Breakout Group B Summary and Recomendations with Group Discussion: Therapuetic Intervetion/Targeted Therapies for Systemic Disease

SLIDES & TRANSCRIPTS
Tuesday, June 18

Breakout Group B Summary and Recomendations with Group Discussion: Therapuetic Intervetion/Targeted Therapies for Systemic Disease

Jaap Verweij, MD, PhD

Slide 1:

DR. VERWEIJ: Thank you, Larry. First of all, obviously I would like to thank Ernie and Murray and Scott for inviting me as the only European on the panel. I truly felt that was an honor. I was very happy yesterday when Dr. Von Eschenbach expressed the willingness to share information and achievements from the United States with the rest of the world. Obviously, I guess he meant it in a slightly different way, but I would like to echo that statement by expressing the willingness of achievements that we have in Europe and bring them to the United States as well.

We basically have four recommendations. I think one of them, which is the first one, will come up in the next breakout session recommendation as well, and came up before as well -- that if we want to develop targeted treatments, we need to know what we are treating, what the diseases are that we are treating, what the molecular deficiencies and characteristics are. So, one major recommendation is to facilitate the development of what was called an "encyclopedia of soft tissue sarcomas", with access to tissues, samples, to sera, as has just been mentioned, to do proteomics and stuff like that.

Actually, there is already an initiative like this in Europe with tissue banking, and it means that we also have to take into account some difficulties that we might face by exchange of actual tissue samples from one country to the other.
There are some differences in the ethical perception in this, and we need to deal with that.

We can work on existing information by creating an international registry to start with, but we should also create something which is more prospective and collect those tissues in a prospective way, in the optimal way to be able to do whatever we want to do with those tissues in the future.

Obviously, if you have such a system in place, you can screen tissues, sera, whatever you want, against the existing TK libraries that are already there, even for existing drugs that might have effects that we do not yet know. There was also the feeling that we need to develop reference sarcoma cell lines to help us in our efforts to create target drugs.

Slide 2:

The second recommendation is just as important and actually was a unanimous recommendation as well. There was -- certainly among the American colleagues -- the feeling that we really need a clinical consortium to do studies in patients. If we get a new target, we need to be able to study that -- and a consortium that could work according to your Cooperative Group model.

Actually, there is a similar system in place already that is trying to start studies on an international level, which is the Connective Tissue Oncology Society, and it would be worthwhile exploring the possibility using this platform that is already existing to build that into a kind of Cooperative Group model. Obviously, that would help us in facilitating the behavior that George mentioned yesterday of targeted drug development on the one hand, but also, on the other hand, make use of clinical observations that may just be as important to study subsets of patients with specific histotypes of soft tissue sarcomas.

We also realized that, while doing Gleevec studies in GIST, we not only identified a very important drug, we also identified that some of the measurements that we have to assess clinical benefit may not be appropriate for all the agents we are currently developing. We all know about patients that seem to have progressive disease, a slight increase in the size of tumors. The patients feel much better and there is a change in the aspect of the tumor on the MRI or on the CT scan. So, we really need to know how to assess this and we have to redefine maybe first tissue sarcomas, how to assess clinical benefit.

Slide 3:

Jonathan has already alluded to potential targets. We were not able to serve all the issues here, of course, not being pathologists or molecular biologists. We felt that we really need to ensure that assays that we are using are validated, that we all speak the same language, that kit is really kit and that c-kit positive really means c-kit positive.

I well remember all these statements that Chris has made at this meeting, and I think that they are very valuable. We need to make sure that a patient that is c-kit positive is not a patient that is pseudo-c-kit positive by antigen retrieval and things like that.
On the other hand, it was also felt that it should not hold up the development too much. We could consider doing the validation of those diagnostics while running clinical trials. Obviously, with all the achievements with cytostatic agents and targeting different growth factors in the soft tissue sarcomas, we may have to consider using those agents in combination with each other.

So, we have to consider target by target, and then explore the possibility of targeting these targets in a combined way.

Slide 4:

Trying to come up with some very pragmatic and practical recommendations, we felt there were targets out there that are worthwhile exploring already currently, with the available data, that seem to justify performing clinical trials.
I would like to mention -- and Larry has shown you just a couple of minutes ago -- EGFR, where there is evidence of over-expression and excitation in synovial sarcoma. HER2/neu is similar, so you can do studies for HER2/neu or EGFR inhibitors, and actually the EORTC is already starting such a study in synovial sarcoma.

Gleevec and the potential value of PDGF-R or phosphorylated Akt could be mentioned as a possibility for further studies. There is evidence that Gleevec is a substrate for Pgp, and that might be related to resistance to Gleevec in the GIST model that we will undoubtedly be seeing in the current and the near future.

There is a possibility of studying farnesyl transferase inhibitors in PNETs and peripheral nerve tumors. There is a bit of evidence that this may be worthwhile.
I think George has already shown fascinating data on the use of PPAR gamma inhibitor, you might say, and we need new agents there to further explore this track. MAP-kinase was mentioned and there is evidence of bcl anti-sense drugs that could be worthwhile in synovial sarcoma.

These are just a few examples. There may be some more, where we have, at least in our opinion, evidence that we can do a justified clinical trial. What we should not forget for the time being, because this is really looking into the future, is that there is also the possibility to study histological subtypes of soft tissue sarcomas as long as we join forces. I would just like to mention the possibility that Taxol, which is considered by many as an inactive agent in soft tissue sarcomas -- whatever that means -- may be active in a subset of angiosarcomas.

We have an ongoing discussion on gemcitabine, which is negative in one trial, seems to be positive in the other. It may just be a matter of numbers and histological subtypes in the various trials, and there are other drugs like that, that may be worthwhile exploring in specific histological subtypes.

Slide 5:

These are the recommendations that I would like to share with you. I have to say that I think this was a fascinating meeting, even if it is considered not to bring what we had thought it would bring.

I would like to thank you and I am happy to take all questions.