A Study to Evaluate Safety and Efficacy of Selinexor Versus Treatment of Physician's Choice in Participants With Previously Treated Myelofibrosis

Study Overview
=================
Brief Summary
-----------------
This is a Phase 2, multicenter, two-arm, open-label study to evaluate the safety and efficacy of selinexor versus treatment per physician's choice (PC) in participants with myelofibrosis (MF) who had at least 6 months of treatment with a Janus kinase (JAK)1/2 inhibitor. Study participants will be randomized in a 1:1 ratio to either receive selinexor or physicians' choice of treatment.

Official Title
-----------------
A Phase 2, Randomized, Open-Label, Multicenter Study to Evaluate Safety and Efficacy of Single Agent Selinexor Versus Treatment of Physician's Choice in Patients With Previously Treated Myelofibrosis

Conditions
-----------------
Myelofibrosis

Intervention / Treatment
-----------------
* Drug: Selinexor
* Other: Physician's Choice Treatment


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: A diagnosis of primary MF or post-essential thrombocythemia (ET) or post-polycythemia (PV) MF according to the 2016 World Health Organization (WHO) classification of myeloproliferative neoplasms (MPN), confirmed by the most recent local pathology report. Previous treatment with JAK inhibitors for at least 6 months. Measurable splenomegaly during the screening period as demonstrated by spleen volume of ≥450 centimeter cube (cm^3) by magnetic resonance imaging (MRI) or computerized tomography (CT) scan. Relapsed, Refractory or Intolerant to JAK inhibitors as defined as meeting one of the criteria below: less than (<) 35% spleen volume reduction by MRI or CT-scan (from baseline) or <50% decrease in spleen size by palpation (from baseline) or an increase of at least 3 cm with the spleen at least 5 cm below the left costal margin or Spleen volume increase greater than (>) 25% from nadir or a return to within 10% of baseline after any initial response or Treatment with JAK inhibitor was complicated by development of red blood cells (RBC) transfusion requirement (2 units per month for 2 month); or grade 3 thrombocytopenia, anemia, hematoma/hemorrhage; or grade 2 non-hematologic toxicity while on JAK inhibitors Participants ≥18 years of age. Eastern Cooperative Oncology Group (ECOG) less than or equal to (≤) 2. Platelet count ≥75*10^9 per liter (/L). Absolute neutrophil count (ANC) ≥1.5*10^9/L. Serum direct bilirubin ≤1.5*upper limit of normal (ULN); aspartate aminotransferase (AST) and alanine aminotransferase (ALT) ≤2.5*ULN. Calculated creatinine clearance (CrCl) >15 milliliter (mL)/minute (min) based on the Cockcroft and Gault formula. Participants with active hepatitis B virus (HBV) are eligible if antiviral therapy for hepatitis B has been given for >8 weeks and viral load is <100 International Units (IU)/mL. Participants with untreated hepatitis C virus (HCV) are eligible if there is a documentation of negative viral load per institutional standard. Participants with history of human immunodeficiency virus (HIV) are eligible if they have cluster of differentiation 4 (CD4)+ T-cell counts ≥350 cells/microliter (mcL), negative viral load per institutional standard, and no history of acquired immunodeficiency syndrome (AIDS)-defining opportunistic infections in the last year. Female participants of childbearing potential must have a negative serum pregnancy test at screening and agree to use highly effective methods of contraception throughout the study and for at least 90 days after the last dose of selinexor, or for the duration as stated on the label (SmPC/USPI) for those on the comparator drug (physician's choice arm). Childbearing potential excludes: Age >50 years and naturally amenorrhoeic for >1 year, or previous bilateral salpingo-oophorectomy, or hysterectomy. Male participants who are sexually active must use highly effective methods of contraception throughout the study and for at least 90 days after the last dose of selinexor, or for the duration as stated on the label (SmPC/USPI) for those on the comparator drug (physician's choice arm). Male participants must agree not to donate sperm during the study treatment period. Participants must sign written informed consent in accordance with federal, local and institutional guidelines. Exclusion Criteria: >5% blasts in peripheral blood or >10% blasts in bone marrow (i.e., accelerated phase). Previous treatment with selinexor or other exportin 1 (XPO1) inhibitors. Use of any standard or experimental anti-MF therapy <21 days prior to Cycle 1 Day 1 (hydroxyurea or growth factors are allowed). Impairment of gastrointestinal (GI) function or GI disease that could significantly alter the absorption of selinexor (Example: vomiting, or diarrhea that is Common Terminology Criteria for Adverse Events (CTCAE) grade >1). Received strong cytochrome P450 3A (CYP3A) inhibitors ≤7 days prior to selinexor dosing or strong CYP3A inducers ≤14 days prior to selinexor dosing. Major surgery <28 days prior to cycle 1 day 1 (C1D1). Uncontrolled (ie, clinically unstable) infection requiring parenteral antibiotics, antivirals, or antifungals within 7 days prior to first dose of study treatment; however, prophylactic use of these agents is acceptable (including parenteral). Any life-threatening illness, medical condition, or organ system dysfunction which, in the Investigator's opinion, could compromise the participants safety, prevent the participant from giving informed consent, or being compliant with the study procedures. Female participants who are pregnant or lactating. Participants with contraindications to use of selinexor or all the drugs intended to be used in the comparative treatment arm.

Ages Eligible for Study
-----------------
Minimum Age: 18 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

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


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Arm S: Selinexor<br>Participants with MF who had previously received at least 6 months of treatment with JAK 1/2 inhibitor will receive a dose of selinexor 80 mg in first 2 cycles followed by selinexor 60 mg in subsequent cycles orally on Days 1, 8, 15, and 22 of each 28-day cycle to participants on Arm S. | Drug: Selinexor<br>* Unit Dose Strength: 20 mg; Dose Formulation: Tablet; Dosage Level: 60 or 80 mg, QW; Route of Administration: Oral<br>|
| Active Comparator: Arm PC: Physician's Choice Treatment<br>Participants with MF who had previously received at least 6 months of treatment with JAK 1/2 inhibitor will receive Physician's choice treatment which will be administered as per clinical practice. | Other: Physician's Choice Treatment<br>* Physician's choice treatment may include ruxolitinib retreatment, fedratinib, chemotherapy (e.g., hydroxyurea), anagrelide, corticosteroid, hematopoietic growth factor, immunomodulatory agent, androgen, interferon (all as per clinical practice) and may include supportive care only with no MF treatment; no investigational therapies are allowed.<br>|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percentage of Participants with Spleen Volume Reduction of Greater Than or Equal to (≥) 35 Percent (%) (SVR35) Assessed by Independent Review Committee (IRC) |  | From Baseline up to Week 48 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percentage of Participants with Total Symptom Score Reduction of ≥50% (TSS50) Measured by Myelofibrosis Symptom Assessment Form (MFSAF) V4.0, Based on Local Assessment |  | From Baseline up to end of last cycle (approximately 48 months) | 
| Percentage of Participants with Spleen Volume Reduction of ≥25% (SVR25) Assessed by IRC |  | From Baseline up to Week 48 | 
| Overall Survival (OS) |  | From Baseline up to 12 months after end of treatment (approximately 60 months) | 
| Percentage of Participants with Anemia Response Assessed by International Working Group-Myeloproliferative Neoplasms Research and Treatment (IWG-MRT ) |  | From Baseline up to 28 Days after last dose (approximately 48 months) | 
| Duration of Spleen Volume Reduction of ≥35% (SVR35) Assessed by IRC |  | From Baseline up to 28 Days after last dose (approximately 48 months) | 
| Duration of Spleen Volume Reduction of ≥25% (SVR25) Assessed by IRC |  | From Baseline up to 28 Days after last dose (approximately 48 months) | 
| Duration of Total Symptom Score is ≥50% (TSS50) Based on Local Assessment |  | From Baseline up to 28 Days after last dose (approximately 48 months) | 
| Overall Response Rate (ORR) Assessed by IWG-MRT |  | From Baseline up to 28 Days after last dose (approximately 48 months) | 
| Number of Participants With Treatment-emergent Adverse Events (TEAEs) by Severity Grade ≥3, Serious Adverse event (SAEs), and AEs Leading to Treatment Discontinuation |  | From first dose of study treatment up to 30 days after end of treatment (approximately 48 months) | 
| Pharmacokinetic (PK) Parameter: Area Under the Plasma Concentration-time Curve (AUC) of Selinexor |  | Cycle 2 Day 1: 1, 2, 4, 6, and 24 hours post dose (each cycle is 28 days) | 
| PK Parameter: Maximum Plasma Concentration (Cmax) of Selinexor |  | Cycle 2 Day 1: 1, 2, 4, 6, and 24 hours post dose (each cycle is 28 days) | 

 Terms related to the study
=================
Keywords Provided by Centre Hospitalier Valida
-----------------
Myelofibrosis, Selinexor, Total Symptom Score, Spleen Volume Reduction, Anemia response, SVR35, SVR25, KPT-330, JAK1, JAK2, XPOVIO, SINE, XPORT-MF-035, Karyopharm, TSS50