Study of Selinexor in Combination With Ruxolitinib in Myelofibrosis

Myelofibrosis Clinical Trial

— SENTRY  

Official title:

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

Clinical Trial Details — Status: Recruiting

Administrative data

• NCT number: NCT04562389
• Other study ID #: XPORT-MF-034
• Secondary ID: 2020-003883-19
• Status: Recruiting
• Phase: Phase 3
• Start date: March 11, 2021
• Est. completion date: March 2028

Study information

• Verified date: April 2024
• Source: Karyopharm Therapeutics Inc
• Contact: Karyopharm Medical Information
• Phone: (888) 209-9326
• Email: clinicaltrials[@]karyopharm.com
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

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.

Recruitment information / eligibility

• Status: Recruiting
• Enrollment: 330
• Est. completion date: March 2028
• Est. primary completion date: September 2025
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years and older

Eligibility

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.

Related Conditions & MeSH terms

• Myelofibrosis
• Primary Myelofibrosis

Intervention

Drug:
• Selinexor
Participants will receive a dose of 40 or 60 mg selinexor oral tablets QW.
• Selinexor
Participants will receive a dose of 60 mg selinexor oral tablets QW.

Other:
• Placebo
Participants will receive a matching placebo of selinexor oral tablets QW

Drug:
• Ruxolitinib
Participants will receive a dose of 15 or 20 mg ruxolitinib oral tablets BID.

Locations

Country	Name	City	State
Canada	Research Institute of the McGill University Health Centre	Montreal	Quebec
France	Centre Hospitalier Universitaire d'Angers	Angers	Pays De La Loire
France	Hôpital Emile Muller	Mulhouse	Grand Est
France	Hôpital Saint-Louis	Paris
France	Hôpital Bretonneau	Tours Cedex	Indre-et-Loire
Israel	Shamir Medical Center (Assaf Harofeh)	Be'er Ya'akov	Central District
Israel	Hadassah University Hospital - Mount Scopus	Jerusalem	Jerusalem District
Israel	Hadassah University Hospital Ein Kerem	Jerusalem	Jerusalem District
Israel	Western Galilee Hospital-Nahariya	Nahariya	Northern District
Israel	Tel Aviv Sourasky Medical Center	Tel Aviv
Italy	Azienda Ospedaliera Ordine Mauriziano di Torino	Torino
Korea, Republic of	Seoul National University Hospital	Seoul
Korea, Republic of	Severance Hospital	Seoul
Romania	Coltea - Spital Clinic	Bucuresti
Spain	Hospital Universitario Lucus Augusti	Lugo
Spain	Hospital Universitario 12 de Octubre	Madrid
Spain	Hospital Clínico Universitario Virgen de la Arrixaca	Murcia
Spain	Complejo Asistencial Universitario de Salamanca - Hospital Clínico	Salamanca
United States	Maryland Oncology Hematology-Satellite	Annapolis	Maryland
United States	UCLA - Satellite Site	Beverly Hills	California
United States	UAB Division of Hematology/Oncology	Birmingham	Alabama
United States	Maryland Oncology Hematology-Satellite	Brandywine	Maryland
United States	Maryland Oncology Hematology	Columbia	Maryland
United States	OhioHealth	Columbus	Ohio
United States	Texas Oncology	Dallas	Texas
United States	City of Hope	Duarte	California
United States	Duke Cancer Institue	Durham	North Carolina
United States	UCLA - Satellite Site	Encino	California
United States	The Cancer & Hematology Centers -Satellite Site	Grand Rapids	Michigan
United States	UCLA	Los Angeles	California
United States	Vanderbilt Ingram Cancer Center	Nashville	Tennessee
United States	Memorial Sloan Kettering Cancer Center	New York	New York
United States	The Cancer & Hematology Centers of Muskegon	Norton Shores	Michigan
United States	The Oncology Institute of Hope & Innovation	Pasadena	California
United States	VCU Massey Cancer Center	Richmond	Virginia
United States	Maryland Oncology Hematology-Satellite	Rockville	Maryland
United States	Huntsman Cancer Institute	Salt Lake City	Utah
United States	Maryland Oncology Hematology-Satellite	Silver Spring	Maryland

Sponsors (1)

Lead Sponsor	Collaborator
Karyopharm Therapeutics Inc

Countries where clinical trial is conducted

United States,  Canada,  France,  Israel,  Italy,  Korea, Republic of,  Romania,  Spain, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	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
Primary	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
Primary	Phase 1: Maximum Tolerated Dose (MTD)		Approximately within the first cycle (28 days) of therapy
Primary	Phase 1: Recommended Phase 2 Dose (RP2D)		Approximately within the first cycle (28 days) of therapy
Primary	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	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
Secondary	Phase 3: Overall Survival		From date of randomization to the date of death due to any cause or EoS (assessed at approximately 48 months)
Secondary	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)
Secondary	Phase 3: Proportion of Participants with SVR35 at any Time Point		From Baseline up to EoS (approximately 48 months)
Secondary	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)
Secondary	Phase 3: SVR35 Response in Participants		From Baseline up to EoS (approximately 48 months)
Secondary	Phase 3: TSS50 Response in Participants		From Baseline up to EoS (approximately 48 months)
Secondary	Phase 3: Anemia Response in Participants		From Baseline up to EoS (approximately 48 months)
Secondary	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)
Secondary	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)
Secondary	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)
Secondary	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)
Secondary	Phase 3: Proportion of Participants with at least Grade 1 Decrease in Bone Marrow Fibrosis		From Baseline up to EoS (approximately 48 months)
Secondary	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)
Secondary	Phase 1: Percentage of Participants with Spleen Volume Reduction of >= 25% (SVR25) Based on Local Assessment		From Baseline up to Week 48
Secondary	Phase 1: Percentage of Participants with Spleen Volume Reduction of >= 35% (SVR35) Based on Local Assessment		From Baseline up to Week 48
Secondary	Phase 1: Overall Survival		From Baseline up to 12 months after last dose
Secondary	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)
Secondary	Phase 1: Duration of SVR35 Based on Local Assessment		From Baseline up to 28 days after last dose (approximately 48 months)
Secondary	Phase 1: Duration of SVR25 Based on Local Assessment		From Baseline up to 28 days after last dose (approximately 48 months)
Secondary	Phase 1: Duration of TSS50 Based on Local Assessment		From Baseline up to 28 days after last dose (approximately 48 months)
Secondary	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)
Secondary	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	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)
Secondary	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)