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.
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
Interventions
Drug | Synonyms | Arms |
---|
Selinexor | | Phase 1a: Cohort -1: Selinexor 20 mg and Ruxolitinib 15/20 mg |
Ruxolitinib | | Phase 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
Name | Type | Description | Interventions |
---|
Phase 1a: Cohort 1: Selinexor 40 mg and Ruxolitinib 15/20 mg | Experimental | 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). | |
Phase 1a: Cohort 2: Selinexor 60 mg and Ruxolitinib 15/20 mg | Experimental | 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. | |
Phase 1a: Cohort -1: Selinexor 20 mg and Ruxolitinib 15/20 mg | Experimental | 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. | |
Phase 1b: RP2D: Selinexor and Ruxolitinib 15/20 mg | Experimental | 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. | |
Phase 2: Selinexor RP2D and Ruxolitinib 15/20 mg | Experimental | 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. | |
Phase 2: Ruxolitinib 15/20 mg | Active Comparator | Participants with MF will receive ruxolitinib oral tablets 15 or 20 mg BID. | |
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