Evaluation of Imetelstat Sodium in Transfusion-Dependent Patients with IPSS Low or Intermediate-1 Risk Myelodysplastic Syndromes Refractory to ESA Therapy

The primary objective of this study is to evaluate the **efficacy** and **safety** of imetelstat in transfusion-dependent subjects with low or intermediate-1 risk **myelodysplastic syndromes (MDS)** that are relapsed or refractory to erythropoiesis-stimulating agent (ESA) treatment. This is clinically relevant as it addresses the need for effective treatment options in patients who do not respond to standard ESA therapy, potentially improving their quality of life and clinical outcomes. In Part 2, the study aims to compare the efficacy of imetelstat to placebo in terms of red blood cell transfusion independence (RBC TI) in the same patient population. The extension phase focuses on evaluating the long-term safety, overall survival (OS), and disease progression, including progression to acute myeloid leukemia (AML), in these subjects receiving imetelstat.

Secondary objectives include: - Assessing the safety of imetelstat in subjects with MDS. - Evaluating the time to RBC TI and duration of RBC TI. - Assessing the rate of hematologic improvement. - Evaluating the rates of complete response (CR), partial response (PR), or marrow complete remission (mCR). - Assessing OS and progression-free survival (PFS). - Evaluating the time to progression to AML. - Assessing the rate and amount of supportive care, including transfusions and myeloid growth factors (Part 2 only). - Evaluating the pharmacokinetics and immunogenicity of imetelstat in subjects with MDS. - Assessing the effect of imetelstat treatment on patient-reported outcomes (PROs). - Evaluating the effect of treatment on medical resource utilization (Part 2 only). - Assessing the effect of imetelstat on the corrected QT (QTc) interval in subjects in the Ventricular Repolarization substudy (to be reported separately from Part 2).

The clinical trial involves a total of **60 participants** diagnosed with **myelodysplastic syndromes (MDS)**, specifically those with low or intermediate-1 risk according to the International Prognostic Scoring System (IPSS). The study population includes both male and female subjects aged 18 years and older, with no upper age limit specified. Participants are required to be transfusion-dependent, having received at least four units of red blood cells over an eight-week period prior to the study's commencement. The trial population was selected based on their MDS diagnosis, confirmed by bone marrow aspirate and biopsy, and their condition being relapsed or refractory to erythropoiesis-stimulating agent (ESA) treatment. The participants must have an Eastern Cooperative Oncology Group (ECOG) performance status of 0, 1, or 2, indicating they are ambulatory and capable of self-care. The trial does not specify any particular lifestyle considerations such as diet or physical activity. The inclusion of a vulnerable population is acknowledged, although specific details are not provided.

The clinical trial is designed to evaluate the efficacy and safety of **imetelstat sodium** in patients with transfusion-dependent **myelodysplastic syndromes (MDS)** that are relapsed or refractory to erythropoiesis-stimulating agent (ESA) treatment. This is a Phase 2/3 randomized, double-blind, placebo-controlled study. The trial is divided into two parts, with an extension phase to assess long-term outcomes. The estimated duration of the trial is from November 6, 2015, to October 13, 2026.

Participants will undergo a series of study visits, beginning with a screening visit to confirm eligibility based on specific inclusion criteria, such as age, diagnosis of MDS, and transfusion dependency. The screening process includes a bone marrow aspirate and biopsy to confirm the diagnosis according to WHO criteria. Following successful screening, participants will be randomized to receive either imetelstat or a placebo. The primary endpoint is the rate of red blood cell transfusion independence (RBC TI) lasting at least 8 weeks, with secondary endpoints including safety assessments, 24-week RBC TI rate, and overall survival.

Study visits will occur at regular intervals to monitor the participants' health and response to treatment. These visits will include assessments of adverse events, vital signs, laboratory tests, and ECGs. The end-of-study visit will conclude the participant's involvement, unless early termination is warranted due to adverse events, withdrawal of consent, or other protocol-specified reasons. The expected length of participant involvement is up to 84 weeks, with conditions for early termination including significant adverse reactions or disease progression.

The clinical trial involves the administration of **Imetelstat**, a nucleic acid-based medication, provided in the form of a **solution for infusion**. The active substance in Imetelstat is **imetelstat sodium**, and it is manufactured by Geron Corporation. The medication is administered intravenously, with a maximum daily dose of 7.5 mg/kg. The treatment period for Imetelstat is set to a maximum of 84 days. This investigational drug is designated as an orphan drug, indicating its use in treating a rare condition. The trial aims to evaluate the efficacy and safety of Imetelstat in subjects with transfusion-dependent myelodysplastic syndrome (MDS) that is relapsed or refractory to erythropoiesis-stimulating agent (ESA) treatment.

In addition to the experimental treatment, a **placebo** is used as a comparator in the study. The placebo is designed to match the administration form of Imetelstat but does not contain any active substance. The placebo is utilized to assess the efficacy of Imetelstat by providing a control group for comparison. The administration route and dosing schedule for the placebo are consistent with those of Imetelstat, ensuring that the study maintains a double-blind design.

Two auxiliary treatments are also included in the trial, categorized under the ATC codes H02A and D04A. These treatments are of chemical origin and are used for systemic corticosteroids and antipruritics, respectively. However, specific details regarding their pharmaceutical form, active substances, and administration routes are not provided. These auxiliary treatments are not the primary focus of the study but may be used to manage symptoms or conditions related to the trial participants.

The efficacy of the clinical trial evaluating **imetelstat** in transfusion-dependent subjects with low or intermediate-1 risk myelodysplastic syndrome (MDS) that is relapsed or refractory to erythropoiesis-stimulating agent (ESA) treatment will be assessed using several endpoints. The primary efficacy endpoint is the rate of red blood cell transfusion independence (RBC TI) lasting at least 8 weeks. This is defined as the proportion of subjects who do not require any RBC transfusion during any consecutive 8 weeks (56 days) starting from Study Day 1, which is the day of the first dose for subjects in Part 1 and the day of randomization for subjects in Part 2.

Secondary efficacy endpoints include the 24-week RBC TI rate, time to the 8-week and 24-week RBC TI, duration of RBC TI, and the rate of hematologic improvement, including HI-E, per modified IWG 2006. Additional secondary endpoints are the rates of complete response (CR), partial response (PR), or marrow complete response (mCR) per modified IWG 2006, overall survival (OS), progression-free survival, time to progression to acute myeloid leukemia (AML), and the amount and relative change in RBC transfusions. The study will also assess the rate of myeloid growth factors usage, quality of life measures using QUALMS, FACT-An, and EQ-5D-5L, pharmacokinetic parameters, and medical resource utilization data.

Data collection will occur at specified intervals throughout the study, with efficacy assessments being conducted using validated scales and laboratory tests. The analysis will be performed to determine the efficacy of imetelstat compared to placebo in achieving RBC TI and other clinical outcomes in the target population.