An Open-Label, Global, Multicenter, Phase 1b/2 Study Of Krt-232, A First-In-Class, Oral Small-Molecule Inhibitor Of Murine Double Minute 2 (Mdm2), Combined With Ruxolitinib In Patients Who Have Myelofibrosis And A Suboptimal Response To Ruxolitinib

Background: Myelofibrosis (MF), which comprises primary MF (PMF), post-polycythemia vera MF (post-PV-MF), and post-essential thrombocythemia MF (post-ET-MF), is a clonal myeloproliferative neoplasm characterized by progressive bone marrow fibrosis, ineffective erythropoiesis, dysplastic megakaryocyte hyperplasia, and extramedullary hematopoiesis. Patients typically have heterogeneous clinical presentation marked by splenomegaly, progressive anemia and constitutional symptoms and are at increased risk of leukemic transformation. Hematopoietic stem cell transplant is the only potentially curative therapy but is associated with high morbidity and mortality. Approved therapies for MF are limited to the Janus kinase inhibitors (JAKi) ruxolitinib and fedratinib which have been shown to reduce spleen volume (≥35% from baseline at week 24) in 32% - 42% of patients and to improve constitutional symptoms, with no clear impact on bone marrow fibrosis. Several studies have shown a correlation between the degree of week 24 spleen response to JAKi treatment and survival outcomes in MF (Vannucchi, et al. Haematologica. 2015; Palandri et al. Leuk Res. 2018), demonstrating the need for novel treatment strategies in patients with a suboptimal response to ruxolitinib treatment.