Pb2198: trial in progress: an open-label, global, multicenter, phase 1b/2 study of tl-895, a bruton’s tyrosine kinase inhibitor (btki), added to ruxolitinib (rux) in patients (pts) with myelofibrosis (mf)

Topic: 16. Myeloproliferative neoplasms - Clinical Background: MF is characterized by dysplastic megakaryocyte hyperplasia, progressive bone marrow fibrosis (BMF), upregulation of proinflammatory cytokines, symptomatic burden, extramedullary hemopoiesis, and pronounced splenomegaly. High expression of IL-8 in MF pts is a risk factor for impaired megakaryopoiesis, severe thrombocytopenia and shortened survival (Tefferi 2011; Dunbar 2021; Emadi 2005). Rux, a Janus kinase 1/2 inhibitor (JAKi) can improve splenomegaly and MF-related symptoms but has limited disease modifying effects. Approximately 50% of pts discontinue rux within one year of starting treatment (Harrison, 2020), suggesting solely inhibiting JAK-STAT signaling may be insufficient to alter the natural history of disease. TL-895 is a highly potent, selective, orally available, covalent small molecule inhibitor of BTK and bone marrow tyrosine kinase X-linked (BMX). TL-895 may augment the activity of JAKi by (i) modulating stromal adhesion and aberrant myeloblast trafficking (Nimmagadda 2019), (ii) inhibiting activated NF-kB signaling and cytokine mediated proinflammatory effects (Neys 2021), (iii) reversing IL-8-driven suppression of megakaryopoiesis and platelet counts (Greil 2021), and (iv) enhancing spleen volume response through blast cell release from a supportive, pro-survival tumor microenvironment into the circulating peripheral blood. We reasoned adding TL-895 to rux may enhance symptom response and potentiate pro-apoptotic effects on malignant MF cells by disrupting stromal support to induce deeper spleen volume reductions (SVR). Aims: Study TL-895-209 (NCT05280509) is an ongoing, global, open-label multicenter, Phase (Ph) 1b/2 clinical trial adding TL-895 to rux in MF pts. Primary objectives are to determine the recommended Ph 2 dose (RP2D [Ph 1b]) and SVR by central review at Week (Wk) 24 (Ph 2). Key secondary objectives include Total Symptom Score improvement ≥50% by MFSAF v4.0 at Wk 24 (TSS-50), rate of conversion from red blood cell transfusion dependence to independence, safety and tolerability of the combination. Methods: The Ph 1b dose escalation portion will enroll up to 18 MF pts with suboptimal response to rux using a 3 + 3 design to evaluate continuous dosing of TL-895 at three dose levels (twice-daily) added to rux administered at the pre-study stable dose (≥8 wks). The Ph 2 expansion will investigate TL-895 added to rux at the RP2D in MF pts who are JAKi-naïve (Cohort 1) or have suboptimal response to rux (Cohort 2). Key eligibility criteria include age ≥18 years, intermediate-1/-2, high-risk (DIPPS) primary, or secondary MF, ECOG ≤2, baseline platelet count ≥50 × 109/L. Pts with suboptimal response to rux must have received ≥12 weeks of treatment. Spleen responses will be evaluated by central review of computed tomography or magnetic resonance imaging, disease response will be assessed per the 2013 International Working Group-Myeloproliferative Neoplasms Research and Treatment (IWG-MRT) and European Leukemia Net (ELN) criteria, TSS-50 will be evaluated per the Myelofibrosis Symptom Assessment Form version 4.0. All pts will provide informed consent. Results: This is a trial in progress; data are expected. Summary/Conclusion: TL-895-209 is an ongoing clinical trial evaluating the novel BTK/BMX inhibitor TL-895 added to rux in MF pts who are JAKi-naïve or have suboptimal response to rux.Keywords: Myelofibrosis, IL-8, Ruxolitinib, Thrombocythemia