1. At the CEGE CC, their CEO stated that there were no circumstances that the 600 patient Vital-1 trial, which compares GVAX to Taxotere in asymptomatic AIPC and was fully enrolled since July, would be stopped for futility as a result of its interim look. All Vital-1 patients would have been randomized and treated at that point. The Vital-1 final look is estimated to occur in 2009. He also expressed his belief that their 600 patient Vital-2 trial that compares GVAX + Taxotere to Taxotere alone in sicker symptomatic patients will be unblinded about the same time in 2009 due to the shorter life expectancy of those enrollees.CEGE also confirmed that once a patient is randomized to the GVAX ITT group in Vital 1, there is no prohibition against them taking Taxotere after their GVAX therapy, such subsequent therapy would not cause them to be censured from the ITT survival data analysis. If an enrollee were randomized to the ITT group and was hit by a bus before any therapy, he would still be counted as an ITT event.
2. Dr. Small's report on the 34.7/35 month survival of the highest dosed Phase 2 GVAX treated patients also mentioned that some had received Taxotere after GVAX. Dr. Petrylak, who did the analysis and presentation of the 13.6 month increase in median survival of the 51 of 147 9901 and 9902a patients who took Taxotere after Provenge is now also a Phase 3 GVAX clinical investigator, along with Drs. Small and Higano who were lead investigators in the 9901 and 9902a Provenge clinical trials.Given their knowledge of the benefits of combining Taxotere with immunotherapies and the recent AACR article by NCI docs to the same effect, I would imagine that many Vital-1 ITT enrolleees will be strongly encouraged to consider Taxotere after their GVAX therapy. Thus, both the Provenge 9902b and GVAX Vital-1 trials may ultimately revolve around their combinatorial effects with Taxotere.
3. 2008 has the potential for being interesting in that at present both the interim survival looks at the Provenge 9902b trial and the GVAX Vital-1 trial should occur then. Statistical purity requires each company to separately allocate some part of their alpha of 0.05 to the interim look, which raises some interesting possibilities. A p value substantially below the allocated alpha or way above it provides s obvious and straightforward outcome. Consider, however, if the allocated alpha is 0.01 or 0.02 and the actual value is 0.03. If interim median survival were a "surrogate" for ultimate median survival, it would be both statistically significant and "reasonably likely" to predict statistical significance for the ultimate median survival at the end of the trial and the earlier result would have a causal connection to the latter, all the necessary elements of the Prentice criteria for Accelerated Approval. The conditional approval that the AC recommended for Provenge on 3/29 was, of course, quite similar to an Accelerated Approval. In addition, FDA regs allow one well controlled trial in a life threatening disease to be sufficient for Regular Approval, so presumably that could be a potential outcome.If either or both Provenge and GVAX missed their allocated alpha, but each was statistically significant would the FDA hold up any revised or new BLA until final survival results, thus denying dying men their earlier availability? What if both were statistically significant, but their alpha allocations were substantially different, and the therapy that beat its alpha actually had worse results than the one that missed its much lower alpha? If the first therapy approved has a better increase in median survival, Hazard Ratio and p value then the one that follows, does the first therapy raise the approval bar for the second? Common sense should suggest that if either or both Provenge or GVAX achieved statistical significance, regardless of their prespecified alpha allocation, that should allow their approval even if one approach, given its particular group of enrollees and follow-on Taxotere dosing, did somewhat better than the other, but are statistical purity and common sense both important FDA goals?
