Pelabresib and Ruxolitinib Combination vs Placebo and Ruxolitinib in JAK Inhibitor-Naïve MF

Bone marrow fibrosis, anemia, splenomegaly, and constitutional symptoms are all hallmarks of myelofibrosis (MF). Myeloproliferation and cytopenias, caused by abnormal megakaryopoeisis and the release of proinflammatory cytokines, ultimately lead to progressive bone marrow fibrosis. BET-mediated gene regulation plays a key role in this process. For the treatment of MF, researchers have been working on a small-molecule inhibitor of the BET protein’s bromodomains called pelabresib (CPI-0610). The goal is to reduce the expression of BET target genes and alter NF-kappa B (NF-kB) signaling. The Phase 2 MANIFEST study (NCT02158858) is exploring the combination of pelabresib and ruxolitinib in patients with MF who are not currently treated with a Janus kinase inhibitor (JAKi). The primary endpoint analyses revealed that 68% of the 84 enrolled patients showed a splenic response, while 56% exhibited a symptom response. Patients with main MF, post-polycythemia vera MF, or post-essential thrombocythemia MF who are JAKi treatment-naive will participate in MANIFEST-2 (NCT04603495), a global Phase 3 randomized, double-blind, active-control study of pelabresib and ruxolitinib against placebo and ruxolitinib. This research aims to see if adding ruxolitinib to pelabresib improves efficacy and safety.

Eligibility requirements include a peripheral blast count of less than 5%, a platelet count of less than 100 109/L, a spleen volume of fewer than 450 ccs as measured by computed tomography or magnetic resonance imaging, and at least two symptoms with an average score of less than 3 or a Total Symptom Score (TSS) of less than 10 using the Myelofibrosis Symptom Assessment Form v4.0. Patients will be randomly assigned to treatment groups based on their platelet count (>200 109/L vs. 100-200 109/L) and spleen volume (1800 cm3 vs. 1800 cm3) as well as their DIPSS risk category (Intermediate-1 vs. Intermediate-2 vs. High). Each treatment cycle consists of 14 days of double-blind treatment (pelabresib or matching placebo) followed by a 7-day rest. The 21-day treatment cycle consists of twice-daily doses of roxolitinib. The key secondary endpoint is the TSS50 response (50% reduction in TSS at Week 24), and the primary endpoint is the SVR35 response (35% reduction in spleen volume from baseline). Secondary endpoints include conversion from transfusion dependence to independence, progression-free survival, overall survival, red blood cell transfusion rate in the first 24 weeks, pharmacokinetics, and changes in bone marrow fibrosis. Researchers enrolled 400 patients (200 in each arm) from North America, Australia, Asia, and Europe.

Source:https://library.ehaweb.org/eha/2022/eha2022-congress/357889/claire.harrison.manifest-2.a.global.phase.3.randomized.double-blind.html?f=menu%3D6%2Abrowseby%3D8%2Asortby%3D2%2Amedia%3D3%2Ace_id%3D2233%2Aot_id%3D26855%2Amarker%3D1769%2Afeatured%3D17676

Clinical Trial:https://clinicaltrials.gov/ct2/show/NCT04603495

Claire Harrison, Raajit K Rampal, Vikas Gupta, Srdan Verstovsek, Moshe Talpaz, Jean-Jacques Kiladjian, Ruben Mesa, Andrew Kuykendall, Alessandro Vannucchi, Francesca Palandri, Sebastian Grosicki, Timothy Devos, Eric Jourdan, Marielle J Wondergem, Haifa Kathrin Al-Ali, Veronika Buxhofer-Ausch, Alberto Alvarez-Larrán, Sanjay Akhani, Rafael Muñoz-Carerras, Yury Sheykin, Gozde Colak, Morgan Harris, John Mascarenhas/MANIFEST-2, A GLOBAL, PHASE 3, RANDOMIZED, DOUBLE-BLIND, ACTIVE-CONTROL STUDY OF PELABRESIB (CPI-0610) AND RUXOLITINIB VS PLACEBO AND RUXOLITINIB IN JAK INHIBITOR-NAÏVE MYELOFIBROSIS PATIENTS/Inc. Library.ehaweb.org. Retrieved May 4, 2023, from https://library.ehaweb.org/eha/2022/eha2022-congress/357889/claire.harrison.manifest-2.a.global.phase.3.randomized.double-blind.html?f=menu%3D6%2Abrowseby%3D8%2Asortby%3D2%2Amedia%3D3%2Ace_id%3D2233%2Aot_id%3D26855%2Amarker%3D1769%2Afeatured%3D17676