Thank you. I would like to thank Frank, Vernon and Scott for the opportunity to present today.

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This slide, which will be familiar to medical oncologists in the audience, this is single agent activity of all those agents which can't quite get us over Mike's hump.

The availability of a large number of chemotherapy agents and a small number of biologic agents gave us the hope that these drugs, in combination, would provide us with better outcome for our patients.

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Early data in the 1980s with doublets or triplets of chemotherapy appeared to fulfill that promise, as we saw better response rates.

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And, at about that same time, there were some early trials, a small phase III trial done in South Africa, looking at the addition of a biologic agent here, high dose interferon added to DTIC, showing some promise with improvement in response rate and durations.

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A larger trial, however, by the Eastern Cooperative Oncology Group, with nearly 250 patients, dispelled that notion, showing that response rates and time to treatment failure were not improved with that manipulation.

 

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If one looks at the overall survival curves, the addition of high dose interferon did not provide a substantial advantage.

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So, for the last 10 to 15 years, when asked, we would say that our standard approved agents are DTIC or IL-2, and that efforts to add combinations -- tamoxifen or high dose interferon in phase III combinations -- have been largely unsuccessful.

The most active area of investigation in the last five to 10 years has been with biochemotherapy regimens.

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IL-2, combined with biochemotherapy has had some theoretical rationale, from the standpoint of individual activity, unique mechanisms and toxicities.

The major questions have been, can chemotherapy augment, or does it interfere, or is it irrelevant to IL-2's biologic effects, and which is the most appropriate sequence of administrations.

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There have been theoretical reasons to think of chemotherapy first, because some drugs are thought to be immunoaugmentive, or they might reduce tumor burden.

To think of IL-2 first, because of the possibility that chemotherapy itself may cause immune suppression, or it might modify tumor cells, making them more susceptible to chemotherapy,

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and to give them concurrently, to alter tumor membranes, making them more susceptible to IL-2, or using IL-2's capillary leak for better drug delivery.

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We looked first to some pre-clinical data for guidance, but the biologic effect of IL-2 required an intact host, and our in vivo studies of sequencing had conflicting and inconsistent results, and we have lacked a good biologic correlate of response to guide us.

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So, we have been left with our usual clinical trials mechanisms to help sort this out, looking at individual phase II trials, summary data and, more recently, phase III experiences.

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This slide summarizes a number of the biochemotherapy trials that were done over the last 10 to 15 years, regiments with DTIC, platinum, IL-2 and interferon.

A majority of the investigators here in the audience today were able to generate response rates in the 30 to 60 percent response rates with a number of durable complete remissions.

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Dr. Keilholz and colleagues published results of over 600 patients treated with infusional IL-2 to which chemotherapy and interferon was added, and seemed to demonstrate improvements in response rates, survival and five-year survival compared with other iterations.

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Similar meta-analysis in large numbers of published studies in over 7,000 patients also appeared to produce the same type of trends for IL-2, combined with interferon and chemotherapy across response rates, survival, and response duration.

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By the time the last five years came for phase III trials, we had several thousand patients treated, with response rates in the 30 to 60 percent range, some durable, complete remissions, responses in most organ sites, but our data was limited by the fact that it was largely phase II in its nature.

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That moves us into the era of our phase III trials. When doing phase III trials, it is important to recognize that in the area that we are looking for clinically a response rate difference of 10 percent, in this range, with 90 percent power and two-sided significance, requires a trial of nearly 400 patients per arm.

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When one looks at other clinical parameters, such as median survival, for a true difference of as small as three months in this range, 90 percent two-sided, also a very large trial.

If we are looking for smaller differences, you can double these numbers. So, it is worth looking at what we have done so far in this context.

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The surgery branch at the National Cancer Institute did a small trial with about 50 patients per arm looking at the addition of high dose IL-2 to DTIC platinum tamoxifen, statistically geared to show a doubling of response rate, which was nearly seen.

Conversely, just the opposite with regard to median survival,

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and the chemotherapy arm had a superior outcome, although it was a small phase III trial.

 

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Dr. Keilholz, in the late 1990s, published an experience in which cisplatinum was added to interleukin-2 and interferon, once again in a small trial, and showed improvement in response rate and time to treatment progression that was statistically significant, but no difference in median survival, a trial it was not geared to show the end point for.

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A larger trial by the EORTC with 350 patients looked at the addition of IV IL-2 to DTIC, platinum and interferon, and was not able to demonstrate a response rate or median survival difference at their first analysis, and Dr. Keilholz may be able to update us on that experience today.

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At the same time, the M.D. Anderson did a two-arm, randomized phase III trial in stage IV disease patients, a three drug regimen CVD, to which IL-2 and interferon was added after, and then both before and after in subsequent treatment cycles.

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In their trial, with about 90 patients per arm, they were able to show a substantial difference in response rates and treatment progression, which were statistically significant, and a trend toward improvement in overall survival.

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Against this backdrop, then, was the ongoing trial, ECOG 3695, an intergroup trial looking at three-drug combination, to which IL-2 and interferon was added in a concurrent treatment regimen.

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When the M.D. Anderson data became available, the trial was amended to a larger trial size to be able to capture this median survival difference.

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In data that Mike Atkins will present at ASCO this year -- and I thank him for sharing this with us in advance -- as one can see, the biochemotherapy arm had some improvement over chemotherapy in response rate and median progression-free survival, but no improvement in median response duration or overall survival, and none of these differences were statistically significant.

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The time to progression curves appears to show some early advantage to biochemotherapy which does not persist.

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When one looks at the overall survival curves, they are overlapping.

 

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So, what can one say in summary about our phase III experiences to date? At best, I think we can say that some trends have been in favor for response rate and time to treatment failure, but statistically significant benefit has not been consistent and has not been seen in overall survival.

Most trials, unfortunately, are small, which allow only very large differences to be identified, and most of our trial designs have only differed by one small active agent.

No trial to date has compared biochemotherapy to what we consider to be the standard, either IL-2 or DTIC. However, given the available data, I think it is fair to suggest that biochemotherapy should not be considered for routine care of patients outside of a clinical research trial, and there are very few of those ongoing at the present time.

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What about other efforts in this area? Well, there are some interesting data that I will share with you from Steve O'Day and his colleagues with regard to maintenance biotherapy, where you have an ongoing adjuvant trial with biochemotherapy, and perhaps for consideration is the consideration of not biochemotherapy, but chemotherapy to maximum benefit, followed by biotherapy.

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Dr. O'Day and his colleagues have done an investigation looking at a maintenance schedule of IL-2 combined with GM-CSF, both in the in and outpatient setting, inpatients who have received concurrent biochemotherapy.

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When they compared this experience with their historic experience, in which patients did not receive the maintenance biotherapy, but had received the concurrent biochemotherapy, the patients that achieved a partial response or stable disease appeared to have significantly improved time to treatment progression, and an overall median survival among the largest seen in our field to date.

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This important observation is being confirmed in a 10-institution trial with 145 patients, in which the patients achieving CRPR are stable disease to concurrent biochemotherapy. After two to six cycles, are then managed with maintenance IL-2 and GM-CSF for up to a year's period of time. We will wait to see if that leads us in a different direction or to different conclusions.

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At the same time, we have an ongoing adjuvant trial that is looking in node positive patients at high dose interferon compared with three cycles of biochemotherapy given in a concurrent fashion.

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We know that, despite high dose interferon, 50 percent or more of our node positive patients will die, and this is a very young age group.

At the time we initiated this trial, there was evidence that biochemotherapy had superior response rates, durable CRs, and in analysis appeared to be superior to chemotherapy as well as cytokines.

Perhaps more relevant for the present day and age is that biochemotherapy has demonstrated activity in patients that have failed adjuvant interferon.

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This is summary data from four investigators who have looked at biochemotherapy in stage IV patients, in whom some of those patients had received prior adjuvant interferon and progressed during or after that therapy.

The response rates to the biochemotherapy in the face of prior adjuvant interferon is still pretty substantial, and certainly higher than what we would expect for interferon alone, even in stage four disease all by itself.

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When one compares the adjuvant setting, we are likely to be dealing with less pre-existing micro-CNS disease, probably less innate tumor resistance, and less tumor related immune suppression.

We have a toxicity profile that is appropriate for a high risk population, and the ability to give a treatment over nine weeks versus a year would potentially be viewed favorably by our patients.

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That trial is including palpable node positive disease and a single microscopic node if the primary is ulcerated, two or more positive nodes identifying a subgroup with a 50 to 90 percent likelihood of relapse and death.

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Looked at in the context of the AJCC staging criteria, it is including all the bad boys and girls of the nodal world, and excluding only the non-ulcerated primaries with a single microscopic positive lymph node.

 

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This trial has accrued over 140 patients, aiming for 400 patients total, looking for a 10 to 15 percent survival advantage.

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Jeff Sosman has developed a biologic correlate to this particular trial, which will look at minimal residual disease in the form of RT-CPR for GP100, Mart1, tyrosinase and mage-3.

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The last question that reviewing all this data raised in my mind was whether chemotherapy may actually be interfering with the biologic effects of IL-2 or interferon.

For consideration is the fact that certainly we view interferon -- or at least some of us do -- as having single agent activity and relapse free and overall survival in stage III disease. Yet its benefit, when added to DTIC in stage IV disease, is negligible.

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The surgery branch trial, which has demonstrated one of the longest survivals to chemotherapy alone, has always been intriguing because it was well matched to a biochemotherapy arm.

The question has always been, did these patients go on to receive IL-2 in other protocolsor in other locations, and what we are really looking at here is maximal chemotherapy followed by maximal biologic therapy.

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Along the same vein is Dr. O'Day's trial. If he demonstrates the same concept of an improved survival with biotherapy after induction with a biochemotherapy regimen, is what we are looking at the effects of maximum chemotherapy followed by a biochemotherapy regimen?

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This is certainly a simple and easy concept to test, in a day of all these agents being available clinically and may be one small thing we can do, while we are waiting for the Gleevec of melanoma to come along.

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With that, I will close. I thought that these remaining slides were probably apropos of both the hour and this audience.

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I don't know who to credit. I found this in a throwaway several years ago. Since I am a David Letterman fan, these are the top ten translational scientific academic euphemisms.

You can decide how many I have used, you can decide how many other people have used in this audience over the course of the afternoon, and I will leave you with that, and thank you all for your attention.

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