MO50-3 Preliminary data from the phase I/II study of TP-3654, an oral PIM-1 kinase inhibitor, in patients with myelofibrosis

Myelofibrosis (MF) is characterized by bone marrow (BM) fibrosis, ineffective hematopoiesis, splenomegaly, and debilitating symptoms. PIM-1 expression is upregulated in MF hematopoietic cells supporting exploration of PIM-1 as a potential therapeutic target in MF. TP-3654 is a selective oral investigational PIM-1 kinase inhibitor.TP-3654 alone and in combination with ruxolitinib reduced spleen size and BM fibrosis in murine MF models (Dutta, 2021). This phase I/II study aims to identify MTD and/or RP2D, and evaluate safety and efficacy of TP-3654 monotherapy in pts with MF (NCT04176198; jRCT2031210490). Key eligibility criteria include primary or secondary MF; intermediate or high-risk MF per DIPSS; previously treated with or ineligible for JAK inhibitor; platelet count ≥25x109/L; splenomegaly; and ≥2 measurable symptoms. As of 11 July 2022, 8 pts enrolled in dose escalation part. At baseline, median age 70 years, median spleen volume 2370 cm3, median total symptom score (TSS) 19, and median platelet 120 x109/L. All pts received prior ≥1 JAK inhibitor. No DLTs occurred. Treatment-related adverse events (TRAEs) in ≥20% of pts included mild to moderate nausea, vomiting, and diarrhea. Grade 3 TRAEs included only 1 case of vomiting. No hematological TRAEs reported. No discontinuation due to AEs. Spleen Volume Reduction (SVR) observed in 5 of 6 evaluable pts (median best change -14%). TSS improvement observed in 5 of 6 evaluable pts (median best change -70%). Reduction in cytokines (TGF-b, IL-18, VEGF, RANTES, MMP-9, and TIMP-1) observed in plasma. Pts with higher cytokine reductions correlated with higher reduction in TSS. The preliminary clinical data show: 1) encouraging signs of clinical activity in SVR, TSS improvement, and cytokine reduction; 2) TP-3654 is well tolerated with limited myelosuppressive AEs. These data support accelerated development of TP-3654 as the optimal partner for combination with JAK inhibitors.