SLIDES & TRANSCRIPTS
Monday, May 12, 2003

Working Group E: New Agents and Drug Resistance

Mary Relling, Pharm.D.
Hagop Kantarjian, M.D.

DR. KANTARJIAN: So, I am going to summarize the data on behalf of the group. What we discussed are several strategies.

It was interesting that, when we started, there was a bit of a depressed mood, but as we came to the end of the session, there were several strategies that I think are worthwhile looking at or investigating.

So, the first one was mentioned, based on the data that FLT3 mutations are, in fact, common at the rate of 15 to 25 percent in MLL rearranged ALL, or in patients with hyper diploid karyotypes, and also in the setting of relapse.

So, Dr. Armstrong showed the data and then he showed some in vitro studies in FLT3 mutated cell lines, where the additional PKC412 showed suppression of the FLT3 expression.

So, he emphasized that, in ALL, most of the abnormalities are mutations as opposed to ITDs, and that they resulted in over-expression of FLT3.

He showed also an animal model where the animals that were given the FLT3 mutated cell lines and left alone showed a lot of disease as opposed to the ones that were treated with PKC, I think 150 milligrams per kilo daily. At four weeks, there was a clear difference in the level of the disease in these animals.

So, the first idea is the FLT3 inhibitors are not specific for AML, but they could be also an effective modality in ALL, and perhaps not only in situations of FLT3 mutations, but also in cases of FLT3 expression. Did I summarize this correctly, Dr. Armstrong? Okay.

So, the second approach was discussed by Dr. Carducci, who showed data in AML and some in CLL that showed that increased methylation was present in those two entities, and they have studies now ongoing with decitabine and with valproic acid, which is a histone deacetylase inhibitor.

The idea is that the combination can enhance the suppression of methylation and improve the outcome. They have also similar concepts in ALL.

One of the questions that came about was, why do we use valproic acid, and it was a simple question of availability. He emphasized that, should we have SAHA or depsipeptide or some of the other more interesting histone deacetylase inhibitors, in combinations of decitabine or azacytidine, could be used there.

Dr. Issa, who is not here, had shown that similar findings are present in ALL. Twenty-five percent of ALLs have methylation of particular subsets of genes, and the patients who have such a methylation profile have the worst prognosis.

So, like Dr. Carducci’s studies, we are entertaining studies with decitabine, and histone deacetylase inhibitors.

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The third drug which is currently in phase I-II studies of interest is liposomal vincristine. This broad issue of an old study that was published by Dr. Devita on MOPP in Hodgkins disease, where he showed that the dose intensity of vincristine improved the cure rate in MOP.

There was the mention that there is now a meta-analysis study in ALL, which was done by the British group on the randomized studies of -- no, that was in methotrexate.

It was mentioned that there was a meta-analysis in methotrexate showing the dose intensity improved the outcome, and the question was whether a similar meta analysis in ALL could be done to see if the dose intensity of vincristine is also related to better prognosis.

There was a mention of a retrospective analysis in childhood ALL where the larger kids that had the dose capped at two milligrams did worse. Of course, this brings the issue of age and other factors.

Nevertheless, there is enough data to suggest that dose intensity of vincristine, if it is not dose limited by neurotoxicity, could improve the outcome of the patients and should be investigated. So, I mention that there is a study now in lymphoma with CHOP replacing vincristine with liposomal vincristine, and we are entertaining studies in adult ALL. We are into the phase II part of the study that Debbie Thomas is chairing at our institution.

The fourth group of agents of interest are the T cell specific agents. Here, there are two which are of interest.

One is in advanced stages, the compound 506. There are both the pediatric studies and the adult CALGB studies, showing that, in the setting of salvage, there are CR rates of about 40 to 50 percent in pediatric and of about 30 percent in adults.

Both these studies are now being entertained for the potential of FDA filing, but the filling has not occurred yet.

Another drug of interest is BCX-1777, which increases the GTP pools. Again, Debbie Thomas is conducting the phase I-II studies.

So, I think these are agents to keep an eye on in the setting of T cell ALL and perhaps in other entities, because compound 506 has been shown to have efficacy in the B cell ALL. So, it may not be specific for only the T cell lymphoid disorders.

The fifth drug of interest is clofarabine. This is a nucleoside analog which is similar to fludarabine and chlorodeoxyadenosine. So, it is a hybrid drugs that combines the favorable properties of both of these agents.

It has now gone through phase I/II studies, and is now in combination studies with AraC and, in the near future, with daunorubicin and AraC.

So, the plans are as follows. In pediatric ALL, the pilot study showed good responses which are durable. When the drug was taken to a larger cooperative group in unselected patients, the results were poor. So, the company could not go for an FDA filing. So, the concept needs to be revisited in pediatric ALL.

In adult AML, we are going to try to find the best combination of clofarabine, either with AraC or with idarubicin AraC, and then take it to the appropriate trial against the standard of care, which would be anthracycline AraC, either in the front line or in the salvage setting.

Gleevec or Imatinib is an obvious idea in Philadelphia positive ALL, and this was already discussed in terms of the intensity, the dose schedule, the duration of therapy and how to intercalate it with chemotherapy up front, or as a maintenance, and intersecting of transplant.

My bias is that you have to use the highest dose possible for the longest duration without interruptions. That is what we are going to do with the high dosage regimen.

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The seventh group of interesting compounds are the monoclonal antibodies. Here, there is the new monoclonal antibody, anti-CD22, which CD22 is expressed in 90 percent of the ALLs, and I think there is the concept for a phase I trial in pediatric ALL, which is going to start.

Rituxin is already ongoing in some of the CD20 positive ALLs, particularly the mature Burkitt ALL with poor prognosis, like the elderly patient, and in the CD20 positive ALLs.

Campath-1H is being entertained by the CALGB as part of their block maintenance, I believe the subcutaneous formulation over a short period of time.

Here, the question was raised as to did they use suppression and the need for anti-CMV prophylaxis in these patients, if that is considered as part of front line therapy.

Then we discussed some of the other new agents simply as concepts because there is no data. So, the MTOR inhibitors, there is rapamycin and there are two MTOR inhibitors, I think CCI-779 and one by Novartis.

Dr. Andreef emphasized, and Dr. Guido Marcucci emphasized the potential value of BCL2 inhibitors, particularly Genasense, which has ongoing studies in AML but not yet in ALL.

The NCI group wanted some ideas regarding the use of proteasome inhibitors and the use of the multi-targeted anti-folates, and I think there was a good interest with Altima, as well as with PS341.

Finally, we discussed the notion of using MDR inhibitors. There was a discussion that the old MDR inhibitors, which were thought to be specific, affected the anthracycline metabolism.

Nonetheless, the subset analysis done by Dr. Collette showed that the younger patients who were able to metabolize the MDR appropriately did better. So, that is going to be the subject of a new study.

There are two new MDR inhibitors which do not inhibit the metabolism of anthracycline, which are available and may be potentially used in the new studies.

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The last set of drugs that we discussed were the old drugs that were revisited in new formulations. So, PEG-asparaginase has been studied both in the pediatric and in the adult setting.

What I heard is that it is easier to give it to prevent immunogenicity in pediatric. It is well tolerated. In the CALGB study, it is well tolerated, but it was mentioned that Dr. Sallan started randomizing patients to PEG-asparaginase versus the regular asparaginase and showed that the regular asparaginase beat the PEG-asparaginase by about a six percent improvement.

So, there was some worry that the PEG-asparaginase was not used in the optimal form, and Dr. Sallan suggested that we have to go back and look at individual metabolism and look at the individual tolerance of these patients, and how they suppress asparagine levels and so on.

Six thioguanine (6TG) is an old drug which was mentioned, because there is one positive study of 6TG versus 6-MP showing the better results with 6TG. There is also the occurrence of veno-occlusive disease at the dose which was used, which was 60 milligrams per meter square.

So, it was mentioned that the new schedule is at the lower dose, and it wasn't sure whether the lower dose schedule would still improve the results.

Later on, it was also mentioned that there are two similar studies, randomized 6TG of the lower dose to 6MP, and neither of them were positive.

So, I think except for one enthusiastic researcher, I think the 6TG is not something that the pediatric investigators are going to take further.

I was asked about the liposomal daunorubicin, because we have done several pilot phase II trials with the liposomal daunorubicin, demonstrating that it could be given at high dosages of up to 360 milligrams per meter squared per course, without target toxicity and without added significant extramedullary toxicity.

We took it to front line in combinations and I think the drug may be ready for a randomized study of the liposomal daunorubicin, at the maximum dose with AraC versus the standard of care, but I don't think any group in the United States was interested in that.

We had extensive discussions on the high dose methotrexate, one gram versus up to five grams per meter square use of continuous infusion over 24 hours. This was based on the meta-analysis that showed that more methotrexate is better.

I was also given some thoughts about the use of aminopterin and also some people came later and said, well, don't worry about this, the high dose methotrexate might not be important. So, I am a bit confused as to where the high dose methotrexate should be taken.

Finally, dexamethasone versus prednisone. It appears that there is both a pediatric and an adult study showing that dexamethasone is better than prednisone.

I think it might be time to replace, in all the studies, to replace prednisone for dexamethasone, and perhaps look at more dose intensive regimens. That is a summary of our discussion. Any additional comments? Any comments from the audience? Any corrections? Okay, thank you.

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