DR. ARMSTRONG: I think, if it is all right with everybody, what we would like to do is have the second speaker come up, and then we can have discussion and questions for the second speaker.

I would like to introduce Dr. Jerry Collins from the NCI, who is going to talk to us about more additional data, about future possibilities for IP therapy.

DR. COLLINS: Good afternoon. This is day nine for me on my new job, and this is the first time they have let me out of the building to talk to an outside audience. So, I am just delighted to be here.

I have just finished an absolutely fabulous sabbatical at the Food and Drug Administration, where I learned all kinds of things that I think will be important for the future of developing therapeutics. After 17 years, NCI thought my sabbatical was over, and they asked me to come back.

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I am all in favor of the future, and delighting in its possibilities, but my own view is that there is a lot that can be done right in the present, and that we ought to spend at least some time focusing on that as well.

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A couple of very simple messages this afternoon on how we might think of improving chemotherapy in ovarian cancer.

First of all, find new drugs, find better drugs. One of the excitements for me in returning to the NCI, and to leading the developmental therapeutics program would be the possibility of working with folks like you in disease specific areas to try to improve the process by which we discover and develop drugs.

No matter how effective we are, and how clever and innovative we are with different routes of administration, there are always going to be unmet needs in terms of resistant disease, and we need to have therapies available for that.

While we are doing that, we have to simultaneously figure out, as you folks do every day in your protocols, how to make existing drugs work even better than they do now, and intraperitoneal delivery is one of the strategies that pushes us along in that direction.

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So, I noticed that the GOG has a developmental therapeutics committee, and the program I have just inherited is called the developmental therapeutics program.

My colleagues from the Cancer Therapy Evaluation Program are just one floor below me on the same building. So, I am certainly very interested in entertaining ways that we can all work together, and that there are other stakeholders who are organized and interested in finding new drugs and better drugs. I think there is plenty of work to be done. We ought to pool our resources.

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I don't think I was invited to give a history lesson, but you know, when I opened my intraperitoneal file, there was Time Magazine from 1978.

At that point, the nephrology community had, a little bit reluctantly, adopted peritoneal dialysis as an alternative to hemodialysis machines.

It is hard to believe, in 2005, that in most Medicaid programs around the country, patients initially put on treatment with end-stage renal disease are treated with peritoneal dialysis. So, it has really moved a long way over the several decades that it has been available.

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I am sure it was just a coincidence that also, in 1978, the classic description of the strategy of peritoneal drug administration, at least the pharmacokinetic rationale, was published by Bob Dedrick and his colleagues in the Journal of Cancer Treatment Reports. So, 1978 was the beginning of the story, but we live in 2005.

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Well, I arrived a little bit later at the NCI, after these folks had already done the heavy lifting. What I found was that there was spectacular modeling that was done pharmacokinetically, but perhaps audiences weren't prepared to swallow all the equations at one time.

Data was very popular. So, if you could show that peritoneal fluid concentrations were 100 or 1,000 times higher than circulating plasma concentrations, that was really the take home message.

If that is, indeed, the take home message, well, it is really just the beginning. First, you deliver higher concentrations. Secondly, you see if those concentrations have any pharmacodynamic effect. If that is the take home message for pharmacokinetics, then we need simpler equations.

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So, although I dearly love differential equations, and the more the better, particularly after lunch audiences' eyes sort of glaze over.

I had an opportunity in 1984 to write a review article for the Journal of Clinical Oncology.

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One of the things that seemed appropriate to me, given what people were doing with pharmacokinetic data, was to think about the two key parameters that make a difference in terms of driving pharmacokinetic differences.

So, this equation, R D , which is just the delivery advantage, is really proportional to total body clearance, how fast the drug is removed from the body in general systemically, divided by the rate of exchange of the drug, from wherever you put it, like the peritoneal cavity, to the rest of the body.

So, these were the only two things that you needed to know about pharmacokinetics. You went around the hall to your local pharmacokinetic department and you said, “What is the total body clearance of this new thing I have,” and how fast does it get in and out of the peritoneal cavity.

Sad to say, this was too complicated also.

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So, this afternoon, for the first time, I am here to announce a new pharmacokinetic equation that makes the science simpler and even easier.

Now, science is multi-parts. The first part is pharmacokinetics. If you don't have a delivery advantage, you don't need to go much farther.

If you do have a delivery advantage, you made a clear victory in your first paper, but the hard work is just beginning. Does a 10- or 100- or 1,000-fold difference in concentration translate into better therapy.

Let's have the simplest pharmacokinetic equation to answer the question raised by the previous speaker, of what would be a good agent to give intraperitoneally. What do you need to know, what do you need to remember when deciding what a good agent is?

I think that the pharmacokinetic answer is just about every drug that has substantial activity against ovarian cancer is an attractive candidate for IP delivery.

Exceptions are things like cyclophosphamide, which aren't activated while they are in the peritoneal cavity, have to be absorbed and then re-circulate. That is no better than giving it systemically.

Almost everything else is very likely to give you a high delivery advantage. So, my own feeling, having worked several decades in the pharmacokinetic and pharmacodynamic arena, is this is one of the areas where you ought to focus on the shape of the dose concentration response curve, and the clinical measures of outcome.

Pharmacokinetics is your friend, but you don't have to dwell on it. You will quickly find out that you can achieve a good delivery advantage.

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Then you are going to say, wow. All that pharmacokinetic stuff is nice. What are the clinical results?

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While I was on sabbatical for 17 years at the FDA, I was a little bit removed from direct clinical research in ovarian cancer.

However, as a member of ASCO, an increasingly thicker journal is delivered to my house every month. In 2001, in February, which isn't the middle of the baseball season, I thought the game was over. There was an editorial from Dr. McGuire saying, all this effort and the best we have is a sacrifice bunt.

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For somebody who was on the sidelines, it was not a pleasant thing. The only thing I could remember was, the other journal that comes to my house frequently, Science, says that it is not unusual in our field to have differences of opinion.

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It was surely delightful, a few months later, a little more than a year later, when Alberts, Markman, and Armstrong, Rothenberg, Musian, and Howell, had their own theory of what is happening with intraperitoneal therapy, and it couldn't be more diametrically different in conclusion than Dr. McGuire's assessment.

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Since then, there has been a lot of debate, and I can't assess how much work has been done.

At this point, I am completely convinced that the debates, although they are healthy, at some point you can't dwell there either. You can't be hung up there.

You need to move forward. You need to design rational trials and continue to refine the data from existing trials.

These trials aren't done overnight. It is a lot of work. It takes a lot of time to get the data, to lock it and so forth.

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There is no need to have an argument over whether IP catheter management is difficult. It is difficult. Just say that up front, and just assess how difficult it is relative to other things that people in this business do every day.

Continuous IV infusion, central lines, are quite a challenge as well. When I was first at the NCI in the late 1970s, infections in central lines were the main reason why people didn't get their full course of therapy.

A couple of days ago, at another Marriott hotel down Route 355, we were at the Phase I investigators' meeting, and we heard presentations of continuous IV infusions of 14 to 21 days without any qualms at all, about is this something that is feasible for first in human studies.

So, as oncologists, as chemotherapists, we are used to challenges in drug delivery, and we can't deny them. We can't be in denial about them, but we can overcome them if the carrot is sufficiently strong enough.

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This is my first time at a State-of the-Science meeting and, having worked at FDA for a long time, we are used to editing things.

The first thing is, it looks to me like one of the things you need here, in addition to science, is some engineering.

If one of the barriers to development of IP chemotherapy has to do with catheters and devices and how you handle them, that isn't what we used to call rocket science. That is engineering.

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So, just a couple of suggestions for those of you who haven't wandered too far on the web recently. The International Society of Peritoneal Dialysis is made up of nephrologists and related specialists who use peritoneal dialysis in the treatment of peritoneal infections and in the treatment of end-stage renal disease.

They have a wonderful site. All you need to remember is ISPD, International Society of Peritoneal Dialysis, lots of information there.

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The two buttons on the right side, treatment guidelines and how to deal with peritoneal dialysis-related infections, really is just tremendous material.

It includes how to train nephrology folks to do it. If nephrologists can do it, how could anybody argue that an oncologist couldn't do it.

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That is not denying that infections occur. It is developing guidelines and procedures for dealing with them, and that is what professional societies do best, and it is all close at hand.

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So, in conclusion, I think our approach to improving chemotherapy of ovarian cancer does depend on the state of the science and the state of engineering.

As my first time out of my office here, I would be delighted to work to form partnerships with those folks who have a passion for developing new drugs, better drugs, and moving therapy forward in that way.

Whether it is a small molecule, whether it is an antibody, whatever kind of approach it is, if it is a therapeutic approach, then it is worth figuring out how to get it tested in human beings.

Secondly, I think the same kind of strategy works for making existing drugs better. When barriers and difficulties and challenges are identified, the way to get around them is to partner.

At every academic medical center that has oncologists, there are also nephrologists. I don't know how big the wall is or how thick the concrete blocks are between them, but I know at least one nephrologist, one chief of nephrology at an academic medical center, who has been funded by the developmental therapeutics program at NCI for 10 years to look at intraperitoneal chemotherapy.

So, it isn't impossible to match those two disciplines if the carrot is strong enough. You folks are far better equipped than I am to evaluate the three randomized phase III trials that have shown some benefit.

If that benefit is substantial, then there are reasons to go after it even more aggressively. Thank you.

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