I want to thank you all for coming. We particularly thank those people who stayed until Saturday morning and we appreciate your help and your input.

Our goal is to see if we can wrap this meeting up in about two hours. We want to go over the recommendations that arose from the discussions yesterday.

We would like to see if we can refine these, make sure that we identify what needs to be done, who is going to work on these projects, and see if we can come up with a timeline for how soon we can get thins started.

So, we welcome your input today on how we can actually implement the recommendations, and we also want to know if there was anything else that was mentioned yesterday that did not get captured under this rubric of action items.

This was based on the notes that I and Mike and Jane took, as well as Mason Schoenfeldt from EMMES, but there may have been some things that we missed and, if so, please tell us.

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This is a topic that Pat Goldman from the Ovarian Cancer National Alliance suggested at the end of the meeting, that we convene a working group of advocates, investigators, including those from the GOG, SPOREs, industry and NCI, to see how we can link, create stronger links, between patients and open trials.

We know that, even with our various websites, clinicaltrials.gov and PDQ, it is hard to patients to find trials.

Certainly, as we heard yesterday, it is hard for trials to find patients. So, this was something that was suggested afterwards and I think could be an excellent idea.

I know certainly the Gynecologic Cancer Foundation has wanted to help in publicizing trials as well. Do we have any comments to this additional?

DR. ALVAREZ: I don't know where it stands at the current time. I know that the Lance Armstrong Foundation had put out an RFP for just this issue, and was wanting to support innovative ideas to address this problem. We are talking fairly substantial amounts of money.

It was for clinical trials, not just testicular. It was for any development of public awareness of clinical trials. So, whatever working group has that, I think they should look into that as a potential funding source.

DR. TRIMBLE: I am not sure, I think that deadline may be up for Lance Armstrong.

MS. BLACK: I do think GCF, we were part of the group that is going to be coordinating with GCF on this. So, I think it is going to be a collaborative effort, that they did apply for that grant. It did go in, and I think we are just waiting to hear about the LOI.

DR. TRIMBLE: Even if that grant does not come through, I think we can still work together. Ronnie, isn't the allied support group meeting coming up?

DR. ALVAREZ: I wanted to make a point that the Allied Support Group is working right now with the GOG to develop a website that will list all the GOG trials.

We have had a lot of discussions with the SPOREs, also with the advocates. I think that, while we are not there yet, we are making headway in addressing this issue.

DR. TRIMBLE: Ronnie, could we ask the Allied Support Group and GCF to take the lead on this, do you think?

DR. ALVAREZ: I think that would be the right thing to do.

DR. SWANSON: I was just going to say I looked on the Lance Armstrong website about two days ago, and the research grants were still open, and then they are taking -- for community action programs, they are taking the spring applications. The fall is closed.

DR. TRIMBLE: Okay, Ronnie, we will put GCF and the Allied Support Group to be responsible for this, and I will make sure that our Office of Education and Special Initiatives is clued into the plans for this.

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Next, histology and trial design. We discussed having separate trials for mucinous and clear cell histology.

In terms of phase II trials, we thought that possibly the GOG Rare Tumor Working Group, as well as the Gynecologic Cancer Intergroup, could focus on this.

In phase III trials we would imagine that they would probably need to be done through the Gynecologic Cancer Intergroup, because these patients are relatively rare. Dave Gershenson, does that sound reasonable to you, for your rare tumor working group?

DR. GERSHENSON: Yes, I think at the SPORE meeting in July we heard from a number of the advocates that they were interested in rare tumors.

I had made a set of recommendations to the GOG about what tumors would fit into this construct, and mucinous and clear cell were certainly among about seven or eight different tumor types. So, I think it is right on target.

DR. ABRAMS: This is one area where we have talked, in other tumor types, about using the CTSU. For rare tumors, it would be good to have the trials up on a national menu.

We right now have allowed phase II trials to go up on the CTSU, and several rare tumor types already, especially sarcoma so far.

So, I would just encourage people to think about that mechanism if you are going to be doing some phase II trials in some rare tumor types.

DR. TRIMBLE: That would be terrific, to get these tumors on the CTSU. So, we can pursue this through Dave's committee. Hopefully at the interim meeting as well as the January meeting of GOG, the Gynecologic Cancer Intergroup is meeting in early November. So, we can make sure we confirm those plans with them. Keiichi, haven't you proposed a trial to the Gynecologic Cancer Intergroup?

DR. FUJIWARA: We are finalizing the phase III protocol. I think we can send an advanced copy to the GCIG and GOG, too.

DR. TRIMBLE: Is that for clear cell or for mucinous?

DR. FUJIWARA: Clear cell.

DR. TRIMBLE: One issue that did come up was whether we need to come up with some early confirmation of eligibility.

I am not sure if we have any -- if maybe Mike Cibull or Steve Qualman can comment on this, but I wasn't sure what the confirmation by the GOG pathology committee of the community diagnosis of clear cell or mucinous was, how accurate that was.

DR. CIBULL: I think that there is no problem with clear cell carcinoma. That is a relatively easy diagnosis to make, not in every case, but in mucinous carcinoma, the problem there is the overlap with metastatic colorectal carcinoma of the ovary.

I am not exactly sure. I think you would probably have to correlate histology with the clinical findings there, in at least some cases.

DR. GABRA: Just on that point, at the last town meeting, we did discuss, with Walter Bodmer, who was there, who some of you may know is interested in colorectal cancer development, whether there were much more specific antibodies for bowel origin tissue.

So, we are evaluating a small panel of antibody that he thinks is very specific. So, watch that space, perhaps.

DR. BIRRER: Just a similar comment, that there are now a number of microarray experiments coming from micro-dissected mucinous tumors of the ovary, with a whole host of interesting, relatively specific markers that are available. Those could actually be worked into these rare tumor trials. I think it would be quite interesting.

DR. GERSHENSON: Rich Zaino is a member of the committee and he was at our inaugural meeting in July of the rare tumor working group.

We agreed at that time that I think a central pathology review early on is going to be key, but I think we will have to have some new paradigms to relate it to the way this group works.

DR. SWANSON: I think it is really great, being a clear cell patient, to have this research, but I was wondering if one might also consider endometriosis-related ovarian cancer and clear cell, since they seem to go together as an entity and might behave differently than regular clear cell.

DR. TRIMBLE: Mike Birrer, would you care to comment? I can't remember how the histologies separate based on the array data, or Bob Bast, or whoever.

DR. BAST: Actually, we have a paper just this week in Clinical Cancer Research that suggests that the clear cell and the endometrial tend to cluster together.

The mucinous were the most distinct, though, and again, there are about 15 different markers for mucinous ovarian cancer.

The clear cell and the endometrioid both tended to resemble normal endometrium in the genes that were disregulated.

DR. TRIMBLE: So, should we put the endometrioid patients in the same trial as clear cell patients?

DR. SWANSON: What I was talking about was the clear cell that grows in endometriosis.

DR. TRIMBLE: So, do we need a separate queue?

DR. GERSHENSON: My experience with that is that it is sometimes very difficult to distinguish the clear cell that arises from endometriosis and that that may not.

I think you are right, that the pathogenesis of clear cell may be predominantly related to endometriosis, but sorting that out may be difficult.

DR. BIRRER: I was actually befuddled there for a moment, because it was confusing between endometrioid histology and endometriosis associated with clear cells.

Endometrioid tumors, I think, should not be separated out. They clearly look differently, but there is not a lot of evidence that they behave a lot differently from PAP serous.

You know, the interesting relationship between endometriosis and clear cells is a biologic interest. That still remains to be exactly proven, that relationship. If we take all clear cells, I think those will be buried in there. I would not segregate them out.

Let me add one other thing that I wanted to mention before. I do think, in relationship to what Jeff said before, there is no reason that clear cells of the endometrium should not be included in this. When we profiled those tumors, they were indistinguishable from clear cells in the ovary.

DR. BOWTELL: One of the pathologists here may want to comment further, but at least in our study it seems very difficult to identify primary invasive mucinous tumors of the ovary seem to be extremely rare in our series.

It seems that you need to have very, very stringent criteria to decide whether they are primary or not.

So, I think any evaluation has to take that into account, and some sort of central review of pathology for those sort of cases, I think, is essential.

DR. BURGER: A couple of points. Our lab has done some work on segregating these types in terms of in terms of in vitro drug response or drug resistance.

It seems to be that they segregate out in terms of drug resistance when you look at pure clear cell and pure endometrioid tumors.

I would say that we should think about, first, looking at pilot data that suggests that, when we treat patients, that we note particularly strong activity of one agent or another or a given histology, before entering it into a Cooperative Group trial, for that specific histology.

DR. TRIMBLE: Any additional comments?

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We also talked about some alternative phase II designs, including randomized phase II, one stage phase II, some novel statistical designs using multiple primary endpoints.

Our proposal here is that we put together a working group, including representatives from GOG, NCI, GCIC, including both statisticians and clinical trialists to see if we could come up with some alternatives to our standards. Mark, how soon can we get to work on this?

DR. BRADY: We have been considering some of these alternative approaches. I think some of these designs, though, in the phase II setting are going to require looking at some of the surrogate endpoints, like the CA 125, and how that could be used to help screen for agents. I think that is going to be a limiting step right now, but we will try to look at that data.

DR. TRIMBLE: Mark, can I charge you and Larry Rubenstein to organize a working group on this with the appropriate representation from the developmental therapeutics committee, from the SPOREs, and from the GCIG? So, we can discuss this.

DR. BARNES: This may be premature, but one issue that was brought up yesterday that is going to be upon us soon is eligibility with regard to admitting people with prior biologic therapy on board, and I think that ought to be added as an action point.

DR. ABRAMS: Do you think we could get FDA to participate in this working group?

DR. TRIMBLE: It would be nice if we could get FDA to come to this meeting. We will certainly invite them. Okay, other comments on this issue?

DR. BOOKMAN: To some extent, as Mark pointed out, the process has already started, in the absence of a formal working group. We hope to continue to develop different models and test cases, that we can try to move forward with.

DR. TRIMBLE: I mean, absolutely. Mark and Mike, I know, have done a lot of work already. There still has been not, shall we say, 100 percent buy-in at the level of CTEP.

So, we need to make sure that CTEP is happy with the proposals and modifications, and obviously we need input from FDA and the other cooperative groups.

So, in terms of a timeline on this? Larry? Mark? Can you report back to us in like three months or something like that? Does that sound reasonable? Okay.

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Okay, accrual to challenging phase I and II trials. We had some discussions of this yesterday morning with the meeting between SPORE and GOG.

Clearly, it is a challenge. We saw some of the data from the SPOREs as well as from the GOG in terms of accrual.

I think Mike Seiden suggested that we get representatives together and lock them in a room for one day and tell them they are not allowed out until they resolved these issues. Isn't that what you suggested, Mike?

I put, report with recommendations by January, just because we need to move this along and help centers figure out how we can work together.

As Jorge Gomez said in the meeting yesterday morning, that we need to be willing to consider a new paradigm to get these studies done. Does this sound reasonable? Any objections? Who is going to represent GOG in this effort? Mike? Mark, and then who do we have from Alabama? Is that going to be you or Ronnie?

So, Fox-Chase, is that you again, Mike? Harvard, is that you, Mike? Seattle, who is it going to be? Okay. So, can you talk to Chuck and figure out who needs to be there for that? Am I forgetting a SPORE? M.D. Anderson, Dave Gershenson.

DR. BOOKMAN: We need someone from GOG leadership, because of the issue of membership per capita and those issues, which is what actually we stumbled on five years ago.

I mean, unless we want to keep repeating history, I mean, if you are going to lock people in the room, you have to include someone who can speak on behalf of the group.

DR. TRIMBLE: We will ask Dr. DaSaia, and Dr. Copeland and Dr. Thigpen and Dr. Stehman and Dr. Thomas to see if they can come up with some representative for this.

Contract holders, who are our big contract holders that do GYN? I know Memorial does, Amit does. Are there other contract holders? We can check with IDB to see if there are other contract holders who need to be involved.

Let's see if we can work on this. Jeff, could we use EMMES to help staff this group? Mason? [AGREEMENT} Okay, we will see if we can find a time and a place to get people together within the next three months to get this moving.

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Faster start and completion of phase II trials. As we heard from Janet Dancey yesterday, there does seem to be a lag between LOI awarding and opening of that trial within GOG.

That is working to GOG's disadvantage because they have not been awarded as many LOIs as GOG might have liked because of that delay.

We talked yesterday morning about potentially reorganizing GOG institutions who are interested in phase II trials into a mini-consortia with perhaps 10 institutions per trial, as well as working with CTEP to see if we could streamline some of the paperwork in terms of which institutions were on which trial.

We also discussed prioritization of translational endpoints, so that we didn't try to build translational endpoints into every clinical trial.

Clearly, this is going to take a fairly intensive effort involving GOG statisticians, data managers, the Committee on Experimental Medicine, the clinical trialists at NCI, to see if we can sort this out.

Mark, can we get you to volunteer to help with this, and I guess we obviously need Betty Stonebreaker, Mike Birrer, Mike Bookman and his colleagues from the developmental therapeutics committee, and whoever you need from our shop.

What is a reasonable timeline? Dr. Bookman, do you think that we can, maybe by the January meeting, try to come up with a proposal?

DR. BOOKMAN: There is also the issue of trying to address some of the practical points, such as eliminating safety reports whenever feasible, and providing another mechanism for central review of safety reports, and streamlining the processes by which we indicate what institutions are participating in the study, so that we don't have to constantly be doing amendments.

I don't mean to get into too many of the nitty-gritty details, but are you anticipating that that is part of this, or is that a separate slide?

DR. TRIMBLE: Separate slide.

DR. BOOKMAN: I think the main challenge here for the group is, can we devise a way to develop these special interest groups of 10 institutions, for example, without adding excessively to the administrative and regulatory work load of the group?

So, we have to look creatively at the operations of the statistical data center and also the protocol development process in the administrative office.

DR. TRIMBLE: I will be happy to volunteer Janet Dancey, who is the new IDB rep in GOG to work with you all, but I really think we need to push this because, for many years, GOG has been the primary engine for evaluating phase II trials rapidly and, for a number of reasons which we have discussed, that GOG accrual has lagged, and the queues have become too slow, and we need to figure out how we can better that.

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Okay, central review and monitoring for select phase II trials. Jeff, do you want to comment here on what we have been able to do, or have been trying to do through CTSU?

DR.ABRAMS: I do think the CTSU provides a centralized mechanism that would allow contract holders, SPORE institutions and GOG investigators, and other Cooperative Group investigators, to have access to these phase IIs.

Of course, you would maintain the ability to still qualify institutions. So, if certain institutions were unqualified to do certain trials or meet the requirements, you wouldn't automatically gain access. The system is capable of having sites meet these qualifications.

As far as the issues that Mike brought up about safety reporting and the redundancy of that, we would have to take these phase II trials and have them reviewed by the central IRB, which we have only begun to do with a few phase II trials.

The central IRB only works, or that process only works, if the institutions around the country actually join the central IRB.

Right now we have about 250 institutions who have joined. I would say there are about 130 that are actively using it.

Really, if this is going to be part of the solution, we really have to expand the use of a central IRB to many more sites, and to get them to actually use it.

One thing that has been positive in our view is, once a site actually starts using it, they use it over and over again, which means to me that they are seeing benefit.

There is that hump to get over in getting an institution to actually start using it for the first time, and getting the IRB to buy into the process.

I mean, it could be a potential solution that could work for some of the problems that were brought up yesterday, that if you are only going to put a few patients on because the tumor is rare, or just because it is a small trial that accrues rapidly, then having a central IRB to do the review and cut down on the expenses makes a lot of sense.

The challenge now is to really spread this process across the country and get IRBs to utilize it. I am sure all of you realize that, at your institutions, the IRB is a separate entity. Except at a few places that are totally cancer-focused, it is an IRB that often goes across all the research at that institution.

So, they sometimes don't like to carve out an area for oncology. That has been part of the problem, and sometimes it has been the question of indemnification.

I think that one, which we have heard at many places, is somewhat of a red herring. As you all know, commercial IRBs have actually been used to bail out some institutions that have gotten in trouble with their IRBs.

These commercial IRBs do not indemnify either. We have checked into that extensively. So, I think it is really, like in many things in industry and in academic, once you start this whole IRB process in your institution, the staff are involved, it is people who see that as their job and they are not anxious to change unless you can really explain why it is going to help the institution and the research that they do.

So, perhaps the only other thing I could say that has been positive about utilizing the CTSU is that having a centralized process does require all investigators to use standards.

You can't be doing your own thing in GOG and your own thing at Memorial and your own thing at M.D. Anderson. It requires you to develop your protocols using common data elements, utilizing forms that look similar to what other people are using.

If you don't have a common driver, often people go off in many different directions. That is sort of the entropy of the system.

We have seen that the trials on the CTSU menu, by and large, do have these characterized, that they are standardized, that they do have common approaches.

For the people at the sites, that does help. It makes it easier to move from one trial to the next more rapidly.

DR. STEHMAN: Where can investigators get a list of the 130 institutions that are actually using the central IRB?

DR. ABRAMS: The list is on the central IRB website. I think it is www.ncicirb.org.

DR. TRIMBLE: Is Indiana University using the central IRB? [WON'T DISCUSS IT] How about the University of Mississippi? [WON'T DISCUSS IT] How about Fox Chase?

DR. BOOKMAN: The IRB will conduct what is called a facilitated review, meaning that they will take the phase III review from the CIRB, but then do an abbreviated review of that. So, it is not totally accepting it as is, but making sure that they support the conclusions of the CIRB.

DR. ABRAMS: That is actually the process. I mean, they do a review, and then the local IRB has to buy into it, so called facilitated review.

Facilitated review can be done either by the chair of the IRB or a small subcommittee. In our experience, that review takes three to five days, as opposed to getting it on the committee agenda, filling out applications, et cetera.

So, it is called facilitated review, because it is not totally replacing the total IRB or usurping its responsibility.

Once they see the quality of the review, most local IRBs have accepted these facilitated reviews quite rapidly.

DR. TRIMBLE: Irvine?

DR. BURGER: The same as Fox Chase.

DR. CIBULL: IRBs don't look to the NCI for -- they are not their boss. You know, if you could get OPR to endorse this strongly, I think that would go a long way in terms of influencing local IRBs to move in that direction.

It is not, in general, I think, protection of turf that drives IRBs to keep this activity. Most IRBs are extremely busy and would love to off-load some of this stuff.

It is the high level of paranoia because, every time any little thing goes wrong, OPR comes down on them like a ton of bricks. I think if you could get their bosses to buy into this, that would be extremely helpful.

DR. ABRAMS: The only thing I can respond to that is their bosses have bought into it. I have sympathy with the oncologists. I am not critical. Many of you have tried and, as you have said, you have met a roadblock.

We are going to try to do an economic analysis which may be something that deans of medical schools and so forth, who control these committees might react to more positively.

The amount of money that could be saved is substantial, if you think about it, and maybe that would reach them.

I don't think we are going to get OHRP to issue anything more than this is in the regs, it is acceptable, it is actually a good idea, which they have said in their letters to us.

Their system is based on local IRBs. So, this is somewhat of an experiment. So, they are not going to criticize the local IRB system in the country. They have said, quite explicitly, that this is a good model for multi-center trials.

DR. SPRIGGS: I have to say that one of the problems that I see here is, it is not the IRB that holds things up.

Once we get to the IRB, we can usually get through in a couple of weeks. The problem that really comes is before it is submitted to an IRB, and I don't know how much time we would save by using a central IRB in that context.

DR. TRIMBLE: How about Oklahoma?

DR. MANNEL: I have brought this up every year for the past several years and still am meeting resistance.

DR. TRIMBLE: Jenny, how about Chicago?

DR. FLEMING: Ditto. I e-mail annually the chair of the IRB with copies to the chair of CLGB, who is at our institution trying to arouse interest.

The chair of the IRB has personally called me and informed me that he thinks facilitated review is more work for him. He has called other IRB chairs and they don't like it, and maybe he will try it on one protocol in four or five years.

DR. FRACASSO: I agree with Dave Spriggs that the work to even just do the facilitated IRB review, our IRB says is as much work. I mean, just getting it to the IRB doesn't really save us time at all.

DR. TRIMBLE: Mike, do you want to comment for Harvard?

DR. SEIDEN: There is a little bit of facilitation but there are still like 40 sign-offs, and it still goes through scientific review. So, it may save us a couple of weeks, but it is still a very long process.

DR. COLEMAN: My experience at M.D. Anderson has been that it is more and more facilitated. It goes through a different set of committees, although it still goes through the IRB. The layers, particularly for scientific review, are less.

DR. TRIMBLE: Peter, Cleveland Clinic?

DR. ROSE: We have a common IRB with Case Western, because that is the way the cancer center is based. There are actually just two sets of IRBs, both the IRB and the cancer IRB. So, it is quite a long process.

DR. MILLER: We have to go through the regular IRB.

DR. TRIMBLE: Ben, do you want to comment for the University of Washington?

DR. GREER: Not using it.

DR. TRIMBLE: Angeles?

DR. SECORD: At Duke we use a facilitated IRB review process, but we have to go through the cancer protocol committee. I think things have improved over the past year.

DR. ABRAMS: The cancer protocol committee, obviously you recognize that the NCI can't do anything about that. That is a local issue.

DR. SECORD: It is a cancer center issue.

DR. ABRAMS: If we can get rid of that requirement, do you really feel that your universities would not review these scientifically? I would bet most of them still will, but that would be interesting.

I don't think, for multi-center trials, that the NCI is going to insist that you have to have a cancer center scientific review. In fact, I don't actually think that is the way it is worded right now, especially for Cooperative Group trials.

If that is the problem, we can probably work on that, but I bet your cancer centers will not get rid of this review. What they are really doing, as you realize, is prioritizing resources.

DR. FLEMING: I would just say that is not our problem. For multi-center GOG and externally reviewed trials, our cancer center committee feels that it has to review them, but they give it what they get -- that is the only thing that actually gets a facilitated review. The chair just signs off on anything that has been externally reviewed by a peer-reviewed process, including the GOG trials. Then it goes straight to the IRB.

DR. FRACASSO: Ours do, too. We don't have to review those in the cancer center review committee. The chair signs off.

DR. BURGER: The CTPMC essentially rubber stamps our NCI-designated cancer center Cooperative Group protocols.

The clinical research office tracks accrual and sends us a letter when we have poor accrual to a trial. Beyond that, the major hold up is in IRB review, and we have made progress.

Some of the other institutions are already introducing the central IRB prepared protocol document in lieu of the usual formatted protocol narrative, and just have a local version of the consent form with a facilitated review for those protocols.

DR. SECORD: I think the review process is probably individualized based on the center. At our center, the cancer protocol committee is our biggest rate limiting factor.

In fact, Brad Monk's study with Avastin in cervical cancer was held up in that committee because of the biopsies. So, it is individualized.

DR. ROSE: Isn't the biggest problem getting the protocol to the institution? When you think about 191 was closed two years ago and we still don't have a protocol document to replace that at a national level --

DR. TRIMBLE: Well, the CIRB did approve 219 in the last week, I think. So, hopefully GOG will be getting you that protocol document. Other comments on this issue?

DR. BOOKMAN: I think the CIRB processes, as you can hear, still are in the process of evolution with regard to phase III trials.

I think it would be premature to try to use the CIRB to support most of our phase II initiatives, particularly at this meeting when we are discussing ways to home in on institutions that will be particularly committed as a group to championing that individual phase II trial.

Getting a national CIRB involved may not be an efficient step in that process, if we can improve the way that we work with those designated sites.

The other issue we didn't really talk through are the safety reports. One solution, yes, would be to have a central IRB review them, but I think the better solution would be just not to review them.

When a safety report comes out on a study, it is reviewed by the study chair and by the group operations office, the statistical data center, to see if an amendment or a change in the consent form or other issues are appropriate.

If there is an amendment, then that gets reviewed at the local level by the IRB and by the investigators, but we ought to just put a stop to sending out countless numbers of safety reports that do not result in any change to the protocol document. There is no value to that process. It numbs the IRB and detracts from the work and important things that the institutions and the IRBs need to do.

So, just having another group review them for us will -- I mean, I don't think it is a practical solution. I think a better solution would be just not to review them, except the study chair and group managing the study, not at the local IRB level.

DR. TRIMBLE: Is that an FDA requirement?

DR. BOOKMAN: It used to be when safety reports came out from industry, that they would say, we recommend you send this to your IRB.

Now they frequently come with language saying, we require that you send this to your IRB, and that is not an FDA requirement.

I think that somehow the playing field has evolved to the point that I showed yesterday, that we are looking at 3,000 of these a year, which is just paralyzing a lot of processes, and I think they do not result in amendments or changes to the study.

They have been signed off by the study chair as, oh, we already knew about that toxicity. We don't need to hear about it again. It doesn't change anything.

It should be part of the record of the trial and part of the record of that drug, but it should not need to go through sign off and review at each local institution. That is wrong.

DR. BURGER: Our system has actually evolved to the point where safety reports that don't result in any modifications are submitted annually to the IRB. So, all together.

We recently received AHARP accreditation. So, they went through that with us, and that was an acceptable strategy.

MS. HUNT: It sounds like a great opportunity to get industry folks together to hammer this out. Although, speaking for my company, on safety reports we may say we require you to go to IRB, but there is no mechanism in place for us to insure that that occurs.

So, it is an accountability that is placed to the site, to the group, and I don't see any reason why you couldn't develop some processes and standards in place, so that that information is communicated, like you are suggesting, Michael. So, if there is a significant safety concern, then it is addressed and action is taken. This would be a great collaborative effort, I bet, if you got some industry partners together.

DR. BOOKMAN: Right now, in the Cooperative Group environment, the general rule of thumb is that you have 90 days to receive and process a safety report.

If you don't, then when you have an audit from your group, you can get a violation for not having processed the safety report, which resulted in absolutely no useful information related to the study.

DR. TRIMBLE: Jeff, do you have any thoughts on how we can resolve this issue? It doesn't seem to be related to --

DR. ABRAMS: In the central IRB they only review serious adverse events. They don't review the lower grades. So, that would be one thing that may help.

There is an OHRP requirement to review serious adverse events. That is the way I understand it. That may be harder to overcome without a change in the guidelines.

MS. KOLKER: Just from the consumer perspective, I think we would be uneasy about a process that did not allow you to address and focus on the serious adverse events as opposed to -- I forget what the grading system is -- the grade ones and twos that are not of serious consequence.

DR. TRIMBLE: Why don't we just -- we are going around in circles here. I can talk with Allison [Hunt] off-line and we will see if we can come up with a potential way to decrease this burden.

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Okay, switching now to CA 125, certainly there was a lot of talk about considering CA 125 for expanded eligibility and evaluation of response in phase II trials.

There were some proposals to include two cohorts in clinical trials, those with measurable disease, and those with CA 125 evaluable disease, and to permit progression to the second phase of clinical trials based on either improvement in CA 125 or standard RECIST criteria.

Certainly there seemed to be general support for the GCIG CA 125 criteria. So, I would propose that we have a working group, perhaps the same working group that is looking at phase II trial design, to look at the CA 125 in our phase II trials. Any additional comments on this?

MS. TAYLOR: One of the issues brought up yesterday, I think it was Dr. Kohn mentioned that she didn't think CA 125 was a really good marker response with some of the biologics. I think there was some discussion around that. So, as we look at this issue, I would just like to be sure that we can look at what limits there are for using CA 125 as a marker for response.

DR. BURGER: There have been anecdotal remarks of lack of correlation in some cases, where patients are responding clinically or showing no sign of progression.

So, clinically improving CA 125 is essentially having a fluctuating pattern that could theoretically fall within the category of disease progression by the Reston criteria.

I think we really need to be careful with doing at least some agent-specific analysis of possible non-specific effects on CA 125 before at least utilizing the criteria for progression, based on CA 125 alone in those types of trials.

DR. BOOKMAN: The path we are trying to take is to include RECIST measurable disease and non-measurable disease, but not necessarily CA 125 only.

In other words, we want to be able to take patients with an evaluable tumor that can be seen on a radiographic imaging procedure or exam, but not necessarily meeting full RECIST measurable requirements.

So, that slide is not exactly in sync with what we are proposing, because there are separate studies and separate queues of investigation, if you will, for patients with CA 125 as their only evidence of disease, including the GOG phase III trial 198, which is thalidomide versus tamoxifen vaccine studies and other initiatives.

On the phase II trials we are really more interested in folks with evaluable, but not measurable, disease by RECIST criteria.

DR. SPRIGGS: I think that, as we learn more about the biology of [UNKNOWN] elaboration, we are certainly going to have a better handle on this.

We had a preliminary abstract at the ACRERTC meeting suggesting that certain cytokines, including IL-1 and EGF have significant effects on the elaboration of CA 125 in cell culture.

I think it is possible to look at this, and I think that now that we have a little bit more information it is going to become a little more clear.

DR. COLEMAN: I would just highlight Mike Bookman's comment. I wanted to make sure we didn't just center on CA 125 as our only non-measurable evaluable marker, and that we utilize our current existing queues of completed trials, although they are short in the biologicals.

We could go back and look and see how those particular markers relate to our overall documented responses.

DR. MANNEL: I think one of our issues here that has actually been fairly well looked at, as Mike and Robert have said, in a phase III setting already, looking at differing criteria.

I think the risk you run is CA 125 going down is probably a pretty good marker of response, but going up may give you some false progression.

So, for right now, on the phase III trials, with the cytotoxics, you have to show progression of disease, not just based on CA 125 measurement, to get it -- because of that reason.

I do think that this is not as black and white as being able to just use the CA 125 for marker progression. A marker of response, it probably does it fairly good job at.

DR. BAST: I think it would help to perhaps go into greater depth with what Elise was mentioning yesterday. Her experience has been that some of her biological agents actually increase effusions.

She has played through that and has found that, in the long run, the effusions get better. It has been known for a long time that CA 125 is increased by any plural effusion or sites, and that is the confusion.

I think this is a setting where you could probably develop guidelines that were common-sensical in terms of the duration of the increase in CA 125. In those patients, CA 125 eventually goes down.

I think, too, that I was careful in my slides yesterday to put biomarkers. I think, taking the longer view, you know, CA 125 is one biomarker, but I bet if you went to the trouble of looking at multiple biomarkers in some of these settings, that you really could find a much more specific indicator for disease progression.

Again, I think certainly Mike Bookman's approach to taking disease that is there but isn't precisely measurable, and using CA 125 as an adjunct, makes sense. It is one stepping stone.

I think, if we keep on doing what we are doing with four percent of patients at best going on protocols, and not figuring out some other criteria that the FDA could buy into, or the drug companies could buy into, we are just not going to make progress as rapidly as possible.

CA 125 may be the most proximal way to do that, but I just would urge that we keep trying to figure out other criteria that we can live with, that won't throw away good drugs, but on the other hand, we will make progress much more rapidly.

DR. SWANSON: As an ovarian cancer patient that has a normal CA 125, I really hope that the criteria up there gets adopted, because I think it will really speed up approval of drugs.

I don't think it is perfect, but you know, we can't all go for perfection. Sometimes we just have to go for expediency, and I think this would work.

The other way I think it would work, it amazes me on my website how many women will say, well, my CA 125 is from 500 to 1,000 and my tumor is getting larger and my doctor is still giving me chemo. Should he change it?

I think if we had a criteria like this for clinical trials, it might end up being a clinical criteria for a treatment goal in ovarian cancer.

I am not an oncologist. So, maybe you should be treating them when their CA 125 is going up, and the tumor is doubling, but I think using this as a guideline for clinicians in the community would also be really helpful.

DR. TRIMBLE: Certainly I think the Gynecologic Cancer Intergroup criteria for use of CA 125 is available on the web and is useful in the setting such as you describe.

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Okay, endpoints in phase III ovarian cancer trials. This is something that we touched on briefly. We had some informal discussions with the FDA about using CA 125 rise as a marker for progression, and some discussions, certainly, at the Gynecologic Cancer Intergroup retreat last year in Germany, on whether progression-free survival could be used as a proxy for survival.

The FDA does plan a workshop on ovarian cancer endpoints. They have asked for input from NCI, and we sent out a request to GOG and members of the Gynecologic Cancer Intergroup asking for potential speakers and panelists.

According to the FDA, they will also ask ASCO and AACR for potential panelists and speakers, but that is as much data as I know. I haven't heard of any date from FDA and they are calling the shots on this.

They then plan to report the proceedings of that workshop to the ODAC. Now, we had also talked about whether it might be reasonable to try to get in the same room the FDA, the EMEA, the Canadian and other regulatory bodies, so that they could see if there was any pattern or consensus among the regulatory bodies about endpoints in ovarian cancer trials.

I think that we would need to see -- certainly there is interest, I know, in the EMEA and the Canadian authorities in such a meeting.

FDA is obviously still working on their workshop and we will have to wait for them to have their workshop and present those findings, I think, before they would be willing to come to the table. Do we have any comments on this? Is there anyone here from the FDA who would like to comment?

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Intraperitoneal therapy, we heard some lively discussion yesterday afternoon. Obviously, as Dr. Alvarez pointed out, we need to decrease the toxicity, we need to explore the mechanism of action, we need to explore novel agents and combinations.

We need to figure out how to combine IP therapy with evaluation of other interventions in patients with optimally debulked stage three disease, and this is clearly going to take the combined efforts of the SPOREs, GOG, cancer centers, NCI, Gynecologic Cancer Intergroup. Are there any additional comments on what we need to do in the future in IP therapy?

DR. HOWELL: One of the biggest challenges is simply the problem of getting the drug into the peritoneal cavity.

There is quite a bit of new bioengineering materials science that could be brought to bear on this challenge.

I wonder if the NCI might take the leadership in organizing a focus around the applications of new catheter technology to this specific problem.

DR. TRIMBLE: I can look into what our National Center for Research Resources, et cetera, can do to help with the bioengineering of IP approaches.

DR. COLEMAN: I believe there was also a concept that was approved at the last GOG looking at distillants as well, as a methodology for improving IP distribution. I don't know if anybody here remembers that.

DR. BOOKMAN: There is a polysaccharide that can be instilled in the peritoneal cavity that results in the retention of drugs for longer periods of time.

I don't know whether it has an impact on adhesion formation, although I think that is one of the other potential advantages.

It has been a little hard to negotiate that agreement with the sponsor to bring that forward, but they are still interested in working with the group to try to do that. So, that is an active concept. Noel Cloven is the study chair working on that.

DR. ABRAMS: Yesterday several speakers brought up, what is the dose that is going to be recommended in the clinical announcement or what is the regimen that is going to be recommended. Could you tell us what it is going to say?

DR. TRIMBLE: That is the next slide. Are there any more comments on the research issues? Okay.

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The clinical announcement, we obviously need to make clear how to avoid toxicity, how to place the catheters and administer the chemotherapy.

We plan to disseminate, with the help of the advocacy groups and the professional societies. We have plans to evaluate uptake in various prospective cohorts.

In terms of the recommended dosage, this continues to be a source of some controversy. Certainly the three large U.S. studies all used 100 milligrams per meter squared of platinum, given IP every three weeks.

As we heard, I think Dr. Armstrong said yesterday it was important to have early dose reduction of that for any toxicity.

Because only one of the three trials used intraperitoneal paclitaxel as well, it was difficult, or there was certainly not consensus about whether some of the Taxol should be given intraperitoneally.

On the other hand, the most recent trial, GOG172, did have the largest survival advantage observed, and certainly a number of centers -- I think, Carol, do you want to comment on how you all made your decision for what are your off-protocol recommendations?

DR. AGHAJANIAN: We are using the 172 regime, but we have modified it slightly in some patients. A couple problems come up.

One is access to inpatient beds or CAD pumps for the 24-hour Taxol infusion. So, we have modified, in some patients, that 24-hour Taxol infusion to a three-hour infusion on day one, and they come back for the IP cisplatinum on day two.

There is really no reason, from prior trials of single agent Taxol, to believe there is a difference in efficacy. There was a concern about increasing neuropathy with the shorter infusion, but we seemed to be doing okay.

We do lower the cisplatinum to 75 very early. I think that one of the things about neuropathy is that a lot of trials only reduce for, say, grade three toxicity, and if that is diarrhea that is okay, but if you get to neuropathy and it is a persistent grade two, it is already too late, and it really takes very little additional drug to get you up to a grade three.

I think the importance is to recognize neuropathy early at a sort of grade one or an intermittent or non-persistent grade two, and reduce that dose from 100 to 75 very early.

I think it is incredibly valuable, even in an off study setting, to use that sort of quick GOG NTX form, and have your nurse run through that with the patients.

I think one of the big problems with neuropathy is that assessment of it is very subjective, and two doctors could walk into the room, one after the other, and someone can call it a grade two, someone can call it a grade one.

Some patient may say, no, my feet aren't numb, but they really might be thinking they are in pain. So, I think careful attention to that is very important.

DR. MANNEL; The GOG ovarian committee has prioritized development of IP therapy for optimally debulked ovarian cancer and has, through very rigorous scientific discussions, has come up with a randomized phase II trial.

We hope to have a document that we will be putting in to the CTEP review process. I guess my reason for stating that, number one, is -- and I realize everybody works as hard as they can, everybody prioritizes -- but truly, I think this is a priority for ovarian cancer.

When we get that document in to the review process, the most expeditious turn around possible would be greatly appreciated.

The second issue on that is, it is a little bit of a unique study design with Dr. Brady and the GOG stat office coming up, working with us to do a randomized phase II trial.

One of the advantages of it is that the cohorts will be quite large, about 100 patients in each of the arms. So, if we have three or four arms, we are talking about a 300 or 400 patient trial.

We feel like this will also be an excellent opportunity to re-introduce IP therapy to a lot of institutions that did it a long time ago and maybe have forgotten some of the technique and, at the same time, to disseminate this newer information that you are talking about.

So, we are committed to working to actually incorporate in the protocol more rigorous guidelines regarding catheter placement, dose modification, et cetera. So, from our standpoint, we are in complete agreement with what you are looking at doing here.

DR. TRIMBLE: Robert, would you comment on how you are treating patients off-protocol at Oklahoma?

DR. MANNEL: We don't have very many of those, Ted, but when we do -- just joking. We have an in-house protocol right now looking at intraperitoneal therapy, splitting the 100 milligram intraperitoneal platinum into two 50-milligram doses a week apart.

So, that is the strategy that we are looking at. So, we are collecting phase II type data on that. Off of that, then we would offer our patients intraperitoneal versus intravenous, and we would explain to them the increased survival advantage of intraperitoneal but the increased toxicity, and we would have them make a decision based upon that.

DR. OZOLS: If the GOG, in its collective wisdom, feels that IP therapy at this point should still be studied on phase II trials, which are inherently obviously experimental, who is this clinical announcement aimed at?

If we are not saying it is standard therapy, and we don't know what doses to give and we are trying to decrease the toxicity, what does this announcement tell the patient, and what does this announcement tell the physician in practice?

DR. COLEMAN: I guess my comments are kind of along the line of a bridge between Dr. Ozols and Dr. Mannel. What we are hearing, and we heard yesterday -- and this will go on and on -- is that the 172 arm is not acceptable to most people off-protocol.

So, everyone in this room -- and we were the same, we were dreaming up ways of modifying that schedule, those doses, those drugs, to come up with an in-house protocol.

I wanted to emphasize the importance of doing the phase II trial within the GOG. because that trial is looking at many of the modifications that have already been discussed, with the exception of the carboplatinum substitution.

So, if you are going to release this announcement, could it be possible that you encourage patients and physicians to go on trials like the GOG, that will be hopefully launched soon, so we can answer those questions and come up with a more tolerable regimen.

DR. SWANSON: What really worries me, hearing about this announcement, is that if patients go to one of your institutions, they are going to get top quality care.

The minute that announcement comes out, then community oncologists are going to start doing this, and they may not have the training to do it safely.

I really hope that, if the announcement comes out that some of the larger institutions, like M.D. Anderson, has programs for community doctors to learn how to do it -- I worry about the safety of patients that go to an oncologist who just does it once a month or once a year. I think that is just something to really consider.

DR. MANNEL: Just to respond to what the advocacy group is saying, we are committed to not just opening the protocol, but we have also committed to training physicians.

We have DVDs, we have programs. We actually have a time set aside at the GOG and at the SGO for workshops. So, this is not something that we are just throwing out there.

There is an aggressive educational commitment as part of this process. In response to Dr. Ozols, I think the standard of care is either IV or IP, based upon the data that is out there, and the wellness of the patient.

Having said that, doing a randomized phase II doesn't mean that the GOG doesn't think that IP should be used up front. It is just looking at the most rapid way of finding a new experimental arm to compare against the standard arm.

So, we have to be careful we don't confuse the fact that we are doing a randomized phase II to think that we don't think that IP therapy is important, or ready for use outside an investigational setting.

DR. SEIDEN: Just to echo the last NCI alert that came out in this field was in cervical cancer. There you could say to the community that these regimens were ready for prime time.

There is going to have to be some recommendation of, do you follow GOG-172 as it's published. That could actually set back IP development, because if community docs have horrible experiences with it, that may slow down accrual.

DR. TRIMBLE: I should say, from having worked on the last clinical announcement concerning chemoradiation in cervical cancer, we had a number of trials, all of which used different regimens.

The only common factor was that they contained platinum. So, we made no recommendations concerning which regimens to recommend.

We did say that the dosage of 40 milligrams per meter squared per week appeared to have less toxicity, but we still, in that announcement, didn't say that you have to use regimen X, because we didn't have data to support what the best regimens were, because the regimens had not been compared head to head.

DR. BURGER: I think that there should be some inclusion of a statement regarding either referrals -- suggesting that referrals be made to institutions that have experience with this, or seek appropriate training.

I agree with the statement made before, but I think there should be something in there, a phrase related to referrals to ovarian cancer treatment institutions.

MS. GOLDMAN: I guess I would echo somewhat with Dr. Seiden and the rest. It is not that the patient advocacy community, I think, is against it, and certainly we encourage people into the trials.

I just look from the standpoint of what happens to us, when you put out a clinical announcement. On a slow news day you are going to get a lot of attention for this, and that will particularly confuse -- our patients are desperate.

They see a headline with 17 more months survival, and they are going to go for it without necessarily getting the appropriate counseling.

I know, Ted, you are committed to putting the right language in there, but it is going to be very difficult for the patient community and for those of us trying to educate them, too.

DR. BAST: I wonder if you considered having a training program for physicians on a website so that, as part of the announcement, you could give out that address, and also possibly an educational program in more depth for patients, because so many patients are web-literate, and I wonder if that would help as well.

MS. KOLKER: Don't forget the nurses. I think they are an important part of the team as well for training.

DR. TRIMBLE: So, thank you for these ideas. I do want to remind people that less than one percent of women with advanced ovarian cancer are currently getting intraperitoneal therapy.

Our goal is to help more women live longer. If we do nothing, then I suspect that the only women being treated with IP therapy are those at institutions which are committed to it.

In terms of the education, we do plan separate educational modules for physicians, nurses and patients. We have reached out to the Society of Gynecologic Oncology Nurses, as well as to a number of the centers with strong expertise in IP therapy, to identify nurses that can help us identify that teaching module.

DR. BOOKMAN: Were the microphones on when Dr. Markman made his impassioned plea yesterday?

DR. TRIMBLE: I think the microphones were on.

DR. BOOKMAN: So, we have a recording of that commentary.

DR. TRIMBLE: Okay, let's move on here.

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Genomics, proteomics. We heard some lengthy discussion about what we might be able to do, particularly looking at microarray data.

Our proposal is to have a working group that would include NCI, the SPOREs, the Director's Challenge grantees, the DOD grantees, particularly Dr. Bowtell, the GOG and the members of the GCIG, to look at what has been published in terms of microarray data, to review ongoing projects and, somewhere in the six to 12-month range, to have a planning workshop on where we need to go next.

At that workshop, we would focus on design and implementation of validation studies. The same working group would also look at monitor tissue collection and use for proteomic studies. So, are there comments on this genomics, proteomics working group?

DR. BIRRER: The one addition on that, that I might make, Ted, that we didn't discuss this morning, is I think there should be a request for -- and this could be in the last recommendation, a request for a more systematic collection of early ovarian cancer specimens. We really still have a dire need for those, to try to do reasonable genomic studies.

DR. TRIMBLE: David, how many early ovarians do you have in your bank?

DR. BOWTELL: I need to check it but around about 22 percent are borderline cases.

DR. TRIMBLE: Stage one and two?

DR. BOWTELL: Yes, I would have to check that.

DR. HOWELL: I am concerned that this is too slow. If I were a company doing this and trying to produce a product, then I would, over a two or three-month period of time, be able to identify what technology I was going to use, what RT-PCR -- validate the RT-PCRs for the genes of interest, and identify the sources of clinical material that currently exist, and the trials that would need to be done prospectively in order to validate that.

That shouldn't take us two years or three years of just organizing to do that. We should be finished in two to three years. The government has a contract mechanism to parallel what a company would do. Why not utilize it?

DR. BIRRER: I guess I don't necessarily feel that this is inconsistent with that. I think the data that we have generated to date in ovarian cancer is not as mature as the data that was available for breast cancer when they moved into an industrial setting.

I do think we need a little bit more time to efficiently and thoughtfully review the available data and, at least two studies that I am aware of that are ongoing, involving very large specimen collections which are not published and not available, but will be, probably in the six month time period.

So, we could have the planning workshop more toward the six month time period than the 12 month. That workshop can make the recommendations that Steve is recommending now, and I think it probably would be a more carefully planned approach.

DR. LIVELY: I think one thing that will help us figure out what our timeline needs to be is, we need to decide what clinical question we are going to try to approach with whatever sort of assay or signature or profile that we are planning to develop.

I think we will certainly try to focus on one that is doable, but some may be harder than others. Until we really settle on what patient groups we are going to be focusing on, I think it is a little premature to say exactly how many months it is going to take us.

DR. HAMILTON: I think one thing that is going to be problematic with regard to the early-stage stuff and thinking about retrospective material, I don't know what the ethics are.

You are going to have to have an awful lot of information about the patient in order to make sense out of the results.

I would assume a lot of the material, there wouldn't be informed consent. So, you would have great difficulty getting paraffin material, even if you had good PCR strategies to test a subset of genes.

DR. HOWELL: There are lots and lots of questions that could be asked, but the immediate and most imperative question that everyone faces as a medical oncologist is, is this lady going to respond or not?

I think the choice of the first question is actually very easy. It is newly diagnosed stage three, stage four patients. Are they going to respond to a platinum taxane program or not? That ought to be the primary focus.

Those patients are fairly abundant. We have past trials from which we can get some samples. We have planned trials in which we can get lots more samples. I don't think we need to make this too complicated. We just need to get on with the process.

DR. TRIMBLE: Do we have volunteers from the SPOREs? M.D. Anderson? Dr. Bast? UAB? Dr. Barnes? Mike Seiden from Harvard? Seattle? Michael and David volunteered.

DR. FOUNTAIN: Ted, I think Andy Birdshuk(?) should also be involved in this activity. He is involved in a SPORE but I am just naming him in his absence.

DR. TRIMBLE: I saw Dr. Howell raise his hand. We will ask the Gynecologic Cancer Intergroup to nominate folks, and we will need obviously people from Buffalo. Mark will let us know. Great. Daniel. You are a Director's Challenge, as I recall, Jeff.

So, I think you are on the list. George? Fox Chase? Andrea. Okay. Any other interested parties in this? All right.

Kathleen, we see you. Any other suggestions for this topic, any thoughts on the issue of proteomics in cancer treatment, not screening, but in cancer treatment? Okay.

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So, we will charge this same group with monitoring tissue collections for use for proteomics studies. We want to make sure that the specimens are available and the right questions are being asked in the proteomics issue in terms of cancer treatment.

DR. ROSE: Isn't it possible that with a small subset of tissues, maybe 20 or 30, you could do a comparison between fresh and paraffins and determine if the paraffin material is adequate for analysis?

If it is, you have a ton of retrospective data that you could use, which otherwise you won't have access to.

You could, for example, write a protocol requesting consent from family members of people who have passed away from ovarian cancer, and I think you would probably be able to pass that at most IRBs.

You are only looking at tissue and outcome. You aren't looking at other details. We get consent for retrospective IRBs if people have passed away. We use their data all the time.

DR. DANCEY: People should be aware that we already have this built into GOG218, to do it prospectively, and it is going to be with more than 30. So, it is built in.

DR. SECORD: We are working on using fresh frozen paraffin embedded tissue for microarray analysis, and we are not quite there yet, but hopefully within the next year or two we will be there, and have worked out that procedure.

DR. BIRRER: I think that my personal bias on this is that I think the technology hurdles to do whole genome profiling off of paraffin is actually quite enormous.

I think it is more practical to set up real-time type PCR equivalents for a more limited gene list, at a paraffin. That clearly has been done in a number of situations.

There are biotech companies who have a variety of technologies. The plan within GOG, actually, is to try to transition to paraffin over the next maybe six months to a year, at the same time that these gene lists are becoming more mature.

DR. TRIMBLE: All right, that concludes the list that Mike and Jane and I put together. Jane, do you have any --

DR. FOUNTAIN: I have a suggestion. In the breakfast meeting that we had yesterday, we talked about prioritizing phase II trials between the GOG and the SPOREs and other interested parties.

Two of the subcommittees that you have come up are working groups, the design one and then there was another one, accrual to challenging phase I, IIs.

I think they would sort of fall under that umbrella and we could make one committee, so that we could sort of economize on individuals' time.

I think it is the same individuals that are probably involved in both of those committees, and I think some of the questions they are going to be addressing, like eligibility issues, you know, all of that, are going to factor into how they prioritize the trials. I would suggest we make that maybe one committee. Is that acceptable to others?

DR. TRIMBLE: I think we do need to see if we can minimize any of the amount of time we are asking you all to contribute to this effort.

DR. FOUNTAIN: I would name it like prioritization of phase II trials, and then basically the design issues, and the accrual issues would sort of fall under that umbrella.

DR. TRIMBLE: We will certainly explore the people who are assigned to be in each group and see where we can be as efficient as possible.

DR. COUKOS: I realize that we are sort of wrapping up here, but I wonder whether we should spend a couple of minutes talking about research priorities for the whole group in terms of translational directions.

I would like to propose that one of those should be the tumor micro-environment. We have heard that the two most exciting and unexpected clinical trials from the last decade in the GOG was the 172 and the Avastin results.

Clearly, in the Avastin results, the micro-environment is a major player. It has been suggested that 172, also tumor micro-environment, may have a lot to do with that. I would like to propose that emphasis be placed in this context.

DR. TRIMBLE: Any comments on George's suggestion to study the tumor micro-environment? Do you want to make that a high priority?

DR. SWANSON: I was just noticing that one group that wasn't here was the radiation oncologists. Sometimes women with ovarian cancer do get radiation for different reasons, and it might be good to include them, maybe a representative in a future meeting or something.

DR. TRIMBLE: We actually do have a very distinguished radiation oncologist here, with a long track record of publications in treatment of ovarian cancer. I don't see her in the room at present, but she has been here for much of the discussion.

DR. BAST: Just to support what George had just mentioned, I think that is right on target. I guess the question is, how do you actually strategize more than one trial at a time.

That is really where the block is, beyond Avastin or the first round of Avastin trials, what are you going to learn from those that will give you the next generation of trials?

I think we have been doing this long enough that we can really start to think more consciously, and perhaps that is already going on in the GOG. To my knowledge, it is not going on in the SPOREs yet.

DR. OZOLS: Just an administrative thing. I think it will be nice if you circulate these committees and the tasks to the people here, so that we can have a chance to think about them and maybe add other people, and give you recommendations. Will you be giving us sort of these committees and charges and a follow up on that?

DR. TRIMBLE; That is a great idea. We will definitely do that.

DR. BURGER: We spent an hour yesterday on the subject of targeted therapeutics, the current status and future directions.

I just want to avoid skipping over that important issue. So, Russ Schilder and I felt that it was important to develop a coordinated effort to identify these crucial activated pathways as targets, and to tighten the linkage between target discovery and early drug development, and also to enhance ovarian cancer-specific preclinical work that is necessary to identify targets to enhance drug development, and to do rational multi-targeting prior to clinical trials.

We have some recommendations for doing this, but I think it is vital that we come together with a working group to address that issue, so we are not doing the usual process of ad hoc reviews of concepts that come in, that are not necessarily in any type of prioritized order, kind of come as it may.

DR. HOWELL: Targeting is a wonderful word. To me, it means getting more drug to go to the tumor, stay there longer, to do its job.

As important as the work that Bob just outlined, of identifying molecular targets and figuring out how to hit those targets, is the whole issue of how do you get more drug delivered to the tumor?

There are some major new developments coming along very rapidly in that field. There is a polymer platinum that has now been through phase I trial that increases delivery of adacplatinum by more than 16 times to tumors in model systems, and has had a very successful phase I trial.

There are several novel nanotechnology drugs under development, particles that really hone to tumors, and can deliver a variety of kinds of drugs very effectively.

Personally, I think that ought to be a very high priority area of investigation over the next five years, because there are lots of new technologies flooding into this part of the field.

MS. SCROGGINS: I suggest that we develop or have a timeline for monitoring progress against the recommendations, and that there be some regular reporting to the participants.

DR. TRIMBLE: We will try to set that up. In terms of early reporting, we are working with one of our contractors to make sure that all of these slides from the presentations and a summary of the discussions are available on one of our NCI websites, and that will be an open website.

As has been suggested, we will try to come up with a list of the action items and proposals with the planned follow up, and preliminary assignments asking for your suggestions, additional names, and we will try to come up with a schedule and timeline, as well as staff support, to get these exciting projects underway. Jane, do you have any additional thoughts?

DR. FOUNTAIN: Not specifically, but I think the SPOREs are really interested in working together with GOG, especially in the phase II arena.

I will do everything I can behind the scenes. I just want to make a personal comment, that Ted and myself and Mike are reasonably energetic and easy to get along individuals. So, please take advantage of us. We are happy to help.

DR. BIRRER: I would like to say that I am not easy to get along with. I would like to bring up just two items before we leave. I would like to re-discuss the IP therapy issue. [Laughter.] The CTSU is one of my other favorite issues. Can we talk about that a little more?

Just as a closing comment, I would like to say, I would certainly like to thank all the GOG members who participated and came here. I think it has been very helpful.

I would point out that I helped to organize this with Ted and Jane. I came to the table with a certain amount of skepticism that we could really accomplish anything under a very short amount of time, but I think we have.

If nothing more, we managed to get really a who's who in ovarian cancer research into one room talking to each other, and I think that is not a small accomplishment. Thank you.

DR. SPRIGGS: I would just like to, on behalf of the participants, thank Mike and Ted and Dr. Fountain for the work that they put into this. A lot of work went on behind the scenes, and I certainly think that we are all very grateful for your efforts.

DR. TRIMBLE: Thank you. Before we close, I would like to ask either Dr. Thigpen or Dr. Copeland to make any comments on behalf of GOG.

DR. THIGPEN: I don't have any substantive comments, just to thank everyone for their participation in the process.

The GOG, at least, speaking on behalf of our group, is going to take these suggestions, go back, and look at them very hard and try to develop a rational plan for further development of translational research in the group over the next five years. Thank you.

DR. TRIMBLE: Ronnie, would you like to speak on behalf of the Gynecologic Cancer Foundation and the SGO?

DR. ALVAREZ: I will speak on behalf of the Gynecologic Cancer Foundation. We thank all the advocates for being here and giving a voice to this process.

DR. TRIMBLE: Thank you again for coming, and have safe trips home.

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