A Phase 1 Study of TP-3654, an Orally-Delivered PIM Kinase Inhibitor, in Patients with Intermediate-2 or High-Risk Primary or Secondary Myelofibrosis

Background: Myelofibrosis (MF) is characterized by bone marrow fibrosis (BMF) and ineffective extramedullary hematopoiesis resulting in splenomegaly and debilitating symptoms. An activating Janus kinase 2 (JAK2) mutation (V617F) has been frequently observed in MF. Ruxolitinib (a JAK1/JAK2 inhibitor) reduces splenomegaly and improves constitutional symptoms, but appears to offer a modest reduction of BMF. Patients with MF who are intolerant to JAK inhibitors or their components, or for whom JAK inhibitors have failed, have limited treatment options. The Proviral Integration site of Moloney murine leukemia virus (PIM) serine/threonine kinases are overexpressed in hematological malignancies. Because PIM kinase expression is regulated by JAK2 signaling, PIM kinase inhibition is a potential therapeutic target for JAK2 mutant-driven malignancies, such as MF. TP-3654, an investigational agent, has been shown to reduce proliferation and increase apoptosis in murine and human hematopoietic cells expressing the JAK2V617F mutation. TP-3654 alone reduced leukocytosis and spleen size in an in vivo murine model of JAK2V617F-induced MF, as well as an apparent reduction of BMF. A phase 1 study is being conducted to evaluate TP-3654 monotherapy in patients with MF.

Study Design and Methods: This phase 1, multicenter, dose-escalation, open-label study is evaluating TP-3654 monotherapy in patients with MF who previously failed a JAK inhibitor or who are ineligible to receive ruxolitinib or fedratinib (NCT04176198). Primary objectives are to determine the incidence of dose-limiting toxicities (DLT) at escalated doses of TP-3654 and treatment emergent adverse events. Secondary objectives are to determine QT interval changes, establish the pharmacokinetic profile, and assess preliminary disease activity. Exploratory objectives are pharmacodynamic markers in peripheral blood and bone marrow biopsy samples. Eligible patients have a primary or secondary MF (post-polycythemia vera-MF/post-essential thrombocythemia-MF) based on the World Health Organization diagnostic criteria and intermediate-2 or high-risk primary or secondary MF based on the Dynamic International Prognostic Scoring System; previously failed, or are ineligible to receive, treatment with a JAK inhibitor; grade ≥2 MF, as confirmed by BM biopsy ≤12 weeks prior to screening; have a platelet count >50x10⁹/L, absolute neutrophil count ≥1x10⁹/L, hemoglobin level ≥8 g/L, peripheral blood blast counts <10%, Eastern Cooperative Oncology Group performance status ≤2, life expectancy ≥3 months, and adequate renal and hepatic function; have spleen length ≥5 cm by palpation or spleen volume ≥450 cm³ by computerized tomography/magnetic resonance imaging, and show ≥2 measurable symptoms per the MF Symptom Assessment Form, version 4.0. Patients must not have received prior systemic antineoplastic therapy or any experimental therapy within 14 days or 5 half-lives before TP-3654; had major surgery ≤2 weeks before first study dose; have had splenic irradiation ≤6 months prior to screening; have acute myeloid leukemia or myelodysplastic syndrome; or had prior stem cell transplantation (SCT) or be eligible for allogeneic bone marrow or SCT. Enrollment of approximately 50 patients is planned. Patients will receive oral TP-3654. Dose-escalation will be performed using a Bayesian logistic regression model with escalation with overdose control. Adverse events occurring during the first cycle will be considered in the determination of the maximum tolerated dose (MTD). Dose escalation will continue until identification of the MTD or a suitable recommended phase 2 dose. This study is currently recruiting patients.