A phase I study of the combination of ruxolitinib and the ERK1/2 inhibitor ulixertinib in previously treated myelofibrosis patients.

Abstract Background: Myelofibrosis (MF) is a clonal hematopoietic stem cell (HSC) malignancycharacterized by aberrant activation of the JAK-STAT signaling pathway. Janus kinase (JAK) inhibitors such as ruxolitinib (RUX) are the standard of care for MF patients with symptomatic splenomegaly or constitutional symptoms. However, these inhibitors often have a limited duration and depth of response, and novel mechanism-based therapies for MF patients are needed. The biologic mechanism of disease persistence despite JAK inhibitor therapy are thought to be due to persistent JAK-STAT signaling after exposure to a JAK inhibitor, as well as the activation of other signaling pathways such as the phosphatidylinositol-3-kinase (PI3K)/AKT pathway and the mitogen-activated protein kinase pathway (MAPK) involving mitogen-activated protein kinase-extracellular signaling-regulated kinases (MEK-ERK). The MEK-ERK pathway promotes cell proliferation and survival via several different effectors. Several mechanisms have been identified leading to MEK-ERK pathway activation in myeloproliferative neoplasms (MPNs). One mechanism is activation of the PDGFRα kinase by its ligand PDGF-BB, leading to persistent activation of the MEK-ERK pathway in a JAK2-independent manner. More recently, phosphoproteomic analysis of downstream effects of mutant JAK2 demonstrated that phosphorylation of the splicing factor Y-box Protein 1 (YBX1) by mutant JAK2 is required for mRNA splicing of the ERK-signaling component MAPK Interacting Serine/Threonine Kinase 1 (MKNK1). MKNK1 is required for maintaining JAK2-mutated cells in the presence of JAK inhibitor and mediates ERK phosphorylation. Genetic and pharmacologic disruption of the MEK-ERK pathway (in combination with JAK inhibitors) have demonstrated biologic effects beyond those seen with JAK inhibition alone, thus implicating the MEK-ERK pathway as a therapeutic target. We hypothesize that the addition of an ERK1/2 inhibitor to RUX in MF patients with persistent disease despite RUX monotherapy is safe and tolerable, and that this combination will result in objective responses in treated participants, and alterations in hallmarks of MF pathobiology. Study Design and Methods: This is a multicenter phase I/II study to determine the safety, tolerability and efficacy of the combination therapy of RUX and the ERK1/2 inhibitor ulixertinib (ULI) in subjects with MF previously treated with RUX monotherapy for at least 3 months, but with persistent evidence of disease (NCT06773195). Participants are eligible for inclusion if they have MF with DIPSS intermediate-2/high or MIPSS-70 Intermediate disease/high risk disease. Participants must be on active RUX treatment for ≥12 weeks with a stable dose (10 mg to 20 mg BID) for the preceding ≥4 weeks at the time of screening. ECOG performance status of 0-2 is permitted. Participants must have evidence of persistent manifestations of disease, including radiographic evidence of splenomegaly and/or symptoms (i.e. the presence of one symptom with score 5 or two symptoms with scores 3 using the MPN Symptom Assessment Form Total Symptom Score MPN-TSS SAF). Platelet count must be ≥50 x 109/L and ANC must be ≥0.5 X 109/L. Serum bilirubin must be 1.5 x institutional upper limit of normal (ULN), ALT/AST ≤3 x institutional ULN, and creatinine clearance ≥ 50 ml/min. Participants with accelerated or blast phase disease (10% peripheral blood or bone marrow blasts) are excluded. The Phase I part of the trial will be a standard 3+3 design with three candidate doses of ULI (in sequential order: 150mg, 300mg, 450mg BID). After the RP2D has been determined, we will enroll up to 25 patients in the Phase II part of the study. The primary endpoint of the Phase II portion is complete response (CR), partial response (PR), or clinical improvement at week 25 as defined by IWG-MRT criteria. The decision of whether the combination RUX + ULI is worthy of further investigation will be based on the planned Simons' two-staged design with the confirmed RP2D, with a response rate of 30% or greater considered promising and worthy of further investigation. Conclusion: These studies, if successful, will likely lead to future investigations combining JAK and ERK inhibitors not only in MF, but also in other diseases characterized by aberrant JAK-STAT signaling, and thus may have broad implications for an array of human diseases.