A Phase 1/2 Study of Nuvisertib (TP-3654), an Investigational Selective PIM1 Kinase Inhibitor, in Combination with JAK Inhibitors Ruxolitinib or Momelotinib in Patients with Myelofibrosis

Background: JAK inhibitors are the current standard of care treatment for patients (pts) with myelofibrosis (MF). Ruxolitinib (RUX), the first approved JAK inhibitor in 2011, showed spleen volume reduction (SVR) and symptom improvement in about 40% pts, but is limited by anemia, thrombocytopenia, or lack of disease-modifying effects (Verstovsek S, 2012). Momelotinib (MMB), a recently approved JAK inhibitor for MF pts with anemia in 2023, showed modest symptom and spleen responses in about 25% pts in relapsed/refractory (R/R) setting (Mesa R, 2022). About 60% pts may not achieve spleen or symptom responses after frontline treatment, and up to 75% R/R MF pts do not achieve adequate responses. Recent Phase 3 combination studies of RUX with Pelabresib (Rampal R, 2023) or Navitoclax (Pemmaraju N, 2023) in treatment naïve MF pts with platelet (PLT) count ≥100 x 109/L showed significant increase only in spleen responses; however, did not improve symptoms response, also were limited by overlapping toxicities of thrombocytopenia. Therefore, combination strategies of JAK inhibitors and agents with unique mechanism of action and minimal overlapping toxicities (e.g., cytopenias) are needed to improve response rates and clinical outcomes in MF. PIM1 expression is upregulated in hematologic malignancies including MF. In preclinical models, PIM1 knockout (KO) was shown to prevent MF progression without affecting PLT counts, whereas pan-PIM KO caused decreased PLT counts (Dutta A, 2021; An N, 2013). Nuvisertib (TP-3654), an oral investigational highly selective PIM1 kinase inhibitor, alone and in combination with RUX, showed spleen size and bone marrow (BM) fibrosis reduction and normalization or increase in hematological counts in murine JAK2V617F and MPLW515L mutant MF models. Preliminary results from the ongoing global Phase 1/2 study in R/R MF pts with PLT count ≥25 x 109/L (NCT04176198, Arm 1) showed that TP-3654 monotherapy was well tolerated with limited myelosuppressive adverse events (AEs), and early signs of clinical activity including SVR, total symptom score (TSS) reduction, and cytokine reductions (Rein L, 2023). Current monotherapy and preclinical data support the development of TP-3654 in combination with JAK inhibitors RUX or MMB in MF pts with low (<100 x 109/L) or normal PLT counts. Methods: The ongoing global Phase 1/2 study of TP-3654 monotherapy (Arm 1) has now been expanded to evaluate TP-3654 add-on to RUX (Arm 2) or in combination with MMB (Arm 3) in pts with MF (NCT04176198). The study aims to identify the MTD and/or RP2D of TP-3654 when given with RUX or MMB, and to assess the safety, clinical activity (SVR and TSS reduction), PK and PD markers. Study population include primary or secondary MF; DIPSS intermediate 1, 2 or high-risk; splenomegaly (≥450 cm3 by imaging); ≥2 measurable symptoms with each score ≥3 or a total average score of ≥10 per the Myelofibrosis Symptom Assessment Form version 4.0 (MFSAF v4.0); PLT count ≥50 x 109/L; adequate hepatic functions (ALT and AST ≤3x ULN [ALT and AST ≤5x ULN if liver involvement secondary to MF], direct bilirubin ≤2x ULN); and adequate renal function (serum creatinine ≤1.5x ULN or creatinine clearance ≥30 mL/min). For TP-3654 add-on to RUX (Arm 2), pts that have been on RUX treatment for ≥6 months and on a stable dose of RUX for ≥8 weeks, but have either lost response or had a suboptimal or plateau in response. For TP-3654 in combination with MMB (Arm 3), pts that have been previously treated with an approved JAK inhibitor (except MMB) for ≥12 weeks, or ≥4 weeks if JAK inhibitor therapy was complicated by a transfusion requirement of ≥4 units of RBC in 8 weeks, or Grade 3/4 AEs of thrombocytopenia, anemia, or hematoma. Combination arms are currently recruiting pts.

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