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A Study to Evaluate Safety and Efficacy of Selinexor in Combination With Ruxolitinib in Participants With Myelofibrosis

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ClinicalTrials.gov Identifier: NCT04562389
Recruitment Status : Recruiting
First Posted : September 24, 2020
Last Update Posted : September 27, 2021
Sponsor:
Information provided by (Responsible Party):
Karyopharm Therapeutics Inc

Brief Summary:
This is a global, Phase 1/2, multicenter, open-label study to evaluate the safety and efficacy of selinexor plus ruxolitinib in treatment naïve myelofibrosis (MF) participants. The study will be conducted in two phases: Phase 1a/1b and Phase 2. The Phase 1a of the study will be dose escalation (non-randomized dose finding study) to determine the maximum tolerated dose [MTD], recommended Phase 2 dose (RP2D), and evaluate safety and preliminary efficacy and will follow a standard 3+3 design. The Phase 1b of the study will be dose expansion (non-randomized efficacy exploration) at the determined RP2D to further assess the safety and preliminary efficacy at this dose level. The Phase 2 (randomized efficacy exploration) of the study will include MF participants who are treatment naïve randomized 1:1 to receive the combination therapy of selinexor and ruxolitinib versus (vs) ruxolitinib monotherapy.

Condition or disease Intervention/treatment Phase
Myelofibrosis Drug: Selinexor Drug: Ruxolitinib Phase 1 Phase 2

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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 237 participants
Allocation: Randomized
Intervention Model: Sequential Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: A Phase 1/2 Study to Evaluate Safety and Efficacy of Selinexor, a Selective Inhibitor of Nuclear Export, in Combination With Ruxolitinib, in Treatment Naïve Patients With Myelofibrosis
Actual Study Start Date : March 11, 2021
Estimated Primary Completion Date : November 2023
Estimated Study Completion Date : November 2024


Arm Intervention/treatment
Experimental: Phase 1a: Cohort 1: Selinexor 40 mg and Ruxolitinib 15/20 mg
Participants with MF will receive a dose of 40 milligrams (mg) of selinexor oral tablets once weekly (QW) on Days 1, 8, 15, and 22 of each 28-day cycle and ruxolitinib oral tablets 15 or 20 mg twice a day (BID).
Drug: Selinexor
Formulation: 20 mg Tablet; Dose: 20, 40 (2 tablets of 20 mg), 60 mg (3 tablets of 20 mg); Route of Administration: Oral

Drug: Ruxolitinib
Formulation: 5, 10 mg Tablet; Dose: 15, 20 mg; Route of Administration: Oral

Experimental: Phase 1a: Cohort 2: Selinexor 60 mg and Ruxolitinib 15/20 mg
Participants with MF will receive a dose of 60 mg of selinexor oral tablets QW on Days 1, 8, 15, and 22 of each 28-day cycle and ruxolitinib oral tablets 15 or 20 mg BID.
Drug: Selinexor
Formulation: 20 mg Tablet; Dose: 20, 40 (2 tablets of 20 mg), 60 mg (3 tablets of 20 mg); Route of Administration: Oral

Drug: Ruxolitinib
Formulation: 5, 10 mg Tablet; Dose: 15, 20 mg; Route of Administration: Oral

Experimental: Phase 1a: Cohort -1: Selinexor 20 mg and Ruxolitinib 15/20 mg
Participants with MF will receive a dose of 20 mg of selinexor oral tablet twice weekly (BIW) of each 28-day cycle and ruxolitinib oral tablets 15 or 20 mg BID.
Drug: Selinexor
Formulation: 20 mg Tablet; Dose: 20, 40 (2 tablets of 20 mg), 60 mg (3 tablets of 20 mg); Route of Administration: Oral

Drug: Ruxolitinib
Formulation: 5, 10 mg Tablet; Dose: 15, 20 mg; Route of Administration: Oral

Experimental: Phase 1b: RP2D: Selinexor and Ruxolitinib 15/20 mg
Participants with MF will receive recommended safe dose (estimated in Phase 1a) of selinexor oral tablets on Days 1, 8, 15, and 22 of each 28-day cycle and ruxolitinib oral tablets 15 or 20 mg BID.
Drug: Selinexor
Formulation: 20 mg Tablet; Dose: 20, 40 (2 tablets of 20 mg), 60 mg (3 tablets of 20 mg); Route of Administration: Oral

Drug: Ruxolitinib
Formulation: 5, 10 mg Tablet; Dose: 15, 20 mg; Route of Administration: Oral

Experimental: Phase 2: Selinexor RP2D and Ruxolitinib 15/20 mg
Participants with MF will receive recommended safe dose (estimated in Phase 1b) of selinexor oral tablets QW on Days 1, 8, 15, and 22 of each 28-day cycle and ruxolitinib oral tablets 15 or 20 mg BID.
Drug: Selinexor
Formulation: 20 mg Tablet; Dose: 20, 40 (2 tablets of 20 mg), 60 mg (3 tablets of 20 mg); Route of Administration: Oral

Drug: Ruxolitinib
Formulation: 5, 10 mg Tablet; Dose: 15, 20 mg; Route of Administration: Oral

Active Comparator: Phase 2: Ruxolitinib 15/20 mg
Participants with MF will receive ruxolitinib oral tablets 15 or 20 mg BID.
Drug: Ruxolitinib
Formulation: 5, 10 mg Tablet; Dose: 15, 20 mg; Route of Administration: Oral




Primary Outcome Measures :
  1. Phase 1: Maximum Tolerated Dose (MTD) [ Time Frame: Approximately within the first cycle (28 days) of therapy ]
  2. Phase 1: Recommended Phase 2 Dose (RP2D) [ Time Frame: Approximately within the first cycle (28 days) of therapy ]
  3. Phase 1: Number of Participants With Adverse Events (AEs) by Occurrence, Nature, and Severity [ Time Frame: From start of drug administration up to 30 days after last dose of study treatment (approximately 48 months) ]
  4. Phase 2: Percentage of Participants who will Achieve Spleen Volume Reduction of at least 35 percentage (%) (SVR35): Assessment by Independent Review Committee (IRC) [ Time Frame: Baseline up to 48 weeks ]

Secondary Outcome Measures :
  1. Percentage of Participants who will Achieve Total Symptom Score Reduction Greater Than or Equal to (≥) 50% (TSS50) as Measured by Myeloproliferative Neoplasm Symptom Assessment Form (MPN-SAF): Assessment by IRC [ Time Frame: Baseline up to 28 days after last dose of study treatment (approximately 48 months) ]
  2. Percentage of Participants who will Achieve Spleen Volume Reduction of at least 25% (SVR25): Assessment by IRC [ Time Frame: Baseline up to 48 weeks ]
  3. Overall Survival (OS) [ Time Frame: Up to 12 months after last dose of study treatment (approximately 60 months) ]
  4. Anaemia Response: Assessment by IRC [ Time Frame: Baseline up to 28 days after last dose of study treatment (approximately 48 months) ]
  5. Number of Participants With AEs by Occurrence, Nature, and Severity [ Time Frame: From start of drug administration up to 30 days after last dose of study treatment (approximately 48 months) ]
  6. Duration of SVR35 [ Time Frame: Baseline up to 28 days after last dose of study treatment (approximately 48 months) ]
  7. Duration of SVR25 [ Time Frame: Baseline up to 28 days after last dose of study treatment (approximately 48 months) ]
  8. Duration of TSS50 [ Time Frame: Baseline up to 28 days after last dose of study treatment (approximately 48 months) ]
  9. Overall Response Rate (ORR) [ Time Frame: Cycle 1 Day 1 (28-day cycle) up to 28 days after last dose of study treatment (approximately 48 months) ]
  10. Phase 1: Maximum Plasma Concentration (Cmax) [ Time Frame: 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) ]
  11. Phase 1: Area Under the Concentration-time Curve (AUC) [ Time Frame: 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) ]
  12. Phase 2: Maximum Plasma Concentration (Cmax) [ Time Frame: 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) ]
  13. Phase 2: Area Under the Concentration-time Curve (AUC) [ Time Frame: 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) ]


Information from the National Library of Medicine

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Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  • Diagnosis of primary MF or post-essential thrombocythemic or post-polycythemia 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 ≥450 cubic centimeter (cm^3) by MRI or CT-scan.
  • Participants with dynamic international prognostic scoring system (DIPSS) risk category of intermediate-1, intermediate-2, or high-risk.
  • Participants ≥18 years of age.
  • Eastern Cooperative Oncology Group (ECOG) performance status of less than or equal to (≤) 2.
  • Platelet count ≥100 * 10^9/Liter (L).
  • Absolute neutrophil count (ANC) ≥1.5 * 10^9/L.
  • Serum direct bilirubin ≤1.5 * upper limit of normal (ULN); Aspartate transaminase (AST) and alanine transaminase (ALT) ≤2.5 * ULN.
  • 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 viral load is less than (<) 100 international units/milliliter (IU/mL).
  • Participants with untreated hepatitis C virus (HCV) are eligible there is documentation of negative viral load per institutional standard.
  • Participants with history of human immunodeficiency virus (HIV), are eligible if participants have cluster of differentiation 4 (CD4)+ T-cell counts ≥350 cells/microliter, 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 one month following the last dose of study treatment. 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 one month following the last dose of study treatment. Must agree not to donate sperm during the study treatment period.
  • Participants must sign the written informed consent in accordance with federal, local and institutional guidelines.

Exclusion Criteria:

  • >5% blasts in peripheral blood or >10% blasts in bone marrow (accelerated phase).
  • Received previous treatment with Janus kinase (JAK) inhibitors for MF (treatment with hydroxyurea for up to 2 weeks is allowed).
  • Previous treatment with selinexor or other exportin-1 (XPO1) inhibitors.
  • Impairment of gastrointestinal (GI) function or GI disease that could significantly alter the absorption of selinexor.
  • 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 (i.e. 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 patient's safety, prevent the patient from giving informed consent, or being compliant with the study procedures.
  • Female participants who are pregnant or lactating.

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT04562389


Contacts
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Contact: Jatin Shah, Chief Medical Officer, MD (617) 658-0600 jshah@karyopharm.com
Contact: Sharon Shacham, President and Chief Scientific Officer, PhD, MBA (617) 658-0600 sshacham@karyopharm.com

Locations
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United States, California
City of Hope Recruiting
Duarte, California, United States, 91010
Contact: Haris Ali, MD    626-356-4673    harisali@coh.org   
Principal Investigator: Haris Ali, MD         
The Oncology Institute of Hope & Innovation Recruiting
Pasadena, California, United States, 91105
Contact: Amitabha Mazumder    562-693-4477    amazumder@airesearch.us   
Principal Investigator: Amitabha Mazumder         
United States, Tennessee
Vanderbilt Ingram Cancer Center Recruiting
Nashville, Tennessee, United States, 37232
Contact: Sanjay Mohan, MD    615-936-8422    sanjay.mohan@vumc.org   
Principal Investigator: Sanjay Mohan, MD         
United States, Utah
Huntsman Cancer Institute Recruiting
Salt Lake City, Utah, United States, 84112
Contact: Srinivas Tantravahi    801-213-6170    Srinivas.Tantravahi@hci.utah.edu   
Principal Investigator: Srinivas Tantravahi         
United States, Virginia
VCU Massey Cancer Center Recruiting
Richmond, Virginia, United States, 23298
Contact: Keri Maher, DO    760-954-3800    Keri.Maher@vcuhealth.org   
Principal Investigator: Keri Maher, DO         
Sponsors and Collaborators
Karyopharm Therapeutics Inc
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Responsible Party: Karyopharm Therapeutics Inc
ClinicalTrials.gov Identifier: NCT04562389    
Other Study ID Numbers: XPORT-MF-034
2020-003883-19 ( EudraCT Number )
First Posted: September 24, 2020    Key Record Dates
Last Update Posted: September 27, 2021
Last Verified: September 2021
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: Undecided

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Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
Keywords provided by Karyopharm Therapeutics Inc:
Myelofibrosis
Selinexor
Ruxolitinib
Janus kinase 2
Myeloproliferative neoplasms
Additional relevant MeSH terms:
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Primary Myelofibrosis
Myeloproliferative Disorders
Bone Marrow Diseases
Hematologic Diseases