KEY TAKEAWAYS
- The phase I/II trial aimed to investigate the safety, effectiveness, and biological mechanisms of oral TP-3654 alone in patients with myelofibrosis.
- The study showed promise for MF with cytokine modulation, symptom improvement, and reduced spleen size/fibrosis while well-tolerated.
Myelofibrosis(MF) involves high PIM1, which boosts cytokines and fibrosis. A drug targeting PIM1 shrank spleens and fibrosis in mouse models and lowered cytokines. Researchers aimed to investigate the safety, effectiveness, and biological mechanisms of oral TP-3654 alone in patients with MF.
According to the Dynamic International Prognostic Scoring System (DIPSS), the study included individuals with intermediate or high-risk MF. Participants had a history of prior treatment with or were ineligible for JAK inhibitors, had a platelet count of ≥25×109 /L, experienced splenomegaly, and had at least two symptoms.
About 15 patients were enrolled across 5 dose levels. Baseline characteristics included a median age of 69 years (range, 61–77), spleen volume of 1936 cm3 (range, 857 to 4408), total symptom score of 18.6 (range, 4–62), platelet count of 129×109 /L (range, 64–520), hemoglobin of 9.7 g/dL (range, 5.9–13.7), and 5 patients requiring red blood cell transfusion.
All patients had prior treatment with ≥1 JAK inhibitor, with a median duration of prior JAK inhibitors being 12.8 months (range, 2.3–72.9). No dose-limiting toxicities(DLTs) occurred, and common treatment-related adverse events (TRAEs) were grade 1-2 nausea, vomiting, and diarrhea. No hematologic TRAEs were reported. Spleen volume reduction (SVR) was observed in 8 of 10 evaluable patients (median best change -13%, range -3% to -42%, 2 patients showed ≥35% SVR).
Total symptom score (TSS) improvements were observed in 9 of 10 evaluable patients (median best change -70%, range -31% to -100%; 6 patients showed ≥50% TSS response). Broad cytokine reduction was observed (e.g., IL-6, IL-8, IL-10, EN-RAGE). At week 12, patients with higher cytokine reductions correlated with higher TSS improvement.
One patient, with improvements in spleen and symptom responses, showed reductions in myelofibrosis-associated cytokines (e.g., IL6 [68%], IL12p40 [83%], MMP9 [56%], and EN-RAGE [68%]) and has been on active treatment for more than 18 months. Enrollment is ongoing.
The study showed promise for MF with cytokine modulation, symptom improvement, and reduced spleen size/fibrosis while well-tolerated.
Source: https://clml-soho2023.elsevierdigitaledition.com/396/index.html
Clinical Trial: https://clinicaltrials.gov/study/NCT04176198
El Chaer F, Rein L, Shimoda K, Yuda J, Haque T, McCloskey J, Takami A, Fukaya M, Shirane S, Kabir S, Mei J, Seki M, Li Z, Wade M, Lebedinsky C, Rampal RK. Preliminary Data From the Phase 1/2 Study of TP‑3654, an Investigational Selective PIM1 Kinase Inhibitor, Showed Cytokine Reduction and Clinical Responses in Relapsed/Refractory Myelofibrosis (MF).
