Overview

The main purpose of this study with corresponding optional expansion is to evaluate the efficacy of selinexor in JAKi-naïve participants with myelofibrosis (MF) and moderate thrombocytopenia based on spleen volume reduction (SVR). Additional efficacy and safety parameters will also be assessed during the study.

Eligibility

Key Inclusion Criteria:

• A diagnosis of MF or post-ET or post-PV MF according to the 2016 World Health Organization (WHO) classification of MPN, confirmed by the most recent local pathology report.
• Measurable splenomegaly during the screening period as demonstrated by spleen volume of greater than equal to (>=) 450 cubic square centimeter (cm^3) by MRI or CT scan (results from MRI or CT imaging performed within 28 days prior to screening are acceptable).
• Participants with DIPSS risk category of intermediate-1 with symptoms, or intermediate-2, or high-risk.
• ECOG Performance Status less than or equal to (<=) 2.
• Platelet count of 50 to less than (<) 100 x 10^9/L without platelet transfusion within 7 days prior to the first dose of selinexor.
• Absolute neutrophil count (ANC) >=1.0 × 10^9/L without need for growth factors within 7 days prior to the first dose of selinexor.
• Adequate liver function as defined by the following: aspartate transaminase (AST) and alanine aminotransferase (ALT) <= 2.5 × upper limit normal (ULN) and serum total bilirubin <= 3×ULN.
• Calculated creatinine clearance (CrCl) greater than (>) 15 milliliter per minute (mL/min) based on the Cockcroft and Gault formula.
• Active symptoms of MF as determined by presence of at least 2 symptoms with a score >= 3 or total score of >= 10 at screening using the MFSAF V4.0.
• Participants must provide bone marrow biopsy samples (samples obtained up to 3 months prior to C1D1 are permitted) at screening and during the study.
• Participants currently not a candidate for stem cell transplantation.
• Participants must be willing to complete the MFSAF V4.0 daily during the study for evaluating the symptom response (i.e., TSS50).

Key Exclusion Criteria:

• More than 10% blasts in peripheral blood or bone marrow (accelerated or blast phase).
• Previous treatment with JAK inhibitors for MF.
• Previous treatment with selinexor or other XPO1 inhibitors.
• Female participants who are pregnant or lactating.
• Prior splenectomy, or splenic radiation within 6 months prior to C1D1.
• History of myocardial infarction, unstable angina, percutaneous transluminal coronary angioplasty (PTCA) or coronary artery bypass graft (CABG), cerebrovascular accident (stroke or transient ischemic attack [TIA]), ventricular arrhythmias, congestive heart failure New York Heart Association (NYHA) class > 2 within 6 months of C1D1.
• Participants unable to tolerate two forms of antiemetics prior to each dose for the first two cycles.