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Impressive results. However,
I am not sure I understand why the co used a discontinuation trial in which the patients are first dosed 12weeks and then randomized rather than being randomized immediately. I believe that using discontinuation trials in oncology is not ethical and should not be used.
I dont know how the dosage differences between this study and Comet 1 will affect the efficacy.
62% of the patients had dose reduced.
I am having hard time comparing the published PFS results across abiraterone and MDV3100 trials.
I find the results impressive but I am cautious. The lead author, David C. Smith, is also cautious.
"Cabozantinib should not be used for CRPC outside of clinical trials at this point"
"I would not recommend off-label use at this time."
http://www.medscape.com/viewarticle/775768
Another good survey would have been if the pps would drop tomorrow on approval.
I closed my long position and now have a very minor short position solely based on that possibility.
Thanks a lot for the reply.
I always assumed that this trial had a futility boundary. However, it seems like you might be right. I went back to the previous presentations. I could not find a mention of futility. Only efficacy. So it seems like they are just adding a futility boundary.
The confusing part for me was, based on the literature, that it seems like it is possible to add yet another conditional power calculation over usual the OBF or Lan-DeMats. I thought that's what the co was doing.
I agree that if this is a regular futility boundary, at ~1/3 events, it wont tell us much.
Conditional power calculation for an interim analysis.
Has anyone ever encountered this in practice? What can we say about a practical interim boundary for an early interim analysis that uses conditional power calculation to decide whether to terminate the trial?
Here is the context.
AEZS is running a P3 trial for perifosine in multiple myeloma. Since perifosine is in the penalty box, investors think that the co is wasting its money on continuing this trial. In response to this, the co promised to end the multiple myeloma trial early if the data does not look good at the interim.
The issue was that until recently the co avoided defining what in addition to a regular futility boundary will be used to check if the data is any good at the interim.
At the last CC, http://seekingalpha.com/article/1007351-aeterna-zentaris-ceo-discusses-q3-2012-results-earnings-call-transcript?part=single , the co clarified this a little bit.
The xtandi docs are now available at FDA's website.
The info I was looking for (time to subsequent therapy) is not there. Thus, I could not completely prove my suspicion that the approval of cabazitaxel & abiraterone acetate during the enzalutamide trial played a role in the OS advantage that Xtandi was able to show.
My theory is simple. If enzalutamide extended the OS even a little bit, more patients in the enzalutamide arm were able to use cabazitaxel & abiraterone acetate (simply because these treatments become available later). This contributed to the HR of enzalutamide.
My intent is not to question whether enzalutamide is active, or better than abi or cabo, etc. It is to quantify the effect of later availability of cabo & abi to the HR and then extend that info to the SYNERGY trial as, similar to the AFFIRM trial, abi & enzalutamide got approved during the SYNERGY trial. If OGX-011 has even a minor OS advantage, would these approvals extend the HR of the SYNERGY trial in favor of OGX-011?
I think yes. However, I cannot prove that.
This is one of those difficult to fail phase 2 trials. Too many endpoints & biomarkers that make sense and can be post-hoc justified. The co needs to be really unlucky not to catch a signal even statistical significance in one of those.
The calculation of HR does not take selection biases into account. HR is nothing but fancy median. The alpha (the p value for statistical significance) should have been reduced with each look. However, SNTA did not publish the alpha required for statistical significance. So there is no mechanism that takes into account such biases.
In this specific case, the co enrolled an unselected group of patients. Then at one point they looked at the data and calculated the HR of many subsets (I'll estimate the co looked at more than 50 subsets if not more). Each HR calculation is done independently. Even if G were placebo (I dont believe it is), by pure luck, there would be a subset that's better than the others. Then they selected that subset (the one that looked the best by pure luck or the one that G really works better on).
To eliminate the selection bias, at that point, they should have discarded all those patients and not carry them forward in the HR calculations they published yesterday. The co did not do so. So there is a selection bias that would continue to linger.
The funny thing is that since they did not do so already, even if they do it now, it does not count.
If I put aside all the shenanigans about dropping the crossover patients, I am actually very intrigued by slide #16.
http://www.thresholdpharm.com/pdf/supplemental_info_survival_pancreas_cancer_09-12.pdf
MOS in second line > 13m? Which is larger than 1st line MOS? How on earth did the co explain that?
PS. Yes. I know. It seems like a perfect example of meaninglessness of p value for repeated subset analysis... I am still intrigued though.
The co announced last week (at UBS) that it has been couple months since the MARQUEE trial hit 375th event. The seller might be thinking that this is earlier than expected (which I also kinda do but I am not the seller). On top of that I am having a hard time believing the median OS of the patients control arm will be ~7m.
Does anyone have any insight about the differences between the P2 non-squamous subgroup and the expected MARQUEE trial's patient population? Shall we expect a larger KRAS mutant ratio?
Thanks
I think due to PFS results and crossovers, the market wrongly assumes that the burden of proof lies with the naysayers. Dont forget that the PFS results in an open label P2 study should be discounted slightly and the # of crossovers should not cancel nearly all the OS benefits.
The number of very early thus right censored patients in the bavi's 3mg arm would be my major concern at this moment.
Congratulations to PPHM holders.
Is a pdf copy (not a presentation copy) of the KM bavi's OS graph available somewhere?
The reason for my desire to see a better copy than the presentation copy is that per the KM graph published, I can see that there are more right censored patients in the 3mg bavi arm than the placebo arm. The number of patients at risk (the number shown at the bottom of the KM graph) indicate that there are also censored patients before 6 and 9 month marks. Since the trial completed enrollment by 10/6/11, there shouldn't be many such patients and there shouldnt be a major imbalance. I can see the censor marks in the placebo (green) and 1mg (orange) arm but not in 3mg arm (the red). So I am looking for a better copy that shows the censor marks on 3mg arm as well.
Does anyone have access to such a copy?
I can barely hear the words but
@6:56 "The trigger was a little a bit off"
@7:08 "we triggered the interim analysis process for the process to collect the data at 730..."
Am I misinterpreting these?
This seems to be a reasonable explanation.
Yes. You are right on that number. However, if you extrapolate from available data, non squamous subgroup, which is adenocarcinoma (246 patients) and "other" (98 patients, MOS=7m) should still have a MOS > 7.5m. That's why I said closer to 8 months.
However, my main point was, after so much R&D in NSCLC, I would assume that MOS in 2+ line non squamous group would be better than what it was ~10 years ago.
While going over the ASCO 11 presentation to see to what p value HR=0.68 corresponds, http://files.shareholder.com/downloads/ARQL/1845104265x0x475367/d057ce4f-843b-4b92-824a-3f5a387ae42e/Phase%203%20NSCLC%20in%20progress%20ASCO%2011.pdf , I was suprised to see the median OS for the control arm is assumed to be 7 months.
Re: ARQL
At Stifel Nicolaus, the co announced that the interim analysis has been triggered, i.e, >370events (1/2 of total) have occurred. HR<0.68 is the boundary for unblinding due to efficacy. I dont know when it was triggered.
The last part of the talk was about the "voluntary" suspension of the ATTENTION trial. The sound quality is terrible.
I dont know which news lifted the stock. If the discussion of the ATTENTION trial, other people have better ears than I.
I havent heard of this portfolio review before. All I could find about it was the following quote in the latest CC.
There is also this possibility in case anyone missed it
http://www.asco.org/ASCOv2/Meetings/Abstracts?&vmview=abst_detail_view&confID=102&abstractID=76766
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IMO, the major issue in investing in OGXI at this moment is that we dont know how these approvals (of abi after (& before?) chemo & mdv3100 after chemo) will mess up the existing OGX trials, especially the SYNERGY trial, which is open label. Even though I trust TEVA, I am not sure if even TEVA can skirt around the interaction issues.
Otherwise, I don't share the other expressed concerns (there is no money/time/room for another drug, OGX-011 & 427 are antisense drugs or the chemo in mCRPC going away).
Thank you.
In a related development (Apologies if this was posted here before)
Does anyone know how to find the application number of an NDA?
I am looking the FDA medical review docs of enzalutamide. These should be public by now.
Something like the following but for enzalutamide
http://www.accessdata.fda.gov/drugsatfda_docs/nda/2011/202379Orig1s000MedR.pdf