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

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Read our disclaimer for details.
 
ClinicalTrials.gov Identifier: NCT02598661
Recruitment Status : Active, not recruiting
First Posted : November 6, 2015
Last Update Posted : April 4, 2024
Sponsor:
Information provided by (Responsible Party):
Geron Corporation

Tracking Information
First Submitted Date  ICMJE October 27, 2015
First Posted Date  ICMJE November 6, 2015
Last Update Posted Date April 4, 2024
Actual Study Start Date  ICMJE November 24, 2015
Actual Primary Completion Date October 13, 2023   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (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  ICMJE
 (submitted: November 4, 2015)
Percentage of participants without any red blood cell (RBC) transfusion during any consecutive 8 week period [ Time Frame: 8 weeks ]
Change History
Current Secondary Outcome Measures  ICMJE
 (submitted: February 8, 2023)
  • Part 1 and Part 2: Number of Participants with Adverse Events (AEs) [ Time Frame: During study (approximately 2 years) ]
  • Part 1 and Part 2: Percentage of Participants Without any RBC Transfusion During any Consecutive 24-Week Period [ Time Frame: During study (approximately 2 years) ]
  • Part 1 and Part 2: Time to the 8-Week RBC Transfusion Independence (TI) [ Time Frame: During study (approximately 2 years) ]
  • Part 1 and Part 2: Duration of RBC TI [ Time Frame: During study (approximately 2 years) ]
  • Part 1 and Part 2: Percentage of Participants with Hematologic Improvement [ Time Frame: 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 [ Time Frame: During study (approximately 2 years) ]
  • Part 1 and Part 2: Overall Survival [ Time Frame: During study (approximately 2 years) ]
  • Part 1 and Part 2: 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.
  • Part 1 and Part 2: Time to Progression to Acute Myeloid Leukemia [ Time Frame: During study (approximately 2 years) ]
  • Part 1 and Part 2: Amount of RBC Transfusions [ Time Frame: During study (approximately 2 years) ]
  • Part 1 and Part 2: Relative Change in RBC Transfusions [ Time Frame: During study (approximately 2 years) ]
  • Part 1 and Part 2: Percentage of Participants Receiving any Myeloid Growth Factors [ Time Frame: During study (approximately 2 years) ]
  • Part 1 and Part 2: Maximum Observed Plasma Concentration (Cmax) [ Time Frame: 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) [ Time Frame: During study (approximately 2 years) ]
  • Part 1 and Part 2: 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.
  • Extension Phase: Number of Participants with Adverse Events (AEs) [ Time Frame: During extension (up to approximately 3 years) ]
  • Extension Phase: Overall Survival [ Time Frame: During extension (up to approximately 3 years) ]
  • Extension Phase: Progression Free Survival (PFS) Survival [ Time Frame: During extension (up to approximately 3 years) ]
    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.
Original Secondary Outcome Measures  ICMJE
 (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  ICMJE Study to Evaluate Imetelstat (GRN163L) in Subjects With International Prognostic Scoring System (IPSS) Low or Intermediate-1 Risk Myelodysplastic Syndrome (MDS)
Official Title  ICMJE 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.

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

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).

Study Type  ICMJE Interventional
Study Phase  ICMJE Phase 2
Phase 3
Study Design  ICMJE Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Double (Participant, Investigator)
Primary Purpose: Treatment
Condition  ICMJE Myelodysplastic Syndromes
Intervention  ICMJE
  • Drug: Imetelstat
    Intravenous injection.
    Other Name: GRN163L
  • Drug: Placebo
    Matching Placebo to Imetelstat will be administered.
Study Arms  ICMJE
  • 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.

    Subjects receiving imetelstat who continue into the extension phase will continue to receive imetelstat treatment per this same schedule.

    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.

    Subjects receiving imetelstat who continue into the extension phase will continue to receive imetelstat treatment per this same schedule.

    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.

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruitment Information
Recruitment Status  ICMJE Active, not recruiting
Actual Enrollment  ICMJE
 (submitted: September 28, 2023)
289
Original Estimated Enrollment  ICMJE
 (submitted: November 4, 2015)
200
Estimated Study Completion Date  ICMJE October 13, 2026
Actual Primary Completion Date October 13, 2023   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

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
Sex/Gender  ICMJE
Sexes Eligible for Study: All
Ages  ICMJE 18 Years and older   (Adult, Older Adult)
Accepts Healthy Volunteers  ICMJE No
Contacts  ICMJE Contact information is only displayed when the study is recruiting subjects
Listed Location Countries  ICMJE 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  ICMJE NCT02598661
Other Study ID Numbers  ICMJE 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  ICMJE Not Provided
Current Responsible Party Geron Corporation
Original Responsible Party Janssen Research & Development, LLC
Current Study Sponsor  ICMJE Geron Corporation
Original Study Sponsor  ICMJE Janssen Research & Development, LLC
Collaborators  ICMJE Not Provided
Investigators  ICMJE
Study Director: Faye Feller, MD Geron Corporation
PRS Account Geron Corporation
Verification Date April 2024

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP