Efficacy and Safety Evaluation of Selinexor and Ruxolitinib in Treatment-Naïve Myelofibrosis Patients: A Phase 1/3 Clinical Trial

The primary objective of this study is to evaluate the **efficacy** of the combination of selinexor and ruxolitinib compared to placebo and ruxolitinib in treatment-naïve patients with **myelofibrosis** (MF). This is clinically relevant as it aims to determine the potential therapeutic benefit of selinexor, a selective inhibitor of nuclear export, in enhancing the treatment outcomes for patients with MF, a chronic and progressive bone marrow disorder.

Secondary objectives include:

• Evaluating additional measures of efficacy of selinexor + ruxolitinib compared to placebo + ruxolitinib in patients with MF.
• Characterizing the pharmacokinetics (PK) of selinexor in patients with MF.
• Evaluating the safety of selinexor + ruxolitinib compared to placebo + ruxolitinib in patients with MF.

The clinical trial involves a total of **130 participants** diagnosed with **myelofibrosis (MF)**, specifically treatment-naïve patients. The study population includes both male and female subjects, with an age range that encompasses adults and older adults. Participants were selected based on specific criteria, including a spleen volume of at least 450 cm³ as measured by MRI or CT scan, a **Dynamic International Prognostic Scoring System (DIPSS)** risk category of intermediate-1, intermediate-2, or high-risk, an **ECOG Performance Status** of 2 or less, and a platelet count of at least 100 × 10⁹/L without the need for platelet transfusion. Additionally, participants must exhibit active symptoms of MF, as determined by the presence of at least two symptoms with a score of 3 or higher, or a total score of 10 or more at screening using the **Myelofibrosis Symptom Assessment Form (MFSAF) V4.0**. The trial does not include a vulnerable population, and no specific lifestyle considerations such as diet or physical activity are highlighted in the selection process.

The clinical trial is designed to evaluate the **efficacy** and safety of **selinexor**, a selective inhibitor of nuclear export, in combination with **ruxolitinib** in treatment-naïve patients with **myelofibrosis**. This study is structured as a randomized, double-blind, controlled trial, with a primary objective to compare the efficacy of selinexor plus ruxolitinib against placebo plus ruxolitinib. The trial is expected to span approximately five years, with an estimated end date in August 2028. Participants will be involved in the study for a maximum treatment period of 105 weeks.

The sequence of study visits begins with an inclusion (screening) visit, where eligibility criteria such as spleen volume, DIPSS risk category, and ECOG Performance Status are assessed. Following successful screening, participants will be randomized into treatment groups. Regular follow-up visits will occur throughout the study to monitor treatment effects and safety, with primary endpoints assessed at Week 24. These include the proportion of patients achieving a spleen volume reduction of at least 35% and changes in the Total Symptom Score. Secondary endpoints will be evaluated at Week 48 and include overall survival, progression-free survival, and incidence of treatment-emergent adverse events.

The end-of-study visit will conclude the participant's involvement, where final assessments are conducted to evaluate long-term outcomes and any residual effects of the treatment. Participants may be withdrawn from the study early if they experience significant adverse events, fail to comply with study protocols, or if the investigator deems it necessary for their safety. The trial's design ensures rigorous monitoring and data collection to support the evaluation of the investigational treatment's potential benefits and risks.

The clinical trial involves the administration of **Selinexor**, a selective inhibitor of nuclear export, in the form of film-coated tablets. The active substance, selinexor, is chemically synthesized and administered orally. The maximum daily dose is 60 mg, with a total dose not exceeding 6.3 grams over a treatment period of 105 days. The medication is specifically supplied for clinical studies and is not a paediatric formulation.

**Ruxolitinib** is used in combination with selinexor. It is available in tablet form with varying strengths of 5 mg, 10 mg, 15 mg, and 20 mg, marketed under the name Jakavi by Novartis Europharm Limited. The maximum daily dose is 40 mg, with a total dose limit of 29.4 grams over the same treatment period. Ruxolitinib is also administered orally and is not formulated for paediatric use.

**Ondansetron** is included as an auxiliary treatment to manage potential side effects. It is provided as an 8 mg orodispersible tablet, marketed by Zydus France. The maximum daily dose is 24 mg, with a total dose not exceeding 3.36 grams. Ondansetron is administered orally and is chemically synthesized.

**Palonosetron** is another auxiliary treatment, available as a hard capsule. The maximum daily dose is 0.5 mg, with a total dose limit of 52.5 mg. It is administered orally and is chemically synthesized.

**Netupitant** is provided in combination with palonosetron in the form of Akynzeo 300 mg/0.5 mg hard capsules, manufactured by Helsinn Birex Pharmaceuticals Ltd. The maximum daily dose is 300.5 mg, with a total dose not exceeding 31.55 grams. This combination is administered orally.

**Aprepitant** is available as EMEND 125 mg+80 mg hard capsules, produced by Merck Sharp & Dohme BV. The maximum daily dose is 125 mg, with a total dose limit of 29.92 grams. Aprepitant is administered orally and is chemically synthesized.

A **placebo** for selinexor is also used in the study, formulated as 20 mg tablets for oral administration. The placebo is used to evaluate the efficacy of selinexor in combination with ruxolitinib compared to the placebo with ruxolitinib in patients with myelofibrosis.

The efficacy of the clinical trial evaluating **selinexor** in combination with **ruxolitinib** for the treatment of **myelofibrosis** will be assessed using specific primary and secondary endpoints. The primary endpoints include the proportion of patients achieving a spleen volume reduction (SVR) of at least 35% (SVR35) at Week 24, as measured by MRI or CT scan, and the absolute mean change in Total Symptom Score (TSS) from baseline to Week 24, assessed using the Myelofibrosis Symptom Assessment Form (MFSAF) v4.0a.

Secondary endpoints will further evaluate efficacy by measuring the proportion of patients with SVR35 at Week 48, overall survival (OS), progression-free survival (PFS), and the proportion of patients with SVR35 at any time point during the study. Additionally, the absolute mean change in TSS from baseline to Week 48 will be assessed, along with the incidence and severity of treatment-emergent adverse events (TEAEs), including treatment-related adverse events (TRAEs) and serious adverse events (SAEs). Pharmacokinetic (PK) endpoints such as area under the curve (AUC), maximum concentration (Cmax), and time to maximum concentration (Tmax) will also be evaluated. The proportion of patients experiencing at least a 1-grade decrease in bone marrow fibrosis at any point in the study will be recorded.