DR. BURGER: We would like to get started on our second session on targeted therapeutics, current status and future directions. This is sort of a re-formation of what is in the agenda.

Dr. Schilder and I would like to thank the committee for allowing us to be involved in this part of the agenda.

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Obviously, everyone understand the challenge in terms of the lethality of the disease, and the effect that cytotoxic therapies traditionally have had limitations, and we are up against those limitations now, in terms of drug resistance mechanisms being the bottleneck.

Generally, these drugs are not specific to mechanisms of disease progress enough to break through that barrier of resistance.

Finally, the impact of toxicity on quality of life is fairly dramatic, especially in patients who are chronic disease patients who have been treated with multiple cytotoxic regimens.

TOP

I think, for the sake of this session, which is only an hour long, we should focus on a few key questions, the first question being what are the relevant targets?

Obviously, we have two excellent speakers this morning who are going to discuss the origin of discovery, if you will, through activated pathway discovery, and also pathway dissociated biomarkers, which have been discussed earlier, and the methods by which these targets are discovered, or should be discovered, in the future.

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The second important question, we felt, was are we on target, for example, in the GOG. Our paradigm has been that, when these targets are identified specifically for epithelial, ovarian, and primary peritoneal cancer, and there is also an agent available for study which targets that pathway, or is specific for that target, where safety and efficacy data have been established in other disease sites with higher incidence and prevalence, because we are a low incidence and prevalence disease, then we can proceed with phase II trial development specific for ovarian cancer.

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There are a number of trials that have been completed or are ongoing in the GOG, involving small molecule, usually tyrosine kinase inhibitors, monoclonal antibodies and immunomodulators with various targets, but mostly relative to growth factor signal transduction pathways, such as EGFR-1, ERB-B2, and some others.

TOP

Then there are a host of trials now, I guess, if you will, in the pipeline under development with similar designs. Usually these are single agent trials with primary disease endpoints of six-month progression-free survival.

A couple of these, down at the bottom of the table, are examples of combination trials

in development, sort of multi-targeting trials.

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The third question I would like people to think about during this discussion is how do we rationally combine agents against multiple targets.

There is the traditional approach of trial and error that seems to be not resource efficient. The second is, what we have borrowed from other disease site experience because we are a low prevalence disease.

I think we should think about more novel ways of gaining knowledge ahead of time with this disease site, with effective preclinical work, both at the level of the GOG and the SPORE programs.

TOP

The final question, which we are not going to answer, but we should think about, we should challenge ourselves, maybe, to develop trials which randomize patients to individualized therapeutics based on bioprofiling information, ahead of time, versus unselected therapy.

With that, Dr. Schilder is going to introduce our speakers, and we will get going.

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