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Phase I/II Trial of Glasdegib in Patients With Primary or Secondary Myelofibrosis
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Dr. Aaron Gerds discusses Phase I/II Trial of Glasdegib in Patients With Primary or Secondary Myelofibrosis at ASCO 2017. For the ability to view on your mobile phone please visit us at

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Hi, my name is Aaron Gerds. I'm an Assistant Professor of Medicine at the Cleveland Clinic Taussig Cancer Institute in Cleveland, Ohio. I'll be discussing today a poster presented here at the ASCO annual meeting on Glasdegib, a hedgehog inhibitor for treatment of patients with myelofibrosis.

If we look at the poster here, and beginning with the background, the treatment of myelofibrosis is really centered around inhibiting the JAK stat pathway. However, many patients do have persistence of symptoms and spleen size. In addition, JAK inhibitors, although improve patient's quality of life and have some survival advantages in some studies, doesn't necessarily affect the underlying biology that we know of this disease by attacking the malignant clone, or reversing the fibrosis.

So the smoothened hedgehog pathway is an ideal target to slow down cell proliferation, as well as the paracrine effects within the bone marrow stroma. So this was a random, initially and open label cohort study, with a plan for a randomization afterwards. However, this is the lead-in portion of that study, the first 21 patients with myelofibrosis treated with this compound.

If I could direct your attention to table one, this outlined these 21 patients. Really what we expect for as in age, and male to female ratio, on average these patients were 78 years old, a male to female ratio of 13 to 8. Interestingly, these patients were all heavily pretreated. These are all patients who had previously received a JAK inhibitor. Seventy-one percent received one previous JAK inhibitor, where 14 percent of patients received two JAK inhibitors, and 15 percent of patients received three or more JAK inhibitors, again very heavily pretreated population.

The primary endpoint in the study was, of course it being a phase one study, was looking at adverse events and safety outcomes. But, also we wanted to look at the proportion of patients that achieved at least a 35 percent reduction in their spleen volume at week 24, as well as patients that achieved at least a 50 percent reduction in their total symptom score. Again, improving a symptom burden at week 24.

There are a number of exploratory endpoints, including patient-reported outcomes, particularly health-related quality of life, as measured by the EORTCQLQ-30 questionnaire.

If I could then direct your attention to table two, this is an outline of the treatment-related adverse events, reported in at least 15 percent of patients. So really, a fair number of grade one and grade two. The main symptoms that patients reported, both anecdotally in clinic, as well as in whole on the study, were dysgeusia and muscle spasms. Otherwise, this medication was pretty well tolerated in this population.

Moving on to figure two. Figure two does show the spleen responses in this population. The line across the middle here at zero shows no change, and everything above that line is increase in spleen size. Everything below that line is decrease in spleen size, where the dotted line represents a 35 percent reduction in total spleen volume. By looking at this figure, a fair number of patients did have a reduction in their spleen size, and even a larger proportion of patients had somewhat of a stabilization of their spleen size. Again, these are heavily pretreated patients that had a large spleen and significant symptom burden while on a JAK inhibitor. And a few patients here at the far end did have an increase in their spleen size. So, overall, a stabilization of spleen size in these patients.

Figure three shows the symptom burden in these patients at week 24. As you can see, some patients did experience at least a 50 percent improvement in their symptom burden at week 12 as well as week 24. But even a larger proportion had a symptom reduction of at least 20 percent, upwards in some domains of 30 to 40 percent.

Figure four shows the symptom burden over time in these patients. The blue line representing total symptom score, the red line identifying a reduction in spleen-related symptoms, green constitutional symptoms, and showing an overall downtrend in the symptom burden over the course of the study. The right hand panel of figure four shows the most severe patients as patients that had the highest scores coming into the study, and even that cohort had an improvement in their symptom burden.

In conclusion, Glasdegib had an acceptable toxicity profile in patients with myelofibrosis who were heavily pretreated with JAK inhibitors. The main treatment-related side effects that we saw were dysgeusia and muscle spasms. With respect to efficacy, we saw largely a stabilization of spleen size, again in these advanced patients who were heavily pretreated. And we did see some improvement in symptom burden.

I think a lot of questions come out of this abstract, mainly focusing on how we measure response in these patients. Perhaps the original ways of measuring symptom response as well as spleen size that we do for patients that are previously untreated, do not necessarily apply to this population. Therefore, setting the bar of a 35 percent reduction in spleen volume, or a 50 percent reduction in total symptom score may not equate with how patients feel on the study. And perhaps stabilization or much more modest improvements in symptom burdens can be meaningful for these patients.

Some limitations to this study include, of course, the small number size - the small number of patients on the study, as well as the sparse collection of patient-reported outcomes. We did collect patient-reported outcomes, particularly quality of life scales, at the beginning and during the study, but it was difficult to correlate those with changes in symptom burden over the course of the study. Of course, another limitation is the fact that this is a single arm, open label study, and there may be some placebo effect. However, some anecdotal results from the study suggest that some patients might have an improvement in transfusion burden, which is further being explored in other studies. And again, a number of clinical correlates are being looked at in terms of changes in fibrosis levels and cytokine levels to better understand the role of inhibition of a hedgehog smoothened pathway in the pathogenesis and treatment of myelofibrosis. Future studies looking at combinations of JAK inhibition and Sonic the hedgehog pathway smoothened inhibition are currently being investigated.

So I'd like to thank you for your attention while reviewing this poster abstract, and look forward to speaking with you again.