Clinical Trials /

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

NCT04562389

Description:

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.

Related Conditions:
  • Myelofibrosis
Recruiting Status:

Recruiting

Phase:

Phase 1/Phase 2

Trial Eligibility

Document

Title

  • Brief Title: A Study to Evaluate Safety and Efficacy of Selinexor in Combination With Ruxolitinib in Participants With Myelofibrosis
  • 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

Clinical Trial IDs

  • ORG STUDY ID: XPORT-MF-034
  • SECONDARY ID: 2020-003883-19
  • NCT ID: NCT04562389

Conditions

  • Myelofibrosis

Interventions

DrugSynonymsArms
SelinexorPhase 1a: Cohort -1: Selinexor 20 mg and Ruxolitinib 15/20 mg
RuxolitinibPhase 1a: Cohort -1: Selinexor 20 mg and Ruxolitinib 15/20 mg

Purpose

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.

Trial Arms

NameTypeDescriptionInterventions
Phase 1a: Cohort 1: Selinexor 40 mg and Ruxolitinib 15/20 mgExperimentalParticipants 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).
  • Selinexor
  • Ruxolitinib
Phase 1a: Cohort 2: Selinexor 60 mg and Ruxolitinib 15/20 mgExperimentalParticipants 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.
  • Selinexor
  • Ruxolitinib
Phase 1a: Cohort -1: Selinexor 20 mg and Ruxolitinib 15/20 mgExperimentalParticipants 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.
  • Selinexor
  • Ruxolitinib
Phase 1b: RP2D: Selinexor and Ruxolitinib 15/20 mgExperimentalParticipants 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.
  • Selinexor
  • Ruxolitinib
Phase 2: Selinexor RP2D and Ruxolitinib 15/20 mgExperimentalParticipants 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.
  • Selinexor
  • Ruxolitinib
Phase 2: Ruxolitinib 15/20 mgActive ComparatorParticipants with MF will receive ruxolitinib oral tablets 15 or 20 mg BID.
  • Ruxolitinib

Eligibility 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.
      
Maximum Eligible Age:N/A
Minimum Eligible Age:18 Years
Eligible Gender:All
Healthy Volunteers:No

Primary Outcome Measures

Measure:Phase 1: Maximum Tolerated Dose (MTD)
Time Frame:Approximately within the first cycle (28 days) of therapy
Safety Issue:
Description:

Secondary Outcome Measures

Measure: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)
Safety Issue:
Description:
Measure:Percentage of Participants who will Achieve Spleen Volume Reduction of at least 25% (SVR25): Assessment by IRC
Time Frame:Baseline up to 48 weeks
Safety Issue:
Description:
Measure:Overall Survival (OS)
Time Frame:Up to 12 months after last dose of study treatment (approximately 60 months)
Safety Issue:
Description:
Measure:Anaemia Response: Assessment by IRC
Time Frame:Baseline up to 28 days after last dose of study treatment (approximately 48 months)
Safety Issue:
Description:
Measure: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)
Safety Issue:
Description:
Measure:Duration of SVR35
Time Frame:Baseline up to 28 days after last dose of study treatment (approximately 48 months)
Safety Issue:
Description:
Measure:Duration of SVR25
Time Frame:Baseline up to 28 days after last dose of study treatment (approximately 48 months)
Safety Issue:
Description:
Measure:Duration of TSS50
Time Frame:Baseline up to 28 days after last dose of study treatment (approximately 48 months)
Safety Issue:
Description:
Measure: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)
Safety Issue:
Description:
Measure: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)
Safety Issue:
Description:
Measure: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)
Safety Issue:
Description:
Measure: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)
Safety Issue:
Description:
Measure: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)
Safety Issue:
Description:

Details

Phase:Phase 1/Phase 2
Primary Purpose:Interventional
Overall Status:Recruiting
Lead Sponsor:Karyopharm Therapeutics Inc

Trial Keywords

  • Myelofibrosis
  • Selinexor
  • Ruxolitinib
  • Janus kinase 2
  • Myeloproliferative neoplasms

Last Updated

August 25, 2021