A phase 1/2, open-label study evaluating twice-daily administration of momelotinib in myelofibrosis

Abstract

Momelotinib, a small-molecule inhibitor of Janus kinase 1 and Janus kinase 2, has demonstrated efficacy in myelofibrosis patients with 300 mg, once-daily dosing. This open-label, non-randomized, phase 1/2 study evaluated the safety and therapeutic benefit of momelotinib with twice-daily dosing. A total of 61 subjects with primary myelofibrosis or post-polycythemia vera/post-essential thrombocythemia myelofibrosis with intermediate- or high-risk disease received momelotinib. A phase 1 dose escalation identified 200 mg twice daily as the optimal dose to be expanded in phase 2. The most frequent adverse events were diarrhea (45.9%), peripheral neuropathy (44.3%), thrombocytopenia (39.3%), and dizziness (36.1%), the latter primarily due to a first-dose effect. The response assessment according to the 2006 International Working Group criteria (≥8 weeks duration at any time point) demonstrated spleen response by palpation of 72% (36/50) and anemia response of 45% (18/40). Spleen response by magnetic resonance imaging obtained at 24 weeks was 45.8% (27/59) for all subjects and 54.0% (27/50) for those with palpable splenomegaly at baseline. The symptoms of myelofibrosis were improved in most subjects. Cytokine analysis showed a rapid decline in interleukin-6 with momelotinib treatment, and a slower reduction in other inflammatory cytokines. In the subgroup of subjects with the JAK2V617F mutation at baseline (n=41), momelotinib significantly reduced the allele burden by 21.1% (median) at 24 weeks. These results provide evidence of tolerability and a potential therapeutic activity of momelotinib for subjects that support further evaluation in ongoing, phase 3 randomized trials. (clinicaltrials. gov identifier:01423058).

Trial registration: ClinicalTrials.gov NCT01423058.

Copyright© Ferrata Storti Foundation.

Figures

Figure 1.

Subject disposition. *2 subjects with loss of response, 1 proceeded to bone marrow transplant, 1 lack of efficacy. BID: twice daily; mITT: modified intention-to-treat.

Figure 2.

(A) Nonhematologic treatment-emergent adverse events (>10% of total subjects) across all momelotinib dose levels. (B) Hematologic treatment-emergent adverse events (>10% of total subjects) across all momelotinib dose levels.

Figure 3.

Spleen response showing percentage reduction from baseline in spleen volume by magnetic resonance imaging (MRI) for subjects with palpable splenomegaly at baseline (n=50). Baseline subjects included all subjects with spleens (n=59). At week 24, 38 subjects underwent MRI. Missed MRIs were due to adverse events (AEs) (9 subjects), withdrawal (5 subjects), missed appointments (4 subjects), progressive disease (2 subjects), and lost to follow-up (1 subject). Dashed red line indicates reduction of 35% from baseline.

Figure 4.

JAK2V617F allele burden. Plot shows baseline levels (n=41) and individual trajectories of allele burden to week 24 (n=18). BL: baseline; W24: week 24.

Figure 5.

Heat map showing median percentage change in cytokine levels at each time point relative to pre-dose. Green and red represent decreased and increased levels from baseline, respectively. Changes from baseline tested using Wilcoxon signed-rank test. P values are indicated for median percent changes ≥10%: *0.01–0.05; †0.001–0.01; ‡<0.001. CRP: C-reactive protein; IGFBP1: insulin-like growth factor binding protein 1; IL: interleukin; IL-12P70: interleukin-12 subunit P70; RANK: receptor activator of nuclear factor kappa B; TGF-β: transforming growth factor beta; TNF-α: tumor necrosis factor alpha; TNFRII: tumor necrosis factor receptor type II; VEGFA: vascular endothelial growth factor A; lL-12P40: interleukin-12 subunit P40.