SLIDES & TRANSCRIPTS
Wednesday, February 2, 2000

Report from Working Group B
Frederick Appelbaum, MD

DR. APPELBAUM: I would like to just echo Bruce's comment that I think this meeting has gone very well. One of the reasons that it works well in leukemia is that in general I think the community has been very interactive and a collegial community and the cooperative groups have already had a number of successes with intergroup studies. So, I am hoping that this will continue.

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We were asked to talk about the topic of antibody therapy and as the other groups have been charged, we were given four areas of discussion to consider. First, to consider: are there Phase III studies ongoing or that we can see on the horizon which we believe merit support? No. 2, are there Phase I or II studies that are starting or will be starting in the near future which we believe deserve emphasis? Three, are there new areas for research or funding opportunities that should be considered, and four, are there impediments to the research?

I should say that in our group there was general unanimity of opinion. There was not a lot of controversy and I think that reflects the fact that the antibody field is relatively sharply focused. Relatively few reagents are available. I would like to think it also reflects the talent of the researchers, but I cannot actually endorse that.

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First, Phase III studies. Considering unmodified antibody, the group from Sloan-Kettering have pioneered the explorations into unmodified antibodies, and there is currently a Phase III study which involves the combination of the unmodified antibody with MEC therapy in patients who are in relapse or who have refractory AML. We believe this is a reasonable question to be addressed, and the study deserves support.

The group from Sloan-Kettering, as you heard, also has intriguing data about the ability to use unmodified antibody to convert APL patients who are PCR-positive patients to PCR negative, in the subset of APL patients who have been induced with ATRA and chemotherapy. This is an intriguing observation. However, we also recognize that there are lots of other very important reagents to be tested in APL, and APL is a relatively rare disease.

So, while we generally endorse the concept of research in that area, we also noted that some sort of innovative trial design is going to have to be considered in order to bring unmodified antibody forward in APL.

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Next, considering modified antibodies there is only one antibody that is in a modified form with a toxin that is ready for Phase III studies or will soon be ready for Phase III studies and that is the CMA-676.

All of us are very interested in seeing this moved forward into Phase III studies, and it appears that the Phase II data with CMA-676 are mature enough to warrant further Phase II studies and moving forward into Phase III.

We considered first of all the idea of using CMA-676 with ARA-C in a situation where you would substitute CMA-676 for an anthracycline and the possibility of using CMA-676 as an addition to an anthracycline plus ARA-C. Both are possibilities. Alternatively, CMA-676 could be used as consolidation or maintenance therapy after patients have achieved complete remission. These approaches will all require pilot studies proving the safety of the approach, followed then presumably by Phase III trials which we encourage.

From the data that have come from Irv Bernstein and our group in Seattle, we have found that there appears to be resistance to CMA-676 in patients who are MDR positive. This observation provides a strong rationale for using an MDR modulator with CMA-676, particularly in a setting where you are targeting chemotherapy and will not be causing increased toxicity because the chemotherapy is not going to any other organs. Therefore, there is a strong rationale for a randomized study of this approach.

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Finally, as far as Phase III studies combining an antibody with a radionuclide: I obviously acknowledge a conflict of interest in presenting this, but the only one that the group agreed was ready for a Phase III trial is the idea of BuCy with the anti-CD45 antibody which Irv presented yesterday and which Dana Matthews and our group at the FHCRC have been piloting. That is going into a broader Phase II before the Phase III study would be considered.

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As far as Phase I-II studies, we were encouraged by some of the early data that Art Frankel presented yesterday combining diphtheria toxin with GMCSF. We believe these studies should be encouraged. There is a possibility that IL3 is a better conjugate with diphtheria toxin. Both of these approaches are very interesting. Then again, there is a group of early studies piloted by the Sloan-Kettering group with their anti-CD33 antibody looking at yttrium, bismuth, and astatine radioimmunoconjugates or linked with other toxins, all of which are early in Phase I studies, and we will be watching these with a great deal of interest.

For most of these, the alpha emitter approaches really are not ready to be disseminated outside of Sloan-Kettering. This is a very technologically challenging area but will probably need some form of industry support if it is going to go more broadly.

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. Finally, Phase I-II studies. There was a great deal of interest in the idea that one could use the targeted therapy that is afforded by antibodies combined with either a radionuclide or antibodies combined with a toxin such as CMA-676 to eliminate the majority of disease in preparation for non-ablative transplant. Data now coming out of a number of our institutions show that you can get the graft and presumably the graft versus leukemia effect without the very toxic preparative regimens which we have commonly used. So, Phase I-II studies combining, for example, Myelotarg or anti-CD45 antibody with non-related transplants are encouraged.

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As far as new research areas, have we really exhausted the use of antibodies in AML? Most of us involved in the field do not believe that is necessarily the case. We have used what has been available to us, but it is quite easy to kill an AML cell if you deprive it of certain stimuli. For instance, if you try to grow AML cells in culture, and you do not have the right adhesion molecule or you do not have the right growth factor, these cells die. That begs the question that if you had antibodies that mimicked ligands and therefore did not signal but blocked signaling, or, if you had ligands that could stimulate apoptosis, would you find situations in which these approaches would work in synergy with chemotherapy? So, one can imagine combining a ligand that blocks the growth factor signal with a chemotherapy agent that might work in a synergistic way making the cell more pro-apoptotic.

There has not been a lot of research about such approaches, but given what we have already seen in breast cancer with Herceptin plus taxol or in the non-Hodgkin's lymphomas with the synergy between anti-CD20 antibodies and chemotherapy, one wonders if this isn't an area that could profit by intense investigation in the future.

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Finally, we had a very brief discussion about impediments to research. I think these are the same things that David Parkinson talked so eloquently about last night. But in addition to the issues he raised, for antibodies and antibody toxin conjugates, we are faced with the problem that these are expensive agents to produce. Pharmaceutical companies don't have a great interest in the area because of the limited market and so we do need help from the NCI. We need help to create new growth factors, growth factor mimics, or toxin conjugates.

So we need continued help from the NCI or the NIH to support the development of these reagents. We, also, share all of your frustrations of getting these into clinical trials rapidly and having those trials expanded, but I think to talk about the other impediments would be redundant from what you will hear from other investigators and what you heard from David last night.

That is generally the report from our group.

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