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Fedratinib in MF: JAKARTA2 and FREEDOM Trials

Panelists: Harry P. Erba, MD, PhD, Duke University; Rami Komrokji, MD, Moffitt Cancer Center; Mary Frances McMullin, MD, FRCP, FRCPath, Queen's University Belfast; Ruben A. Mesa, MD, FACP, UT Health San Antonio MD Anderson Cancer Center; Jamile M. Shammo, MD, FASCP, FACP, Rush University Medical Center
Published: Thursday, Aug 29, 2019



Transcript:

Harry P. Erba, MD, PhD:
Rami and Mary Frances, I couldn’t have done this better. It is such an incredible segue to our last segment. What’s on the horizon? I’m going to start with Ruben to bring us through some of the development of fedratinib.

Ruben A. Mesa, MD, FACP: Sure. Fedratinib is a JAK2 and FLT3 inhibitor. It had had large studies in which most of us participated. There was the JAKARTA study, in which, compared with placebo, it was superior for control of spleen and symptoms. However, in that process, there were a small number of neurological events, which occurred in about 8 of 900 patients, that led to an FDA clinical hold on the drug. And for a variety of reasons, the drug was put on the shelf. Those data were analyzed, and that was really felt to be this unmet need for patients with myelofibrosis. These data were analyzed intently, and they realized that of these 8 patients, maybe 1 had a genuine Wernicke encephalopathy. The other 7 were probably a range of different things. There was a great interest in trying to resurface this drug that had had a clear efficacy and was on a pathway to approval.

In parallel with that JAKARTA study, we had conducted a JAKARTA2 study, of which we’re presenting a reanalysis here at this year’s ASCO [American Society of Clinical Oncology Annual] Meeting. The JAKARTA2 study was in patients that had failed ruxolitinib and received fedratinib as a second-line therapy.

We conducted this several years ago, back in 2013. We’ve learned a lot since then. This reanalysis is a stricter, more modern definition of what RUX [ruxolitinib] failure looks like. When we started this study, RUX [ruxolitinib] had just recently become approved, and there were a lot of patients that had had a very brief exposure—5 days of ruxolitinib and things of that nature —that were a bit misleading, so we reanalyzed this. We now have a bulletproof set of patients—66—that at least had an adequate trial of ruxolitinib prior to starting fedratinib. They had a clear reason for being resistant or intolerant, and they had 6 months of fedratinib to be evaluable for response. 

We reported at this meeting about a 30% response rate for both the spleen and symptoms in this fairly clean group. That transitions to the other presentation we have at this year’s ASCO, which is really a trial in process. That is the FREEDOM study, led by my colleague Srdan Verstovsek, MD. I and many others here are coauthors and coinvestigators on that study. We’re prospectively going to look at that fairly clean group of patients who are resistant or intolerant to ruxolitinib, the same criteria we use for this reanalysis for JAKARTA2, and it’s going to be a single-arm study. We’re going to treat those patients.

In parallel, we’re going to be doing active monitoring for any neurological adverse effects. We’re going to be monitoring thiamine levels, because this issue of thiamine and Wernicke encephalopathy has been raised, and they’ll be receiving thiamine supplementation. Again, we’re going to try to mitigate any of that to the degree that we can. Then all that data will be looked at in aggregate by the new company that holds the drug, Celgene Corp, to make a case for whether an approval should be forthcoming on the aggregate experience with fedratinib.

Harry P. Erba, MD, PhD: I’m going to ask you to back up right to the beginning—maybe I missed this. Fedratinib is a JAK inhibitor.

Ruben A. Mesa, MD, FACP: Correct, it’s a JAK2 and FLT3 inhibitor.

Harry P. Erba, MD, PhD: Why is there a preclinical reason or a rationale for why this might be expected to be effective in patients who are resistant to ruxolitinib? Were these mostly patients intolerant to ruxolitinib who needed another therapy?

Ruben A. Mesa, MD, FACP: It was a mix of both. In many areas where we have more than 1 drug in a class, they never are really exactly the same. The expectation, again, is that a range of folks who did not have an adequate trial, who are resistant or intolerant, may respond to a drug that is coming as JAK in a slightly different way. It may be a bit more potent or a bit more selective. Clearly, it’s impacting the kinome in a slightly different way, as well as the empirical data that we have from JAKARTA2. Although we may not have everything worked out mechanistically, there’s evidence of clear response in the second-line setting.

Again, we’re with an azacitidine and decitabine in the same class, but there are clearly patients who respond to 1 and second-line for the others, or the nilotinib and dasatinib patients who respond to 1 after having had the other.

Transcript Edited for Clarity

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Transcript:

Harry P. Erba, MD, PhD:
Rami and Mary Frances, I couldn’t have done this better. It is such an incredible segue to our last segment. What’s on the horizon? I’m going to start with Ruben to bring us through some of the development of fedratinib.

Ruben A. Mesa, MD, FACP: Sure. Fedratinib is a JAK2 and FLT3 inhibitor. It had had large studies in which most of us participated. There was the JAKARTA study, in which, compared with placebo, it was superior for control of spleen and symptoms. However, in that process, there were a small number of neurological events, which occurred in about 8 of 900 patients, that led to an FDA clinical hold on the drug. And for a variety of reasons, the drug was put on the shelf. Those data were analyzed, and that was really felt to be this unmet need for patients with myelofibrosis. These data were analyzed intently, and they realized that of these 8 patients, maybe 1 had a genuine Wernicke encephalopathy. The other 7 were probably a range of different things. There was a great interest in trying to resurface this drug that had had a clear efficacy and was on a pathway to approval.

In parallel with that JAKARTA study, we had conducted a JAKARTA2 study, of which we’re presenting a reanalysis here at this year’s ASCO [American Society of Clinical Oncology Annual] Meeting. The JAKARTA2 study was in patients that had failed ruxolitinib and received fedratinib as a second-line therapy.

We conducted this several years ago, back in 2013. We’ve learned a lot since then. This reanalysis is a stricter, more modern definition of what RUX [ruxolitinib] failure looks like. When we started this study, RUX [ruxolitinib] had just recently become approved, and there were a lot of patients that had had a very brief exposure—5 days of ruxolitinib and things of that nature —that were a bit misleading, so we reanalyzed this. We now have a bulletproof set of patients—66—that at least had an adequate trial of ruxolitinib prior to starting fedratinib. They had a clear reason for being resistant or intolerant, and they had 6 months of fedratinib to be evaluable for response. 

We reported at this meeting about a 30% response rate for both the spleen and symptoms in this fairly clean group. That transitions to the other presentation we have at this year’s ASCO, which is really a trial in process. That is the FREEDOM study, led by my colleague Srdan Verstovsek, MD. I and many others here are coauthors and coinvestigators on that study. We’re prospectively going to look at that fairly clean group of patients who are resistant or intolerant to ruxolitinib, the same criteria we use for this reanalysis for JAKARTA2, and it’s going to be a single-arm study. We’re going to treat those patients.

In parallel, we’re going to be doing active monitoring for any neurological adverse effects. We’re going to be monitoring thiamine levels, because this issue of thiamine and Wernicke encephalopathy has been raised, and they’ll be receiving thiamine supplementation. Again, we’re going to try to mitigate any of that to the degree that we can. Then all that data will be looked at in aggregate by the new company that holds the drug, Celgene Corp, to make a case for whether an approval should be forthcoming on the aggregate experience with fedratinib.

Harry P. Erba, MD, PhD: I’m going to ask you to back up right to the beginning—maybe I missed this. Fedratinib is a JAK inhibitor.

Ruben A. Mesa, MD, FACP: Correct, it’s a JAK2 and FLT3 inhibitor.

Harry P. Erba, MD, PhD: Why is there a preclinical reason or a rationale for why this might be expected to be effective in patients who are resistant to ruxolitinib? Were these mostly patients intolerant to ruxolitinib who needed another therapy?

Ruben A. Mesa, MD, FACP: It was a mix of both. In many areas where we have more than 1 drug in a class, they never are really exactly the same. The expectation, again, is that a range of folks who did not have an adequate trial, who are resistant or intolerant, may respond to a drug that is coming as JAK in a slightly different way. It may be a bit more potent or a bit more selective. Clearly, it’s impacting the kinome in a slightly different way, as well as the empirical data that we have from JAKARTA2. Although we may not have everything worked out mechanistically, there’s evidence of clear response in the second-line setting.

Again, we’re with an azacitidine and decitabine in the same class, but there are clearly patients who respond to 1 and second-line for the others, or the nilotinib and dasatinib patients who respond to 1 after having had the other.

Transcript Edited for Clarity
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