This open-label, multi-center, phase Ib/II platform study design consists of 3 parts. Part 1 is a phase Ib dose escalation and safety run-in for the 5 novel agents in combination with ruxolitinib to assess safety, tolerability and to confirm recommended Phase II dose. Dose escalation cohorts are treated with ruxoltinib + siremadlin or ruxolitinib + rineterkib. Safety run in cohorts are treated with either ruxolitinb + sabatolimab, ruxolitinb + crizanlizumab or ruxolitinib + NIS793 Parts 2 and 3 are phase II selection and expansion respectively, to assess preliminary efficacy of the combination treatments from Part 1 that are evaluated as safe and tolerable. The number of combination treatment arms opening in part 2 will depend on the results of Part 1. In Part 2, an interim analysis was planned to determine if combination treatment (s) can be expanded in Part 3.~In June 2022, Novartis decided to permanently halt the study enrollment in all ongoing parts (part 1 and part 2) and part 3 (expansion) will not be initiated. With protocol amendment 8, an extension treatment phase of 12 cycles is added in Part 1 to allow access to the combination treatment for ongoing subjects deriving clinical benefit. in consideration of the enrollment halt, Parts 2 and 3 objectives will not be pursued and Part 1 objectives are updated accordingly.
The purpose of this study is to investigate the safety, pharmacokinetics and preliminary efficacy of combination treatment of ruxolitinib with 5 novel compounds: siremadlin, crizanlizumab, sabatolimab, rineterkib and NIS793 in myelofibrosis (MF) subjects.