A Study of Selinexor Monotherapy in Subjects With JAK Inhibitor (JAKi)-naïve Myelofibrosis and Moderate Thrombocytopenia

Study Overview
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Brief Summary
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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.

Official Title
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A Phase 2 Study to Evaluate the Efficacy and Safety of Selinexor Monotherapy in Subjects With JAK Inhibitor (JAKi)-naïve Myelofibrosis and Moderate Thrombocytopenia

Conditions
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Myelofibrosis, Moderate Thrombocytopenia

Intervention / Treatment
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* Drug: Selinexor 60 mg
* Drug: Selinexor 40 mg
* Drug: Ruxolitinib
* Drug: Pacritinib
* Drug: Momelotinib


Participation Criteria
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Eligibility Criteria
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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.

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Non-Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Selinexor 60 mg (Arm 1)<br>Participants will receive selinexor 60 milligrams (mg) oral tablets once weekly (QW) (Days 1, 8, 15, and 22 of each 28-day cycle) until PD, intolerable toxicity, or until they meet the criteria for discontinuation of study treatment, death, or withdrawal of consent, whichever comes first and followed by optional add-on medication dosing may be initiated based on Spleen Volume Reduction (SVR) values. | Drug: Selinexor 60 mg<br>* Participants will receive selinexor 60 mg oral tablets QW.<br>* Other names: KPT-330;Drug: Ruxolitinib<br>* Participants will receive ruxolitinib 5 mg or 10 mg twice daily.<br>* Other names: JAKAFI;Drug: Pacritinib<br>* Participants will receive pacritinib 200 mg twice daily.<br>* Other names: VONJO;Drug: Momelotinib<br>* Participants will receive momelotinib 200 mg once daily.<br>* Other names: OJJAARA;|
| Experimental: Selinexor 40 mg (Arm 2)<br>Participants will receive selinexor 40 mg oral tablets QW (Days 1, 8, 15, and 22 of each 28-day cycle) until PD, intolerable toxicity, or until they meet the criteria for discontinuation of study treatment, death, or withdrawal of consent, whichever comes first and followed by optional add-on medication dosing may be initiated based on SVR values. | Drug: Selinexor 40 mg<br>* Participants will receive selinexor 40 mg oral tablets QW.<br>* Other names: KPT-330;Drug: Ruxolitinib<br>* Participants will receive ruxolitinib 5 mg or 10 mg twice daily.<br>* Other names: JAKAFI;Drug: Pacritinib<br>* Participants will receive pacritinib 200 mg twice daily.<br>* Other names: VONJO;Drug: Momelotinib<br>* Participants will receive momelotinib 200 mg once daily.<br>* Other names: OJJAARA;|
| Experimental: Selinexor 60 mg (Optional Expansion Arm)<br>Participants will receive selinexor 60 mg oral tablets QW (Days 1, 8, 15, and 22 of each 28-day cycle) until PD, intolerable toxicity, or until they meet the criteria for discontinuation of study treatment, death, or withdrawal of consent, whichever comes first. Optional add-on medication (ruxolitinib [5 mg or 10 mg twice daily], pacritinib [200 mg twice daily], or momelotinib [200 mg once daily]) may be initiated for participants whose SVR is less than (<) 10% at Week 12 or <35% at Week 24 based on the participants platelet count values (i.e., ruxolitinib if platelets greater than or equal to [>=] 50 x 10^9/L, pacritinib if platelets <50 x 10^9/L, momelotinib if platelets is >=50 x 10^9/L and hemoglobin level is < 10 gram per deciliter [g/dL]). | Drug: Selinexor 60 mg<br>* Participants will receive selinexor 60 mg oral tablets QW.<br>* Other names: KPT-330;Drug: Ruxolitinib<br>* Participants will receive ruxolitinib 5 mg or 10 mg twice daily.<br>* Other names: JAKAFI;Drug: Pacritinib<br>* Participants will receive pacritinib 200 mg twice daily.<br>* Other names: VONJO;Drug: Momelotinib<br>* Participants will receive momelotinib 200 mg once daily.<br>* Other names: OJJAARA;|
| Experimental: Selinexor 40 mg (Optional Expansion Arm)<br>Participants will receive selinexor 40 mg oral tablets QW (Days 1, 8, 15, and 22 of each 28-day cycle) until PD, intolerable toxicity, or until they meet the criteria for discontinuation of study treatment, death, or withdrawal of consent, whichever comes first. Optional add-on medication (ruxolitinib [5 mg or 10 mg twice daily], pacritinib [200 mg twice daily], or momelotinib [200 mg once daily]) may be initiated for participants whose SVR is <10% at Week 12 or <35% at Week 24 based on the participants platelet count values (i.e., ruxolitinib if platelets >= 50 x 10^9/L, pacritinib if platelets <50 x 10^9/L, momelotinib if platelets is >=50 x 10^9/L and hemoglobin level is < 10 g/dL). | Drug: Selinexor 40 mg<br>* Participants will receive selinexor 40 mg oral tablets QW.<br>* Other names: KPT-330;Drug: Ruxolitinib<br>* Participants will receive ruxolitinib 5 mg or 10 mg twice daily.<br>* Other names: JAKAFI;Drug: Pacritinib<br>* Participants will receive pacritinib 200 mg twice daily.<br>* Other names: VONJO;Drug: Momelotinib<br>* Participants will receive momelotinib 200 mg once daily.<br>* Other names: OJJAARA;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Proportion of Participants with Spleen Volume Reduction 35 (SVR35) at Week 24 as measured by Magnetic Resonance Imaging (MRI) or Computed Tomography (CT) Scan |  | At Week 24 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Participants with Treatment-emergent Adverse Events (TEAEs), Severity of TEAEs, Treatment Related Adverse Events (TRAEs) and Serious Adverse Events (SAEs) |  | From start of drug administration up to 30 days after the last dose of study treatment (approximately 48 months) | 
| Proportion of Participants with Total Symptom Score 50 (TSS50) at Week 24 as Measured by the Myelofibrosis Symptom Assessment Form (MFSAF) V4.0 |  | At Week 24 | 
| Proportion of Participants with Anemia Response at Week 24 as per the International Working Group Myeloproliferative Neoplasms Research and Treatment and European Leukemia Network (IWG-MRT and ELN) Criteria |  | At Week 24 | 
| Overall Survival (OS) |  | From date of randomization to the date of death due to any cause or EoS (assessed at approximately 48 months) | 
| Overall Response Rate (ORR) as per IWG MRT and ELN Criteria |  | From Cycle 1 Day 1 (28-day cycle) up to EoS (approximately 48 months) | 
| Proportion of Participants with SVR35 at Any Time Point as Measured by MRI or CT Scan |  | From Baseline to EoS (approximately 48 months) | 
| Proportion of Participants with TSS50 at Any Time as measured by the MFSAF V4.0 |  | From Baseline to EoS (approximately 48 months) | 
| SVR35 Response in Pre-specified MF Participant Subgroups (Including by Gender, Age, and Geographic Region) |  | From Baseline up to EoS (approximately 48 months) | 
| TSS50 Response in Pre-specified MF Participant Subgroups (Including by Gender, Age, and Geographic Region) |  | From Baseline up to EoS (approximately 48 months) | 
| Anemia Response in Pre-specified MF Participant Subgroups (Including by Gender, Age, and Geographic Region) |  | From Baseline up to EoS (approximately 48 months) | 
| SVR35 Response in Participants who Receive as add-on Treatments (Ruxolitinib or Pacritinib or Momelotinib) to Selinexor and Single-agent Selinexor Only |  | At Week 24 | 
| TSS50 Response in Participants who Receive as add-on Treatments (Ruxolitinib or Pacritinib or Momelotinib) to Selinexor and Single-agent Selinexor Only |  | At Week 24 | 
| Anemia Response in Participants who Receive as add-on Treatments (Ruxolitinib or Pacritinib or Momelotinib) to Selinexor and Single-agent Selinexor Only |  | At Week 24 | 
| Number of Participants with TEAEs, Severity of TEAEs, TRAEs and SAEs in Participants who Receive as add-on Treatments (Ruxolitinib or Pacritinib or Momelotinib) to Selinexor and Single-agent Selinexor Only |  | From start of drug administration up to 30 days after the last dose of study treatment (approximately 48 months) | 
| Area Under the Concentration-time Curve (AUC) of Selinexor |  | Pre-dose, 0.5, 1, 2, 4, 6, and 24 hours post-dose on Cycle 1 Day 15 and 2 hours post-dose on Cycle 2 Day 15 (28-day cycle) | 
| Maximum Plasma Concentration (Cmax) of Selinexor |  | Pre-dose, 0.5, 1, 2, 4, 6, and 24 hours post-dose on Cycle 1 Day 15 and 2 hours post-dose on Cycle 2 Day 15 (28-day cycle) | 
| Time at Which Cmax is Achieved (Tmax) of Selinexor |  | Pre-dose, 0.5, 1, 2, 4, 6, and 24 hours post-dose on Cycle 1 Day 15 and 2 hours post-dose on Cycle 2 Day 15 (28-day cycle) | 
| Duration of Receptor Occupancy or Exportin 1 (XPO1) mRNA Induction |  | From Baseline up to EoS (approximately 48 months) | 
| Proportion of Participants with Post-treatment Changes in Bone Marrow |  | From Baseline up to EoS (approximately 48 months) | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Ruxolitinib, Momelotinib, Thrombocytopenia, Myelofibrosis, Selinexor, Total Symptom Score, Myelofibrosis Symptom Assessment Form, Spleen Volume Reduction, TSS50, SVR35, JAK2, KPT-330, Pacritinib