At the 2019 ASH Annual Meeting, Jacqueline Garcia, MD, Dana Farber Cancer Institute, Boston, MA, discussed results from a phase 2 study of navitoclax in combination with ruxolitinib in patients with primary or secondary myelofibrosis.

Transcript:

My name is Jacqueline Garcia. I'm a clinical investigator at Dana Farber Cancer Institute. I'm here to talk about a clinical abstract that looks at the Phase 2 results with adding Navitoclax to ruxolitinib for patients with primary or secondary myelofibrosis. This information was presented at the ASH 2019 annual meeting.

Patients with myelofibrosis have very limited therapies, in particular, there are no therapies approved after progressive disease or after sub-optimal responses seen with the current JAK inhibitors, ruxolitinib or the newly-approved fedratinib. And so, there's a big unmet need for our patients with myelofibrosis with advanced disease.

Navitoclax is an oral BH3 mimetic that targets cells that are dependent on the anti-apoptotic proteins BCL-XL primarily, and also targets cells that are dependent on BCL-2 and BCL-W less so.

In pre-clinical data, there is strong suggestion that even in a JAK2-mutated cell setting, even in a setting of JAK2 inhibitor resistance, there is activity with BCL-XL inhibition. And notably, there's synergistic activity when JAK2 inhibitors and BCL-XL inhibitors are used.

A clinical trial was performed that was designed for patients that were on a stable dose of long-term ruxolitinib with the idea of adding on oral Navitocax.

Navitoclax was started at a dose of 50 milligrams daily and slowly up-titrated on a weekly basis up to 300 milligrams daily based on tolerability and platelet levels.

The primary endpoint for this study was looking for differences in splenic volume reduction between baseline and Week 24 assessment.

The secondary endpoints include looking at other clinical parameters of meaningful response, including looking at total symptom score burden, looking for bone marrow fibrosis reduction, and looking for safety parameters.

In the 34 patients that were put on study, half the patients had primary myelofibrosis, the other half had secondary myelofibrosis. The overwhelming majority carried a JAK2 mutation.

There were no triple-negative patients on study. Everyone had confirmed palpable splenomegaly greater than 5 centimeters. And notably, on imaging, this confirmed the impressive splenomegaly for patients with advanced disease.

For patients coming on study, we found that of the 34 patients, the median time of prior ruxolitinib was for 21 months, with all patients except for 1 having been on ruxolitinib for greater than six months, really representing a heavily pre-treated population.

Notably, half the patients on study had evidence for a high molecular-risk mutation, and half of those had evidence of two or more of these high-risk, molecular mutation, suggesting that this was a very resistant population.

In terms of tolerability of this drug, we found that patients were able to stay on therapy with a median of 330 days, really demonstrating good tolerability. Only 9 of 34 patients came off study at some point, and only 2 for formal disease progression, and 3 for adverse event.

Patients, regardless of study drug attribution, everyone experienced some low-level grade adverse event, but it was overall very well-tolerated.

What is notable is that there was only one Grade 4, isolated thrombocytopenia that was thought to be due to the drug. But after dose hold temporarily, plus dose modification, drug was able to be resumed in this patient.

Further, things that we were able to see based on clinical assessment was that hemoglobins remained stable, white blood cells counts were able to be normalized. Further, platelet levels were able to be nadired and plateaued after six to eight weeks with the majority of patients having safe platelet counts and not having any bleeding events.

What we further saw in the study was that when looking at clinical meaningful responses, we were able to see that 43 percent were able to achieve a splenic value reduction 35 or SVR-35 on study, which was quite impressive, including in the majority of patients with high molecular-risk mutations.

Further, when looking at total symptoms score, when comparing baseline to Week 24 assessment, greater than 65 percent of patients were able to have noted symptom benefit or symptom reduction overall. About a third of patients had a 50-percent reduction in total symptoms score at that point on study.

Altogether, we have a clinical trial that shows a novel combination of adding the oral primary BCL-XL inhibitor and Navitoclax to standing ruxolitinib for patients that have been previously heavily treated with ruxolitinib therapy and had sub-optimal responses.

We saw that patients enjoyed really nice splenic volume reductions and that they were able to have improvement in their overall symptoms.

Notably, as megakaryocytes are BCL-XL-dependent, we were very pleasantly surprised to see that patients tolerate therapy well and that any Navitoclax-induced thrombocytopenia was able to be mitigated and managed quite well with temporary holds, dose interruptions, and dose reduction. They were able to resume therapy, suggesting that this is all manageable and could be done safely.

We look forward to further follow-up of these patients and ongoing studies are continuing with a combination and with Navitoclax as monotherapy in the same disease population.