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

• ClinicalTrials.gov Identifier: NCT02598661
• Recruitment Status: Recruiting
• First Posted: November 6, 2015
• Last Update Posted: April 8, 2022
• Sponsor: Geron Corporation
• Information provided by (Responsible Party): Geron Corporation

Tracking Information

• First Submitted Date: October 27, 2015
• First Posted Date: November 6, 2015
• Last Update Posted Date: April 8, 2022
• Actual Study Start Date: November 24, 2015
• Estimated Primary Completion Date: January 15, 2023 (Final data collection date for primary outcome measure)
• Current Primary Outcome Measures (submitted: November 16, 2021): Part 1 and Part 2 (Main Study): Percentage of Participants Without any Red Blood Cell (RBC) Transfusion During any Consecutive 8-Week Period [ Time Frame: Approximately 12 months ]
• Original Primary Outcome Measures (submitted: November 4, 2015): Percentage of participants without any red blood cell (RBC) transfusion during any consecutive 8 week period [ Time Frame: 8 weeks ]

Current Secondary Outcome Measures (submitted: November 16, 2021)

• Number of Participants with Adverse Events (AEs) [ Time Frame: During study (approximately 2 years) ]
• Percentage of Participants Without any RBC Transfusion During any Consecutive 24-Week Period [ Time Frame: During study (approximately 2 years) ]
• Time to the 8-Week RBC Transfusion Independence (TI) [ Time Frame: During study (approximately 2 years) ]
• Duration of RBC TI [ Time Frame: During study (approximately 2 years) ]
• Percentage of Participants with Hematologic Improvement [ Time Frame: During study (approximately 2 years) ]
• Percentage of Participants with Complete Remission (CR) or Partial Remission (PR) as Per International Working Group (IWG) Response Criteria 2006 [ Time Frame: During study (approximately 2 years) ]
• Overall Survival [ Time Frame: During study (approximately 2 years) ]
• Progression Free Survival (PFS) [ Time Frame: During study (approximately 2 years) ]
  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.
• Time to Progression to Acute Myeloid Leukemia [ Time Frame: During study (approximately 2 years) ]
• Amount of RBC Transfusions [ Time Frame: During study (approximately 2 years) ]
• Relative Change in RBC Transfusions [ Time Frame: During study (approximately 2 years) ]
• Percentage of Participants Receiving any Myeloid Growth Factors [ Time Frame: During study (approximately 2 years) ]
• Maximum Observed Plasma Concentration (Cmax) [ Time Frame: During study (approximately 2 years) ]
• Area Under the Drug Concentration-Plasma Time Curve From Time Zero to Last Measurable Concentration (AUC0-t) [ Time Frame: During study (approximately 2 years) ]
• Percentage of Participants with Antibodies to Imetelstat [ Time Frame: During study (approximately 2 years) ]
• Part 2 (Main Study): Medical Resource Utilization Data [ Time Frame: During study (approximately 2 years) ]
• Part 2 (Main Study): Assessment of Functional Assessment of Cancer Therapy-Anemia-Related Effects (FACT-An) [ Time Frame: During study (approximately 2 years) ]
  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.
• Part 2 (Main Study): Assessment of EuroQol 5 Dimension Questionnaire (EQ-5D-5L) [ Time Frame: During study (approximately 2 years) ]
  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).
• Part 2 (Main Study): Assessment of Quality of Life in Myelodysplasia Scale (QUALMS) [ Time Frame: During study (approximately 2 years) ]
  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.
• Part 2 (Main Study): Assessment of Participant Global Impression of Change (PGIC) [ Time Frame: During study (approximately 2 years) ]
  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".
• Part 2 (Ventricular Repolarization Substudy): Change in QT Interval by Fridericia's Correction Method [ Time Frame: Baseline and Day 1 ]
  Change from baseline in QTc interval by Fridericia's correction method (ΔQTcF) will be assessed in participants in the Ventricular Repolarization substudy.

Original Secondary Outcome Measures (submitted: November 4, 2015)

• Number of Participants with Adverse Events (AEs) [ Time Frame: up to follow-up (30 days post-treatment [approximately 2 years]) ]
• Percentage of participants without any red blood cell (RBC) transfusion during any consecutive 24 week period [ Time Frame: up to 2 years after enrollment of the last participant ]
• Time to the 8-week RBC transfusion independence (TI) [ Time Frame: up to 2 years after enrollment of the last participant ]
• Duration of RBC TI [ Time Frame: up to 2 years after enrollment of the last participant ]
• Percentage of Participants with hematologic improvement [ Time Frame: up to 2 years after enrollment of the last participant ]
• Percentage of Participants with Complete remission (CR) or Partial remission (PR) as Per International Working Group (IWG) Response Criteria 2006 [ Time Frame: up to 2 years after enrollment of the last participant ]
• Overall survival [ Time Frame: up to 2 years after enrollment of the last participant ]
• Time to Progression to Acute Myeloid Leukemia [ Time Frame: up to 2 years after enrollment of the last participant ]
• Percentage of Participants with Transfusion [ Time Frame: up to 2 years after enrollment of the last participant ]
• Amount of Transfusions [ Time Frame: up to 2 years after enrollment of the last participant ]
• Percentage of Participants receiving any myeloid growth factors [ Time Frame: up to 2 years after enrollment of the last participant ]
• Maximum Observed Plasma Concentration (Cmax) [ Time Frame: During treatment (approximately 2 years) ]
• Area under the drug concentration-plasma time curve from time zero to last measurable concentration (AUC0-t) [ Time Frame: During treatment (approximately 2 years) ]
• Percentage of Participants with antibodies to imetelstat [ Time Frame: up to 2 years after enrollment of the last participant ]
• Medical resource utilization data [ Time Frame: up to 2 years after enrollment of the last participant ]
• Change from baseline in Functional Assessment of Cancer Therapy Based on Anemia-Related Effects (FACT-An) Score [ Time Frame: up to 2 years after enrollment of the last participant ]
• Change from baseline in Functional Assessment of Cancer Therapy Based on EuroQol-EQ-5D-5LESA (EQ-5D-5L) Score [ Time Frame: up to 2 years after enrollment of the last participant ]

• Current Other Pre-specified Outcome Measures: Not Provided
• Original Other Pre-specified Outcome Measures: Not Provided

Descriptive Information

• Brief Title: Study to Evaluate Imetelstat (GRN163L) in Subjects With International Prognostic Scoring System (IPSS) Low or Intermediate-1 Risk Myelodysplastic Syndrome (MDS)
• Official Title: 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
• Brief Summary: 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.

Detailed Description

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.

• Study Type: Interventional
• Study Phase: Phase 2; Phase 3
• Study Design: Allocation: Randomized; Intervention Model: Parallel Assignment; Masking: Double (Participant, Investigator); Primary Purpose: Treatment
• Condition: Myelodysplastic Syndromes

Intervention

• Drug: Imetelstat
  Intravenous injection.
  Other Name: GRN163L
• Drug: Placebo
  Matching Placebo to Imetelstat will be administered.

Study Arms

• Experimental: Part 1: Imetelstat
  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.
  Intervention: Drug: Imetelstat
• Experimental: Part 2 (Main Study): Imetelstat
  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.
  Intervention: Drug: Imetelstat
• Placebo Comparator: Part 2 (Main Study): Placebo
  Matching Placebo to Imetelstat will be administered.
  Intervention: Drug: Placebo
• Experimental: Part 2 (Ventricular Repolarization Substudy): Imetelstat
  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.
  Intervention: Drug: Imetelstat
• Placebo Comparator: Part 2 (Ventricular Repolarization Substudy): Placebo
  Matching Placebo to Imetelstat will be administered.
  Intervention: Drug: Placebo

• Publications *: Steensma DP, Fenaux P, Van Eygen K, Raza A, Santini V, Germing U, Font P, Diez-Campelo M, Thepot S, Vellenga E, Patnaik MM, Jang JH, Varsos H, Bussolari J, Rose E, Sherman L, Sun L, Wan Y, Dougherty S, Huang F, Feller F, Rizo A, Platzbecker U. Imetelstat Achieves Meaningful and Durable Transfusion Independence in High Transfusion-Burden Patients With Lower-Risk Myelodysplastic Syndromes in a Phase II Study. J Clin Oncol. 2021 Jan 1;39(1):48-56. doi: 10.1200/JCO.20.01895. Epub 2020 Oct 27.

Recruitment Information

• Recruitment Status: Recruiting
• Estimated Enrollment (submitted: November 16, 2021): 278
• Original Estimated Enrollment (submitted: November 4, 2015): 200
• Estimated Study Completion Date: October 13, 2023
• Estimated Primary Completion Date: January 15, 2023 (Final data collection date for primary outcome measure)

Eligibility Criteria

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

Sex/Gender

• Sexes Eligible for Study: All

• Ages: 18 Years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Contacts

Contact: Faye Feller, MD; mds3001-info@Geron.com

Contact: Souria Dougherty; mds3001-info@Geron.com

• Listed Location Countries: Belgium, Canada, Czechia, France, Germany, Israel, Italy, Korea, Republic of, Netherlands, Poland, Russian Federation, Spain, Switzerland, Turkey, Ukraine, United Kingdom, United States
• Removed Location Countries: Brazil, Mexico

Administrative Information

• NCT Number: NCT02598661
• Other Study ID Numbers: CR107947; 63935937MDS3001 ( Other Identifier: Geron Corporation ); 2015-002874-19 ( EudraCT Number )
• Has Data Monitoring Committee: Yes

U.S. FDA-regulated Product

• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No

• IPD Sharing Statement: Not Provided
• Responsible Party: Geron Corporation
• Study Sponsor: Geron Corporation
• Collaborators: Not Provided

Investigators

• Study Director: Faye Feller, MD; Geron Corporation

• PRS Account: Geron Corporation
• Verification Date: April 2022