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DewDiligence

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Sunday, 11/20/2005 10:43:40 AM

Sunday, November 20, 2005 10:43:40 AM

Post# of 251852
DNDN
Review and commentary of Higano
paper by Dr. Cora Sternberg:

[Dr. Sternberg’s five-minute review and commentary of Dr. Higano’s 9902a paper at ECCO can be found at the same website as Higano’s presentation. Chase the link below and follow these directions:
http://www.sessions2view.com/ecco05c1/index.php
1.Click on acceptance box on bottom of screen.
2.Click on ENTER button at bottom of screen.
3. Click on “Speakers” link at bottom of screen.
4. Click on the letter “S” for Dr. Sternberg.
5. Scan to bottom of page.
6. Click on the icon for the audio presentation.]

Transcript of Dr. Sternberg’s presentation follows:

>>
Cora N Sternberg, Rome, Italy
[Discussant - Higano: Immunotherapy (APC8015) for Androgen Independent Prostate Cancer]

Good afternoon. It's a pleasure to be here today to discuss these two papers. The first study is the immunotherapy abstract presented by Dr. Higano with APC in patients with androgen independent prostate cancer, and this is the first time that this second Phase III trial [9902a]is being presented.

She explained to you quite nicely the reluctance to start chemotherapy in patients with asymptomatic patients, and the fact is that randomized trials have not addressed the optimal timing, duration, or sequencing of the chemotherapy.

Now the APC cells are produced by leukapheresis, which means taking the cells out of the patient's body, by then pulsing them, which is putting them in culture with PAP, GM-CSF protein, and then re-infusing them back into the patient, usually all within 48 hours.

This [referring to slide #5] was the design of Dr. Small's study, which was very similar, actually identical to the study just presented. I'd just like to note that after progression, those patients randomized to placebo were then offered the APC. The endpoints were slightly different in the two trials. Dr. Small did present some data, immunologic data, but not on all of the patients, only on some of the patients.

And what he saw, which was quite remarkable, was a 4.0 months difference in median survival, although this had not been a primary or even a secondary endpoint as planned in that first trial.

Now the second trial is the identical design, but the secondary endpoint was amended to overall survival after having seen the results of the first trial. Both trials were negative as far as intention to treat in their time to progression which had been the primary endpoint.

The Higano trial did not show a difference in survival, but as mentioned, this was stopped early, so perhaps not enough patients were entered. But what we can say that is in the meta-analysis of these two separate trials that were run at a very similar time period, they had an identical inclusion criteria therapy and design. The combined analysis of the two studies shows a significant survival advantage of 4.3 months difference in median survival.

As far as post-progression survival, as I mentioned to you, the patients randomized to placebo at the time of progression were given the APC. Now if APC is not better than placebo in the intention to treat progression-free survival analysis, we don't really know that those patients who went off study after first receiving APC, what happened to them. Perhaps they received more active therapy such as chemotherapy. So this a bit confuses the analysis.

As far as the target for dendritic cells, acid phosphotase is not expressed on all prostate cancer cells. There's a 40 hour pulsing, which apparently in this kind of technique is apparently enough, but it's not so in other types of immunologic vaccine trials. And the fact is that immunologic data are lacking in the majority of patients on both of these trials.

The studies are small and they were really not designed for survival, so what we have here is a huge, huge alpha error.

The combined analysis of the two studies seems to give a significant survival advantage. A retrospective analysis, based on prognostic factors, seems to show an advantage for vaccination, but this is not a scientific answer to a question.

I think that it's well placed for asymptomatic patients, the treatment is not toxic, the treatment is costly in view of the technology used, and it's a promising approach, which, however, cannot yet be recommended.
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