Evaluation of Selinexor Monotherapy Versus Physician's Choice in Patients with Previously Treated Myelofibrosis: A Phase 2, Randomized, Open-Label Study

Trial ID: 2024-513605-31-00
Protocol: XPORT-MF-035
Sponsor: Karyopharm Therapeutics Inc.

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Diseases & Conditions

Myelofibrosis Primary myelofibrosis

Objectives

The primary objective of this study is to determine the **clinical activity** of **selinexor** monotherapy compared with physician's choice (PC) in patients with previously treated **myelofibrosis** (MF). This is clinically relevant as it aims to establish the efficacy of selinexor as a potential treatment option for MF, a condition characterized by bone marrow fibrosis, which can lead to severe anemia, splenomegaly, and other debilitating symptoms.

Secondary objectives include:

Evaluating additional measures of clinical activity of selinexor compared to PC in patients with MF.
Assessing the survival outcome of patients with MF receiving selinexor compared with PC.
Determining the safety profile of selinexor and comparing it to PC in patients with MF.
Characterizing the pharmacokinetics (PK) of selinexor in patients with MF.

Participants

The clinical trial involves a total of **21 participants** diagnosed with **myelofibrosis**, including primary myelofibrosis or post-essential thrombocythemia (ET) or post-polycythemia vera (PV) myelofibrosis, as per the 2016 WHO classification of myeloproliferative neoplasms. The study population comprises both male and female subjects aged **18 years and older**, with an Eastern Cooperative Oncology Group (ECOG) performance status of 0 to 2. Participants were selected based on specific health criteria, including a calculated creatinine clearance greater than 15 mL/min, platelet count of at least 75 × 10^9/L, and an absolute neutrophil count of at least 1.5 × 10^9/L. The trial excludes vulnerable populations and requires participants to have previously been treated with JAK inhibitors for at least six months. Lifestyle considerations such as diet and physical activity are not specified. The trial ensures that participants with active hepatitis B or untreated hepatitis C are eligible under certain conditions, and those with a history of HIV are included if specific health criteria are met. Female participants of childbearing potential must adhere to strict contraceptive measures, and male participants must agree to similar precautions and refrain from donating sperm during the study period.

Plans and Procedures

The clinical trial is a **phase 2**, randomized, open-label, multicenter study designed to evaluate the safety and efficacy of **selinexor** as a single agent compared to the treatment of physician's choice in patients with previously treated **myelofibrosis**. The primary objective is to determine the clinical activity of selinexor monotherapy. The trial is expected to run from July 30, 2021, to July 30, 2025. Participants will be randomly assigned to receive either selinexor or a treatment selected by their physician. The study will involve oral administration of selinexor, with a maximum daily dose of 80 mg and a total dose not exceeding 640 mg over a 28-day treatment period.

Participants will undergo a series of study visits, beginning with an inclusion (screening) visit to confirm eligibility based on criteria such as a diagnosis of primary myelofibrosis or post-essential thrombocythemia or post-polycythemia vera myelofibrosis, adequate organ function, and previous treatment with JAK inhibitors. Follow-up visits will be scheduled to monitor the rate of spleen volume reduction, total symptom score reduction, overall survival, and anemia response, among other secondary endpoints. The end-of-study visit will conclude the participant's involvement, which is expected to last until the study's completion or until early termination criteria are met.

Participants may be withdrawn from the study early if they experience unacceptable toxicity, withdraw consent, or if the investigator determines it is in the participant's best interest. The study will also assess the occurrence, nature, and severity of adverse events, as well as pharmacokinetic parameters such as AUC and Cmax. The trial's design ensures a comprehensive evaluation of selinexor's efficacy and safety in the target population, contributing valuable data to the treatment landscape for myelofibrosis.

Treatment

The clinical trial involves the use of **SELINEXOR**, an experimental medication, as a single-agent treatment for patients with previously treated **myelofibrosis**. **SELINEXOR** is administered in the form of a film-coated tablet, with the active substance being of chemical origin. The medication is taken orally, with a maximum daily dose of 80 mg and a total maximum dose of 640 mg over a treatment period of 28 days. The chemical name of the active substance is (Z)-3-{3-[3,5-bis(trifluoromethyl)phenyl]-1H-[1,2,4]-triazol-1-yl}-N'-(pyrazin-2-yl)acrylohydrazide. The product is identified by the sponsor product code KPT-330 and has been designated as an orphan drug under the designation number EU/3/14/1355.

In addition to the experimental treatment, the study includes a comparator treatment, which is the treatment of the physician's choice. This non-experimental treatment serves as a standard-of-care therapy against which the efficacy and safety of **SELINEXOR** are evaluated. The trial is designed as a phase 2, randomized, open-label, multicenter study, aiming to determine the clinical activity of **SELINEXOR** monotherapy compared to the physician's choice in the specified patient population. Participant compliance with the dosing schedule is monitored throughout the study to ensure adherence to the treatment protocol.

Efficacy

The efficacy of **selinexor** in the clinical trial will be assessed using several primary and secondary endpoints. The primary endpoint is the Rate of Spleen Volume Reduction of ≥35% (SVR35). Secondary endpoints include the Rate of Total Symptom Score reduction of ≥50% (TSS50) in the myelofibrosis symptom assessment form (MFSAF) V4.0, Rate of Spleen Volume Reduction of ≥25% (SVR25), Overall Survival (OS), and Anemia response as defined per the IWG-MRT criteria. Additional secondary endpoints involve the Duration of SVR35 and SVR25, Duration of TSS50, Overall Response Rate (ORR) including Complete Response (CR), Partial Response (PR), and Clinical Improvement (CI) by IWG-MRT criteria, and the occurrence, nature, and severity of adverse events (AEs). Population pharmacokinetic (PK) parameters such as Area Under the Curve (AUC) and maximum concentration (Cmax) will also be evaluated.

Inclusion and Exclusion Criteria

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Inclusion Criteria

A diagnosis of primary MF or post-ET or post-PV MF according to the 2016 WHO classification of MPN, confirmed by the most recent local pathology report.
Previous treatment with JAK inhibitors for at least 6 months.
Measurable splenomegaly during the screening period as demonstrated by spleen volume of > or = 450 cm3 by MRI or CT scan
Relapsed, refractory or intolerant to JAK inhibitors as defined as meeting one of the criteria below: <35% spleen volume reduction by MRI or CT-scan (from baseline) or b. <50% decrease in spleen size by palpation (from baseline) or an increase of at least 3 cm with the spleen at least 5 cm below the left costal margin or c. Spleen volume increase >25% from nadir or a return to within 10% of baseline) after any initial response or d. Treatment with JAK inhibitor was complicated by development of RBC transfusion requirement (2 units per month for 2 month); or grade 3 thrombocytopenia, anemia, hematoma/hemorrhage; or Grade 2 non-hematologic toxicity while on JAK inhibitors
Patients > or = 18 years of age
ECOG < or = 2
Platelet count > or = 75 × 10^9/L
Absolute neutrophil count (ANC) > or = 1.5 × 10^9/L
Serum direct bilirubin < or =1.5 × ULN; AST and ALT < or = 2.5 × 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 hepatitis B has been given for >8 weeks and viral load is <100 IU/mL.
Patients with untreated hepatitis C virus (HCV) are eligible if there is a documentation of negative viral load per institutional standard.
Patients with history of human immunodeficiency virus (HIV) are eligible if they have CD4+ T-cell counts > or = 350 cells/microL, negative viral load per institutional standard, and no history of acquired immunodeficiency syndrome (AIDS)-defining opportunistic infections in the last year.
Female patients 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 at least 90 days after the last dose of selinexor, or for the duration as stated on the label (SmPC/USPI) for those on the comparator drug (physician's choice arm). Childbearing potential excludes: Age >50 years and naturally amenorrhoeic for >1 year, or previous bilateral salpingo-oophorectomy, or hysterectomy.
Male patients who are sexually active must use highly effective methods of contraception throughout the study and for at least 90 days after the last dose of selinexor, or for the duration as stated on the label (SmPC/USPI) for those on the comparator drug (physician's choice arm). Male patients must agree not to donate sperm during the study treatment period.
Patients must sign written informed consent in accordance with federal, local and institutional guidelines.

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Exclusion Criteria

>5% blasts in peripheral blood or >10% blasts in bone marrow (i.e., accelerated phase).
Previous treatment with selinexor or other XPO1 inhibitors.
Use of any standard or experimental anti-MF therapy <21 days prior to Cycle 1 Day 1 (hydroxyurea or growth factors are allowed).
Impairment of gastrointestinal (GI) function or GI disease that could significantly alter the absorption of selinexor (Example: vomiting, or diarrhea that is CTCAE grade >1).
Received strong cytochrome P450 3A (CYP3A) inhibitors < or = 7 days prior to selinexor dosing OR strong CYP3A inducers < or = 14 days prior to selinexor dosing.
Major surgery <28 days prior to 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 patients who are pregnant or lactating.
Patients with contraindications to use of selinexor or all the drugs intended to be used in the comparative treatment arm.