Study of Selinexor in Combination With Ruxolitinib in Myelofibrosis

Study Overview
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Brief Summary
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This is a global, multicenter Phase 1/3 study to evaluate the efficacy and safety of selinexor plus ruxolitinib in JAK inhibitor (JAKi) treatment-naïve myelofibrosis (MF) participants. The study will be conducted in two phases: Phase 1 (open-label) and Phase 3 (double-blind). Phase 1 (enrollment completed) was an open-label evaluation of the safety and recommended dose (RD) of selinexor in combination with ruxolitinib and included a dose escalation using a standard 3+3 design (Phase 1a) and a dose expansion part (Phase 1b). In Phase 3, JAKi treatment-naïve MF participants are enrolled in 2:1 ratio to receive the combination therapy of selinexor + ruxolitinib or the combination of placebo + ruxolitinib.

Official Title
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A Phase 1/3 Study to Evaluate Efficacy and Safety of Selinexor, a Selective Inhibitor of Nuclear Export, in Combination With Ruxolitinib in Treatment-naïve Patients With Myelofibrosis

Conditions
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Myelofibrosis

Intervention / Treatment
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* Drug: Selinexor
* Drug: Selinexor
* Other: Placebo
* Drug: Ruxolitinib


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: A diagnosis of primary MF or post-essential thrombocythemia (ET) or postpolycythemia- vera (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 or equal to (>=) 450 cubic 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 international prognostic scoring system (DIPSS) risk category of intermediate-1, or intermediate-2, or high-risk. Participants >=18 years of age. Eastern Cooperative Oncology Group (ECOG) Performance Status less than or equal to (<=) 2. Platelet count >= 100*10^9/liter (L) without platelet transfusion. Absolute neutrophil count (ANC) >=1.0 *10^9/L without need for growth factors within 7 days prior to C1D1. 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 <= 2 × ULN. Calculated creatinine clearance (CrCl) greater than (>) 15 milliliters per minute (mL/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 the viral load is less than (<) 100 international units/milliliter (IU/mL). Participants with history of hepatitis C virus (HCV) are eligible if they have received adequate curative anti-HCV treatment and HCV viral load is below the limit of quantification. Participants with history of human immunodeficiency virus (HIV) are eligible if they have CD4+ T-cell counts >= 350 cells/microliter (cells/mcL), negative viral load, and no history of acquired immunodeficiency syndrome (AIDS)-defining opportunistic infections in the last year and should be on established antiretroviral therapy (ART) for at least 4 weeks. Female participants of childbearing potential must have a negative serum pregnancy test at screening and within 3 days prior to first dose on C1D1 and agree to use highly effective methods of contraception throughout the selinexor treatment period and for 90 days following the last dose of selinexor treatment. A woman is considered of childbearing potential, i.e., fertile, following menarche and until becoming post-menopausal unless permanently sterile. Permanent sterilization methods include hysterectomy, bilateral salpingectomy and bilateral oophorectomy. A postmenopausal state is defined as no menses for 12 months without an alternative medical cause. Male participants who are sexually active must use highly effective methods of contraception throughout the study treatment period and for 90 days following the last dose of selinexor treatment. Male participants must agree not to donate sperm during the study treatment period and for at least 90 days after the last dose of selinexor treatment. Participants must sign written informed consent in accordance with federal, local, and institutional guidelines. 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 Myelofibrosis Symptom Assessment Form (MFSAF) V4.0. Participant currently not eligible for stem cell transplantation. Participants must provide bone marrow biopsy samples (samples obtained up to 3 months prior to C1D1 are permitted) at screening and during the study. Life expectancy of greater than 6 months in the opinion of the investigator. Participants with no other concomitant malignancies or history of another malignancy within 2 years prior to C1D1 except for adequately treated early-stage basal cell or squamous cell carcinoma of skin, adequately treated carcinoma in situ of breast or cervix or organ confined prostate cancer, or PV or ET. 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. Impairment of gastrointestinal (GI) function or GI disease that could significantly alter the absorption of selinexor (e.g., vomiting or diarrhea > CTCAE v 5.0 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 (Phase 1 participants only) Major surgery < 28 days prior to C1D1. Uncontrolled (i.e., clinically unstable) infection requiring parenteral antibiotics, antivirals, or antifungals within 7 days prior to C1D1; 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, or confound the ability to interpret study results. Female participants who are pregnant or lactating. Prior splenectomy, or splenic radiation within 6 months prior to C1D1. Unable or unwilling to undergo CT scan or MRI per protocol. Participants with contraindications or known hypersensitivity to selinexor or ruxolitinib or excipients. History of pulmonary hypertension. 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 at least 2 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: Randomized
Intervention Model: Parallel Assignment
Interventional Model Description: Phase 1, open-label, selinexor dose escalation and expansion part (enrollment completed). Phase 3, randomized, double-blind, placebo-controlled part.
Masking: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Phase 1a: Cohort 1: Selinexor 40 mg + Ruxolitinib BID<br>Participants with MF will receive a dose of 40 milligrams (mg) selinexor oral tablets once weekly (QW) on Days 1, 8, 15, and 22 of each 28-day cycle in combination with 15 or 20 mg ruxolitinib twice a day (BID) based on the participants baseline platelet count. | Drug: Selinexor<br>* Participants will receive a dose of 40 or 60 mg selinexor oral tablets QW.<br>* Other names: KPT-330;Drug: Ruxolitinib<br>* Participants will receive a dose of 15 or 20 mg ruxolitinib oral tablets BID.<br>|
| Experimental: Phase 1a: Cohort 2: Selinexor 60 mg + Ruxolitinib BID<br>Participants with MF will receive a dose of 60 mg selinexor oral tablets QW on Days 1, 8, 15, and 22 of each 28-day cycle in combination with 15 or 20 mg ruxolitinib BID based on the participants baseline platelet count. | Drug: Selinexor<br>* Participants will receive a dose of 40 or 60 mg selinexor oral tablets QW.<br>* Other names: KPT-330;Drug: Ruxolitinib<br>* Participants will receive a dose of 15 or 20 mg ruxolitinib oral tablets BID.<br>|
| Experimental: Phase 1b: Selinexor and Ruxolitinib BID<br>Participants with MF will receive a dose of 40 or 60 mg selinexor oral tablets QW on Days 1, 8, 15, and 22 of each 28-day cycle in combination with 15 or 20 mg ruxolitinib BID based on the participants baseline platelet count. | Drug: Selinexor<br>* Participants will receive a dose of 40 or 60 mg selinexor oral tablets QW.<br>* Other names: KPT-330;Drug: Ruxolitinib<br>* Participants will receive a dose of 15 or 20 mg ruxolitinib oral tablets BID.<br>|
| Experimental: Phase 3: Selinexor 60 mg + Ruxolitinib BID<br>Participants with MF will receive a fixed starting dose of 60 mg selinexor (RD) oral tablets QW on Days 1, 8, 15, and 22 of each 28-day cycle in combination with a starting dose of 15 or 20 mg ruxolitinib BID based on the participants baseline platelet count. | Drug: Selinexor<br>* Participants will receive a dose of 60 mg selinexor oral tablets QW.<br>* Other names: KPT-330;Drug: Ruxolitinib<br>* Participants will receive a dose of 15 or 20 mg ruxolitinib oral tablets BID.<br>|
| Active Comparator: Phase 3: Placebo + Ruxolitinib BID<br>Participants with MF will receive a matching placebo of selinexor oral tablets QW on Days 1, 8, 15, and 22 of each 28-day cycle in combination with a starting dose of 15 or 20 mg ruxolitinib BID based on the participants baseline platelet count. | Other: Placebo<br>* Participants will receive a matching placebo of selinexor oral tablets QW<br>Drug: Ruxolitinib<br>* Participants will receive a dose of 15 or 20 mg ruxolitinib oral tablets BID.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Phase 3: Proportion of Participants with Spleen Volume Reduction (SVR) of Greater than or Equal to (>=) 35 Percent (%) (SVR35) at Week 24 |  | At Week 24 | 
| Phase 3: Proportion of Participants with Total Symptom Score (TSS) Reduction of >= 50% (TSS50) at Week 24 Measured by the Myelofibrosis Symptom Assessment Form (MFSAF) V4.0 |  | At Week 24 | 
| Phase 1: Maximum Tolerated Dose (MTD) |  | Approximately within the first cycle (28 days) of therapy | 
| Phase 1: Recommended Phase 2 Dose (RP2D) |  | Approximately within the first cycle (28 days) of therapy | 
| Phase 1: Number of Participants With Adverse Events (AEs) by Occurrence, Nature, and Severity |  | From start of drug administration up to 30 days after last dose of study treatment (approximately 48 months) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Phase 3: 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 | 
| Phase 3: Overall Survival |  | From date of randomization to the date of death due to any cause or EoS (assessed at approximately 48 months) | 
| Phase 3: Overall Response Rate as per IWG-MRT and ELN criteria |  | From Cycle 1 Day 1 (28-day cycle) up to EoS (approximately 48 months) | 
| Phase 3: Proportion of Participants with SVR35 at any Time Point |  | From Baseline up to EoS (approximately 48 months) | 
| Phase 3: Proportion of Participants with TSS50 at any Time as measured by the MFSAF V4.0 |  | From Baseline up to EoS (approximately 48 months) | 
| Phase 3: SVR35 Response in Participants |  | From Baseline up to EoS (approximately 48 months) | 
| Phase 3: TSS50 Response in Participants |  | From Baseline up to EoS (approximately 48 months) | 
| Phase 3: Anemia Response in Participants |  | From Baseline up to EoS (approximately 48 months) | 
| Phase 3: Number of Participants With Treatment-emergent Adverse Events (TEAEs), Treatment Related Adverse Events (TRAEs), and Serious Adverse Events (SAEs) |  | From start of drug administration up to 30 days after last dose of study treatment (approximately 48 months) | 
| Phase 3: Area Under the Concentration-time Curve (AUC) of Selinexor |  | Predose, 0.5, 1, 2, 4, 6, and 24 hours post-dose on Cycle 1 Day 15 and 2.5 hours post-dose on Cycle 2 Day 15 (28-day cycle) | 
| Phase 3: Maximum Plasma Concentration (Cmax) of Selinexor |  | Predose, 0.5, 1, 2, 4, 6, and 24 hours post-dose on Cycle 1 Day 15 and 2.5 hours post-dose on Cycle 2 Day 15 (28-day cycle) | 
| Phase 3: Time at Which Cmax is Achieved (Tmax) of Selinexor |  | Predose, 0.5, 1, 2, 4, 6, and 24 hours post-dose on Cycle 1 Day 15 and 2.5 hours post-dose on Cycle 2 Day 15 (28-day cycle) | 
| Phase 3: Proportion of Participants with at least Grade 1 Decrease in Bone Marrow Fibrosis |  | From Baseline up to EoS (approximately 48 months) | 
| Phase 1: Percentage of Participants with TSS Reduction of >= 50% (TSS50) in the MFSAF V4.0 Based on Local Assessment |  | From Baseline up to 28 days after last dose (approximately 48 months) | 
| Phase 1: Percentage of Participants with Spleen Volume Reduction of >= 25% (SVR25) Based on Local Assessment |  | From Baseline up to Week 48 | 
| Phase 1: Percentage of Participants with Spleen Volume Reduction of >= 35% (SVR35) Based on Local Assessment |  | From Baseline up to Week 48 | 
| Phase 1: Overall Survival |  | From Baseline up to 12 months after last dose | 
| Phase 1: Anaemia Response in Participants as per International Working Group -Myeloproliferative Neoplasms Research and Treatment (IWG-MRT) Criteria |  | From Baseline up to 28 days after last dose (approximately 48 months) | 
| Phase 1: Duration of SVR35 Based on Local Assessment |  | From Baseline up to 28 days after last dose (approximately 48 months) | 
| Phase 1: Duration of SVR25 Based on Local Assessment |  | From Baseline up to 28 days after last dose (approximately 48 months) | 
| Phase 1: Duration of TSS50 Based on Local Assessment |  | From Baseline up to 28 days after last dose (approximately 48 months) | 
| Phase 1: Overall Response Rate Based on Local Assessment |  | Cycle 1 Day 1 (28-day cycle) up to 28 days after last dose (approximately 48 months) | 
| Phase 1: Number of Participants with Adverse Events (AEs) by Occurrence, Nature, and Severity |  | From start of drug administration up to 30 days after last dose of study treatment (approximately 48 months) | 
| Phase 1: Maximum Plasma Concentration (Cmax) of Selinexor and Ruxolitinib |  | Predose, 0.5, 1, 2, 4, 6, and 24 hours post-dose on Cycle 1 Day 15 and Cycle 1 Day 16 (28-day cycle) | 
| Phase 1: Area Under the Concentration-time Curve (AUC) of Selinexor and Ruxolitinib |  | Predose, 0.5, 1, 2, 4, 6, and 24 hours post-dose on Cycle 1 Day 15 and Cycle 1 Day 16 (28-day cycle) | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Myelofibrosis, Selinexor, Ruxolitinib, Janus kinase 2, Myeloproliferative neoplasms