase I to phase III in less than 10 years is pretty normal as far as these things go, not a failure.
Lately I have been wondering about the timing of the release of trial results. I think Peregrine has enough latitude here to present data as they like. They can always just let the data "mature" more until the timing suits them. So, I have been wondering if there would be an advantage to announcing the updated results from the second-line NSCLC trial and the MOS for the first-line NSCLC and pancreatic trial together. Say, around the first of March. Maybe it would depend on whether or not there is a partner all signed up and ready to go. Which way would the partner prefer this to happen? If there is no partner by then would announcing all at once be preferred over spreading things out over a month or so?
Of course, I could have my pet monkey flip a coin and over the long-term would average 50%.
You people are all doing exactly what AF wants you to do. Relax, breathe deeply. I believe that pharmacokinetic
data is usually collected as part of a PHASE I trial. It has to be known before anything else is done.
It involves studying how the drug behaves in test subjects. They want to know what is the half-life, etc.
I am not at all surprised that this was only done with 18 subjects. There shouldn't be any need to
do it again. Maybe they did do it again for 18 patients, but the point is this is not something that needs
to be done in every patient and isn't.
http://en.wikipedia.org/wiki/Pharmacokinetic
This is the paper published about the phase I trial.
http://www.ncbi.nlm.nih.gov/pubmed/21989064
Phase I safety and pharmacokinetic study of bavituximab, a chimeric phosphatidylserine-targeting monoclonal antibody, in patients with advanced solid tumors.
Gerber DE, Stopeck AT, Wong L, Rosen LS, Thorpe PE, Shan JS, Ibrahim NK.
Source
Harold C. Simmons Cancer Center, University of Texas Southwestern Medical Center, Dallas, Texas, USA.
Abstract
PURPOSE:
Bavituximab is a chimeric immunoglobulin G1 phosphatidylserine-targeting monoclonal antibody that triggers vascular disruption and enhances antitumor immune response. This phase I study assessed the safety and pharmacokinetics of bavituximab in patients with advanced solid tumors.
EXPERIMENTAL DESIGN:
Patients with refractory advanced solid tumors were enrolled into four sequential dose-escalation cohorts (0.1, 0.3, 1, or 3 mg/kg bavituximab weekly) with two dosing schedules. Patients in the 0.1 and 0.3 mg/kg cohorts received bavituximab on days 0, 28, 35, and 42. Patients in the 1 and 3 mg/kg cohorts were administered bavituximab on days 0, 7, 14, and 21. Safety, pharmacokinetics, and tumor response were assessed.
RESULTS:
Twenty-six patients were accrued. No maximum tolerated dose was reached. Six serious adverse events occurred in five patients, including one pulmonary embolism at 3 mg/kg, which was the only dose-limiting toxicity (DLT) in the study. Bavituximab half-life ranged from 37 to 47 hours, with no accumulation seen following administration of multiple doses. Activated partial thromboplastin time was modestly prolonged in vitro at the highest dose tested. As assessed on day 56, a total of 18 patients were evaluable for efficacy, of whom 10 had disease progression and none had an objective response.
CONCLUSIONS:
Bavituximab was well tolerated at doses ranging up to 3 mg/kg weekly. Pharmacokinetic studies support a weekly dosing regimen. Additional phase I and II clinical trials are in progress to investigate bavituximab in combination with chemotherapy and other molecularly targeted agents.
I had previously reported on a meta-analysis of 34 randomized phase II and phase III trials in advanced pancreatic cancer. From that paper
Paul, didn't mean to criticize. $10/share would be a lot of money to me too. I guess it
depends on how close you are to retirement age. I hope to hold Peregrine for a
long time yet. In 10 years who knows where it will be at.
Paul, why do you want to sell the company for $10/share when you can just sell all of your shares at $10?
Take your money and run and leave the rest of us alone. I think most of us long-term investors feel
that $10 is nothing.
The references to bavituximab are all about HCV and the trial done with bavituximab.
Nothing new there. It is a review paper.
Since you are in the pharma business I would like your guess as to what company you think is most
likely to partner with Peregrine for bavituximab.
Thanks
Thanks. Three up tomorrow.
How about sorting them by ascending date so we can see them fail as we go along.
Another trial for pancreatic cancer bites the dust. This one is for gemcitabine in combination with Lenalidomide (Revlimid by Celgene).
Lenalidomide in combination with gemcitabine as first-line treatment for patients with metastatic carcinoma of the pancreas: A Sarah Cannon Research Institute phase II trial
Cancer Biology & Therapy
Volume 14, Issue 4 March 2013
Authors: Jeffrey R. Infante, Hendrik-Tobias Arkenau, Johanna C. Bendell, Mark S. Rubin, David Waterhouse, George Tripp Jones, David R. Spigel, Cassie M. Lane, John D. Hainsworth and Howard A. Burris, III
Abstract:
Objectives: To evaluate the 6-month overall survival, safety, and tolerability of lenalidomide in combination with standard gemcitabine as first-line treatment for patients with metastatic pancreatic cancer. Methods: Eligibility included: previously untreated metastatic adenocarcinoma of the pancreas with metastases incurable by surgery/radiation therapy; ECOG PS 0-2; adequate organ function; prophylactic anticoagulation for venous thromboembolic events (VTEs). Patients received lenalidomide 25mg PO (days 1-21) and gemcitabine 1000mg/m2 IV (days 1, 8 and 15) each 28-day cycle, with response evaluations every 8 weeks. Results: Between 5/2009-4/2010, 72 patients (median age 64 years; 68% male; 42% ECOG PS 0) were enrolled in this multicenter, community-based study. Six-month OS was 37% (95% CI 26-48%). Median PFS and OS were 2.3 (95% CI 1.9-3.5) and 4.7 (95% CI 3.4-5.7) months, respectively. Eight partial responses (11%) were documented. Thirty-nine patients (54%) experienced thrombocytopenia (2 patients, 3% grade 4). Hematologic toxicities resulted in dose modifications for the majority of patients. Twenty patients (28%) developed VTEs during treatment. Conclusions: The observed 6-month OS (37%) of lenalidomide with gemcitabine does not suggest improvement compared to historical results with gemcitabine alone. Toxicities and dose modifications likely limited dose intensity. Further development of this regimen in pancreas cancer is not recommended.
Slim Pickens
Here is a open access journal from the Moffitt Cancer Center in Tampa. The Jan 2013 issue is entitled
From Bench to Bedside: Bringing Immunotherapy Into the Clinic
http://www.moffitt.org/research--clinical-trials/cancer-control-journal/from-bench-to-bedside-bringing-immunotherapy-into-the-clinic
Here is a phase I trail of BMS's anti-PD-1 antibody. There are 13 arms in the trial testing the antibody in
many combinations including the anti-CTLA-4 antibody. This is what you can do when you have the money.
http://www.clinicaltrials.gov/ct2/show/NCT01454102?term=NCT01454102&rank=1
I wrote about anti-PD-1 and anti-CTLA-4 previously. Can't seem to find the link right now. I expect the side
effects are worse than bavi and won't work as well since they are both downstream in the immune
response pathway from where bavi works. That is, they are both directed to work in the adaptive part of the
immune response which depends on the innate part to get things started. I don't think they will do anything
to reverse the immunosuppression that limits the effectiveness of the adaptive response, or to switch
macrophages from the pro-tumor M2 type to the anti-tumor M1 type. Anti-CTLA-4 has worked well in melanoma,
but bavi might work better. It is too early to tell much about anti-PD-1 and anti-PD-L1.
Here is my table of 12 phase III trials in pancreatic cancer. It Bavi + gem can beat the FOLFIRINOX
trial then it will be a homerun. That has the best survival results, although the bad side effect profile limits its use.
http://investorshub.advfn.com/boards/read_msg.aspx?message_id=77501263
Did you see the list of 32 phase 2 & 3 trials I posted?
http://investorshub.advfn.com/boards/read_msg.aspx?message_id=79790425
There is another way to look at the second-line NSCLC trial. It is just an exercise, but consider
the that the three arms are these
1) "effective" dose of 0.25 mg/kg
2) "effective" dose of 0.75 mg/kg
3) dose of 3 mg/kg
By "effective" what I mean is that the survival curves are what you would see if everyone got that dose
instead of the original dose. So the survival curve for original placebo arm is close to the curve that
would result if the patients got 0.25 mg/kg instead of just placebo. Then you have a progression of increasing
doses that increases survival in response. What the "effective" dose is would depend on what actually happened.
Just another way of looking at it.
Yes indeed. I noticed that too late. I am suffering from a lack of sleep.
This is my last post for the weekend. I need to see my girlfriend!
CP, how about this scenario?
The results for first-line NSCLC are announced in conjunction with a data dump on the second-line NSCLC trial.
This is quickly followed by a partnership announcement. The results from both the first and second-line NSCLC
trials are used to support each other and used to seek phase III trials for both indications, in parallel, by
"the partner" and Peregrine.
Could catch. The enrollment was completed in June 2012.
Greg, that is interesting. Maybe an increase in infiltrating immune cells that swells the tumor indicating a response.
The normal response metrics just don't seem to apply very well in cancer immunotherapy. That is something
people will have to come to accept.
MD1225, not to jump on your case, but why is there this big deal about Avastin being the competition for Bavi?
We all know about the black box warnings that come with Avastin and the relative lack of side effects with bavituximab.
Look at the appoved indications for Avastin
Metastatic Renal Cell Carcinoma
Second-Line Treatment of Glioblastoma
First-Line Treatment of Non-Small Cell Lung Cancer (NSCLC)
Second-Line Treatment of Metastatic Colorectal Cancer
First-Line Treatment of Metastatic Colorectal Cancer
The only overlap with Bavi is first-line NSCLC. Avastin didn't do that well there, but good enough to get approved.
I think Bavi could fit right in with Avastin. Roche can just not do trials with Bavi for the other approved indications.
Bavi could be tested by Roche for breast cancer, pancreatic, liver, etc, anything else..
CP, Avastin is still bringing in over 2.5 billion dollars a year to Roche/Genentech, after its first approval in 2004.
I don't think Garnick wanted to kill it. I believe he left Genentech after Roche bought up the rest of Genentech,
not to join Peregrine. I am sure he made a bundle on his stock.
There were two breast cancer phase IIa trials, which were "signal seeking" single-arm trials (N = 49) . All the info about
them is in the iBox that CJ has compiled. Check it out. The survival looked good, but since there was no control
arm it is difficult to gauge how good. Peregrine chose to go with lung cancer first as a strategic decision, they didn't
have the resources to do more at the time.
Andy, if the percentages of stage III and IV, or with PS 0, PS 1, PS 2 don't add to 100% it is because sometimes
there are patients with unknown numbers, sometimes there is a patient with stage II, etc. I just used what was reported.
I found two more second-line NSCLC trails and have added them to a new table which also lists the ECOG
performance status (PS), and the stage III/IV percentages. Note that the Fossella et al, 2000 trial is fairly similar
in MOS, PS, and stage III/IV to the Peregrine trial. Not all data was reported and so there are some blanks in the table.
I found some survival plots which show the difference due to PS and disease extent (stage III or IV).
These are from the Kindler et al, 2010 trial of Avastin and gemcitabine compared with placebo and gemcitabine
in pancreatic cancer. You can see Avastin added nothing to gemcitabine, i.e. it acted like a placebo.
These show you how the mixture of PS and disease extent could make quite a difference in survival.
Not necessarily sicker. Survival has been shown to depend on the ECOG/WHO performance status and on the
extent of disease (locally advanced or metastatic). However, there is always the element of chance too.
The Bavi trial only had 40 patients in the placebo arm, not a very big number, so there is a lot of noise in
the outcomes.
I think Bavi will be superior in overall survival and side effects for first-line NSCLC. I also think Bavi will work
very well for breast cancer and pancreatic cancer, both of which Avastin does not do well at all.
Here is what Avastin is approved for.
http://www.cancer.gov/cancertopics/druginfo/fda-bevacizumab
Metastatic Renal Cell Carcinoma
Second-Line Treatment of Glioblastoma
First-Line Treatment of Non-Small Cell Lung Cancer (NSCLC)
Second-Line Treatment of Metastatic Colorectal Cancer
First-Line Treatment of Metastatic Colorectal Cancer
Avastin does not work at all for pancreatic cancer and is not approved for pancreatic cancer.
Gemcitabine plus bevacizumab compared with gemcitabine plus placebo in patients with advanced pancreatic cancer: phase III trial of the Cancer and Leukemia Group B (CALGB 80303).
Kindler HL, Niedzwiecki D, Hollis D, Sutherland S, Schrag D, Hurwitz H, Innocenti F, Mulcahy MF, O'Reilly E, Wozniak TF, Picus J, Bhargava P, Mayer RJ, Schilsky RL, Goldberg RM.
Source
University of Chicago Cancer Research Center, Chicago, IL 60637-1470, USA. hkindler@medicine.bsd.uchicago.edu
Abstract
PURPOSE:
The combination of gemcitabine plus bevacizumab produced a 21% response rate and a median survival of 8.8 months in a multicenter phase II trial in patients with metastatic pancreatic cancer. These encouraging data led Cancer and Leukemia Group B (CALGB) to conduct a double-blind, placebo-controlled, randomized phase III trial of gemcitabine/bevacizumab versus gemcitabine/placebo in advanced pancreatic cancer patients.
PATIENTS AND METHODS:
Eligible patients had no prior therapy for advanced disease, Eastern Cooperative Oncology Group (ECOG) performance status 0 to 2, no tumor invasion of adjacent organs, and no increased bleeding risk. The primary end point was overall survival. Patients were stratified by performance status, extent of disease, and prior radiotherapy. Patients received gemcitabine at 1,000 mg/m(2) over 30 minutes on days 1, 8, and 15 every 28 days and bevacizumab at 10 mg/kg or placebo on days 1 and 15 every 28 days.
RESULTS:
Between June 2004 and April 2006, 602 patients were enrolled onto the study and 535 were treated. Median overall survival was 5.8 months for gemcitabine/bevacizumab and 5.9 months for gemcitabine/placebo (P = .95). Median progression-free survival was 3.8 and 2.9 months, respectively (P = .07). Overall response rates were 13% and 10%, respectively. Patients with a performance status of 0, 1, and 2 survived a median of 7.9, 4.8, and 2.4 months, respectively. The only statistically significant differences in grades 3 and 4 toxicity occurred for hypertension (10% v 3%; P < .001) and proteinuria (5% v 1%; P = .002); venous thrombosis grade > or = 3 was equivalent in both arms (14% and 15%, respectively).
CONCLUSION:
The addition of bevacizumab to gemcitabine does not improve survival in advanced pancreatic cancer patients.
I hope breast cancer is the next big cancer for bavituximab.
From Cancer Discovery News Dec 13, 2012.
Bevacizumab Fails to Up Breast Cancer Survival
The antiangiogenic agent bevacizumab (Avastin; Genentech) did not produce statistically significant improvements in survival in 2 randomized phase III clinical trials, one for patients with triple-negative breast cancer and one for patients with HER2-negative, hormone receptor (HR) –positive breast cancer, reported at the San Antonio Breast Cancer Symposium on December 7.
In the BEATRICE study, 2,591 patients with primary triple-negative breast cancer were randomly assigned to receive either adjuvant chemotherapy or chemotherapy plus a year of bevacizumab treatment. The 2 groups showed no statistically significant differences in invasive disease–free survival (the primary endpoint) or in interim overall survival.
“Sadly, for these patients, we have nothing extra to add to chemotherapy,” said lead author David Cameron, MD, professor of oncology at Edinburgh University in Scotland.
“It's getting to be difficult to know the role of bevacizumab, if any, in breast cancer,” commented Kent Osborne, MD, director of the Dan L. Duncan Cancer Center in Houston, TX, who was not involved in the study. “If it's going to work, you'd think it would work in this case,” by suppressing growth of vasculature for emerging metastatic tumors.
Results also were discouraging in the LEA trial, in which 380 postmenopausal women with advanced HER2-negative, HR-positive breast cancer were given first-line therapy of either letrozole (Femara; Novartis) or fulvestrant (Faslodex; AstraZeneca), or one of those drugs combined with bevacizumab.
It was hoped that bevacizumab would be helpful in dealing with high VEGF levels associated with decreased response to endocrine therapy, said lead author Miguel Martin, PhD, of the Instituto de Investigación Sanitaria Gregorio Marañón in Madrid, Spain. “Unfortunately, the LEA study fails to demonstrate a statistically significant improvement in progression-free survival (PFS) for endocrine therapy and bevacizumab.”
The median PFS was 18.4 months for the group taking bevacizumab versus 13.8 months for the control group, and overall survival rates have been essentially identical to date.
LEA drew much attention as the first study to report on combining bevacizumab with endocrine therapy rather than chemotherapy, noted Peter Ravdin, MD, PhD, director of the Breast Health Clinic at the Cancer Therapy and Research Center at the University of Texas Health Science Center in San Antonio, who was not involved in the work.
“This study is part of a general disappointment about bevacizumab in breast cancer,” Ravdin said. “There are people who definitely benefit by this drug, but we don't have a good biomarker to identify them. Bevacizumab also has toxicity and it's fearsomely expensive.”
Overall, in breast cancer treatment, “this drug has activity, but in an unselected base of patients, it often doesn't have enough activity to have a big hit,” remarked Edinburgh's Cameron. “It's an open question whether, in the subgroups that show more activity, bevacizumab has enough activity to become firmly established.”
You got it.
Very close to my rough estimates
http://investorshub.advfn.com/boards/read_msg.aspx?message_id=83234820
That is exactly why I think the discrepancies didn't have much of an effect, if they did then that implies the "true" control
arm MOS would be less than 5.6 months. From the table of 12 phase III trials you can see that 5.6 months would be
the smallest. The first trial, Shepherd et al 2000, is the trial that established docetaxel as the standard of care (SOC).
In this case I have the docetaxel arm listed as the "control" arm so it can be compared with the later control
arms of docetaxel only. In fact, at the time the trial was done the SOC was nothing but pain medication,
known as best supportive care (BSC), so that was the "control" arm then and adding docetaxel to BSC would
be the treatment arm. With BSC only, patients lived only 4.6 months, so that marks the smallest value for the MOS.
That is why I think the control arm of the second-line NSCLC was affected very little by the discrepancies.
Call me sometime: J.P. Morgan Healthcare Conference pickup lines
http://www.bizjournals.com/sanfrancisco/blog/biotech/2013/01/jp-morgan-healthcare-conference-tweet.html
Thurly, I agree that comparison with the mean of the historic control arms would
make more sense, at least to me. The trial has really become a single arm trial, but
randomized and double-blinded at the same time. However, there is the logic that the
original control arm if corrected by removing treatments with 1 mg/kg would result
in an even smaller MOS than 5.6 months. That is why I think whatever happened didn't make
much difference at all. If the only requirements for moving to phase 3 are that treatment
with bavi is safe, and there is good indication of efficacy, then I think it can happen.
Since the 3 mg/kg arm was not significantly different from the original control (p = 0.07)
it certainly would be less so for the new control.
Yes, to do it correctly, but I don't have the data. Peregrine should release the new "control"
arm data with the correct MOS.