A Phase 2 study to evaluate the efficacy and safety of selinexor monotherapy in subjects with JAK inhibitor-naïve myelofibrosis and moderate thrombocytopenia.

Overview

Sponsor-declared trial summary

Key facts

Sponsor

Karyopharm Therapeutics Inc.

Participant type

Patients

Age range

18-64 years, 65+ years

Gender

Male and Female

Therapeutic area

Diseases [C] - Hemic and Lymphatic Diseases [C15]

Trial duration

17 Jul 2024 → ongoing

Decision date (initial)

2024-06-12

Transition trial

No

Low-intervention

No

Rare-disease indication

Yes

Vulnerable population

Yes

Funding sources

Karyopharm Therapeutics Inc.

Trial design

CTIS Part I — objectives, methods, condition coding

Main objective

Scope: Safety, Efficacy

To evaluate the efficacy of single-agent selinexor in JAK-naïve patients with MF based on SVR

Secondary objectives 12

1. To evaluate additional measures of efficacy of single-agent selinexor in patients with MF
2. To evaluate additional measures of efficacy of single-agent selinexor in patients with MF
3. To evaluate the additional measures of efficacy of single-agent selinexor in patients with MF
4. To evaluate additional measures of efficacy of single-agent selinexor in patients with MF
5. To evaluate additional measures of efficacy of single-agent selinexor in patients with MF
6. To evaluate additional measures of efficacy of single-agent selinexor in patients with MF
7. To evaluate additional measures of efficacy of single-agent selinexor in pre-specified MF patient subgroups
8. To evaluate the safety of the single-agent selinexor and selinexor with add-on treatments in patients with MF
9. To characterize PK of single-agent selinexor in patients with MF
10. To evaluate the PDn activity of single-agent selinexor and its relationship to exposure to selinexor
11. To assess changes in bone marrow fibrosis of single-agent selinexor in patients with MF
12. Evaluar la estabilización de la hemoglobina conseguida con selinexor como agente único en pacientes con MF

Conditions and MedDRA coding

moderate thrombocytopenia

Eligibility criteria

Principal inclusion / exclusion criteria as submitted by sponsor

Inclusion criteria 22

1. A diagnosis of MF or post-ET or post-PV MF according to the 2016 World Health Organization (WHO) classification of MPN in Appendix 2 (Barbui 2018), confirmed by the most recent local pathology report.
2. Measurable splenomegaly during the screening period as demonstrated by spleen volume of ≥450 cm3 by MRI or CT scan (results from MRI or CT imaging performed within 28 days prior to C1D1 are acceptable).
3. Patients with DIPSS risk category of intermediate-1 with symptoms, or intermediate-2, or high-risk.
4. Patients ≥18 years of age.
5. ECOG Performance Status ≤2, see Appendix 3 (Oken 1982).
6. Platelet count of ≥50 × 109 /L without platelet transfusion within 7 days prior to the first dose of selinexor.
7. Absolute neutrophil count ≥1.0 × 109 /L without need for growth factors within 7 days prior to the first dose of selinexor.
8. Adequate liver function as defined by the following: aspartate transaminase (AST) and alanine transaminase ≤2.5 × upper limit normal (ULN) and serum total bilirubin ≤3× ULN.
9. Calculated creatinine clearance (CrCl) >15 mL/min based on the Cockcroft and Gault formula.
10. Patients with active hepatitis B virus (HBV) are eligible if antiviral therapy for HBV has been given for >8 weeks and the viral load is <100 IU/mL.
11. Patients 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.
12. Patients with history of human immunodeficiency virus (HIV) are eligible if they have cluster of differentiation 4 (CD4) + T-cell counts ≥350 cells/μL, 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.
13. Female patients 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 and other IMPs. They must agree to refrain from egg donation from first dose until at least 90 days following the last dose of any treatment. As noted in the SmPC for EMEND® (aprepitant), the efficacy of hormonal contraceptives may be reduced during and for 28 days after the administration of EMEND. Therefore, patients using EMEND for anti-emetic prophylaxis must use an effective alternate non-hormonal contraceptives such as condoms and spermicides during treatment with EMEND, and for 2 months following the last dose of EMEND. A woman is considered of childbearing potential (ie, fertile) following menarche and until becoming postmenopausal 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.
14. Male patients who are sexually active must use a barrier method in addition to a highly effective methods of contraception throughout the study treatment period and for 90 days following the last dose of selinexor treatment and other IMPs. As noted in the SmPC for EMEND (aprepitant), the efficacy of hormonal contraceptives may be reduced during and for 28 days after the administration of EMEND. Therefore, patients using EMEND for anti-emetic prophylaxis must use an effective alternate non-hormonal contraceptives such as condoms and spermicides during treatment with EMEND, and for 2 months following the last dose of EMEND. Male patients must agree not to donate sperm during the study treatment period and for at least 90 days after the last dose of selinexor treatment.
15. Patients must sign written informed consent in accordance with federal, local, and institutional guidelines.
16. Active symptoms of MF as determined by presence of at least 2 symptoms with an average score ≥5 or an average total score of ≥12 at screening (at least 5 of 7 consecutive days immediately preceding C1D1) using the MFSAF v4.0.
17. Patients must provide bone marrow biopsy samples (samples obtained up to 3 months prior to C1D1 are permitted) at screening and during the study.
18. Life expectancy of greater than 6 months in the opinion of the Investigator.
19. Patients 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.
20. Patient is currently not eligible for stem cell transplantation.
21. Patients must be willing to complete the MFSAF) v4.0 daily during the study for evaluating the symptom response (ie, TSS50).
22. Patients must be able to voluntarily provide informed consent per all relevant rules and institutional policies before any study procedures are performed. No incapacitated patients will be recruited for participation.

Exclusion criteria 13

1. More than 10% blasts in peripheral blood or bone marrow (accelerated or blast phase).
2. Previous treatment with JAK inhibitors for MF.
3. Previous treatment with selinexor or other XPO1 inhibitors.
4. Impairment of gastrointestinal (GI) function or GI disease that could significantly alter the absorption of selinexor (eg, vomiting or diarrhea Common Terminology Criteria for Adverse Events [CTCAE] v5.0 Grade 2 or higher) and uncontrolled or currently progressing ocular toxicities.
5. Major surgery <28 days prior to C1D1.
6. Uncontrolled (ie, 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).
7. 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, or confound the ability to interpret study results.
8. Female patients who are pregnant or lactating.
9. Prior splenectomy, splenic radiation, or splenic embolization within 6 months prior to C1D1.
10. Unable or unwilling to undergo CT scan, MRI, or bone marrow biopsy per protocol.
11. Patients with contraindications or known hypersensitivity to selinexor or excipients.
12. History of myocardial infarction, unstable angina, percutaneous transluminal coronary angioplasty, coronary artery bypass, graft cerebrovascular accident, transient ischemic attack (TIA), ventricular arrhythmias, or congestive heart failure class >2 per New York Heart Association within 6 months of C1D1.
13. Patients unable to tolerate 2 forms of anti-emetics prior to each dose for the first 2 cycles.

Endpoints

Primary and secondary outcome measures (English text)

Primary endpoints 1

1. Proportion of patients with SVR35 at Week 24 as measured by MRI or CT scan by Investigator assessment

Secondary endpoints 12

1. Abs-TSS from baseline to Week 24 as measured by the MFSAF v4.0 a
2. Proportion of patients with SVR35 at Week 48 as measured by MRI or CT scan by Investigator assessment
3. Abs-TSS from baseline to Week 48 as measured by the MFSAF v4.0a
4. PFS as defined in the SAP
5. OS defined as the time interval from the start of selinexor dosing to the date of death due to any cause
6. Proportion of patients with SVR35 in the study as measured by MRI or CT scan at any time point
7. TD vs TI, driver mutation (JAK2, CALR, MPL), high risk mutations (ASXL1, EZH2, IDH1/2, SRSF2, or U2AF1)
8. Incidence and severity of TEAEs including TRAEs, and SAEs
9. PK endpoints including but not limited to AUC, maximal concentration (Cmax), and time at which Cmax is achieved (tmax)
10. Extent and duration of receptor occupancy or XPO1 mRNA induction
11. Proportion of patients with at least a 1-grade decrease in bone marrow fibrosis at any point in the study
12. Proportion of patients with hemoglobin stabilization at any timepoint • Change in total number of RBC transfusion units between a 3-month period prior to start of study, 3-month period after start of study, and the periods between Week 12 and 24 and Week 24-48 in all patients that remain on study treatment. • Rate of RBC transfusion over the first 24 wks of treatment and the second 24 wks of treatment • Conversion from RBC transfusion dependence at baseline to independence

Investigational products

Investigational medicinal products (IMPs), comparators, placebo, auxiliary

Test 1

Auxiliary 7

Sponsors and contacts

Sponsor organisations, regulatory contacts, third parties

Karyopharm Therapeutics Inc.

Sponsor organisation

Karyopharm Therapeutics Inc.

Address

85 Wells Avenue

City

Newton

Postcode

02459-3298

Country

United States

Scientific contact point

Organisation

Karyopharm Therapeutics Inc.

Contact name

Clinical Trials Information Desk

Public contact point

Organisation

Karyopharm Therapeutics Inc.

Contact name

Clinical Trials Information Desk

Third parties 12

Locations

13 EU/EEA countries · 50 investigational sites

By country

Investigational sites

Country notifications

Trial-start, recruitment-start, end and early-termination notifications submitted per Member State

Results and documents

Annex IV summary of results, Annex V layperson summary, and all documents registered in CTIS for this trial

Documents 228 files

Public protocol annexes, IB summaries, regulatory submissions and post-authorisation documents registered in CTIS.

Application history

7 submissions — initial application plus substantial / non-substantial modifications