A Phase 2 Study of Cpi-0610, a Bromodomain and Extraterminal (BET) Inhibitor, in Patients with Myelofibrosis (MF)

MF is a myeloproliferative neoplasm characterized by abnormal megakaryocytes and elevated proinflammatory cytokines which results in bone marrow fibrosis, progressive hepatosplenomegaly due to extramedullary hematopoiesis, and debilitating constitutional symptoms. Current treatments, including ruxolitinib (the only approved drug for MF), provide symptomatic relief but have limited effects on the underlying disease. Effective therapies with potential MF disease course modification and second line therapies are urgently needed.CPI-0610 has been evaluated in 3 Phase 1 studies in > 140 patients with lymphoma, multiple myeloma and acute leukemias/myelodysplastic syndrome/MF. Although CPI-0610 was tested at doses as high as 400 mg PO QD, the maximum tolerated dose was 225 mg PO QD for 2 weeks on, 1 week off. Clear anti-tumor activity was observed in patients with lymphomas, particularly ABC-DLBCL (Blum et al. TAT conference 2018). Preclinical data on CPI-0610 demonstrated downregulation of pro-inflammatory cytokines through its effects on NF-B pathway as well as inhibition of megakaryocyte differentiation. Both of these features are thought to be important in the pathogenesis of MF. In addition, a recent preclinical publication using a mouse model of MF, suggests that BET inhibition reduces inflammatory cytokine production, platelet counts, spleen volume and bone marrow fibrosis, the effects of which were further magnified when combined with ruxolitinib (Kleppe et al. 2018). Tak...
Source: Blood - Category: Hematology Authors: Tags: 634. Myeloproliferative Syndromes: Clinical Source Type: research