Efficacy and Safety Evaluation of Selinexor Monotherapy in JAK Inhibitor-Naïve Myelofibrosis Patients with Moderate Thrombocytopenia
- Trial ID
- 2024-511309-47-00
- Protocol
- XPORT-MF-044
- Sponsor
- Karyopharm Therapeutics Inc.
Trial statistics
Diseases & Conditions
Objectives
The primary objective of this Phase 2 study is to evaluate the **efficacy** of single-agent **selinexor** in subjects with JAK inhibitor-naïve **myelofibrosis** (MF) and moderate thrombocytopenia, based on Spleen Volume Reduction (SVR). This is clinically relevant as it aims to determine the potential of selinexor to reduce spleen size, which is a significant symptom and complication in patients with MF, potentially improving their quality of life and disease management.
Secondary objectives include:
- Evaluating the safety of single-agent selinexor in subjects with MF.
- Assessing the efficacy of selinexor based on Total Symptom Score (TSS).
- Evaluating anemia response in subjects receiving selinexor.
- Assessing survival outcomes in subjects receiving selinexor.
- Evaluating additional measures of efficacy of selinexor.
- Assessing the efficacy of selinexor in pre-specified MF subject subgroups.
- Evaluating the efficacy and safety of study drug treatments in subjects receiving add-on treatments to selinexor and those receiving selinexor only.
- Characterizing the pharmacokinetics (PK) of selinexor in subjects with MF.
- Evaluating the pharmacodynamic (PDn) activity of selinexor monotherapy and its relationship to exposure.
- Assessing changes in bone marrow in subjects receiving selinexor.
- Evaluating progression-free survival (PFS) in patients receiving selinexor.
Participants
The clinical trial involves a total of **20 participants** diagnosed with **JAK inhibitor-naïve myelofibrosis** and moderate thrombocytopenia. The study population includes both male and female subjects, aged **18 years and older**, with an **ECOG Performance Status** of 2 or less. Participants were selected based on specific inclusion criteria, including a confirmed diagnosis of myelofibrosis or related conditions, and measurable splenomegaly. The trial population is characterized by a diverse health status, allowing for the inclusion of individuals with controlled hepatitis B, hepatitis C, and HIV, provided certain medical conditions are met. Lifestyle considerations such as diet and physical activity are not specified, but participants must adhere to contraception guidelines if of childbearing potential. The trial does not include individuals with other concomitant malignancies or those who are candidates for stem cell transplantation. The selection process ensures a focus on individuals with a life expectancy greater than six months and those who are not vulnerable to other significant health risks.
Plans and Procedures
The clinical trial is designed to evaluate the efficacy and safety of **selinexor** monotherapy in subjects with JAK inhibitor-naïve **myelofibrosis** and moderate **thrombocytopenia**. This is a Phase 2, randomized, double-blind, controlled study. The trial is expected to commence recruitment on June 3, 2024, and conclude by November 30, 2028. Participants will be involved in the study for a maximum treatment period of 105 days, with the possibility of early termination if specific conditions arise, such as adverse events or non-compliance with the study protocol.
The study will include several visits, starting with a screening visit to confirm eligibility based on the inclusion criteria, such as a diagnosis of myelofibrosis according to the 2016 WHO classification, and adequate liver and renal function. Following the screening, participants will undergo a series of follow-up visits to monitor the efficacy and safety of the treatment. These visits will include assessments such as MRI or CT scans to measure spleen volume reduction (SVR35) and evaluations of treatment-emergent adverse events (TEAEs). The primary endpoint is the proportion of subjects achieving SVR35 at week 24. Secondary endpoints include the incidence and severity of TEAEs, overall survival, and anemia response.
The end-of-study visit will occur after the completion of the treatment period, where final assessments will be conducted to evaluate the overall response rate and any post-treatment changes. Participants are expected to adhere to the study protocol, including the use of contraception for a specified period post-treatment. Conditions that may lead to early termination include significant adverse events, withdrawal of consent, or failure to meet the study requirements. The trial aims to provide valuable insights into the potential benefits of selinexor for patients with myelofibrosis and moderate thrombocytopenia.
Treatment
The clinical trial involves the administration of **Selinexor**, a film-coated tablet, as the primary experimental medication. Selinexor is administered orally with a maximum daily dose of 60 mg and a total dose limit of 3.6 grams over a treatment period of up to 105 days. The active substance, **Selinexor**, is of chemical origin and is designated as an orphan drug for this study. The trial aims to evaluate the efficacy of Selinexor monotherapy in subjects with JAK inhibitor-naïve myelofibrosis and moderate thrombocytopenia.
**Jakavi** is used as a comparator treatment in the study. It is available in two formulations: 5 mg and 10 mg tablets, both containing the active substance **Ruxolitinib**. The tablets are administered orally, with a maximum daily dose of 20 mg and a total dose limit of 14.7 grams over the same treatment period of 105 days. Ruxolitinib is a chemically derived substance, and the product is manufactured by Novartis Europharm Limited.
**Ondansetron** is included as an auxiliary treatment. It is provided in tablet form and administered orally. The maximum daily dose is 24 mg, with a total dose limit of 3.36 grams over 105 days. Ondansetron is a chemical substance used to manage nausea and vomiting associated with the treatment.
**Palonosetron** is another auxiliary treatment, available as a hard capsule. It is administered orally with a maximum daily dose of 0.5 mg and a total dose limit of 52.5 mg over the treatment period. Palonosetron is a chemical substance used to prevent chemotherapy-induced nausea and vomiting.
**Aprepitant** is provided in hard capsule form and administered orally. The maximum daily dose is 125 mg, with a total dose limit of 29.92 grams over 105 days. Aprepitant is a chemical substance used as an antiemetic to prevent nausea and vomiting.
**Pacritinib** is included as an auxiliary treatment in capsule form. It is administered orally with a maximum daily dose of 400 mg and a total dose limit of 294 grams over the treatment period. Pacritinib is a chemical substance used in the management of myelofibrosis.
**Netupitant** is provided as a hard capsule and administered orally. The maximum daily dose is 300 mg, with a total dose limit of 31.5 grams over 105 days. Netupitant is a chemical substance used to prevent nausea and vomiting associated with chemotherapy.
Participant compliance with the dosing schedule is monitored throughout the study to ensure adherence to the treatment regimen. All medications are administered orally, and the trial is conducted under strict clinical guidelines to evaluate the safety and efficacy of the treatments in the specified patient population.
Efficacy
The efficacy of the clinical trial will be assessed primarily through the **Spleen Volume Reduction** (SVR35) at week 24, as measured by MRI or CT scan. This endpoint evaluates the proportion of subjects achieving a 35% or greater reduction in spleen volume. Secondary efficacy endpoints include the incidence and severity of treatment-emergent adverse events (TEAEs), the proportion of subjects achieving a **Total Symptom Score** (TSS50) at week 24, and anemia response as defined by the International Working Group for Myeloproliferative Neoplasms Research and Treatment (IWG-MRT) and European LeukemiaNet (ELN) criteria. Overall survival (OS) and progression-free survival (PFS) will also be monitored, with OS defined as the time from the start of selinexor dosing to death from any cause.
Additional secondary endpoints include the overall response rate (ORR), which encompasses complete response (CR), partial response (PR), and clinical improvement (CI) at any timepoint, as well as the proportion of subjects achieving SVR35 and TSS50 at any time during the study. The efficacy parameters will be analyzed by various subgroups, including gender, age, geographic region, ECOG performance status, DIPSS risk, myelofibrosis type, transfusion requirements, driver mutation, and high-risk mutations. Pharmacokinetic (PK) endpoints such as area under the curve (AUC), maximal concentration (Cmax), and time to Cmax (Tmax) will also be evaluated. The extent and duration of receptor occupancy or XPO1 mRNA induction, post-treatment changes in bone marrow, and other relevant biomarkers will be assessed to provide a comprehensive evaluation of the treatment's efficacy.
Inclusion and Exclusion Criteria
Inclusion Criteria
- 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.
- 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).
- Patients with DIPSS risk category of intermediate-1 with symptoms, or intermediate-2, or high-risk.
- Patients ≥18 years of age.
- ECOG Performance Status ≤2, see Appendix 3 (Oken 1982).
- Platelet count of ≥50 × 109 /L without platelet transfusion within 7 days prior to the first dose of selinexor.
- Absolute neutrophil count ≥1.0 × 109 /L without need for growth factors within 7 days prior to the first dose of selinexor.
- 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.
- Calculated creatinine clearance (CrCl) >15 mL/min based on the Cockcroft and Gault formula.
- 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.
- 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.
- 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.
- 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.
- 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.
- Patients must sign written informed consent in accordance with federal, local, and institutional guidelines.
- 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.
- Patients must provide bone marrow biopsy samples (samples obtained up to 3 months prior to C1D1 are permitted) at screening and during the study.
- Life expectancy of greater than 6 months in the opinion of the Investigator.
- 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.
- Patient is currently not eligible for stem cell transplantation.
- Patients must be willing to complete the MFSAF) v4.0 daily during the study for evaluating the symptom response (ie, TSS50).
- 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
- More than 10% blasts in peripheral blood or bone marrow (accelerated or blast phase).
- Previous treatment with JAK inhibitors for MF.
- Previous treatment with selinexor or other XPO1 inhibitors.
- 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.
- Major surgery <28 days prior to C1D1.
- 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).
- 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.
- Female patients who are pregnant or lactating.
- Prior splenectomy, splenic radiation, or splenic embolization within 6 months prior to C1D1.
- Unable or unwilling to undergo CT scan, MRI, or bone marrow biopsy per protocol.
- Patients with contraindications or known hypersensitivity to selinexor or excipients.
- 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.
- Patients unable to tolerate 2 forms of anti-emetics prior to each dose for the first 2 cycles.
Trial Status by Country
| Country | Status | Start of Recruitment | Planned Patients |
|---|---|---|---|
 Belgium | Recruiting | 03 Jun 2024 | 1 |
 Bulgaria | Recruiting | 03 Jun 2024 | 3 |
 Czechia | Recruiting | 03 Jun 2024 | 1 |
 Denmark | Recruiting | 03 Jun 2024 | 1 |
 France | Recruiting | 03 Jun 2024 | 7 |
 Germany | Recruiting | 03 Jun 2024 | 1 |
 Greece | Recruiting | 03 Jun 2024 | 3 |
 Hungary | Recruiting | 03 Jun 2024 | 1 |
 Italy | Recruiting | 03 Jun 2024 | 7 |
 The Netherlands | Recruiting | 03 Jun 2024 | — |
Sites & Investigators
Investigational Products
Details about the medicinal products being studied in this clinical trial.
| Product Name | Role in Trial | Formulation | Administration | Max Daily Dose | Treatment Duration | EU MP Number |
|---|---|---|---|---|---|---|
APREPITANT | Other | — | ORAL | 125 | 105 | SUB20017 |
Jakavi 10 mg tablets | Other | TABLETS | ORAL | 20 | 105 | PRD2387737 |
NETUPITANT | Other | — | ORAL | 300 | 105 | SUB130488 |
SELINEXOR | Test | — | ORAL | 60 | 105 | SUB177942 |
Jakavi 5 mg tablets | Other | TABLETS | ORAL | 20 | 105 | PRD3949635 |
PALONOSETRON | Other | — | ORAL | 0.5 | 105 | SUB09593MIG |
PACRITINIB | Other | — | ORAL | 400 | 105 | SUB114513 |
ONDANSETRON | Other | — | ORAL | 24 | 105 | SUB09445MIG |