Jerry L,
I will try answer your question.
Dendreon completed enrollment of 176 men in the early stage pre-CRPC study P-11( PROTECT) for Provenge; randomized 2 Provenge to 1 placebo in June 2005. End points were PSA measurement and time to distant metastasis.
The primary objectives are to compare the time to biochemical failure (BF, PSA greater than or equal to 3 ng/mL) between sipuleucel-T (treatment group) and placebo (control group), and to study the safety of sipuleucel-T. The secondary objectives are to compare time to distant failure (DF, distant metastatic disease), PSA doubling time (PSADT), and survival between the 2 treatment groups.
Preliminary Study Results (from 2006 press release):
• Biochemical Endpoints: As specified in the protocol, an analysis of PSADT calculated from 90 days following randomization until biochemical progression or the initiation of systemic therapy demonstrated that patients randomized to receive PROVENGE had a 35 percent increase in their PSADT compared to patients randomized to receive placebo (p-value = 0.046). To adjust for potential variations in the rate of testosterone recovery following hormonal therapy, the PSADT was also calculated after a patient's testosterone returned to baseline levels. This analysis demonstrated that patients randomized to receive PROVENGE had a 49 percent increase in
their PSADT compared to patients randomized to receive placebo (p-value = 0.038). In addition, although not statistically significant, there was a positive trend in the overall delay in the time to reach a PSA level of 3.0 ng/ml for patients in the PROVENGE arm compared to patients in the placebo arm.
• Clinical Endpoints: There was a delay of approximately 27 percent (HR = 0.73) in the time to distant metastasis for patients randomized to receive PROVENGE compared to patients randomized to receive placebo. Because only 16 percent of patients in the study had a distant failure event at the time of this analysis, it is
not yet powered to evaluate statistical significance. Per protocol, patients will continue to be followed for the clinical endpoints of distant failure and overall survival.
• Overall Survival : no known
My conclusion:
Primary endpoint: time to BF is not statistically significant, but positive.
Secondary endpoints:
PSADT is statistically significant (SS), becouse a stat-sig lenthening of PSADT of 49%.
Time to Distant metastasis (TTDM) with hazard ratio of .73 is probably SS, but only 16% had reached that endpoint in 2006; too few participants with mets.
investor.dendreon.com/releasedetail.cfm?Releaseid=217760P-11 wasn't intended to be a registration quality trial. And since the time the trial was conducted alot has been learned such that the primary endpoint of time to biochemical failure (PSA>3ng/ml) has little correlation to a clinically relevant endpoint like OS or even time to distant mets (which itself isn't fully accepted as a surrogate). Further P-11 was not sufficiently powered to detect either of those endpoints. Don't forget it is started on September 2001 when nobody even knew if this treatment will work .
Now Dendrion started new trial Sipuleucel-T in Metastatic Castrate Resistant Prostate Cancer (CRPC) Patients Previously Treated on Dendreon Study P-11.
Anticipated duration of the study is approximately 6 years. Study Start Date-November 2011. Estimated Primary Completion Date-March 2017 (Final data collection date for primary outcome measure).
open-Label Multicenter Study. Estimated Enrollment - 90.
Tomasz M. Beer, MD, professor of medicine, hematology & medical oncology and Director of the Prostate Cancer Research Program, Oregon Health & Science University presented
open-label, multicenter study of sipuleucel-T in men with metastatic castrate resistant prostate cancer (mCRPC) previously treated with sipuleucel-T:
Evaluation of antigen presenting cell (APC) activation and ELISPOT data at the ASCO 2013 .
They evaluated antigen-presenting cell (APC) activation, a measure of product potency. The study included men who received one or more infusions of Provenge in PROTECT and progressed to mCRPC. In the current study, all men were retreated with three infusions of sipuleucel-T.
He told that it is very interesting study and relatively unique. Patients (7 of them) received Provenge ( full curse) after previous curse of treatment that carried
more then 10 years ago. It was retreatment protocol. To be eligible for this study patients should progressed to metastases, no placebo arm in Protect study, they should have CRPC.
What they've seen - some degree immune memory 5-10 years later.
Dr. Beer concluded that these data indicate the presence of existing immunological memory to the immunizing antigen several years after initial treatment. In addition, retreatment with Provenge appeared to boost product potency compared with prior treatment.
This is the first trial to demonstrate the feasibility of Provenge retreatment following treatment for an earlier stage of PCa.
He hope to have more interesting data from this study in future meetings.
Data from the PROTECT study suggest THE PRESENCE OF EXISTING IMMUNOLOGICAL MEMORY TO PROVENGE YEARS FOLLOWING INITIAL TREATMENT and after patients progressed to mCRPC, and retreatment produced a boost in product potency compared with prior treatment," said Tomasz M. Beer, M.D., Grover C. Bagby Endowed Chair for Prostate Cancer Research, professor of medicine, hematology & medical oncology and Director of the Prostate Cancer Research Program, Oregon Health & Science University.
"These data suggest that THE IMMUNE RESPONSE FROM PROVENGE CONTINUES WELL BEYOND THE DATE OF INFUSION and supports our understanding of how PROVENGE works over time."The data on CD54 upreg for patients in PROTECT (P-11) retreated is remarkable. The immune system memory lasts for many years and reacts strongly on booster shot. Since the second and third infusions did not increase the upreg rate like booster shot. So it could point to using single-infusion Provenge as a maintenance regime every few years.
You can also watch video from PatientPower: "Unlocking Immune Memory in Advanced Prostate Cancer Treatment"
Dr. T. Beer lead investigator for the PROTECT study, shares important research that shows immune memory response in advanced prostate cancer treatment. It has potential induce long term responce and making body of patient less welcoming a cancer. This different from the chemotherapy that kills contact with your system,
but when it is out of your system , it is gone. It is first pieces of evidence in human been that show immunologic manipulation like Provenge does in fact has potential to have long term effect on immune system. Booster shot can enhance this effect. No this kind result we can see with other drugs.www.patientpower.info/video/unlocking-immune-memory-in-advanced-prostate-cancer-treatment?autoplay=1Provenge could eventually be seen as the foundational therapy to be used in earlier stages of the disease. The cd54 data from patients in P-11 retreated with Provenge were a very important indicator of how Provenge could protect patients long term with once every few years reboot if they were treated early.
Your questing how long we need to wait? For Protect - this trial is finished and now started new trial with patients from Protect trial :
www.clinicaltrials.gov/ct2/show/NCT01338012?term=Provenge&rank=1If your question about
when will be offering to patient in early setting before MCRPC- Maybe never. Why?
Because this whole saga of Provenge is such a tragedy.
In late March 2007, the FDA's own hand-picked Advisory Council (replete with a few Dr. Pazdur loyalists like Dr. H. Scher., Dr. M. Hussein) had voted 17-0 that Provenge was safe (an unheard of vote for a cancer treatment), and voted 13-4 that it was efficacious. Dr. Scher had made a weak and asinine argument from the floor that Provenge approval would screw up the R&D efforts then under way in many companies—since Approval would negate their Trials and new ones would have to be initiated testing against Provenge instead of a pure placebo (as they then already were doing). The sick and dying sickened and died unnecessarily. 90,000 of them died at a time when they had no viable option. Dr.R. Pazdur, Dr. A. Eschenbach was helping his friends ( Milken and his cronies stave off competition and thus to continue coining money of the realm. Dendreon was a small company that did not understand how “the game” worked.
In this time Big Money continue sabotage this drug and thousands of patients still continue to die without trying Provenge. Look at UM ( Dr. M Hussain), Memorial Sloan-Kettering Cancer Center( Dr. H. Scher): they even don't offer Provenge to PC patients. It is why I believe FDA maybe will never approve Provenge in early setting ( with power and influence of big money of PCF they could do it ). Ka-ching!
Vendetta is continue, so tragedy is continue too.