Safety and efficacy of the combination of sonidegib and ruxolitinib in myelofibrosis: a phase 1b/2 dose-finding study

Abstract

The sonidegib and ruxolitinib combination was assessed in an open-label study in JAK inhibitor-naive patients with myelofibrosis (MF). The primary objective of phase 1b was to establish the maximum tolerated dose (MTD) and/or recommended phase 2 dose (RP2D) and phase 2 was to assess spleen volume reduction at weeks 24 and 48. Fifty patients were enrolled. In the dose-escalation phase (n = 23), doses for sonidegib once daily/ruxolitinib twice daily were 400/10 mg (level 1, n = 8), 400/15 mg (level 2, n = 10), and 400/20 mg (level 3, n = 5). Two patients had dose-limiting toxicity at level 2: increased blood creatine phosphokinase (grades 3 and 4, n = 1 each). MTD/RP2D was determined as sonidegib 400 mg daily + ruxolitinib 20 mg twice daily. In phase 1b expansion and phase 2 stage 1 (n = 27), by weeks 24 and 48, ≥35% reduction in spleen volume was observed in 44.4% and 29.6% patients, respectively. By weeks 24 and 48, 42.0% and 26.0% patients had ≥50% reduction in Myelofibrosis Symptom Assessment Form total symptom score, respectively. Most common treatment-related adverse events (grade 3/4) were increased blood creatine phosphokinase (18%), anemia (14%), and thrombocytopenia (12%). Four deaths were reported due to multiple organ dysfunction syndrome (on-treatment; no relationship with study treatment), acute myeloid leukemia, MF progression, and aspiration pneumonia. Although well tolerated, this combination will not be further developed in MF patients due to modest overall benefit compared with historical ruxolitinib monotherapy. This trial was registered at www.clinicaltrials.gov as #NCT01787552.

Conflict of interest statement

Conflict-of-interest disclosure: V.G. declares accepting grants from Novartis and Incyte; personal fees from Novartis, Incyte, Celgene, and Sierra Oncology; and other grants from serving on the advisory boards of Novartis, Celgene, and Sierra Oncology. A.M.V. reports personal fees from Novartis, CTI, Celgene, and Incyte outside of the submitted work. F.C. reports financial activity from the advisory boards of Novartis, Celgene, and Farmitalia; and as a member of the speakers bureaus at Novartis and Celgene. S.K. reports receiving grant, personal fees, nonfinancial support, and AdBoard and travel reimbursement from Novartis during the conduct of the study, and grant, personal fees, and AdBoard and travel reimbursement from BMS, AOP pharma, and Janssen; and personal fees and AdBoard and travel reimbursement from Incyte/Ariad, CTI, Roche, Sanofi, Shire, Celgene, and Bayer. Y.L., T.D., M.W., and S.B. report personal fees from Novartis as employees. In addition, M.W. and S.B. report stock incentives from Novartis. C.H. reports payment for research and grant from Novartis and personal fees from Novartis, AOP pharma, Celgene, Janssen, Sierra Oncology, and Promedior, and travel costs from CTI. H.H. reports grants from Novartis Healthcare A/S and provides consultation for AORPHAN. D.W. declares no competing financial interests.

© 2020 by The American Society of Hematology.

Figures

Graphical abstract

Figure 1.

Waterfall plot of best percentage reduction in spleen volume (cm3) as per MRI/CT for phase 1b expansion phase and phase 2 stage 1 (full analysis set).