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iwfal:
The CEGE CEO also staed at their CC, that Vital 1 also used the conservative O'Brien Fleming rules to allocate its interim alpha p value. A nonstatistician googling that would still be somewhat confused, except to confirm that it is considered to be one of the most conservative approaches;
“O'Brien-Fleming's method, corresponding delta = 0, is very conservative in early rejection of the null hypothesis. Pocock's method, corresponding delta = 0.5, spends Type I error uniformly across different stages. Generally speaking, a large delta (e.g. 0.8) will lead to a design that spends Type I error more at earlier stages than later stages”
If you assume that the number of events required for the interim was 200 (out of a total planned 600, and total actual enrollees of 626), what would your guess be as to the actual p value that CEGE allocated for the interim. TIA.
The presentation of Dr. Kristan Hege at: Bringing Therapeutic Cancer Vaccines and Immunotherapies Through Development to Licensure (Day 1) Thursday, February 08, 2007 Begin at Time: 56 minutes. http://videocast.nih.gov/PastEvents.asp?c=1&s=31
One of the fascinating aspects of DNDN's antigen cassette technology, which uses a chemical linker to fuse an antigen with GM-CSF, and CEGE's GVAX, which genetically engineers metastatic cancer cell lines to express GM-CSF in vivo and irradiates them to stop in vivo prolifertaion, is that their different approaches to coupling GM-CSF, an immune stimulant, appears to be so critical to success. CEGE showed slides at the FDA/NCI workshop that showed that merely dosing GM-CSF as a separate recombinant protein at the same time, as the failed Canvaxin melanoma vaccine tried, not only doesn't work, but that GM-CSF if overdosed can potentially act as an immune suppressor. DNDN tried dosing just the fusion protein in its Ph2 trials, but that also didn't work well. It would be an interesting experiment to see if pulsing GVAX cells ex vivo with a patient's immune cells per the "method of Hsu" used by DNDN offers any advantages over injecting patients with the GVAX cells. All JMHO.
>>Do you have any comments regarding the seemingly increased gap of time between interim and predicted final analysis? It came up on the call but Sherwin wouldn't bite directly but did keep repeating about the slower onset of effect of immunotherapies.<<
One possibility is the fact that Vital-1 is a very atypical clinical trial. For example,while the interim and final results are blinded, there is no blinding at randomization since the GVAX immunotherapy treatement, described as similar to allergy shots, is different than infusing Taxotere with far more linited side effects, but both have an initial course of six months. Patients in the GVAX experimental arm can elect to continue monthly GVAX therapy after the initial six month dosing, so long as they do not commence another therapy, but there is no restriction otherwise from starting any therapy, including Taxotere. The GVAX single arm Ph2 trials not only showed that the same high dosing subgroup (n=32) as is being used in Vital 1 had a median survival of some 35 months, but as of 9/07, the even smaller subgroup (n=9) that had subsequent Taxotere, had still not reached median survival at 40 months. The positive impact that subsequent Taxotere has on cancer vaccine efficacy was also seen with Provenge as well as with Therion's PROSTVAC. So imagine, the experimental arm patients start the initial GVAX 6 month therapy and so long as they don't progress, they take monthly boosters. Chances are the immediate impact on PSA etc. is initially much more pronounced in the Taxotere arm, but even if subsequent GVAX were beneficial, there is no crossover to GVAX and no really good follow-on options exist for that group. OTOH, if a GVAX patient progresses to symptomatic AIPC, their oncologist would undoubtedly recommend Taxotere, since it not only is the indicated standard of care for symptomatic patients, but is better for pain relief than mitoxantrone. In addition, they would be aware of the putative major survival benefit arising from Taxotere after GVAX. Ultimately, therefore, the number of early events in the GVAX and Taxotere arms and their event rate might not differ much, but given more time, the experimental arm would in effect become a combination GVAX + Taxotere arm. The event rate in the Taxotere arm would remain the same, but the event rate in the combination arm would decline substantially, which could have the effect of increasing the elapsed calendar time between the interin and the final looks as compared to any elapsed period from the start of enrollment to the interim.
That also ties in to a reason for the Vital 2 trial. Vital 1 would only demonstrate value in asymptomatic AIPC, so patients deferring any therapy until they become symptomatic technically would not be offered GVAX. Testing simultaneous GVAX and Taxotere as compared to Taxotere alone in symptomatic AIPC addresses that need. All JMHO.
Good point, although when CEGE began Vital-1 enrollment in July 2004, they probably did not have a breakdown for the median survival of 22 to 23 months for the 45% asymptomatic subgroup in its Taxotere TAX327 pivotal trial in AIPC, nor the median survival for the 32 high dose GVAX patients in its two Phase 2 trials, which has since been reported as 34.9 months an 35.0 months respectively. CEGE's CEO took great pains yesterday to point out that the Phase 2 trials were multi-institutional; he claimed that measures were taken to reduce any selection bias; and he pointed out that there were both T cell and B cell based immune responses. All of this is not to suggest that GVAX statistical significance or FDA approval is assured, but I've yet to come across any strong reason why it's likley to fail. JMHO.
Fair enough. You might ask David, however, why BSR still does not follow CEGE, especially given the large amount of knowledge BSR would have acquired over the years about therapeutic cancer vaccines in following DNDN's Provenge. As I recall, someone posted that BSR thought long ago that CEGE would abandon GVAX in AIPC for futility and that there were some GVAX storage problems(?). The futility issue should be settled this quarter with the maturing of interim data, and CEGE's CEO has repeatedly stated that GVAX will not be abandoned for futility since all Vital 1 patients have been treated. It also seems to me that so long as viable GVAX cells are shipped from the GVAX production facility which gets an annual cGMP inspection from the State of Califonia every year, the GVAX cells should have no greater a storage problem than the Provenge immune cells. IMHO, both Provenge and GVAX will be approved in AIPC, probably in 2009. If so, and in view of the lower CEGE market cap, it might even be a better investment. All JMHO.
Help, calling iwfal. Yesterday, CEGE's CEO stated at the JPM conference that interim results were now expected in its 600 patient Vital 1 trial in early 1H08. Vital-1 was fully enrolled with an actual 625 patients with asymptomatic AIPC in early July 2007 and compares high dose GVAX with boosters with boosters ceasing upon any subsequent therapy (eg, Taxotere) vs. Taxotere alone. Taxotere is reported to have median survival of 22 to 23 months in asymptomatic AIPC. The 32 patients in the GVAX high dose subgroup in its Phase 2 trials in AIPC had a median survival of 35 months. A developing issue is whether this near term maturing of interim data gives any clue as to whether statistically significant results are even possible. Two Yahoo MB posts opine on this (one is mine):
http://messages.finance.yahoo.com/Stocks_%28A_to_Z%29/Stocks_C/threadview?m=tm&bn=3352&tid=42344&mid=42387&tof=5&rt=1&frt=2&off=1
http://messages.finance.yahoo.com/Stocks_%28A_to_Z%29/Stocks_C/threadview?m=tm&bn=3352&tid=42388&mid=42388&tof=1&frt=2
While this is a DNDN MB, the timing and results of the interim and final analysis of CEGE's Vital 1 and Vital 2 trials in AIPC should be of obvious interest to any DNDN investor.
I realize that your skepticism of any statements from biotech companies is well deserved,but your thoughts would be much appreciated.
Interesting article on the possibility of using an oncolytic virus for vaccination: "Adoptive transfer of normal T cells loaded with oncolytic virus into individuals with cancer would be technically easy to implement both to reduce the distribution of metastases and to vaccinate the affected individual in situ against micrometastatic disease. As such, this adoptive transfer could have a great therapeutic impact, in the adjuvant setting, on many different cancer types."
Purging metastases in lymphoid organs using a combination of antigen-nonspecific adoptive T cell therapy, oncolytic virotherapy and immunotherapy
Nature Medicine 14, 37 - 44 (2007)
Published online: 9 December 2007 | doi:10.1038/nm1681
http://www.nature.com/nm/journal/v14/n1/abs/nm1681.html
Another scientific article focusing on a compound that inhibits immunotherapy, in this case, by inhibiting the ability of ICAM-1 (CD54) to allow adhesion to endothelium cells.
Endothelin B receptor mediates the endothelial barrier to T cell homing to tumors and disables immune therapy
Nature Medicine 14, 28 - 36 (2007)
Published online: 6 January 2008 | doi:10.1038/nm1699
http://www.nature.com/nm/journal/v14/n1/abs/nm1699.html
"Overexpression of the endothelin B receptor (ETBR) was associated with the absence of TILs and short patient survival time." TILs are tumour infiltrating lymphocytes.
Long-term survival data from the Taxotere pivotal TAX327 pH 3 trial is reported in the current issue of JCO:
Docetaxel Plus Prednisone or Mitoxantrone Plus Prednisone for Advanced Prostate Cancer: Updated Survival in the TAX 327 Study
Dominik R. Berthold, Gregory R. Pond, Freidele Soban, Ronald de Wit, Mario Eisenberger, Ian F. Tannock
Journal of Clinical Oncology, Vol 26, No 2 (January 10), 2008: pp. 242-245
http://jco.ascopubs.org/cgi/content/abstract/26/2/242
Purpose: The TAX 327 study compared docetaxel administered every 3 weeks (D3), weekly docetaxel (D1), and mitoxantrone (M), each with prednisone (P), in 1,006 men with metastatic hormone-resistant prostate cancer (HRPC). The original analysis, undertaken in August 2003 when 557 deaths had occurred, showed significantly better survival and response rates for pain, prostate-specific antigen (PSA), and quality of life for D3P when compared with MP. Here, we report an updated analysis of survival.
Methods: Investigators were asked to provide the date of death or last follow-up for all participants who were alive in August 2003.
Results: By March 2007, data on 310 additional deaths were obtained (total = 867 deaths). The survival benefit of D3P compared with MP has persisted with extended follow-up (P = .004). Median survival time was 19.2 months (95% CI, 17.5 to 21.3 months) in the D3P arm, 17.8 months (95% CI, 16.2 to 19.2 months) in the D1P arm, and 16.3 months (95% CI, 14.3 to 17.9 months) in the MP arm. More patients survived 3 years in the D3P and D1P arms (18.6% and 16.6%, respectively) compared with the MP arm (13.5%). Similar trends in survival between treatment arms were seen for men greater than and less than 65 years of age, for those with and without pain at baseline, and for those with baseline PSA greater than and less than the median value of 115 ng/mL.
Conclusion: The present analysis confirms that survival of men with metastatic HRPC is significantly longer after treatment with D3P than with MP. Consistent results are observed across subgroups of patients.
FDA Approves Fewest Drugs Since 1983.
http://blogs.wsj.com/health/2008/01/08/fda-approves-fewest-drugs-since-1983/?mod=yahoo_hs
doc and iwfal:
I tread carefully in commenting on any discussion that you are involved in since both individually and collectively you know more about this than I do. I will point out, however, that the pivotal TAX327 trial was an event based trial (of a therapy already approved in breast cancer) where approval came relatively soon after the approved experimental arm and the control arm passed the median survival points in a relatively large trial. Recent long-term survival data for the TAX 327 data places 36 montn survival at 18.6% to 20% (depending on the analysis done) vs. the 11% for the control arm in 9901, which was initiated in asymptomatic AIPC, and 45% of the TAX327 patients were symptomatic. I am not arguing against the position that long term survival of the 9901 experimental arm in 9901 at 34% was better, but, IMHO, those 51 of 147 patients in 9901 and 9902a that received the combination of Provenge and Taxotere and had a median survival of 34 months according to Dr. Petrylak's analysis were an important element in that result.
COMMENTS AND CONTROVERSIES
Randomized Trials in Oncology Stopped Early for Benefit
Journal of Clinical Oncology, Vol 26, No 1 (January 1), 2008: pp. 18-19
http://jco.ascopubs.org/cgi/content/full/26/1/18
"The relative risk (RR), either reported or calculated, and total number of events were available for all those RCTs reporting dichotomous end points (n = 27). The median RRs and total number of events were 0.54 (interquartile range, 0.3 to 0.7) and 61 (interquartile range, 23 to 144), respectively. Nine of the 12 RCTs that reported a RR the median RR reported more than the median number of events. Conversely, the majority of RCTs (73%) that found an RR less than the median also reported fewer than the median number of events, suggesting that RCTs stopped early after only a few events accrued tend to report large treatment affects. Indeed, the odds of reporting a large treatment effect (ie, a RR less than the median) were 12.2 times (95% CI, 2.0 to 75.1) greater when the studies accrued fewer than the median number of events than when they stopped later, after more events had occurred. The correlation between the number of events and the apparent treatment effect, expressed as an RR, was highly significant (r = 0.75; P < .0001). Therefore, the risk of significantly overestimating the treatment effect diminishes when the number of events accrued is large. While preliminary explorations suggest that subsequent trials confirmed the statistical significance of 64% of trials stopped early for benefit in oncology, we are concerned with the overestimation of the true treatment effect and how this could affect risk-benefit tradeoffs necessary for sound clinical decision making.3 Given the strong correlation between the apparent treatment effect and the number of events, it would seem prudent to perform interim analyses only after a sufficient number of events have occurred so as to reduce the likelihood of overestimating the true treatment effect."
Interesting. It's becoming increasingly apparent that as knowledge of the complexities of the immune system increases, the development of cancer, especially as people age, will be increasingly linked to problems in immune protection. An article in the December issue of PNAS also relates an immune defect as leading to poor prognosis in prostate cancer:
B7-H3 and B7x are highly expressed in human prostate cancer and associated with disease spread and poor outcome
Published online before print November 27, 2007, 10.1073/pnas.0709802104
PNAS | December 4, 2007 | vol. 104 | no. 49 | 19458-19463
http://www.pnas.org/cgi/content/abstract/104/49/19458?maxtoshow=&HITS=10&hits=10&RESULTFORMAT=&fulltext=B7-H3&searchid=1&FIRSTINDEX=0&resourcetype=HWCIT
B7-H3 and B7x are recently discovered members of the B7-CD28 family thought to dampen peripheral immune responses via negative costimulation. We evaluated their potential expression in human prostate cancer using a large cohort of patients with 7 years of follow-up. We identified 823 patients with tissue available treated with radical prostatectomy between 1985 and 2003. Immunohistochemistry was performed on tissue microarray sections using anti-B7-H3 and -B7x. The percentage and intensity of immunoreactivity by tumor cells were blindly evaluated by two urological pathologists, and outcome analyses were conducted. Both B7-H3 and B7x were highly expressed; 93% and 99% of tumors had aberrant expression, respectively. The median percentage of tumor cells staining positive was 80% for each molecule. Strong intensity for B7-H3 and B7x was noted in 212 (26%) and 120 (15%) patients, respectively. Patients with strong intensity for B7-H3 and B7x were significantly more likely to have disease spread at time of surgery (P < 0.001 and P = 0.005, respectively). Additionally, patients with strong intensity for B7-H3 and B7x were at significantly increased risk of clinical cancer recurrence (P < 0.001 and P = 0.005) and cancer-specific death (P = 0.004 and P = 0.04, respectively). To our knowledge, we present the largest investigation of B7 family molecules in a human malignancy and a previously undescribed evaluation of B7x in prostate cancer. B7-H3 and B7x are abundantly expressed in prostate cancer and associated with disease spread and poor outcome. Given the proposed immune-inhibitory mechanisms of B7-H3 and B7x, these molecules represent attractive targets for therapeutic manipulation in prostate cancer.
Interesting NYT articles on cancer stem cells:
http://www.nytimes.com/2007/12/21/science/21stem.html?hp
The following study hypothesized that a gene expression diagnostic possibly indicates whether cancer stem cells are present in a patient's cancer and predict a poor prognosis:
“Microarray analysis identifies a death-from-cancer signature predicting therapy failure in patients with multiple types of cancer” (emphasis on prostate cancer): http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=15931389&query_hl=1
Cell Genesys Announces Sale of Lentiviral Gene Delivery Technology for $12 Million http://biz.yahoo.com/prnews/071220/aqth106.html?.v=28
This came out of nowhere. Even if CEGE and its investigators occasionally spin data analysis, their spin-off of Abgenix, Ceregene and now this and their continuing collaboration with John Hopkins in oncology are pretty impressive.
Medscape Article on Prospective Tissue Vaccines for Prostate Cancer:
http://www.medscape.com/viewarticle/567111?src=mp
Depressing. I certainly don't trust Gold. I admit that I'm not very knowledgeable about CEGE's top management. I tend to place more confidence in the scientific studies published in various journals. The close and continuing relationship that John Hopkins has with GVAX and CEGE in different cancers is also somewhat encouraging. It is a shame to have to think of biotech investing as a potential game of Liar's Poker where the insiders always win. I have also noticed over the years that many biotech managers who had no role in the invention or development of a therapy or diagnostic, have never treated a patient or managed a successful business, think that they are entitled to a disproportionate share of compensation and congratulations for performing noble work. I suppose our male egos always have a way of distorting reality. Perhaps there should be a Hazard Ratio for biotech management. JMHO.
Since the powering calculation for Vital 1 would have been done in early 2004 prior to commencing enrollment, your lower estimate of the powering would correspond to their diminished expectations at that point as compared to the subsequent estimates based on Ph 2 results, which your earlier and higher powering estimates, I understood,were based on the later 2007 inputs that I provided.
Wall:
FWIW I also minimized the competitive threat of CEGE's GVAX to DNDN's Provenge in 11/05 before all the events of the last 12 months. See:http://www1.investorvillage.com/smbd.asp?mb=971&mn=11568&pt=msg&mid=770730
As more data has been made available, however, I have moderated those views. BTW, the CEGE CEO has acknowledged that any of its trials can be stopped for safety concerns, which presumably would include more fatalities in the experimental arm than the control arm, as recently occurred with NOVC's calcitrol. The context was that he was referring to stopping Vital 1 for futility because of lack of efficacy at the interim, which he said will not occur.
FWIW, The CEGE CEO responded to a question after a recent presentation that there is no provision for stopping Vital-1 for futility since all Vital 1 patients in the experimental arm will have been treated at the time of any interim. My comment wrt the powering of Vital 1 and to its Hazard Ratio of 2 assuming a 23 month control arm median survival and a 35 month experimental arm median survival was based on a response provided by iwfal on Ihub (other than using a 22.5 median survival for the control arm) since I make no claim to being a statistician. See:
http://investorshub.advfn.com/boards/read_msg.asp?message_id=24563706
It would also seem that the odds for success of Vital-1 would have increased over the three year period preceding the publication of the analysis of Taxotere TAX327 asymptomatic subgroup data since the median survival of 35 months for the high dose subgroups in the 2 Ph 2 trials (n=32) were not known until the last 8 months and the GVAX high dose smaller subgroup (n=9) that subsequently took Taxotere had still not reached median survival in September when it was already >40 months. This suggests that if crossover rates to subsequent Taxotere of the PH3 high dose patients in Vital 1 is even higher, the GVAX median survival results may be even better than Ph2. In any event, the possible treatment effect based on Ph2 GVAX high dose data has increased even more than the median survival calculated by the retrospective analysis of the TAX group asymptomatic patients over the median survival of 18.9 months previously reported for all Tax 327 patients treated with Taxotere every three weeks. The caveat, of course, is that the Provenge Ph3 increase in median survival of the integrated 9901 and 9902a patient experimental arm over their mixed control group involving crossover patients treated with the lower dose of frozen then thawed Provenge, some treated subsequently with Taxotere and some not, and some non crossover patients receiving Taxotere and some not is a far more reliable indication of 9902b results than a projection of the median survival of 32 high dose patients in Ph2 GVAX in asymptomatic AIPC to Phase 3 and a comparison to a reference Taxotere control group. If 9902b's experimental arm has the same 25.9 month median survival as that of the 9901 experimental arm and it were to be compared to a 23 month Taxotere control arm, would it be sufficiently powered to be statistically significant? Who knows? In biotech, it seems that everyone should be prepared for the unexpected. All JMHO.
In the 2 GVAX Ph2 trials, the high dose subgroup had a median survival in asymptomatic AIPC of 34.9 and 35 months. GVAX is being compared to Taxotere. In the pivotal Ph3 Taxotere trial, the asymptomatic subgroup had a median survival of 23 months. The number of events (deaths) required for the interim look should be about 200 to 220. CEGE has stated that they expect this to occur in 1H08. The trial began enrollment in July 2004. Median refers to the point at which 50% of a group reaches a defined point.Since as in all randomized clinical trials there is an experimental arm and a control arm, if you assume a positive treatment effect, the overall median for both trial arms will be greater than the median for the control arm and less than the experimental arm median. Thus, if the final number of events required to open either of the 600 patient Vital or Vital 2 trials is 400 (the number of events required to end the DNDN Ph3 9902b trial is 360) and half of that is required to open the interim, twice the number of patients required to open the interim (2X200?) should be enrolled at least 23 months prior to the interim at a minimum, but actually even for a longer period to account for a slower event rate in 50% of enrollees who are in the experimental arm. Fast foward to 6/08, and that would suggest that in June of 06 or a bit earlier, 400 of the 600 patients in Vital 1 would have been enrolled at a point approximately two thirds through the period of total enrollment (7/04 to 7/07), which seems a bit optimistic on the enrollment front and a bit conservative on the treatment arm front. Then again, CEGE has the actual enrollment/treatment rate and we don't.If the PH2 high dose subgroup results are repeated in Vital 1, it would suggest a Hazard Ratio of over 2, which would make GVAX statistically significant (p=<0.05) at the interim, which depending on the allocated alpha (p=0.01?) possibly a basis for opening the data and filing a BLA. As a reference, DNDN's 225 patients in their 9901 and 9902a trials had 164 events with an integrated increase in median survival of 4.3 months, a Hazard Ratio of 1.5 and a Kaplan Meier p value of 0.011. A greater treatment effect combined with a greater number of events in Vital 1 could push the p value below 0.01 and increase the treatment effect Hazard Ratio above 2. DNDN is projecting that their 9902b interim will be reached midway through 2H08.
Interestingly, both CEGE and DNDN consider the allocated alpha (p value)at their interim points proprietary. This could be a very competitive situation for both companies. The general alpha allocation rule in Ph3 trials is to keep an interim look alpha extremely low so as to maximize the chance of success at the final point when more data will have matured, increasing the power of the trial to report a p value lower than what remains of the alpha after subtracting that allocated for the interim. In this case, there is a significant likelihood that the two competitive immunotherapies will be statistically significant (p=<0.05) at their interim points. However assume for discussion that both the GVAX Vital 1 and Provenge 9902b have a p value of 0.02 at the interim and less than 0.01 at their final opening. The company that allocated a p value greater than 0.02 at the interim would have a significant lead in receiving earlier FDA approval as compared to a competitor taking a much lower conservative allocation. It seems to me that this situation, especially wrt two survival trials, does not put the interests of terminal AIPC patients first. Possible mitigation of this situation could occur if the independent Data Safety Monitoring Boards in each trial were to end the trial beyond the interim but earlier than the projected final if maturing patient data made achieving the remaining alpha a virtual certainty. All JMHO.
This was posted on a CEGE MB in response to some comments there, but is of obvious relevance to DNDN as well.JMHO
A new report on Taxotere use as a frontline therapy in breast cancer after surgery in combination with cyclophosamide was presented today.
http://biz.yahoo.com/prnews/071213/nyth038.html?.v=101
Two things stand out in the report IMO: cyclophosamide is used by the NCI to deplete Tregs before the infusion of their adoptive T cell therapy in melanoma. The combination with Taxotere, that activates macrophages as well depleting Tregs according to Dr. Petrylak, a Taxotere expert, raises the possibility that cancer cell specific reduction of Tregs known to protect tumors and their microenvironment may be enough of a push for some immune systems to overcome tolerance. The other observation is that the follow-up period in this study was seven years. This is an excellent indication that substantial advances are being made against breast cancer, but also a cautionary note for prospective trials of Neuvenge or GVAX in breast cancer that pivotal trials for regulatory approval are likely to be increasingly long and expensive. JMHO.
While both DNDN and CEGE have used the terms "allocated alpha" or alpha spend" both the CEGE CEO and DNDN's Schiffman seem to concentrate on the importance of the Hazard Ratio at the interim rather than the p value. In looking at Slides 9 through 12, there seems to be a similar preference for Hazard Ratios. Slide 9 states that statiscians like Hazard Ratios because all data is used and there is smoothing. With a given number of events at the interim and an allocated p value, is the Hazard Ratio determined automatically or does the shape of the curve or some other factor(s) make it a variable independent of events and p value? Previously, I believe that our resident stat experts indicated a relationship between power, projected treatment effect and Hazard Ratio. TIA for any enlighenment.
Although this is a DNDN MB, there are so may aspects of DNDN's Provenge and CEGE's GVAX that relate to dealing with similar issues (and the CEGE MBs are relatively inactive) that I have posted a summary of relevant clinical activity of CEGE for anyone wanting to keep track of both at:
http://www1.investorvillage.com/smbd.asp?mb=247&mn=227&pt=msg&mid=3649880
Times change. The days of drug chemistry are ending at Pfizer and the days of biologicals are dawning. The Chief Chemist who helped develop Lipitor with an estimated $13 billion in sales this year is being laid off by a company headed by an attorney who just joined Pfizer a few years ago. Life isn't necessarily fair.
http://online.wsj.com/article/SB119733600536720234.html?mod=hps_us_pageone
1. An unfortunate outcome that is perhaps instructive in other ways. OvaRex apparently used a non humanized, murine monoclonal antibody which incorporates a CA125 antigen common in ovarian cancers to elicit a human anti-murine antibody (HAMA) against it. The idea is that the reaction against the mouse CA125 would cause the in vivo generation of B-cell related antibodies against CA125 antigen expressing ovarian cancer cells.http://www.mctrc.org/en/rp/studies/altare.htm
There are potentially several problems with this approach, a major one being that T cell tolerance against CA125 antigens may already be established by the tumors, meaning that a likely attenuated macrophage only response against OvaRex marked cancer cells might ensue.
2. There is a fascinating if complex report on two studies and an editorial in the current Journal of Immunology titled "Pillars of Immunology" that states, in part: “These B cells exposed to a TNP-conjugated carrier, presented the carrier-derived epitopes to carrier specific class II MHC restricted T cells 1000-fold more efficiently than did TNP-specific B cells exposed to an unmodified carrier” Bridging B cell and T cell Recognition of Antigen, PILLARS OF IMMUNOLOGY, J Immunol 2007 179: 7191-7192 http://www.jimmunol.org/current.shtml
3. One possible reading of this material is that an immune attack that combines targeting of cancer cells with B cell antibodies, a th2 humoral immune attack, as well as with a T cell, th1 cellular immune attack, might be far superior to either one alone or to a straight math sum of each response taken alone.
4. There may be some foundation for this in Dr. Small’s Ph2 report on Provenge at: http://jco.ascopubs.org/cgi/content/full/18/23/3894 In it, he reported: “No patient had pre-existing T-cell responses to PAP isolated from human seminal fluid; whereas after treatment with Provenge, 10 (38%) of 26 patients developed a T-cell response to PAP” and “None of the patients had pre-existing antibodies to PAP (isolated from human seminal fluid); whereas after treatment, 16 (52%) of 31 patients had antibodies” This would also be consistent with Neuvenge increasing efficacy against HER2/neu breast cancer after failure of Herceptin, a hmab targeting the same antigen.
5. Small’s study also noted interesting aspects relating to the use of GM-CSF and the importance of whole protein as opposed to peptides for cellular immunotherapies. “The GM-CSF element in our prostate antigen is essential to in vitro antigen processing, but there are several reasons why we believe that GM-CSF does not otherwise contribute to Provenge’s in vivo effects. First, the cells are washed extensively before infusion, and the quantity of residual GM-CSF is negligible. Secondly, most investigators use dendritic cells prepared in the presence of GM-CSF, and there is, to our knowledge, no evidence that the in vivo activity of those dendritic cells is caused by an adjuvant effect of GM-CSF. Thirdly, our preclinical studies compared infusions of dendritic cells pulsed with the fusion protein with injections of the fusion protein itself. Unlike the antigen-pulsed dendritic cells, the PAP-GM-CSF fusion protein did not elicit T-cell responses to PAP. Finally, we have performed a clinical trial that involved subcutaneous injections of the fusion protein and observed that the injections did not stimulate T-cell or antibody responses”
“Protein-pulsed dendritic cells may be more effective than single peptide-pulsed dendritic cells for stimulating immunity because of the larger repertoire of antigens present in the protein and the resulting ability to elicit both CD4+ helper cells and CD8+ effector cells.”
6. All of this is also consistent with increasing efficacy with subsequent docetaxel since it is reported to activate macrophages, thereby improving the antibody effected killing of cancer cells by phagocytosis, as well as depleting rapidly proliferating Tregs, increasing the efficacy of a T cell attack. Other cellular based immunotherapies that also have an antibody arm, such as GVAX, may have similar attributes. JMHO.
The current issue of the Journal of Immunology gives great importance to new insights on how T cells and B cells work together in two studies and editorial comments in its Pillars of Immunology section..
“These B cells exposed to a TNP-conjugated carrier, presented the carrier-derived epitopes to carrier specific class II MHC restricted T cells 1000-fold more efficiently than did TNP-specific B cells exposed to an unmodified carrier” Bridging B cell and T cell Recognition of Antigen, PILLARS OF IMMUNOLOGY, J Immunol 2007 179: 7191-7192 http://www.jimmunol.org/current.shtml
Question for any immunologist / scientist: The two studies seem to suggest that a combined antibody reaction and T cell reaction in cancer immunotherapy is substantially more effective than either alone (eg, a hmab and primed T cells against the same antigen may be far superior to either alone or a straight sum of their individual effects). Knowledgeable comments appreciated.
An interesting diagnostic in AIPC: http://biz.yahoo.com/bw/071203/20071203005357.html?.v=1
iSBTc 22nd Annual Meeting Presentations are available at:
http://www.isbtc.org/meetings/am07/complete_schedule.php
Several make for interesting reading. Cancer immunotherapy is obviously a very active and very complex field.
Thank you for an interesting refrerence. Appendix 1 as well as Question 17 is a worthwhile read.The whole approach to stopping rules used by DSMB's can be quite complex and are all based on that grey area when alpha is missed but statistical significance at the end of the trial is assured. If you eliminate the futility stopping rules since all Provenge and GVAX patients will have completed primary treatment before the interim look in each (and the CEGE CEO specifically stated that Vital 1 would have no futility analysis) that suggests that DSMB stopping rules (other than for safety problems) would only apply to efficacy stopiing. Perhaps this is why Gold has given mixed signals (eg, no p value given at interim) while appearing optimistic that final results will be known well before 2010. I would assume that a contributing factor will be that (1) it is a non subjective survival trial, (2) in a terminal (and painful disease) and (3)experienced investigators (including Drs. Small, Higano and Petrylak) are involved in large, multi institutional trials.
Any Bayesian analysis might use the Taxotere TAX 327 as a reference dataset wrt treatment effect, required events to stop the trial(both absolute and %), hazard ratio and p value at any potential stopping point. IAW, given the likely subsequent use of Taxotere after both Provenge and GVAX, if the prospective stopping point would not be likely to result in clearly superior results, let the trial continue. A summary of that data from NEJM is as follows:
"From March 2000 through June 2002, 1006 men with metastatic hormone-refractory prostate cancer received 5 mg of prednisone twice daily and were randomly assigned to receive 12 mg of mitoxantrone per square meter of body-surface area every three weeks, 75 mg of docetaxel per square meter every three weeks, or 30 mg of docetaxel per square meter weekly for five of every six weeks." "There were three comparisons of interest between the docetaxel and mitoxantrone groups: docetaxel given every three weeks was compared with mitoxantrone, weekly docetaxel was compared with mitoxantrone, and the combined docetaxel groups were compared with mitoxantrone. The study was designed to detect with 90 percent power a hazard ratio of 0.75 for death in the docetaxel groups as compared with the mitoxantrone group, with a two-sided type I error of 0.05 and with the data analyzed according to the intention to treat. The sample size was established as 1002 patients, and analysis was planned after 535 deaths had occurred. To allow for multiple comparisons, a P value of 0.04 was considered to indicate statistical significance for the comparison of the combined docetaxel groups with the mitoxantrone group, and a P value of 0.0175 was considered to indicate statistical significance for the comparison of each docetaxel group with the mitoxantrone group (all P values were two-sided), thus ensuring an overall significance level of 0.05." "One planned interim analysis of safety was conducted after the recruitment of 120 patients. No interim analysis for efficacy was performed." There were 672 men in the FDA approved three weekly docetaxel dosing and control arms in TAX 327. There were 166 deaths in the d3w arm and 201 in the mitantrone + prednisone (M_P) control arm (total: 367) (55% of the enrollees in the two arms had died.) The hazard ratio three weekly docetaxel was 0.78 and the Kaplan Meier stratified log rank p value for survival was 0.009, Confidence Interval 0.62, 0.94). The reported treatment effect was 2.4 months. http://content.nejm.org/cgi/content/full/351/15/1502
JMHO.
From an ethical point of view, at what point (if at all) would a statistician advising a DSMB in 9902b and Vital-1 decide that the trial should be unblinded and reported to the sponsor since it would be a virtual certainty that the end trial alpha adjusted p value would b bettered? Is there a precedent for this?
Two from clarksterh plus a question on the IV MB worth reading:
http://www1.investorvillage.com/smbd.asp?mb=971&mn=165509&pt=msg&mid=3514858
and
http://www1.investorvillage.com/smbd.asp?mb=971&mn=165546&pt=msg&mid=3516030
and
http://www1.investorvillage.com/smbd.asp?mb=971&mn=165549&pt=msg&mid=3516133
Thank you for your last response. More questions if you have the time:
1. My question was confusing since it ultimately asked about statistical significance, and meant to ask concerning the chances that at the interim, Vital 1 would be below a p value of 0.01.What would be the difference in the two (p= 001, p=0.05) at the Interim? Chance of statistical significance of 0.04 at the final? From your answer, I am assuming that depending on curve shapes, etc, that percent power represents the chances or probability of both the treatment effect happening and being detected. Is that accurate? (It appears that Dr. Small was involved in both actual vs, the Halabi projected median survivals in both of CEGE's two GVAX Ph2 trials as well as the Provenge 9901 trial)
2. DNDN has reported that the diagnostic factors present at randomization in the recently enrolled 500 patient 9902b trial when used with the Halabi nomogram yield a projected median survival of 21.4 months compared to 20.4 months for 9901 trial. Dr. Small reported that the actual survival in 9901 was 5.8 months longer than the predicted survival. The HR and p value (Kaplan Meier)for the integrated 9901 and 9902a clinical trials, which had a total of 164 deaths were respectively 1.5 and 0.011. Assuming the treatment effect for 9902b is 5.8 months (using Dr, Small's Halabi numbers) and 180 events needed for the interim and 360 events needed for the final, what are the chances of Provenge bettering a assumed alpha of 0.01 at the interim? Statistical significance of 0.05 at the interim? Statistical significance of 0.04 at the final look?
TIA for your assistance and comments.
If you were a C. Elegans, wouldn't you need an antidepressant.
Sorry, I couldn't resist. Have a great Thanksgiving.
1. Taxotere (docetaxel) has been the standard of care and the only therapy to have demonstrated increased median survival (2.4 months in its TAX327 pivotal trial) in AIPC/HRPC since the FDA approved its use in May 2004.http://content.nejm.org/cgi/content/full/351/15/1502
2, The Provenge 9901 and 9902a trials commenced enrollment in 2000. The crossover protocol allowing control patients to take the lower dose of Provenge processed from frozen and thawed immune cells upon progressionwas before FDA approval of docetaxel but after Ph2 testing showing that Provenge was safe and well tolerated and increased Time to Progression. Crossover protocols were also allowed in the Tax327 trial and in the 160 patient Ph3 pivotal trial that lead to FDA approval of mitoxantrone and prednisone (the control arm in Tax327)for palliation of symptoms in 1996. Docetaxel use after GVAX, of course, proved beneficial in the GVAX Ph2 trials, which took place long after the Provenge Ph2 trials.
3. As a general rule in all cause survival studies, patients cannot be censored once randomized. There is also a significant question as to whether it is ethical to withold standard of care tretment once an experimental treatment protocol had been completed. Provenge's 9901, 9902a and 9902b trials as well as the GVAX Vital-1 trial aim for approvals in asymptomatic AIPC/HRPC. Since docetaxel is the standard of care in the later symptomatic stage, there should be no problem with earlier Provenge or GVAX (both have protocol limitations on prior use of chemos). Also, while Drs. Small and Petrylak noted the use of docetaxel after Provenge, no records were required of the cycles/dosing used. Finally, there would be little reason to rule out either immunotherapy as succesful "pre-adjuvants" (prequel/sequel?)to the docetaxel standard of care.
4. As for 9901 and 9902a and CD54 ranges, you should review the slides and transcripts of DNDN's Dr, Provost's 2/06 presentation to the CTGT AC at: http://www.fda.gov/ohrms/dockets/ac/06/transcripts/2006-4205T1.pdf
and
http://www.fda.gov/ohrms/dockets/ac/06/slides/2006-4205s1.htm
Hope this is helpful.
BSR_David:
>>For active immunos like Provenge that provide a lasting immune response, chemo after may also be effective not because of effects on the T-cell system but because they might pop open cells that release the target antigen and spur a "revitalization" of the immune system response. <<
I recently happened to view the following videa webcast: Modulating Autoimmunity and Tumor Immunity
Wednesday, June 27, 2007
Pamela Sumiko Ohashi, Ph.D., University of Toronto
at: http://videocast.nih.gov/PastEvents.asp?c=28
The presenter detailed a series of experiments to determine what happens to antigens released by cells that undergo apoptosis.The conclusion was that T cells are tolerized to the antigens rather than activated and thereafter may be rapidly deleted in the lymph system.
I suggest that Mitch does more homework.
Walldiver:
You are right about there being no GVAX randomized trial data yet, pending results from CEGE's Vital 1 and Vital 2 Ph 3 trials. However, their Ph2 dosing studies did compare lower doses vs. high dose GVAX and Dr. Small compared the entire GVAX radiologic group to a Halabi nomogram predicted median survival, much as he did for showing that the actual survival of Provenge 9901 ITT patients exceeded Halabi nomogram predicted median survival by 5.8 months. The median survival of the GVAX high dose followed by chemo (primarily docetaxel)subgroup exceeded 35.2 months as of the last Ph2 study revision in April and reportedly had still not been reached in September. Even given the small subgroup and the Halabi nomogram estimated accuracy of 69%, a suggested benefit in median survival of over 20 months is impressive. IMO, the sometimes expressed theory that only the healthier patients would select docetaxel afer Provenge or GVAX is dubious, especially where Drs. Petrylak and Small both use Halabi as a standard reference. A relevant quote from the GVAX Ph2 study:
>>Survival. In the radiologic group, the overall median survival after initiation of treatment was 26.2 months (95% CI, 17,36), including 24.0 months in the low dose (95%CI, 11, 35) and 34.9 months in the high dose (95% 8, 57). Based on a pretreatment nomogram established by Halabi et al (20), an expected median survival time of 19.5 months was estimated for the 34 patients in the radiologic group. At the end of the study 13 of 34 patients in the radiologic group received subsequent chemotherapy (taxane in 9/13); their median survival was more than 35.2 months (95%CI, 29, 44). The median survival of the non-chemotherapy treated patients was 17.2 months (95% CI, 9, 32).<<
Granulocyte Macrophage Colony-Stimulating Factor�Secreting Allogeneic Cellular Immunotherapy for Hormone-Refractory Prostate Cancer
Eric J. Small 1, Natalie Sacks2, John Nemunaitis3, Walter J. Urba4, Eugene Dula5, Arthur S. Centeno6, William G. Nelson7, Dale Ando2, Catherine Howard2, Flavia Borellini2, Minh Nguyen2, Kristen Hege2 and Jonathan W. Simons Clinical Cancer Research 13, 3883-3891, July 1, 2007. doi: 10.1158/1078-0432.CCR-06-2937 http://clincancerres.aacrjournals.org/cgi/content/abstract/13/13/3883
Wall & Doc:
1. Dr. Petrylak used data from both 9901 and 9902a. In 9902a 56.1% of ITT patients received a subsequent taxane (38.6% docetaxel) vs. 40.5% subsequent taxane (34.4% docetaxel) of crossover patients. http://www.fda.gov/ohrms/dockets/ac/07/briefing/2007-4291B1_03a.htm
2. The GVAX Ph2 clinical trial in HRPC clearly demonstrated the importance of a higher cell dosing for improved efficacy. Table 7 Analysis and Cell Dose of the Provenge FDA Statistical Briefing Materials for the AC meeting shows that while the Total Nucleated Cell Count (TNC) of all the processed immune cells in Provenge was statistically significant for increased survival (p=0.018), it was not statistically significant for increased survival for either CD54 upregulation (post/preprocessing) (p=0.395) or CD54 cell count (p=0.098). CD54 was the chosen as the marker for the approximate 20% of a patient’s cells that are dendritic antigen presenting cells matured as a result of processing. The TNC data indicates both that other immune cells, including, for example, B cells related to antibodies,may play an important role in the efficacy of Provenge, and that the total number of all nucleated immune cells, are important for increased survival.
3. The control arms in both the 9901 and 9902a Provenge trials were given the opportunity to crossover to 8015F upon progression; approximately 70% did. One third of a control patient’s immune cells supplied as a leukapherisis product were returned for infusion without processing to maintain blinding. The other two thirds were frozen and then thawed for processing the three Provenge 8015F doses for control patients receiving crossover treatment. Thus, the crossover patients would have received one third fewer total nucleated cells even in the somewhat unlikely event that the processing of frozen and thawed immune cells was as effective as processing fresh cells.
4. Thus, the benefit of docetaxel after lower dose Provenge given to crossover patients as compared to the higher dosing of its ITT patients is strikingly similar to the comparative effects of docetaxel after low dose and high dose GVAX. Clinical data for both Provenge and GVAX strongly support the conclusion, however, that the synergistic efficacy of each immunotherapy and docetaxel is substantially better that that of docetaxel alone, and docetaxel is the present standard of care in both asymptomatic and asymptomatic AIPC/HRPC.
Dr. Petrylak’s 11/06 presentation to the Chemotherapy Foundation on the use of Taxotere (docetaxel) after Provenge is at: http://chemotherapyfoundation.org/professional_education/meetingarchives_tcf2006_main.html
If you do the math with Dr. Small's Halabi data, the increased survival for the roughly 1/3 (51 of 147) patients in integrated 9901 and 9902a ITT database who received the combination Provenge + Taxotere therapy represent about 80% of the increased median survival of the combined P and P+T ITT patients and the Provenge alone patients represent < 2 months of increased survival. It implicitly raises a question whether the treatment effect of Provenge (or any immunotherapy in AIPC) could achieve statistical significance without the assist of docetaxel. The Ph2 GVAX data also supports the importance of docetaxel after GVAX therapy for increased median survival. As Sgt Friday used to say: Just the facts.