A Phase 3 Randomized Open-Label Study of Imetelstat Versus Best Available Therapy in Intermediate-2 or High-Risk Myelofibrosis Refractory to JAK-Inhibitors

The primary objective of this study is to compare the **overall survival** (OS) of participants treated with imetelstat versus Best Available Therapy (BAT) in patients with intermediate-2 or high-risk **myelofibrosis** (MF) who have relapsed or are refractory to Janus Kinase (JAK)-inhibitor treatment. This is clinically relevant as it aims to determine the efficacy of imetelstat in extending the survival of patients with limited treatment options due to resistance or relapse following JAK-inhibitor therapy.

Secondary objectives include evaluating imetelstat versus BAT with respect to:

• Symptom response rate at Week 24, defined as the proportion of participants achieving a ≥ 50% reduction in total symptom score (TSS) from baseline, as measured by the Myelofibrosis Symptom Assessment Form (MFSAF) v4.0 e-diary questionnaire.
• Progression-free survival, defined as the time interval from randomization to the first date of disease progression or death from any cause.
• Spleen response rate at Week 24, defined as the proportion of participants achieving a ≥ 35% spleen volume reduction (SVR) from baseline, assessed by magnetic resonance imaging (MRI) or computed tomography scan and evaluated by Central Radiology Review. Additionally, SVR of ≥ 20% and ≥ 10% at Week 24 will be assessed.
• Complete remission, partial remission, clinical improvement, spleen response, symptoms response, and anemia response per modified 2013 IWG MRT criteria.

The clinical trial involves a total of **94 participants** diagnosed with **myelofibrosis**, specifically those with intermediate-2 or high-risk disease that is relapsed or refractory to JAK-inhibitor treatment. 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 inclusion criteria, including a confirmed diagnosis of primary myelofibrosis (PMF) or post-essential thrombocythemia myelofibrosis (PET-MF) or post-polycythemia vera myelofibrosis (PPV-MF), as well as measurable splenomegaly and active symptoms of myelofibrosis. The trial also considers vulnerable populations. Lifestyle factors such as diet and physical activity are not specified in the available data. The selection process ensures that participants have hematology laboratory test values within defined limits, and they are not eligible for allogeneic stem cell transplantation (ASCT) at screening. The trial does not provide additional information on general health status or specific lifestyle considerations beyond the medical condition and treatment history.

The clinical trial is designed as a **randomized**, open-label, Phase 3 study to evaluate the efficacy of **imetelstat** versus Best Available Therapy (BAT) in patients with intermediate-2 or high-risk **myelofibrosis** who have relapsed or are refractory to Janus Kinase (JAK)-inhibitor treatment. The primary objective is to compare the overall survival of participants treated with imetelstat versus BAT. The trial is expected to run from March 31, 2021, to December 31, 2027, with participant involvement lasting up to 21 days for the treatment period.

Participants will undergo a series of study visits, beginning with an inclusion (screening) visit to confirm eligibility based on criteria such as diagnosis of primary myelofibrosis (PMF) or post-essential thrombocythemia myelofibrosis (PET-MF) or post-polycythemia vera myelofibrosis (PPV-MF), and relapsed/refractory status to JAK-inhibitor treatment. The screening will also assess measurable splenomegaly and active symptoms of myelofibrosis. Following randomization, participants will receive either imetelstat or BAT, with the primary endpoint being overall survival, defined as the time from randomization to death from any cause.

Secondary endpoints include symptom response rate at Week 24, progression-free survival, and spleen response rate at Week 24. Follow-up visits will be conducted to monitor these endpoints and assess any adverse events. The end-of-study visit will conclude the participant's involvement, with data collected on overall survival and secondary outcomes. Conditions that may lead to early termination from the study include significant adverse events or withdrawal of consent by the participant. The trial will adhere to rigorous scientific and ethical standards to ensure the validity and reliability of the results.

The clinical trial involves the administration of **Imetelstat**, an experimental medication, which is a **solution for infusion**. The active substance is **imetelstat sodium**, classified under the ATC code PRD257254. The pharmaceutical form is a solution for infusion, and the route of administration is **intravenous**. The dosage is set at a maximum of 9.4 mg/kg per day, with a total treatment period of 21 days. Imetelstat is an orphan drug, designated with the number EU/3/15/1593, and is provided by Geron Corporation under the sponsor product code GRN163L.

In addition to the experimental treatment, the study includes a comparator group receiving **Best Available Therapy (BAT)**, which serves as the standard-of-care product. This group includes various non-experimental treatments, such as **other antineoplastic agents**, **alkylating agents**, **antimetabolites**, **immunostimulants**, **immunosuppressants**, **corticosteroids for systemic use**, **other sex hormones and modulators of the genital system**, **other antianemic preparations**, and **vitamin B12 and folic acid**. These treatments are administered in various pharmaceutical forms, including PHF00024MIG, PHF00245MIG, and PHF2355, with routes of administration currently unspecified. The maximum treatment period for these comparator treatments is 1 day, with no specified daily or total dose amounts.

Efficacy in this clinical trial will be assessed using several key endpoints. The primary endpoint is **Overall Survival (OS)**, defined as the time interval from the date of randomization to the date of death from any cause. This will provide a direct measure of the treatment's impact on patient longevity. Secondary endpoints include the Symptom Response Rate at Week 24, which is defined as the proportion of patients achieving a ≥ 50% reduction in Total Symptom Score (TSS) from baseline, as measured by the Myelofibrosis Symptom Assessment Form (MFSAF) v4.0. Additionally, Progression-Free Survival will be evaluated, defined as the time from randomization to the first occurrence of disease progression or death from any cause. The Spleen Response Rate at Week 24 will also be assessed, defined as the proportion of patients achieving a ≥ 35% reduction in spleen volume from baseline, as determined by imaging scans.

The efficacy parameters will be measured and collected at specific timepoints, with the primary and secondary endpoints being evaluated at Week 24 and at the end of the treatment period. The MFSAF v4.0 will be utilized for assessing symptom response, while imaging scans will be employed to measure changes in spleen volume. Data analysis will focus on comparing the outcomes between the treatment group receiving Imetelstat and the group receiving Best Available Therapy (BAT), providing insights into the relative efficacy of the investigational treatment in patients with intermediate-2 or high-risk Myelofibrosis who are relapsed or refractory to JAK-inhibitor treatment.