Treatment Paradigm in Lower-Risk MDS (LR-MDS) Patients

EP: 1.ASCERTAIN Trial Overview

EP: 2.TP53 Mutation and Its Impact on Patient Outcomes in MDS

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EP: 3.Treatment Paradigm in Lower-Risk MDS (LR-MDS) Patients

EP: 4.Treatment Patterns in the Management of MDS

Guillermo Garcia-Manero, MD: Hypomethylating agents were approved in the United States close to 20 years ago. In those days we did not have the level of sophistication we have now in understanding this disease. If you look at the labels of azacitidine and decitabine, they were approved for basically any type of MDS [myelodyplastic syndrome] that included up to 30% blasts, something that is considered AML [acute myelogenous leukemia], today. And it included patients with low-risk disease. Subsequently, when these drugs were approved in Europe, at least azacitidine, the label was restricted to patients with higher-risk disease. So there’s a bit of dichotomy between what we do in the United States and Europe. But a number of years ago I developed this oral azacitidine; I was doing phase 3 and phase 1 trials of this compound. We found that the PK [pharmacokinetics] profile of oral azacitidine, the CC-486, was low compared to that of IV [intravenous] or subcutaneous azacitidine. Then I thought maybe we could go with a lower schedule of this drug in lower-risk disease. We call this attenuated hypomethylating agent dosing.

So we designed a number of trials. They’ve all been published in Blood, JCO [Journal of Clinical Oncology], etc, looking at 3-day decitabine, 3-day aza [azacitidine], and we see that this schedule is effective in this disease, and indeed they’re in the NCCN [National Comprehensive Cancer Network] guidelines. Again, they don’t have a label in Europe, but we use it a lot here in the United States. So based on that, there was a study with CC-486, the oral azacitidine, which was designed for low-risk disease. That study had a lot of problems, meaning the schedule that was selected, and the type of patients. But the reality is that we did not see a benefit, and there was a bit of toxicity with some mortality early, in that particular trial. So that impeded the approval of oral azacitidine for low-risk MDS. That study has been revised, and there’s a new phase 3 study now being evaluated.

But in parallel, when we got decitabine with cedazuridine, the drug that you were asking me about earlier, we thought that maybe we could do a study in low-risk disease, learning from all this experience we have. Last year we presented data from the ASCERTAIN study, looking at a cohort of patients with the lower-risk disease, and we saw nice activity and safety. Basically, with all this information I gave you, we designed this phase 1 study looking at proper doses of this low-dose decitabine. But here what we did was look at a different dose of the decitabine, so instead of 35 mg, we used 10 mg. Then we looked at different days, 5, 10 days, things like that. In the presentation, I believe there were 6 different cohorts that we studied in this randomized phase 1 trial. The data we showed in the presentation were the results of this phase 1 trial where we looked at these 6 different cohorts. In the end, we didn’t study all of them, we thought one was going to be too toxic. We came up with this particular cohort that we think actually is the best in terms of safety and level of activity, the methylation activity.

Now we’re going to move that into a randomized study comparing that dose with what could be considered the standard dose, which would be 35 mg of the decitabine with the cedazuridine for 3 days. Basically in one, we give 5 doses; this would be the dose that was recommended by the phase 1, a lower dose of 10 mg. Then it’s going to be compared with the standard dosing of decitabine and cedazuridine that is the formulation approved right now. That study is going to be an interesting one to see if we can establish a dose of this drug that could be safe and effective in low-risk myelodysplastic syndrome. I think this is an important need for our patients.

We’re learning, thanks to some of this new analysis by the IPSS-M [International Prognostic Scoring System-Molecular] and things like that, that what we call low-risk disease maybe is not always low-risk disease. Actually, it could be a really difficult disease to have if you’re the patient. So we’re starting to divide it into different subsets of patients. You have people who are truly low risk with very benign features that basically just need observation, to patients who if you use more modern molecular classifications, really have a poor prognosis. That’s No. 1. We’re starting to learn that they are not all the same. This is becoming a very important topic. Some of these patients may have cytopenia, for instance, anemia could be the key. But for others, you may see neutropenia, anemia, thrombocytopenia, etc. Those patients, we think, will benefit from an intervention like this with a hypomethylating agent.

The formulation here is a lower dose of the decitabine, 10 mg, for a bit longer, 5 days, and the same dose of cedazuridine, 100 mg. We are going to compare it with what is, not really approved by the FDA, but the commonly used schedule of decitabine, which is daily for 3 days at the standard dose, which would be 35 mg. We are comparing a bit lower dose and a bit longer exposure vs this 3-day standard type of approach.

I don’t know how we’re going to take this forward, it will be up to the sponsor. But I think if we can come up with a nice dose and schedule, then we need to prove that this helps our patients. The question will be what kind of design and so forth. I think this is a very important area also, a more effective early treatment for low-risk MDS.

This is an interesting concept [seclidemstat]. This drug is an epigenetic regulator that works through a different mechanism of action as opposed to DNA methylation. For instance, that is what azacitidine and decitabine do. It would make sense that molecularly these compounds will synergize. The data presented were from a small pilot trial. We saw activity in patients with relapsed/refractory disease with this combination [with azacitidine]. But right now that study is on hold by the FDA because of some potential toxicity with the investigational inhibitor in this study. But we have not seen that in MDS. I believe that in MDS we use this compound at a lower dose than in some of these other studies. But I think the toxicity that was observed in some of these other trials was severe enough that it mandated the FDA to stop these programs until they get better clarification in terms of what really happened here. We were disappointed because we were starting to see a signal of activity in this group of patients with refractory disease with a very interesting epigenetic combination.

These are what they call LSD [lysine-specific demethylase] inhibitors. They basically modify histone code, and this cross talks with DNA methylation. So they’re part of this inactivating histone promoter coding that allows for expression or not…. This has been the topic when we developed these drugs. In the past, we used HDAC [histone deacetylase] inhibitors. We have these new classes of compounds. There are other drugs in this category, not maybe exactly, but for instance, BET inhibitors and things like that, that affect commonalities in these pathways that are showing activity in other diseases as well.

Transcript edited for clarity.