Gone for good.
Register for free to join our community of investors and share your ideas. You will also get access to streaming quotes, interactive charts, trades, portfolio, live options flow and more tools.
Register for free to join our community of investors and share your ideas. You will also get access to streaming quotes, interactive charts, trades, portfolio, live options flow and more tools.
If you search the Form 10-Q from Dec 10, 2012, the one to which this CTO pertains to,
the only places where something is removed due to confidentiality are sections dealing
with various loan agreements. Nothing about any mergers or buyouts.
Just look in the 10-Q.
The only references in the form 10-Q are to terms of loans that were kept confidential.
May 15 at 6:00 PM (EST) Abstracts released on ASCO.org
Here is the poster for TH-302 presented at the recent GI symposium.
http://www.thresholdpharm.com/pdf/Po_ASCO_GI_TH302_130123_final.pdf
Here is the presentation made at the ESMO meeting in Sept. Lots of detail about the cross-over effect.
http://www.thresholdpharm.com/pdf/borad_et_al_th-302_in_pancreas_cancer_esmo_9-12_with_supplement.pdf
If the discrepancies had little effect then why would you expect the addition of a wrong dose to increase the MOS?
The control arm performed below the average. There are always values below and above the average,
that is why it is an average. It doesn't necessarily mean there is a problem.
I would agree with you on these points.
How quickly we forget. The pancreatic trial only enrolled metastatic patients.
http://www.clinicaltrials.gov/ct2/show/NCT01272791?term=Bavituximab+OR+Peregrine&rank=1
Bob, 5.6 months is on the low side, but nothing abnormal about it. There was a phase III trial with 5.7 months for a control
arm of docetaxel only. 5.6 months is about 1.5 standard deviations from the mean of these 14 trials. On the low side,
but not totally out there. If it was lower than that I expect it was not by much. Notice that both trials had 90% metastatic patients.
RRdog, I couldn't agree with you more. I said the same thing about the control arm here
http://investorshub.advfn.com/boards/read_msg.aspx?message_id=83271066
and here
http://investorshub.advfn.com/boards/read_msg.aspx?message_id=83160760
It is hard to refute the logic that the control arm wasn't affected that much by the discrepancies.
Even if the final MOS for the 3 mg arm was reduced to 11 months we would have an excellent result.
Data from another pancreatic phase II trial presented at the 2013 Gastrointestinal Cancers Symposium. This one is for TH-302 (Threshold Pharmaceuticals),
same data as presented at the ESMO meeting on Sept 29, 2012. From the abstract:
A phase 3 study of TH-302 (340 mg/m ) in combination with G is planned with OS as the primary efficacy endpoint.
It is still recruiting patients. The dates of the study on the ClinicalTrials webpage need updating to reflect this. Probably just a slow rate of accrual.
Past posts on the bavi liver cancer trial and HCC
http://investorshub.advfn.com/boards/read_msg.aspx?message_id=73502561
http://investorshub.advfn.com/boards/read_msg.aspx?message_id=73658060
http://investorshub.advfn.com/boards/read_msg.aspx?message_id=70621607
http://investorshub.advfn.com/boards/read_msg.aspx?message_id=70636674
I wondered what had become of him. Too bad he didn't make it.
http://www.giveforward.com/helpingwalter
What we don't know is what dose he was on, 0.3, 1.0, or 3.0 mg/kg of bavi.
http://www.clinicaltrials.gov/ct2/show/NCT01264705?term=Bavituximab+OR+Peregrine&recr=Open&rank=5
Here are two recent open-access papers on this topic
Metastatic Pancreatic Cancer: Are We Making Progress in Treatment?
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3523135/
Immunotherapy updates in pancreatic cancer: are we there yet?
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3539275/
As a follow-up to this data I looked at one notable failure from these phase III trials. That is the Avastin
phase III trial from which these plots of the effect of PS and disease extent originate. I looked at the
phase II trial that prompted the phase III trial. So what went wrong?
From the Kindler et al, 2010 paper on the phase III trial.
Beautiful. Now whenever anyone quotes AF this can be used to discredit him.
I don't have any doubt either. The increase in MOS of 1.8 months (27%) wasn't much, but it
was highly significant. It was one of the largest trials ever done in pancreatic cancer. That is
what it takes to get significance for such a small increase.
I really don't know what the argument is about. A bunch of people who have no idea what they are talking about.
Having the ability of measuring how much of the antibody is in the blood at a known time after administering the drug
is basic. As is the ability of measuring the concentration of antibody in a vial containing the antibody and saline.
These are basic things that are done all the time. In this paper, that I referred to before, the concentrations of
bavituximab are shown at different times after a dose was injected. As you can see in the table and figure doses of
1.0 mg/kg and 3 mg/kg are shown and easily distinguished. In the figure the serum concentrations are on a log scale.
As for the 18 samples measured controversy. I believe they were just repeating the PK measurements to
check the original results using 6 patients from each of the three trial arms. There is nothing more to say.
The paper which shows the pharmacokinetics of bavituximab is freely available to anyone here:
http://clincancerres.aacrjournals.org/content/17/21/6888.long
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.
Clin Cancer Res. 2011 Nov 1;17(21):6888-96. doi: 10.1158/1078-0432.CCR-11-1074. Epub 2011 Oct 11.
Patients and Methods
Pharmacokinetics
From patients in the 0.1 and 0.3 mg/kg dose cohorts, pharmacokinetic samples were collected prestudy and on days 0, 1, 2, 4 ± 1, 7, 10, 14, and every 7 days from days 21 to 70. From patients in the 1 and 3 mg/kg dose cohorts, pharmacokinetic samples were collected prestudy and on days 0, 1, 2, 4 ± 1, 7, 14, 21, 22, 23, 25 ± 1, and every 7 days from days 28 to 56.
Bavituximab blood levels were determined by a validated ELISA. Noncompartmental pharmacokinetic analyses were conducted on individual serum bavituximab concentration–time data with WinNonlin Professional (version 5.2; Pharsight Corporation).
Results
Pharmacokinetics
Bavituximab exhibited linear single-dose (day 0, for all cohorts) and multiple-dose (for the 1 and 3 mg/kg cohorts on day 21; there was insufficient data for the 0.1 and 0.3 mg/kg cohorts on day 42) pharmacokinetic characteristics (Table 4 and Fig. 1). Following time to peak concentration (Tmax), mean serum bavituximab concentrations seemed to decline generally in an apparent monoexponential manner. Mean serum bavituximab concentrations on days 0 and 21 within dose groups were similar. Specifically, there were no significant differences in Tmax (P = 0.88), area under the plasma concentration-time curve from time zero to time t (AUCT; P = 0.96), AUCinf (day 1) versus AUCtau (day 21; P = 0.37), half-life [the time required to reduce the plasma concentration to one half its initial value (t1/2); P = 0.22], mean residence time [the average total time molecules of a given dose spend in the body (MRT); P = 0.68], apparent volume of distribution at steady state (Vz; P = 0.07), apparent volume of distribution during terminal phase (Vss; P = 0.16), clearance [the volume of plasma in the vascular compartment cleared of drug per unit time by the processes of metabolism and excretion (CL); P = 0.94], or AUCinf/dose (day 1) versus AUCtau/dose (day 21; P = 0.37). Mean half-life estimates ranged 37 to 44 hours on day 0 and 46 to 47 hours on day 21. With the 1 mg/kg dose, bavituximab concentration remained above 2 µg/mL (the predicted therapeutic threshold based on preclinical modeling) for 6 days. With the 3 mg/kg dose, bavituximab concentration remained above 2 µg/mL for 7 days.
Results from the phase IIa first-line NSCLC were reported in June 2011. The PR stated:
Actually, bavituximab is quite different than Avastin. They are both monoclonal antibodies but their targets are
not the same, and their mechanisms of action are very different. They also have a much different side effect profile.
I would not say that bavituximab is a super-charged Avastin.
Putting a Number on Smoking’s Toll
http://well.blogs.nytimes.com/2013/01/23/putting-a-number-to-smokings-toll/?hpw
I think it comes down to how the enrollment proceeded in both trials.
The second-line NSCLC trial took 16 months (June 4, 2010 - Oct 6, 2011) to enroll 121 patients.
The pancreatic trial took 17.5 months (Jan 5, 2011 - June 25, 2012) to enroll 70 patients.
At the time the data was reported for the second-line NSCLC trial the MOS of 13 months was only
2 months more than the time since enrollment closed. If the pancreatic trial took about 3 months to enroll
the last 10% of the patients I can see how the MOS could be much longer than the time since the enrollment closed.
Slight error in your numbers
Carl Woese, a great scientist, died recently from pancreatic cancer. Most of you have probably never heard of him.
I trained in the lab of Dr. Norm Pace, a long-time colleague of Woese, and quoted in this NY Times piece about Woese.
http://www.nytimes.com/2013/01/01/science/carl-woese-dies-discovered-lifes-third-domain.html
This is good too.
http://en.wikipedia.org/wiki/Carl_Woese
The Abraxane pancreatic trial makes the NY Times. Will Peregrine be so lucky?
http://www.nytimes.com/2013/01/23/business/pancreatic-cancer-drug-found-to-extend-life.html?partner=yahoofinance
Andy, I agree with his estimate. If the gemcitabine control arm has a MOS of about 6.5 months then a
MOS of 11.5 months for the bavi + gem arm would be a new record for increased number of months and
percentage increase. It still might not be statistically significant due to the small number of patients in
each arm, but it should get the go ahead for a phase 3 trial.
It is good for patients that it worked, but the 1.8 month increase in survival (27%) isn't that great.
Still, given the long list of failures in phase III trials for pancreatic cancer at least it is another
option for patients. When the data comes out I will add it to my tables on pancreatic cancer trials.
If you look at the survival curves presented at ASTRO it sure looked like the 1 mg arm had more censored patients.
So now you have evidence that patients were paid off in the Ukraine? Enough of this nonsense.
If it was sabotage why didn't they do a better job of it? Why leave out the 3 mg/kg arm? I think you have
been watching too many spy movies.
Abraxane in Advanced Pancreatic Cancer (APC). Also see my post on Abraxane in NSCLC
http://investorshub.advfn.com/boards/read_msg.aspx?message_id=83655317
Combination of Abraxane and gemcitabine improves survival of patients with pancreatic cancer
Published on November 17, 2012
A new cancer drug combination demonstrated significant improvement in overall survival of late-stage pancreatic cancer patients compared to those receiving standard treatment, according to results of a Phase III clinical trial led by physicians from Scottsdale Healthcare's Virginia G. Cancer Center Clinical Trials, a partnership with the Translational Genomics Research Institute (TGen).
Physicians at the Virginia G. Piper Cancer Center at Scottsdale Healthcare were first to design a clinical trial to determine the safety, tolerability and effectiveness of nab-paclitaxel (Abraxane) in combination with the standard drug gemcitabine in patients with advanced pancreatic cancer. Results of that multicenter study chaired by Dr. Daniel Von Hoff were encouraging enough that it led to one of the largest international studies ever done in pancreatic cancer, with 861 patients. Full results are expected to be presented at the American Society of Clinical Oncology (ASCO) 2013 Gastrointestinal Cancers Symposium in Jan. 24-26 in San Francisco.
http://www.news-medical.net/news/20121117/Combination-of-Abraxane-and-gemcitabine-improves-survival-of-patients-with-pancreatic-cancer.aspx
Tomorrow we will find out what the survival numbers look like. I thought I would look at the phase I/II trial of Abraxane in APC which led to the phase III trial.
Gemcitabine plus nab-paclitaxel is an active regimen in patients with advanced pancreatic cancer: a phase I/II trial.
Von Hoff DD, Ramanathan RK, Borad MJ, Laheru DA, Smith LS, Wood TE, Korn RL, Desai N, Trieu V, Iglesias JL, Zhang H, Soon-Shiong P, Shi T, Rajeshkumar NV, Maitra A, Hidalgo M.
http://www.ncbi.nlm.nih.gov/pubmed/21969517
The first thing to note is that the phase I/II trial was a single-arm, non-randomized, open-label trial, with a total of 67 patients.
At the dose selected for the phase III trial, 125 mg/m^2, there were 44 patients. Of those 44 patients 50% had PS = 0, and 50% had PS = 1.
From the paper:
Efficacy Results
Survival. In patients treated at the MTD of 125 mg/m2 of nabpaclitaxel
(n 44), the median PFS was 7.9 months (95% CI, 5.8 to
11.0 months), median OS was 12.2 months (95% CI, 8.9 to 17.9
months; Fig 1A), and the 1-year survival was 48%.
The last paragraph from the paper:
News of a phase 3 trial of Abraxane + gemcitabine in advanced pancreatic cancer (APC) will be coming
out tomorrow. I thought I would do a little review of the drug and trials for NSCLC and APC. Abraxene is a version
of paclitaxel which is bound to the protein albumin to increase efficacy and decrease toxicity.
http://en.wikipedia.org/wiki/Abraxane
Abraxane is owned by Celegene, which bought out Abraxis BioScience in 2010 for $2.9 billion.
http://www.nytimes.com/2010/07/01/health/01drug.html?_r=0
NSCLC:
Results of phase 3 trial which led to the approval in first-line NSCLC on October 12, 2012.
Weekly nab-paclitaxel in combination with carboplatin versus solvent-based paclitaxel plus carboplatin as first-line therapy in patients with advanced non-small-cell lung cancer: final results of a phase III trial
http://www.ncbi.nlm.nih.gov/pubmed/22547591
The drug was approved for first-line NSCLC based on a significantly improved ORR, the primary endpoint.
PFS and MOS were not increased significantly. sb-paclitaxel is the usual solvent-based paclitaxel for injection.
Both arms also got carboplatin. About 70% of the patients were from Russia/Ukraine.
Editorial from the Journal of the National Cancer Institute, April 18, 2012.
http://jnci.oxfordjournals.org/content/104/8/568.full.pdf+html
Why Do Phase III Clinical Trials in Oncology Fail so Often?
Laleh Amiri-Kordestani, Tito Fojo
Correspondence to: Tito Fojo, MD, PhD, Medical Oncology Branch, Center for Cancer Research,
National Cancer Institute, National Institutes of Health,
Bldg 10, Rm 12N226, 9000 Rockville Pike, Bethesda, MD 20892 (e-mail: fojot@mail.nih.gov).
Achieving success in the development of a cancer drug continues to
be challenging. Given the increasing costs (1) and the small number
of drugs that gain regulatory approval (2), it is crucial to understand
these failures. In this issue of the Journal, Gan et al. (3) reviewed
235 recently published phase III randomized clinical trials (RCTs).
They report that 62% of the trials did not achieve results with statistical
significance. Trying to explain the high failure rate, they
note the actual magnitude of benefit achieved in a clinical trial
(designated B) is nearly always less than what was predicted at the
time the trial was designed (designated d) and conclude, “investigators
consistently make overly-optimistic assumptions regarding treatment
benefits when designing RCTs.”
But really should we be surprised that phase III trials, the venue
for detecting “small” differences, so often disappoint? Almost by
definition, phase III studies are designed to detect small differences
(4,5). The problem is that small has given way to “marginal” as
outcomes have fallen below our already modest expectations. And
who or what is to blame? Are investigators really overly optimistic
regarding experimental therapies and, as the authors suggest,
responsible for the large number of negative studies? Although we
agree that optimism regarding clinical benefit may lead to an
underpowered trial, we disagree that optimistic investigators are
those we should blame. We would ask, how do Gan et al. (3) define
optimism? Where do they place the line between an optimistic and
a realistic expectation? The authors demonstrated a poor correlation
between the expected and observed benefits but in the majority
of trials also found the “expected benefits” were less than 4
months—a duration many would argue represents a modest and
defensible expected benefit for the majority of solid tumors. So
that, rather than excessive optimism, we believe several factors
including inaccurate assessments of “limited data from early phase
trials and/or investigators’ experience” interpreted in what the
authors themselves acknowledge “is usually an empirical process”
lead to the differences that Gan et al. (3) found between the actual
(B) and predicted (d) benefit. Although there are models that use
the results of phase I/II trials to predict the outcome of phase III
studies, no model is perfect (6–8). For example, the response rate,
which is part of the limited dataset available in designing phase III
trials, has been correlated with survival and clinical benefit (9,10).
But other factors such as the duration of response make response
rate less reliable and lead to discrepancy in the results of phase II
and III studies (11). Similarly, the rate of stable disease and the
“clinical benefit rate,” two measures increasingly reported in early
phase studies, have never been shown to correlate with outcomes
yet are regarded by many as measures of efficacy (12–14). Hence,
we would argue that inaccurate assessments of limited data and
reliance on endpoints that have not been validated are likely more
important than overoptimism.
To be sure, Gan et al. (3) recognize it is not just about statistical
validity when they acknowledge “significant benefit could also
result from overpowered studies that detect differences that are
not clinically meaningful.” Noting that their data showed many
positive studies in which the observed difference was less than
predicted but still statistically significant, they wonder, as have
others, whether these “positive” studies merit regulatory approval
in the absence of additional supporting data (15).
We agree with the authors’ opinion that more research is
needed to determine how to better define d; a goal they suggest
might be achieved by “using statistical modeling rather through
empiricism.” But pending the outcome of that research, they
advocate more frequent use of interim analyses with options of
early study termination for futility or efficacy and adaptive trial
designs. In regards to the latter, they note, “up to 50% of RCTs
that do not show a statistically significant benefit might actually
be false-negative trials.” Their suggestion that these studies did
not enroll enough patients and are underpowered because of
unreliable d values has the inherent assumption that marginal
benefits matter. But with 100 275 patients enrolled in 158 negative
trials, and an average trial size of 635 patients, many would
not consider the magnitude of benefit missed to be “clinically
meaningful” or worth the enrollment of hundreds of additional
patients to confirm. Furthermore, their assertion that “if d is
set unrealistically high, the trial will be underpowered to detect
a smaller but still clinically meaningful benefit, resulting in a
negative trial” assumes that marginal differences can confer
clinically meaningful benefit, an assumption with which we disagree
(14,16).
It is interesting how so much is reported and can be analyzed
about what constitutes a “statistically significant benefit”; yet, so
little is reported or devoted to assess the statistical validity of toxicity
and the risk to benefit ratio of a therapy. Indeed, one would
be hard-pressed to find an experimental arm deemed statistically
superior in terms of efficacy described as anything but tolerable.
Unfortunately, increasingly it appears that any toxicity is tolerable
or acceptable provided some gain, no matter how marginal, is
achieved. But as efficacy gains become increasingly smaller, toxicity
becomes increasingly important. And as Gan et al. (3) remind
us, unfortunately for cancer patients, toxicity is all too often more
than a grade 1 rash. Toxicity can be both severe and life altering
and unfortunately at times is accompanied by a statistically inferior
outcome. Remarkably, among 158 negative studies, Gan et al.
found a trend toward detriment in the experimental arm in 42
studies and a statistically significant detriment in eight RCTs that enrolled 5287 patients.
The observation that trials with industry funding were more likely to be positive and associated with a small but statistically significant increased risk of detriment in the experimental arm is of concern. Their greater likelihood to achieve a positive outcome may well reflect their larger trial size because of better funding. We can only speculate as to why there would be an increased risk of detriment in the experimental arm, but the possibility that toxicity emerging in phase I/II trials would be less likely to derail a product in which a substantive investment has been made cannot be discounted. Furthermore, targeted agents—the principal if not exclusive components of the portfolios of all major companies—were no better when toxicity in the experimental arm was concerned. Because targeted agents will dominate the oncology enterprise for the rest of this decade, these observations are discouraging.
Although our goals may initially be lofty, they eventually meet reality. And in cancer drug development, reality is all too often failure (2). The challenge in oncology is to be sure that we remain focused on true clinical benefit—prolonging life. Our goals must remain lofty, and we must remember that marginal benefit should never be that goal (14,16). We need to be vigilant and as soon as it becomes apparent that any benefit will be marginal, we must discard that strategy and move on, ensuring we do not redefine failure as success. The data of Gan et al. (3) warn us that we are at risk of losing our focus. Conducting larger trials, doing more interim analyses, or using adaptive trial designs are not the solutions (17–19). We do not need more marginal results that are then pronounced “new treatment paradigms” or a “new standard of therapy.” What we need are meaningful goals and better drugs—much better drugs aimed at targets that are really important!
References
1. Collier R. Rapidly rising clinical trial costs worry researchers. CMAJ. 2009;180(3):277–278.
2. Bates SE, Amiri-Kordestani L, Giaccone G. Drug development: portals of discovery. Clin Cancer Res. 2012;18(1):23–32.
3. Gan HK, You B, Pond GR, Chen EX. Assumptions of expected benefits in randomized phase III trials evaluating systemic treatments for cancer.
J Natl Cancer Inst. 2012;104(8):590–598.
4. Wu W, Shi Q, Sargent DJ. Statistical considerations for the next generation of clinical trials. Semin Oncol. 2011;38(4):598–604.
5. Hoering A, Leblanc M, Crowley JJ. Randomized phase III clinical trial designs for targeted agents. Clin Cancer Res. 2008;14(14):4358–4367.
6. Claret L, Girard P, Hoff PM, et al. Model-based prediction of phase III overall survival in colorectal cancer on the basis of phase II tumor
dynamics. J Clin Oncol. 2009;27(25):4103–4108.
7. Chen TT, Chute JP, Feigal E, Johnson BE, Simon R. A model to select chemotherapy regimens for phase III trials for extensive-stage small-cell lung cancer. J Natl Cancer Inst. 2000;92(19):1601–1607.
8. Bruno R, Lu JF, Sun YN, Claret L. A modeling and simulation framework to support early clinical drug development decisions in oncology. J Clin Pharmacol. 2011;51(1):6–8.
9. Tsujino K, Shiraishi J, Tsuji T, et al. Is response rate increment obtained by molecular targeted agents related to survival benefit in the phase III trials of advanced cancer? Ann Oncol. 2010;21(8):1668–1674.
10. Buyse M, Thirion P, Carlson RW, Burzykowski T, Molenberghs G, Piedbois P. Relation between tumour response to first-line chemotherapy and survival in advanced colorectal cancer: a meta-analysis. Meta-Analysis Group in Cancer. Lancet. 2000;356(9227):373–378.
11. Pazdur R. Response rates, survival, and chemotherapy trials. J Natl Cancer Inst. 2000;92(19):1552–1553.
12. Vidaurre T, Wilkerson J, Simon R, Bates SE, Fojo T. Stable disease is not preferentially observed with targeted therapies and as currently defined has limited value in drug development. Cancer J. 2009;15(5):366–373.
13. Tolcher AW. Stable disease is a valid end point in clinical trials. Cancer J. 2009;15(5):374–378.
14. Ohorodnyk P, Eisenhauer EA, Booth CM. Clinical benefit in oncology trials: is this a patient-centred or tumour-centred end-point? Eur J Cancer. 2009;45(13):2249–2252.
15. Ocana A, Tannock IF. When are “positive” clinical trials in oncology truly positive? J Natl Cancer Inst. 2011;103(1):16–20.
16. Booth CM, Ohorodnyk P, Eisenhauer EA. Call for clarity in the reporting of benefit associated with anticancer therapies. J Clin Oncol. 2009;27(33):e213–e214.
17. Emerson SS, Fleming TR. Adaptive methods: telling “the rest of the story”. J Biopharm Stat. 2010;20(6):1150–1165.
18. Chow SC, Corey R. Benefits, challenges and obstacles of adaptive clinical trial designs. Orphanet J Rare Dis. 2011;6:79.
19. Berry DA. Adaptive clinical trials in oncology. Nat Rev Clin Oncol. 2011.
Yes, I believe that the MOS is a material event, but how you define when that occurs is the issue.
MOS is when 50% of the patients are left alive, but in every trial a period of time after that event is
allowed to go by, the "follow up period". They could wait until 60%, or 70%, or 80% of the patients
have died before they declare the MOS "final" and release the results. That is what I am driving at.
This so called rule is totally meaningless. There must have been hundreds of phase III cancer trials over the past 10 years, and yet they pick out 58 to include in their "rule". What about the rest of them? What would the statistics be if they included more than 58, or all of them? Sounds to me like they picked out the 58 so that their "rule" was sure to be "proved". Could there be bias involved here?