First-in-Human Phase I/IIa Safety and Efficacy of Flonoltinib Maleate, a New Generation of JAK2/FLT3 Inhibitor in Myelofibrosis

Background

Myelofibrosis is a myeloid malignancy associated with anemia, splenomegaly, and constitutional symptoms. Flonoltinib Maleate (FM) is a new generation of JAK2/FLT3 inhibitor. Different to marketed JAK2 inhibitors binding to JAK2 JH1 domain, FM exhibits high selectivity to JAK2 by simultaneously binding to the pseudokinase domain (JH2) and the kinase domain (JH1) of JAK2. The IC₅₀ for JAK2, FLT3 are 0.8 and 15 nM, respectively, with >600-fold selectivity over JAK1 and JAK3. This multicenter phase I/IIa study evaluated the maximum tolerated dose (MTD), safety, and clinical activity of FM in patients (pts) with myelofibrosis (MF) (NCT05153343). The recommended doses of phase 2b were obtained with intermediate-2 or high risk MF.

Methods

Pts aged ≥18 with primary MF, post-PV MF or post-ET MF, DIPSS at least medium-risk -1 to high-risk, palpable splenomegaly, and with or without prior treatment with JAK inhibitors were enrolled. In the dose escalation phase, pts took the corresponding doses of FM tablets (25 mg, 50 mg, 100 mg, 150 mg, 225 mg and 325 mg). FM was taken orally once in the single administration stage (day 1-day 4) and once daily for 14 days in the multiple administration stage (day 5-day 21). In the extended dosing phase (D23), each cycle was taken on a continuous fasting schedule for 14 days, once daily. In expansion phase, FM will administrate once daily for a14-day cycle for 12 cycles of treatment. pts will continue to receive FM until disease progressing or intolerable toxicity, if the researchers considered that they were likely to be sustained benefit after 12 cycles treatment (approximately 6 months). The primary end points were the safety and tolerability, dose-limiting toxicity (DLT), maximum-tolerated dose (MTD), and pharmacokinetic (PK) behavior of FM. The secondary end point was a ≥35% reduction in spleen volume at week 24 as determined by magnetic resonance imaging, palpation response and disease related symptom improvement response.

Results

31 pts, including 25 (80.64%) with primary myelofibrosis, 5 (16.13%) with secondary myelofibrosis, and 1 (3.23%) with thrombocytosis. 14 pts (45.2%) had a grade 2-3 anemia at enrolment, 5 pts (16.1%) were blood transfusion dependent at enrolment; 7 pts (22.6%) had PLT grade 1-2 at enrollment. One patient in dose escalation was excluded from this analysis due to the diagnosis of essential thrombocythemia and this patient achieved hematologic remission with C2 therapy. Thirty MF pts were treated, including 15 in the dose-escalation phase and 15 in the dose-expansion phase with 100 mg QD. The maximum tolerated dose was 225 mg/day. No patient experienced dose-limiting toxicity during cycle 1 of phase 1. As of February 29, 2024, twenty-two pts have completed 12 cycles of treatment, 17 of 22 pts achieved SVR ≥35% (77.3%) at week 24 including 8 pts (72.7%, 8/11) in the dose-escalation stage and 9 pts (81.8%, 9/11) in the expansion phase. Five patients had obviously bone marrow fibrosis improvement at week 24 with 2 patients in escalation phase and three patients in expansion phase. The best SVR ≥35% were 83.3% (25/30) and the best TSS50 rates were 80.0% (24/30). Subgroup analysis found that there was no significantly statistic difference in spleen response rates between patient exposure to JAK inhibitors or Naïve to JAK inhibitors before enrollment. The SVR35 rates at week 24 were 70.0% (7/10) for pts with exposure to JAK inhibitors and 83.3% (10/12) for pts Naïve to JAK inhibitors, respectively. More than 60% patients reached palpation response and disease related symptom improvement response (TSS50) in 2 cycles.

The most common grade ≥3 hematological TEAEs were anemia (48.4%), thrombocytopenia (29.00%), decreased lymphocyte count (16.1%), leukopenia (19.4%) and neutropenia (16.1%). The Most common grade ≥3 nonhematological TEAEs were abdominal pain (3.2%), hypertension (3.2%), pneumonia (9.7%), fibrinogen decreased (3.2%) and abnormal liver function (3.2%).

Conclusions

FM demonstrated significant clinical benefits in MF pts for spleen response or improved symptom response. FM may be a new treatment option for myelofibrosis pts. A randomized, open-label, positive-controlled, multicenter Phase II trial is currently underway in patients with moderate-risk myelofibrosis treated with FM.