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

• ClinicalTrials.gov Identifier: NCT04562389
• Recruitment Status: Recruiting
• First Posted: September 24, 2020
• Last Update Posted: January 31, 2023
• Sponsor: Karyopharm Therapeutics Inc
• Information provided by (Responsible Party): Karyopharm Therapeutics Inc

Study Description

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

Study Design

• 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

Arms and Interventions

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

Outcome Measures

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) ]

Eligibility Criteria

• 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.

Contacts and Locations

Contacts

Contact: Karyopharm Medical Information; (888) 209-9326; clinicaltrials@karyopharm.com

Locations

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

More Information

• 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
• Last Update Posted: January 31, 2023
• Last Verified: January 2023

Individual Participant Data (IPD) Sharing Statement:

• Plan to Share IPD: Undecided

• 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:

Primary Myelofibrosis; Myeloproliferative Disorders; Bone Marrow Diseases; Hematologic Diseases