Two Phase 1b Studies Evaluating the Safety and Tolerability of BET Inhibitors, ABBV-744 and Mivebresib, as Monotherapies and in Combination with Ruxolitinib or Navitoclax in Patients with Myelofibrosis

Background: Myelofibrosis (MF) is a myeloproliferative neoplasm (MPN) characterized by uncontrolled inflammation and fibrotic deposition in the extracellular bone marrow space, resulting in cytopenias, constitutional symptoms, and splenomegaly. A minority of patients are eligible for allogeneic hematopoietic stem cell transplant (allo-HSCT), which can be curative but is associated with substantial risks. Janus-associated kinase inhibitors (JAKi), including ruxolitinib (Rux), are approved for treatment of MF but do not reliably alter the disease course or generate durable responses. The limited treatment options for MF after Rux failure highlight a clear unmet need. In murine models of MPN, bromodomain and extra-terminal family protein inhibitors (BETi) reduced inflammatory cytokine levels and, combined with JAKi, reduced MF disease burden (Kleppe et al, 2018). BETi also modulated key nodes in the intrinsic apoptosis pathway and synergized with the B-cell lymphoma-2 (BCL-2) family inhibitor navitoclax (Nav) in solid tumor models (data on file). Pan-BETi have shown activity in patients with MF, including reduction in spleen volume and improvements in symptom burden, anemia, and bone marrow fibrosis as monotherapy and in combination with Rux (Mascarenhas et al, 2019). Selective BETi may reduce off-target toxicity relative to pan-BETi. The studies described here aim to evaluate the safety, pharmacokinetics (PK), and preliminary efficacy of ≥2 dosing regimens of 2 novel BETi: mivebresib, an oral pan-BETi that demonstrated antitumor activity in preclinical models of malignancy, and ABBV-744, a novel, potent small molecule that selectively inhibits bromodomain II of the BET family. Both BETi will be investigated as monotherapy and in combination with Nav or Rux in patients with MF. Methods: The 2 Phase 1b, multicenter, open-label studies will recruit patients with MF to receive ABBV-744 (NCT04454658) or mivebresib (NCT04480086), respectively, as monotherapy or in combination with Nav or Rux. Patients ≥18 years with intermediate-2 or high-risk MF, measurable splenomegaly (intermediate-1 with palpable splenomegaly ≥5 cm below costal margin eligible for Segment A) and Eastern Cooperative Oncology Group Performance Status