Study to Evaluate Imetelstat (GRN163L) in Subjects With International Prognostic Scoring System (IPSS) Low or Intermediate-1 Risk Myelodysplastic Syndrome (MDS)

Study Overview
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Brief Summary
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The purpose of this study is to evaluate the efficacy and safety of imetelstat in transfusion-dependent participants with low or intermediate-1 risk myelodysplastic syndrome (MDS) that is relapsed/refractory to erythropoiesis-stimulating agent (ESA) treatment in Part 1 of the study and to compare the efficacy, in terms of red blood cell (RBC) transfusion independence (TI), of imetelstat to placebo in transfusion-dependent participants with low or intermediate-1 risk MDS that is relapsed/refractory to ESA treatment in Part 2 of the study. An Extension Phase has been included to allow continued treatment for those subjects who are benefitting from imetelstat and to continue to evaluate the long-term safety, overall survival (OS), and disease progression, including progression to acute myeloid leukemia (AML) in transfusion-dependent participants with low or immediate-1 risk MDS that is relapsed/refractory to ESA treatment.

Detailed Description
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This is a Phase 2/3, multicenter study of imetelstat that consists of 2 parts and approximately 280 participants may be enrolled. Part 1 is an open-label, single-arm design to assess the efficacy and safety of imetelstat. A total of 57 participants were enrolled in Part 1, including the expansion cohort. Part 2 is a double-blind, randomized design to compare the efficacy of imetelstat with placebo. In the main study in Part 2, 178 participants were enrolled and randomized in a 2:1 ratio to receive either imetelstat or placebo, respectively. In a separate Ventricular Repolarization substudy of Part 2, approximately 45 participants will be enrolled and randomized 2:1 to receive either imetelstat or placebo. If after a minimum of 2 treatment cycles in the Ventricular Repolarization substudy, a participant has no significant change to pRBC transfusion burden or evidence of clinical benefit per Investigator, after discussion with the Sponsor the participant may be unblinded. If the participant was on placebo treatment, he/she may be permitted to start treatment with imetelstat. The Extension Phase will begin after the end of the main study (24 months after the last subject was randomized in the main study of Part 2) and continue until participants who entered Part 2 of the main study participate in the study for up to 5 years from the first dose of imetelstat (including treatment and follow-up), or 3 years of post-treatment follow-up from the last dose of study treatment, whichever occurs later, or until death, withdrawal of consent, study termination, or until a subject is lost to follow-up. Patients ongoing on imetelstat and considered to be benefiting from treatment per Investigator in Part 2 of the study, will have the option to continue receiving imetelstat in the Extension Phase. Patients in the follow-up phase for Part 2 of the study will have the option to continue the follow-up in the Extension Phase. Part 1 and Part 2 of the study consist of 3 phases: a Screening phase (up to 28 days); a treatment phase; and a post-treatment follow-up phase which will continue until death, lost to follow-up, withdrawal of consent, or the End of the Study (whichever occurs first). The Extension Phase of the study will consist of an extended treatment phase and an extended follow-up phase which will continue until death, lost to follow-up, withdrawal of consent, or the End of the Study (whichever occurs first).

Official Title
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A Study to Evaluate Imetelstat (GRN163L) in Transfusion-Dependent Subjects With IPSS Low or Intermediate-1 Risk Myelodysplastic Syndrome (MDS) That is Relapsed/Refractory to Erythropoiesis-Stimulating Agent (ESA) Treatment

Conditions
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Myelodysplastic Syndromes

Intervention / Treatment
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* Drug: Imetelstat
* Drug: Placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Man or woman greater than or equal to (>=) 18 years of age Diagnosis of myelodysplastic syndrome (MDS) according to World Health Organization (WHO) criteria confirmed by bone marrow aspirate and biopsy within 12 weeks prior to Cycle 1 Day 1 (C1D1) (Part 1) or randomization [Part 2 (Main Study)]. In Part 2 (Ventricular Repolarization Substudy), diagnosis of MDS or myelodysplastic/myeloproliferative neoplasm with ring sideroblasts and thrombocytosis (MDS/MPN-RS-T) according to WHO criteria confirmed by bone marrow aspirate and biopsy within 12 weeks prior to C1D1 International Prognostic Scoring System (IPSS) low Risk or intermediate-1 risk MDS Red blood cell (RBC) transfusion dependent, defined as requiring at least 4 RBC units transfused over an 8-week period during the 16 weeks prior to Study Entry; pre-transfusion hemoglobin (Hb) should be less than or equal to 9.0 gram per deciliter (g/dL) to count towards the 4 units total Eastern Cooperative Oncology Group (ECOG) performance status 0, 1 or 2 Exclusion Criteria: Participant has known allergies, hypersensitivity, or intolerance to imetelstat or its excipients Participant has received an investigational drug or used an invasive investigational medical device within 30 days prior to Study Entry or is currently enrolled in an investigational study Prior treatment with imetelstat Have received corticosteroids greater than (>) 30 milligram per day (mg/day) prednisone or equivalent, or growth factor treatment within 4 weeks prior to study entry Has received an erythropoiesis-stimulating agent (ESA) or any chemotherapy, immunomodulatory, or immunosuppressive therapy within 4 weeks prior to study entry (8 weeks for long-acting ESAs) Part 2 (Main Study): a) Prior treatment with a hypomethylating agent (example [eg], azacitidine, decitabine); b) Prior treatment with lenalidomide Additional Exclusion Criteria for Part 2 (Ventricular Repolarization Substudy) Concurrent therapy with medications known to prolong the QT interval and have been associated with Torsade de pointes arrhythmia (TdP) Cardiac function abnormalities on screening ECG as follows: Resting heart rate outside of 50 to 100 beats per minute QTcF >470 millisecond (msec) (or QTcF >490 msec in the presence of a right bundle branch block or ventricular conduction delay [QRS >119 msec]), determined by central assessment based on the average value of a triplicate set of ECGs Diagnosed or suspected congenital long QT syndrome Family history of sudden unexpected death from cardiac-related causes if indicative of a pathogenic mutation of cardiac ion channels Family history of congenital long QT syndrome History of Mobitz II second degree or third degree heart block Implantable pacemaker or automatic implantable cardioverter defibrillator Complete left bundle branch block Chronic or persistent atrial arrhythmia including atrial fibrillation and atrial flutter History or presence of clinically relevant heart rhythm disturbances including atrial, junctional, re-entry, and ventricular tachycardia Unusual T-wave morphology (i.e., bifid T-wave) likely to interfere with QT measurements History or evidence for any of the following: severe or unstable angina, myocardial infarction, symptomatic congestive heart failure, arterial or venous thromboembolic events (example, pulmonary embolism, cerebrovascular accident including transient ischemic attacks) within 12 months prior to Cycle 1 Day 1, New York Heart Association (NYHA) Class II to IV heart disease Presence of uncontrolled hypertension (persistent systolic blood pressure [BP] ≥160 mmHg or diastolic BP ≥100 mmHg). Participants with a history of hypertension are permitted, provided that BP is controlled to within these limits by anti-hypertensive treatment Any skin condition likely to interfere with electrocardiographic electrode placement or adhesion History of thoracic surgery likely to cause abnormality of the electrical conduction through thoracic tissues

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Placebo Comparator: Part 2 (Main Study): Placebo<br>Matching Placebo to Imetelstat will be administered. | Drug: Placebo<br>* Matching Placebo to Imetelstat will be administered.<br>|
| Experimental: Part 2 (Ventricular Repolarization Substudy): Imetelstat<br>Imetelstat will be administered at a starting dose of 7.5 mg/kg given intravenously every 4 weeks, until disease progression, unacceptable toxicity, or withdrawal of consent, or lack of response. Subjects receiving imetelstat who continue into the extension phase will continue to receive imetelstat treatment per this same schedule. | Drug: Imetelstat<br>* Intravenous injection.<br>* Other names: GRN163L;|
| Placebo Comparator: Part 2 (Ventricular Repolarization Substudy): Placebo<br>Matching Placebo to Imetelstat will be administered. | Drug: Placebo<br>* Matching Placebo to Imetelstat will be administered.<br>|
| Experimental: Part 1: Imetelstat<br>Imetelstat will be administered at a starting dose of 7.5 milligram per kilogram (mg/kg) given intravenously every 4 weeks, until disease progression, unacceptable toxicity, or withdrawal of consent, or lack of response. | Drug: Imetelstat<br>* Intravenous injection.<br>* Other names: GRN163L;|
| Experimental: Part 2 (Main Study): Imetelstat<br>Imetelstat will be administered at a starting dose of 7.5 mg/kg given intravenously every 4 weeks, until disease progression, unacceptable toxicity, or withdrawal of consent, or lack of response. Subjects receiving imetelstat who continue into the extension phase will continue to receive imetelstat treatment per this same schedule. | Drug: Imetelstat<br>* Intravenous injection.<br>* Other names: GRN163L;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Part 1 and Part 2 (Main Study): Percentage of Participants Without any Red Blood Cell (RBC) Transfusion During any Consecutive 8-Week Period |  | Approximately 12 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Part 1 and Part 2: Progression Free Survival (PFS) | Progression free survival will be assessed as the time interval from study Day 1 to the first date of disease progression or death from any cause, whichever occurs first. As per IWG criteria disease progression is defined as: at least one of the following: at least 50 percent (%) decrement from maximum response levels in granulocytes or platelets; reduction in hemoglobin by greater than or equal to (>=) 1.5 gram per deciliter (g/dL); transfusion dependence. | During study (approximately 2 years) | 
| Part 1 and Part 2: Time to Progression to Acute Myeloid Leukemia |  | During study (approximately 2 years) | 
| Part 1 and Part 2: Amount of RBC Transfusions |  | During study (approximately 2 years) | 
| Part 1 and Part 2: Relative Change in RBC Transfusions |  | During study (approximately 2 years) | 
| Part 1 and Part 2: Percentage of Participants Receiving any Myeloid Growth Factors |  | During study (approximately 2 years) | 
| Part 1 and Part 2: Maximum Observed Plasma Concentration (Cmax) |  | During study (approximately 2 years) | 
| Part 1 and Part 2: Area Under the Drug Concentration-Plasma Time Curve From Time Zero to Last Measurable Concentration (AUC0-t) |  | During study (approximately 2 years) | 
| Part 1 and Part 2: Percentage of Participants with Antibodies to Imetelstat |  | During study (approximately 2 years) | 
| Part 2 (Main Study): Medical Resource Utilization Data |  | During study (approximately 2 years) | 
| Part 2 (Main Study): Assessment of Functional Assessment of Cancer Therapy-Anemia-Related Effects (FACT-An) | The Functional Assessment of Cancer Therapy Anemia (FACT-An), is included in order to provide an assessment of the subject's functional status, well-being, and symptoms over time. | During study (approximately 2 years) | 
| Part 2 (Main Study): Assessment of EuroQol 5 Dimension Questionnaire (EQ-5D-5L) | The EQ-5D-5L is a generic measure of health status. EQ-5D-5L is a 5 item questionnaire that assesses 5 domains including mobility, self-care, usual activities, pain/discomfort and anxiety/depression plus a visual analog scale rating health today with anchors ranging from 0 (worst imaginable health state) to 100 (best imaginable health state). | During study (approximately 2 years) | 
| Part 2 (Main Study): Assessment of Quality of Life in Myelodysplasia Scale (QUALMS) | The QUALMS is a 38-item measure that assesses health-related quality of life for patients with MDS. Thirty-three items are used to calculate the total score, as well as the 14 item physical burden (QUALMS-P), 3-item benefit-finding (QUALMS-BF), and 11-item emotional burden (QUALMS-E) subscales. | During study (approximately 2 years) | 
| Part 2 (Main Study): Assessment of Participant Global Impression of Change (PGIC) | The Participant Global Impression of Change (PGIC) is a single-item questionnaire designed to provide an overall assessment of treatment from the participant's perspective since the start of the study. It is measured on a 7-point scale, where 1=very much improved and 7=very much worse. A participant is considered a responder if they have a response of very much improved or much improved. | During study (approximately 2 years) | 
| Part 2 (Ventricular Repolarization Substudy): Change in QT Interval by Fridericia's Correction Method | Change from baseline in QTc interval by Fridericia's correction method (ΔQTcF) will be assessed in participants in the Ventricular Repolarization substudy. | Baseline and Day 1 | 
| Extension Phase: Number of Participants with Adverse Events (AEs) |  | During extension (up to approximately 3 years) | 
| Extension Phase: Overall Survival |  | During extension (up to approximately 3 years) | 
| Extension Phase: Progression Free Survival (PFS) Survival | Progression free survival will be assessed as the time interval from the end of the Main study until death, withdrawal of consent, study termination, or until a subject is lost to follow-up. As per IWG criteria disease progression is defined as: at least one of the following: at least 50 percent (%) decrement from maximum response levels in granulocytes or platelets; reduction in hemoglobin by greater than or equal to (>=) 1.5 gram per deciliter (g/dL); transfusion dependence. | During extension (up to approximately 3 years) | 
| Part 1 and Part 2: Number of Participants with Adverse Events (AEs) |  | During study (approximately 2 years) | 
| Part 1 and Part 2: Percentage of Participants Without any RBC Transfusion During any Consecutive 24-Week Period |  | During study (approximately 2 years) | 
| Part 1 and Part 2: Time to the 8-Week RBC Transfusion Independence (TI) |  | During study (approximately 2 years) | 
| Part 1 and Part 2: Duration of RBC TI |  | During study (approximately 2 years) | 
| Part 1 and Part 2: Percentage of Participants with Hematologic Improvement |  | During study (approximately 2 years) | 
| Part 1 and Part 2: Percentage of Participants with Complete Remission (CR) or Partial Remission (PR) as Per International Working Group (IWG) Response Criteria 2006 |  | During study (approximately 2 years) | 
| Part 1 and Part 2: Overall Survival |  | During study (approximately 2 years) | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Myelodysplastic Syndromes, Imetelstat, GRN163L, Relapsed/refractory to ESAs, Transfusion dependent, IMerge