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I believe I read some (seemingly trustworthy) place that Dendreon was going to give a presentation on January 29. This presentation should include an 'update' on provenge. My questions are:
1) Has anyone else heard about this event?
2) Is it likely that DNDN would present unblinded data, which they could claim beat the expectation of 21.9 months median survival and take that as indication that Provenge works?
BTW, didn't Gold promise to give an update about Trp8 early 2008?
Thanks!
Bengt
FYI: Editorial in Nature Biotechnology discusses Provenge in relation to the FDA's decission not to approve.
BR
Bengt
I believe Dr. Gold once mentioned in a conference call that the fact that some patients would have been on the study since July 2003, it would be an advantage relative to D9901 & D9902A. I took that as an indication that there was not a 36 months cut off.
I'm pretty sure that's what I heard, but I'm not sure about my interpretation...
B.
DNDN, crossover trial. Did anyone notice that the enrollment target for the crossover part of D9902B is set to only 92 patients (out of 166 possible)? Could it be that the last patients are going to be denied the salvage treatment? According to clinicaltrials.gov, the crossover trial is still recruiting, which I take to mean that there are less than 92 patients enrolled (?)
And what about the inclusion criteria for the salvage treatment, were D9901 and D9902A also designed so that both bone scans AND pain events should be met? If only bone scans were needed for qualifying for the salvage treatment, the pain criterion strikes me as a possible way to minimize the number of crossover patients?
Thanks!
B.
Thanks, Wall and Ranch. I had yet another look a the KM curve for the docetaxel treated population, and i wondered if - based on the observation that size of the steps down on the KM curve - it is so that more or less all of the docetaxel treatments were very close to the provenge treatment (close after Provenge treatment, as Dr. Petrylak mentioned that most docetaxel treatments took place after Provenge)?
A scarry thought came to my mind after reading Ranch's comment about the split of median survival improvement between docetaxel treated provenge patients and provenge-only treated patients. Could the FDA argue that the ITT population only had a survival benefit if also treated with docetaxel, and since such a treatment regime was not prespecified, sorry DNDN (and longs), any conclusions based on D9902B are just 'exploratory' (or whatever word is used)...?
And final question (for now): In the BLA appendix, it appears that the D9902B patients had a higher lower limit for CD54 cells than was the case for D9901 and D9902A - is this relevant as a predictor for the number of TNC?
Again, as usual, thanks for taking your time to answer my previous questions and TIA for the answers/comments I hope to get to the questions listed above.
B.
Thanks for your answer and for directing me to Dr. Petrylak's presentation - I hadn't seen it before.
It really looks like there is synergy between docetaxel and Provenge, but I'm not quite sure what to read from the KM graph showing the survival of the 51+31=82 patients in D9901+D9902A who received docetaxel. Thus, considering the timing of the Provenge studies and the timing of the docetaxel approval, it seems impossible that anyone could have received docetaxel (and died after being on a Provenge study for only 6-9 months (the approximate time for the first death on the KM curve). So what is it actually that is shown on the graph? Is there an obvious answer that I missed?
Basically, I try to piece together a coherrent picture of what the data are, and such a discrepancy-look-alike like the one I mentioned above - while perhaps not obviously crucial - may still be interesting.
Thanks!
B.
Docetaxel before/after Provenge: Is there any synergy?
Docetaxel was approved in May 2004, which is almost 3 years after the last patient was randomized in D9901 (which happened 08 OCT 2001). Thus, the only proven effective treatment became available very late in the study. As for the suggested synergy between Provenge and Docetaxel, isn't it then just so that the very long median survival time for provenge+docetaxel is due to those 2-3 months extra survival that docetaxel gives added ON TOP OF an already long survival time (you have to be a long term survivor in order to get docetaxel)? Consequently, there may not be any synergy whatsoever?
Do we know anything about the use of docetaxel in D9902A?
Thanks!
B.
I found the following on the DNDN board. To me, it sounds as if androgen deprivation, which I consider to be the extreme version of low T, is actually related to high baseline glucose=diabetes. Consequently, if Androxal can increase T, it may also decrease baseline glucose levels, which was recently suggested as an endpoint for the androxal study. Thus, the 'datamining' that RPRX did to find a meaningful clinical endpoint (glucose baseline=a well defined biochemical endpoint) instead of QoL may actually be for real, and not just datamining.
Any comments?
Thanks!
Dr. B.
Androgen Deprivation Therapy For Localized Prostate Cancer And The Risk Of Cardiovascular Mortality
Main Category: Prostate / Prostate Cancer News
Article Date: 11 Nov 2007 - 0:00 PST
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UroToday.com- Androgen deprivation therapy (ADT) is associated with metabolic syndrome, which includes the development of type II diabetes mellitus and coronary artery disease. In the October 17, 2007 issue of the Journal of the National Cancer Institute evaluated whether ADT induced metabolic changes result in an increased risk of cardiovascular (CV) death.
The longitudinal, observational prostate cancer registry CaPSURE was used to study a cohort of 4,892 men. Of these, 1,015 patients were treated with ADT with local therapy and 3,977 men were not treated with ADT. ADT was used in 266 patients who had RP and in 749 men who received nonsurgical treatment. The primary endpoint of the study was death due to CV causes. This was defined as myocardial infarction, sudden cardiac arrest, coronary artery disease, cardiac ischemia, arrhythmia, pulmonary embolism, or stroke.
Median patient age was 64 years and median followup was 3.8 years. Patients receiving radiotherapy, cryotherapy, or brachytherapy as primary treatment in combination with ADT were older than men who had RP. The overall median duration of ADT therapy was 4.1 months. The proportion of patients with baseline hypertension and heart disease were similar among those who did and did not receive ADT. The proportion of patients with baseline diabetes was statistically higher in patients using ADT than in patients not using ADT. Analysis of patients treated with RP, both ADT and older age were associated with significantly increased risks of death from CV causes but the presence of baseline heart disease or diabetes was not. This risk of CV death was evident in patients younger and older than 65 years. The cumulative incidence of death from CV causes among the younger patients using ADT was 3.6%, as compared to 1.2% in those not using ADT. Among patients treated with radiotherapy, brachytherapy, or cryotherapy only older age was associated with an increased risk of death from CV disease. Patients older than age 65 years who were treated with RP and ADT also had higher 5-year estimates of death from CV causes. In multivariable analysis among patients treated with RP, ADT use was associated with increased risk of death from any cause. Older age, Gleason score greater than 8, and presence of baseline diabetes were also associated with an increased risk of death from any cause. Among those who did not undergo RP a shorter time to all-cause mortality was not associated with ADT use but was associated with advancing age.
Tsai HK, D'Amico AV, Sadetsky N, Chen MH, and Carroll PR
J. Natl. Cancer Inst. 99(20): 1516- 1524, October 2007
doi:10.1093/jnci/djm168
Reported by UroToday.com Contributing Editor Christopher P. Evans, M.D
UroToday - the only urology website with original content written by global urology key opinion leaders actively engaged in clinical practice.
To access the latest urology news releases from UroToday, go to: www.urotoday.com
I didn't watch the AC-presentation by Dendreon, but I recollect from the IV-board that they showed a slide with cause-specific mortality for D9902A. Does anyone have any information on what the data looked like?
TIA
Bengt
Knowing this is old news (a prospectus from 11/28/05), I still missed a reference to yesterday's IV messages on the cox-regression being pre-specified. However, I found the following by googling, and according to this, a PRESPECIFIED Cox analysis was used.
Just in case anyone would like to see it directly from a company SEC filing.
And, Walldiver, Rancherho, Ocyan and others, thanks for posting here and on the IV board.
Br.
Bengt
SEC File 333-127521 · Accession Number 1193125-5-232799
A pre-specified Cox multivariate regression analysis, which adjusts for prognostic factors known to influence survival, was used to test the validity of the survival benefit seen in this study. Those results showed that patients who received placebo had a relative risk of dying more than twice as high as that of patients who received Provenge (p-value = 0.002, adjusted hazard ratio = 2.1).
Keep in mind that the 26 patients are Provenge-NO-docetaxel-BUT-possible-treated-wiht-another-chemotherapy. Relating these 26 patients to Provenge-NO-anything is not fair.
Anyway, now that Provenge-Docetaxel came out with such good survival, one would intuitively expect the value of the remaining group of patients to be somewhat lower than the 33% (or so) survival so that the overall survival would be 33% (?)
Br.
Bengt
36 mos survival analysis is better than median survival analysis.
Instead of median survival data, I used 36 mos survival data, and my initial worries have been dampened a little by doing that.
I used the following data:
In 9901-9902a, a total of 82 patients received Docetaxel
We know from Dr. Small's presentation that 37% of the (82) D9901-provenge patients received docetaxel, i.e. 0.37 x 82=30 provenge-arm patients received docetaxel. We also know from the same presentation that 49% of the placebo-arm patients received docetaxel. This translates into 22 placebo-arm patients receiving docetaxel. Thus, in total, 22+30=52 patients from D9901 received docetaxel. Subtracting these 52 patients from the total of 82 (D9901 and D9902a) docetaxel receiving patients, we get that D9902a contributed with 30 docetaxel treated patients. We have no data that enables us to split these 30 patients between the placebo and the provenge arm, so lets assume for the moment that the went 50-50 to the to arms. Thus, D9902a contributed with 15 Provenge-docetaxel treated patients to the analysis, making the total number of Provenge-docetaxel treated patients in the two arms equal 30+15=45 provenge-docetaxel treated patients. We know that this group had a median survival that slightly conservatively equals 36 mos. Thus, the provenge-docetaxel treated group contributes with 45/2=22 or 23 patients to the group of survivors after 36 mos.
Out of 147 provenge treated patients, 33% were alive after 36 mos, i.e. 48 or 49 patients were alive at that time. 22 or 23 of these 48 or 49 survivors belong to the provenge-docetaxel treated group of patients, and consequently, the remaining 26 patients belong to the provenge-NO-docetaxel treated group of patients. These 26 patients who survived without the help of Docetaxel should be related to the total group of provenge-treated patients who did NOT receive docetaxel. This latter number is calculated by subtracting the 15 D9902a-provenge-docetaxel treated patients and the 30 D9901-provenge-docetaxel treated patients from the total of 147 provenge treated patients. This makes the survival rate of provenge-NO-docetaxel treated patients equal 26/(147-15-30)= 25.5%
This number (25.5%) is not too bad compared to the 9901+9902 placebo-arm survival rate of 15%. AND, there is reason to believe that the assumption of splitting the 30 D9902a-docetaxel treatments evenly between the placebo-arm and the Provenge-arm is too conservative (more placebos got docetaxel).
Assuming that the split is 10-20 (provenge-placebo) increases the 25.5% above to 26.6%.
FURTHERMORE, 15% survival in the placebo-arm (combined 9901 and 9902 arms) benefits greatly from the cross-overs who got docetaxel, so looking only at the placebo-crossovers-NO-docetaxel is likely to be quite a bit lower.
CONCLUSION, we may not be in such a bad shape after all...
Walldiver, a quick question:
The Provenge+Docetaxel effect is extremely good, but it leaves me with an odd feeling that Provenge as a monotherapy may only have a very small effect. Could it be so that the survival advantage of provenge vs. placebo is driven more or less exclusively by the survival advantage of Provenge+Docetaxel?
Br.
Bengt
D9901 enrollment estimate: Ocyanblue
First, to correct a mistake, I meant the censoring shown for the progression data would give a hint to the enrollment pattern, not the survival data. Sorry about that mistake. Hoooow-ever, I may still have a point. What I did to get an impression of the D9901 enrollment pattern was the following:
For the analysis, I used the (time, % non-progression) data points for the 10 censored patients in the treatment arm.
If, say, a patient is censored after 20 weeks and if 25% of the patients would have progressed by this point in time, it is reasonable to assume that 1/25%=4 patients were enrolled 20 weeks before the trial was locked (three of the four patients would statistically have evented before 20 weeks, and the one who was censored would event some time after 20 weeks). Doing this for all the 10 patients gives a set of 10 new (time, number of patients) data points.
The time frame for the progression results is 75 weeks, and to transform the time values to time after the start of this 75 week period, a new set of data points is generated by subtracting the time of censoring from 75, i.e. (75 - time, number of patients). Plotting the accumulated number of patients as a function of the "new" time, gives (I hope...), an impression of the enrollment pattern.
I made the plotting, and linear regression gave the following equation:
<accumulated number of patients>=0.8217*<"new" time>+14.6. R2=0.928...
Test1: Inserting "new" time=75 gives an accumulated number of patients (in the treatment arm) of 76, which is not too far from the real life number of 82.
Test2: Inserting "new" time = -9 (75+9=84, keeping in mind that the enrollment of D9901 took 84 weeks) gives an accumulated number of patients of 7. Which is perhaps a little off the real life number of zero, however, I don't think it invalidates the approach - this is not supposed to be exact!
I have to admit that this is at the very best a very rough indication of the enrollment pattern, but I think (until Iwfal convinces me of the opposite) that this is a valid approach. Comments are utmost welcome!
Br.
Bengt
PS! The data set that I used is based on very quick and dirty readings from fig.2 in the 2006 JCO-paper by Dr. Small. Some uncertainty is introduced by this lack of precission.
D9901 was not backloaded at all.
I know that this statement is a bit of a long shot, but I think that an impression of the enrollment pattern can be obtained by looking at the time points at which the non-PCa-deaths were censored (Dr. Small's presentation from 10/20). These patients were censored because their deaths were unrelated to PCa, therefore, the timing and number of these deaths - together with the likelyhood of being alive at the time of censoring - can give an indication of the enrollment pattern.
I made some rough estimates, and to me it appears as if the last half of the patients were enrolled at a constant rate.
Please have a look at the graph, and let me know if you see my point.
Br.
Bengt
What did Dr. Provost mean by the following?
"These are the four phase III clinical trials that we have gone through. Two of these are finished and the efficacy data are analyzed. 9902B is still in progress, P11 just finished enrolling. We have got a few stragglers left, but we are just about done."
"P11 just finished enrollment" Huh? That was more than half a year ago at the time the presentation was given? In my opinion, half a year is a long time for a trial with an expected median time to eventing of around 6-12 months?
This one is also a bit ambiguous: "We are just about done" done with what? reaching the trigger point or done with randomization or?
Particularly the last sentence strikes me as something that might indicate a long tail on the treatment arm (since we still have not reached the prespecified number of events, and I think it is likely that referrence was made to the number of events). However, I am not a native English speaker, and the subtle details of what Dr. Provost said may be beyond me. Therefore, please help me. Thanks.
Br.
Bengt
Thanks :)
B.
A couple of questions:
The Halabi-nomogram showed no real difference between placebo and Provenge. Keeping this in mind, how come that using Cox regression analysis improved the p-value from 0.010 to 0.002 ( the last p-value may be incorrect, but it was definitely smaller than 0.010)? Is this fact indicating that the Halabi-nomogram or the Cox regression analysis are contradicting each other?
Yet another question, is it normal not to include cross-over as a part of a Cox regression analysis? I think it kind of odd that this wasn't included.
BTW: I agree that the analysis of cross-overs vs. pure placebois is quite interesting. However, I have a feeling that we won't be as pleasantly surprised with these data as we were with today's data. I can't recall exactly what Dr. Provost presented, but I think that there were some stability issues with the product that made me think that a freeze-thaw cycle wouldn't do the product (the to-be-provenge) any good. Furthermore, the Provenge dose was smaller in the cross-over than in the pure Provenge arm.
Best regards,
Bengt
Ocyan: Could you please enlighten me on:
- who is Dr. Petrylak and
- when (and why) is he going to give presentation
Do you happen to have an indication of when the 9902A results are likely to be made public in more detail (such as cause specific mortality).
TIA
Br.
Bengt
Gametherory101: Do you refer to the first line in the abstract when you say that there were 12 survivors at the time of the last editing of the JCO-paper?
If so, the line reads: "Of the 127 patients, 115 had progressive disease at the time of data analysis, and all patients were followed for survival for 36 months."
DNDN apparently performed the data analysis on the TTP after 90% (90.5% to be precise) had progressed - thus 90% was the trigger point for the progression events. Along the same line, the "time of data analysis" is therefore not referring to the time of final analysis (in this case the analyses needed for writing the JCO paper), but the time of analysis refers to the point in time when those 90.5% of the patients had evented.
As far as I can see from the JCO paper, it doesn't mention anything about the number of survivors at the time the paper was written. Please correct me if I'm wrong.
Best regards,
Bengt
Thanks Iwfal.
The presentation by Dr. Kylstra is dated with respect to the enrollment numbers, finally I see this (but I think the lack of an easy-to-find date of the presentation is kind of an excuse...). Another mistake of mine: A bit more careful inspection of the P11 trial design in the above presentation made me see that the PSA level to be met by the Lupron shots was not "undetectable" as I mistakingly wrote but 1 ng/ml. I don't know where I got the impression that "undetectable" was the threshold.
Sorry for the confusion.
I have spent some time looking for references that could give some indication as to how long time to expect for the placebo part to event. Do you have a good suggestions for my reading (I have free access to most scientific journals)? TIA
BTW, the history of Provenge includes several events that could possible trigger a (temporary?) increase or decrease in the enrollment rate, particularly the D9901 results, and there was also a temporary halt of enrollment. Is it possible to include such pieces of information in a meaningful way in terms of enrollment as function of time? - x^2 or x^4 etc. seems to be extremely arbitrary to me.
Just wanted to direct your thoughts in this direction. I realize that including any such enrollment assumptions in the model is at best only going to give a questionable results, but to me, x^4 and the like is even more abstract?
Best regards,
Bengt
I'm still not quite sure what to think about "enrollment" vs. "randomization", personally (which I'm perfectly aware doesn't count for anything anywhere) I would consider a patient enrolled if he met the entrance criteria for getting the Lupron-shots in the first place. He would then be eligible for randomization to either Provenge or Placebo only if he reached the "undetectable" level, but even if not meeting these requirements, he would still be counted as enrolled. Assuming that I'm right, this would explain the low number of Provenge treated patients (104 patients) in Dr. Provost's presentation and it would also explain why Dr. Kylstra mentions 160 patients as treated (Iwfal: I didn't quite get your comment to my post #749 about design n... please have a look at Dr. Kylstras presentation once again and check if that is what was meant).
I believe I came across a paper describing that patients that reached the undectable level from ADT had a tremendously better chance of surviving (on continued ADT) than patients who did not. I can't quite remember, but I think median survival was about 12 years(?). I therefore think that it is likely that the patient group in this study may not progress as fast as one could have expected from other studies.
Anyway, I still think my points in post #749 are pretty valid (irrespective of IR responses telling the opposite) and I also think the treated population - i.e. those who achieved the undectable PSA level - represents a special group that may progress slower. Then again, a single shot of Lupron shouln't keep the testosteron at bay for much longer than about 4-5 months, and as such, the patients might progress rapidly no matter their PSA being very responsive to ADT.
I don't know what to think, but I get kind of worried when reading Iwfal's latest guestimates on the chances of stat sig of P11, I would certainly have expected these numbers (chances of stat sig) to be more favourable for a long position...
Best regards,
Bengt
Please help me understand what the following means:
"We will have some data later on in the fourth quarter that suggest that patients can go on chemotherapy and what that looks like with Provenge."
Thanks!
Bengt
A question and a comment...
Talking about 5 yr follow up on D9901 (&D9902A, when that time comes) - is it possible or even likely that Dendreon would (be allowed to?) collect data on the 5 yr post randomization survival?
I read somewhere that survival at 5 yrs post androgen independence is virtually zero - and even a small percentage of survivors would therefore be (somewhat) compelling evidence of the effect of Provenge?
Br.
Bengt
About enrollment, randomization and P-11
Fact 1: There were 160 treated patients in P-11 (slide 4 in Dr. Kylstra's presentation - see links provided in the readme section of this board).
Fact 2: Dr. Provost shows that there are 104 patients who were treated at least once with Provenge. My take: With a 1:2 randomization between placebo and treatment, the 104 patients in the treatment arm amounts to a total of 156 patients, which is - I believe - as good as it gets in an attempt make a 1:2 randomization of a total of 160 patients.
Fact 3: 175 patients were enrolled in P-11 (see quote from a 10 K filing below).
My take: I think that 175 patients were asked if they wanted to participate in P-11. If they agreed, they were given the Lupron shot(s), and by doing this, they were considered enrolled. This enrollment was completed June 2005. However, 15 of these patients didn't have a sufficient PSA reduction, and therefore not treated, reducing the number of treated patients (Dr. Kylstra's presentation) to 160. Thus, the randomization procedure was NOT finished in June 2005, but the enrollment was - those two things are not the same IMHO.
The unfortunate consequence of this is that we have to subtract the Lupron-treatment time from the time that has passed since June 2005 to get the Provenge treatment time (for the last patient that was enrolled).
Br.
Bengt
Clinical Trial—P-11. We completed enrollment in a double-blind, placebo-controlled Phase 3 clinical trial called PROTECT (PROvenge Trial of Early Prostate Cancer Treatment), or P-11, to evaluate the safety and potential effectiveness of Provenge in treating men with early-stage, androgen-dependent prostate cancer. Men whose prostate cancer is responsive to hormone treatment are considered androgen-dependent. There are 175 patients enrolled in the trial at 19 sites in the United States. We expect to receive the initial analysis of this study in 2006.
iwfal:
>>But not the correct number P-11 patients even though it was 7 months after enrollment was complete. Massive worry? No. Something to chase down? <<
I'm sorry if completely missed your point about the number of P-11 patients, but to me, 104 patients seems to be pretty much what one would have expected to be included in the treatment arm of P-11. Being randomized 1:2, the total number of enrolled patients should equal something like 104*1.5=156, which is not tremendously far from the apprx. 175 patients (if this is the correct number) that have been reported to be enrolled?
Would such a discrepancy (maximum 19 patients out of 175) be unlikely using standard (whatever that means) randomization procedures?
Br.
Bengt
PS! iwfal, Ranch, Wall and others: Thanks for posting.