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

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.

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 arrythmia (TdP)
• Cardiac function abnormalities on screening ECG as follows:
• Resting heart rate outside of 50 to 100 beats per minute
• QTcF >470 millisecond (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 bundle branch block or ventricular conduction delay (QRS >119 msec)
• 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

This is a Phase 2/3, multicenter study of imetelstat that consists of 2 parts and

approximately 270 participants may be enrolled.

Part 1 is an open-label, single-arm design to assess the efficacy and safety of imetelstat.

Approximately 55 participants were enrolled in Part 1, including the expansion cohort, and be

followed-up for safety, hematologic improvement and reduction in transfusion requirement.

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.

Each part of the study will 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

End of the Study is defined as 2 years after the study entry of the last participant in the

main study of Part 2 or anytime the sponsor terminates the study, whichever comes first.

Trial Phase Phase II/III

Trial Type Treatment

Lead Organization
Geron Corporation

• Primary ID CR107947
• Secondary IDs NCI-2015-02285, 2015-002874-19, 63935937MDS3001
• Clinicaltrials.gov ID NCT02598661