DR. SIMON; I would say we are not on target, and the main reason we are not on target is because we have insufficiently stringent standards for molecular targets.

I would say it is not enough to just find that some gene is either silenced or over-expressed in some very advanced tumor, that there are at least hundreds of such genes in a genomically unstable, proliferating cell population, most of which are not the key, don't represent the key, events that cause the oncogenesis.

That is really the rate-limiting step. I think we need much more stringent standards for what we go about developing.

I think, if you have the right target, and you have a whole pharmaceutical industry that is very good at developing a drug that will inhibit that target, and we have a whole machinery that can do phase II and phase II trials for evaluating a drug, but the reason we have very limited progress is that the targets may not be the right targets.

I think, by having drugs that inhibit multiple lousy targets, you don't turn that into one really key target.

DR. SCHILDER: Do you have any suggestions on how we better figure out what the driver of the tumor is, because it may not be the same driver for everybody's ovarian cancer.

DR. SIMON: I saw one slide, I think it was at the AACR last year, that said, “It's the mutations, stupid.” So, I think that should really be part of our criteria for what makes for a good target, and we should really look for the genes that are mutated at a high percentage, or the pathways that have mutated a high percentage and very early tumors of that type.

DR. BROWN: One of the rate-limiting steps, it seems to me also, with the biologic and targeted therapies, is the preclinical model.

I wanted to ask the question, what is the best preclinical model? Is it ovarian cancer cell lines, is it a particular ovarian cancer mouse model, where you can test the effects of these target therapies also in combination with chemotherapy?

Also, is there any work being done on virtual modeling, such as mathematical models or computer generated models, where you could test some of these target therapies and their potential interactions with cytotoxic chemotherapy, that could sort of speed up the process of seeing if something could be taken to the patient?

DR. SOOD: I guess just a couple of comments I would make related to that would be, you know, one is that two-dimensional or in vitro assays for a lot of the biologicals are really a very, very small component, and they really are not always reflective of what is going to happen at an in vivo level, primarily because you have to take into account the micro environment.

Frequently, the target will be the host, not only the tumor cell in itself. So, my view with that regard would be, at a minimum, really, if one is going to study preclinically, that it has to be done in an orthotopic animal model type of setting.

Clearly, there are arguments about what are relevant animal models and so on, but with multiple molecules now it is clear that subcutaneously grown tumors do not behave the same way as compared to orthotopic settings.

A classic example would be the angiostatin/endostatin story. Another example would be IL8. If you inhibit IL8, you will get the exact opposite results, whether the tumor is growing subcu or in a more ectopic type of a setting.

Again, I think the tumor micro-environment, as well as an orthotopic type of a setting certainly has to be taken into account in order to screen these things.

Now, with regard to using different cell lines, the way I view it, each cell line basically represents a patient, in essence. So, you really have to test a variety of things.

Second is, I think, to also consider, most people do growth inhibition studies in an animal setting, and then they will take that to a 10-centimeter tumor in a human patient and expect that to regress. Why would you? That is unrealistic.

So, I think, in order to really screen things carefully, you have to escalate the number of hurdles that a drug has to pass at preclinical levels.

Some examples of doing that would be to use not only drug-sensitive cell lines, but use drug-resistant cell lines.

Then a third approach would be not only to do growth inhibition studies, but form bulky tumors and see if there is regression.

I think if you go through that type of rigor with regard to screening things, perhaps they would be a little more predictive.

There was a paper that reviewed how predictive preclinical models are of success in the clinic, and ovary was one of the models that, if studied in an orthotopic setting, it is predictive, in a free setting, of responses.

DR. KOHN: I would like to come back to Dr. Simon's comment. I think it would be great if we had an addiction site and a primary mutation for every cancer.

I don't know that that is going to be the case. My bias is that probably it is a polygenic process, but it is going to take us a while to get to that answer.

In the meantime, I think we have to look at how to make progress without a driving mutation, and one way to look at that I think Godwin alluded to nicely, is that we have to look at the different pathways, but I think we have to look at how we might inhibit pathways at multiple sites.

In response to Dr. Brown, there are some mathematical models for mixing drugs that have biochemical targets at different places, suggesting that you might be able to use less of each and get an equivalent biological endpoint. That is certainly a testable hypothesis.

As preliminary data from our combination of sorafenib, the Bayer compound, and bevacizumab, we are actually seeing that.

We are using low doses of both and we are having very striking effects in ovary, not the expected targets of melanoma or kidney, where they may need to have full dose.

So, I think we need to have several different approaches that we move forward. Otherwise we are going to be sitting quietly until we identify what those addiction events are.

DR. BIRRER: At the risk of being somewhat controversial, I wonder whether, as we evolve toward more and more small molecule inhibitors and what I would all quasi-targeted therapies, that we ought to revisit the concept that most of our early trials -- phase I, phase II trials -- are being done without the necessary biopsies to interpret the efficacy of that therapy.

Rather than -- of course, there are real reasons we do that. One is cost. One is the issue of invasive procedures solely for research.

We may be getting to the point where we need to rethink that, and look at phase I, phase II trials without the appropriate biopsies as being, at a minimum, bad science and, at a maximum, unethical.

DR. BURGER: You know, it is funny, because we started that way and it is currently a movement within the GOG -- in fact, 229D was just amended to get rid of the biopsies so the studies can get done.

We are now in danger of having these studies close due to lack of accrual. So, we find that proverbial rock and a hard place of, we all know that it should be done, but yet we are having IRBs at key institutions or other external factors funding that are going contrary just to that point.

DR. OZOLS: I think we need to have a paradigm shift, too, about we never put together agents that individually weren't active.

What is going to drive us to help us select which agents should we use when individually they may not be active. The permutations are going to be incredible.

Second of all, with chemotherapy, as Andy pointed out, there are all these agents that have very low response rates.

We know from some of the biological agents, like Avastin, like Rituxan, with chemotherapy they do better. So, are we going to make that leap of faith that, even if the agent isn't very active, biological agent, that we are going to try it with chemotherapy?

I agree with Dr. Simon in one sense, and I also agree with Elise, that we obviously want that killer mutation, that one that is really there, but I agree that we are not going to find it immediately. So, we are not going to stand still.

We need, I think, some type of a rational approach to how we combine these multiple biological agents which are coming and, if an individual phase I trial or phase II trial is negative, do we just say, okay, the next study is to combine it with chemotherapy and sometimes we are going to do that and sometimes we are not?

We need, I think, a very quick process to try to figure out how to go through this multitude of agents that are being developed.

DR. SEIDEN: I think, getting back to Michael Birrer's controversial comment, I think one of the things the academic community has trouble grasping and dealing with is, while from a scientific point of view, incorporating molecule imaging, generating standard operating procedures, validating markers is extraordinarily important to making your clinical trials good and potentially ethical; on the other side, there is a tremendous push to make trials available to patients across the country at giant centers, at little centers.

There is no money to validate surrogate markers. There is precious little money to incorporate molecular imaging into clinical trials.

IRBs are becoming ferocious about not forcing patients to sign up for serial biopsies on clinical trials. In fact, our institution is now potentially facing a lawsuit over a patient who wasn't allowed on a trial because he didn't want the biopsy and the trial was written that they had to have the biopsy to get on the trial.

I think there is pure science, which makes sense, but we cannot deny the fact that there is no money to make these trials scientifically robust.

There is very little money to validate these techniques as being biologically meaningful, and there is a huge push from the advocacy world to have access to these agents fast, and not to wait for all of these trials to have beautiful surrogate markers and molecular imaging and molecular path. I am not suggesting I have an answer to this, but this is the universe we live in.

DR. BAST: I would wonder if the advocates who are here could really speak to this issue. We had a very interesting experience at Anderson because we face this same issue.

With our IRB, if you make the surrogate endpoints the endpoint of the trial, rather than simply response or no response, you can, in fact, have the biopsies and serum tests as an integral part of the trial.

We had raised this with our own advocacy advisory group, which is an integral part of our SPORE. Really, to our surprise, they were very supportive of these, because they wanted to get at the therapies that really worked. I wonder, we have got several advocates here, if they would want to speak to either side of that issue.

DR. SWANSON: As I stated before, I think that the issue of biomarkers is really essential in terms of speeding up approval of drugs.

Then I was thinking about the tissue typing and the tissue cultures, and I wonder if one way to address that problem would be to encourage doctors in the community to send their tissues to a central bank, or have a national bank of ovarian cancer.

There are so many doctors in the community who are gynecologists that really care about their patients, that if they knew that that would be something that would be helpful, I think they would do it, if it was something that could be done. I don't really know.

DR. SCHILDER: One thing I hope we address at this conference at some point is looking at under-representation of the women with ovarian cancer enrolling on these trials as one of the significant barriers to progress.

MS. BUTLER: I think, without exception, the key to recruitment is the same as it always has been, and that is a strong need to show efficacy, to show an outcome that is meaningful. I don't mean successful treatment, but a meaningful outcome.

I have observed -- I think others may speak to this -- that the IRB restrictions and language being used in consenting forms has become almost frantic and extremely negative in many trials.

I think this is a significant barrier that does need to be addressed. If women understand that this is important to do, they will come. So, whatever we have to do in that mix to change that, we have to do.

DR. OZA: We recently conducted a study which, in fact, addressed this question, in patients, IRB members, as well as physicians, who took part in clinical trials, phase I and phase II.

One of our fellows did a survey of patients who had participated on clinical trials that had involved sequential biopsies.

They also surveyed patients who had participated in other clinical trials, to gauge whether the biopsies would be a potential deterrent, and the physicians looking after them as well as IRB members.

In fact -- this was presented at ASCO earlier this year -- the findings were that patients, in fact, were quite comfortable in participating in trials which involved sequential biopsies, and were able to assess the risk benefit.

There was more resistance from IRB, and the physicians themselves had some degree of comfort if the risks of biopsies were greater than 10 percent.

If the data is presented properly, then the patients will seem to be fairly willing to participate on these clinical trials, as long as it was explained properly, and that came from both patients who had participated on studies that had involved biopsies, as well as patients who had participated in other studies. That should be coming out in one of the journals fairly soon.

DR. AGHAJANIAN: You know, I think even if the patients are willing to do it, I think the cost becomes an enormous problem.

Russell [Dr. Schilder] noted on GOG trials, these trials don't come with -- I am not criticizing. It is a very expensive process to do serial biopsies on patients, whether that is done in interventional radiology or operatively with a laparoscope. That is an enormous amount of money and the institutions don't have the money to spend on that.

The other problem becomes, regardless of whether we decide that the patients are willing to do it or not, over the last few years, we can look at these trials and the ones that take biopsies take very long to accrue, much longer than trials without biopsies.

If we are going to impede our ability to find effective agents to that degree, it becomes increasingly difficult.

One might take another approach to screen without biopsies, and then to do smaller pilot studies of drugs that look like they might have some activity that include biopsies, so that that might make the IRB more comfortable.

We are trying to move forward on a drug showing promise already, and how we might combine it with another drug or with chemotherapy by using the results of those biopsies to guide us in the next step, when we have already seen that it might be helpful.

DR. SCHILDER: Thank you. We have time for one more comment, I am told, and then we can have sidebars afterward.

DR. MARKMAN: I think it is appropriate to also bring up all the problems that have been mentioned as very important and need to be resolved, but there is another very important issue, that this is a very reasonable forum to bring up, because it includes the NCI at their national level, the advocacy community, academic centers, and industry, and that is the incredibly serious problem, and increasingly serious problem of industry's total unwillingness to share, and it is getting worse. It is not getting better.

There is not an industry representative here that is responsible for it, because this is entirely legal, and this is entirely the issue of risk and the concern about risk of funding things.

So, the answers are clearly going to be across trials, looking at multiple samples, looking at multiple targets, across samples and different drugs.

Contracts that are now being negotiated and signed are increasingly restrictive because it is entirely controlled by the legal community and the legal concerns.

The FDA had a meeting about this recently at M.D. Anderson to talk about this, and very prominent industry leaders participated with the FDA, and with the NCI.

At the very high level, everybody agrees that it needs to be resolved. I can tell you, at the level of actually writing and signing the contracts, the information has not gotten through to the lawyers.

So, until this gets resolved -- and the NCI has to play a big part in this -- the advocacy community has to play a part in this and industry itself, we will not be able to share the data that is necessary to come up with these answers.

DR. SCHILDER: Thank you. I would like to thank our speakers for the time they took to prepare and share with us, and their thoughtful comments. Now I would like to introduce Dr. Doris Benbrook from the University of Oklahoma , and Dr. Beth Karlan from Cedars Sinai, president of the SGO.

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