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ASH 2021 | New Phase III trial of imetelstat versus BAT in JAK inhibitor-refractory myelofibrosis
John Mascarenhas, MD, The Mount Sinai Hospital, New York, NY, introduces an ongoing Phase III randomized study (IMpactMF; NCT04576156) of imetelstat versus best available therapy (BAT) in patients with intermediate-2 or high-risk myelofibrosis refractory to JAK inhibitors. Currently, JAK inhibitors ruxolitinib and fedratinib are the only approved treatment options for myelofibrosis and there is a great unmet need for new agents for patients non-responsive to JAK inhibitors. Imetelstat has shown promising survival benefits in previous investigations, including the Phase II IMbark trial (NCT02426086). Approximately 320 patients will be enrolled and randomized 2:1 to imetelstat or investigator selected BAT. The primary endpoint will be overall survival, with symptom and spleen response at week 24, progression-free survival, duration of response, and bone marrow fibrosis scores included as secondary endpoints. Enrollment is underway and an interim analysis is planned for when ≥70% of death events have occurred. This interview took place at the 63rd ASH Annual Meeting and Exposition congress in Atlanta, GA.
Transcript (edited for clarity)
The randomized Phase III study, which is called the IMpactMF study, is a study of … It’s an ongoing study of imetelstat, the telomerase Inhibitor, in patients who have refractory myelofibrosis refractory to a JAK inhibitor and they’re randomized to imetelstat at 9.4 Milligrams per kilogram, every 21 days in a 2:1 fashion or best available therapy and best developed therapy does exclude a JAK inhibitor, but is physician selected prior to randomization...
The randomized Phase III study, which is called the IMpactMF study, is a study of … It’s an ongoing study of imetelstat, the telomerase Inhibitor, in patients who have refractory myelofibrosis refractory to a JAK inhibitor and they’re randomized to imetelstat at 9.4 Milligrams per kilogram, every 21 days in a 2:1 fashion or best available therapy and best developed therapy does exclude a JAK inhibitor, but is physician selected prior to randomization. The point of this study is to determine whether there is an overall survival benefit of this novel telomerase inhibitor in patients who have refractory disease to a JAK inhibitor. The Phase II study, which was a randomized study, looking at two different doses of imetelstat, 9.4 and 4.7 milligram per kilogram IV every three weeks demonstrated modest spleen symptom improvement, but encouragingly a survival of about almost 30 months in the 9.4 milligram per kilogram arm.
These are patients who were relapse refractory from JAK inhibitor, which at least five different independent studies would suggest the survival is approximately 12 to 15 months. And Andrew Kuykendall, from Moffitt did a beautiful real world data comparison with the propensity score matching that compared a cohort of patients at Moffitt to a similarly match cohort of patients treated in the Phase II study with 9.4 milligram per kilogram of imetelstat. And again, it, it replicated this finding that there was a clear survival advantage at least twice what you would see with conventional therapies. So this data was quite encouraging. It is collectively what inspired this Phase III study and it’s, I think it’s an exciting study in general for the field, because it’s the first study that I’m aware of, and it’s a registration study where overall survival is the primary endpoint.
And I think we will learn a lot from this study. We will understand better the nature of rux failure and whether modulating the disease and perhaps reducing the burden of malignant stem cells through telomerase inhibition can improve the survival, which is an important outcome, which is often overlooked because there’s been a lot of emphasis on spleen and symptom for good reason, but this is a step forward in trying to improve outcomes in a different way. Enrollment is, is ongoing. This is a global Phase III so it’s a large study, many centers across the world. We’re really looking for patients who’ve been on ruxolitinib, meet failure criteria and can receive drug. In some cases, this may be a bridge to transplant for some patients, other patients, this may be definitive treatment. And, I think this is a, it’s obviously an important study to move the field forward. So I would definitely encourage those physicians in the community that treat patients. If you see the patient is perhaps not doing well, losing response to ruxolitinib and progressive spleen symptom burden, consideration for referral to this trial, I think is really appropriate.