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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)

Primary Purpose

Myelodysplastic Syndromes

Status

Active

Phase

Phase 2

Locations

International

Study Type

Interventional

Intervention

Imetelstat

Placebo

About this trial

This is an interventional treatment trial for Myelodysplastic Syndromes focused on measuring Myelodysplastic Syndromes, Imetelstat, GRN163L, Relapsed/refractory to ESAs, Transfusion dependent, IMerge

Eligibility Criteria

18 Years - undefined (Adult, Older Adult)All SexesDoes not accept healthy volunteers

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

Sites / Locations

UAB Comprehensive Cancer Center
Acrc/Arizona Clinical Research, Inc.
CBCC Global Research, Inc.
UCLA Ronald Regan Medical Center
Yale-New Haven Hospital (YNHH) - Smilow Cancer Hospital
BRCR Medical Center
University of South Florida (USF) - H. Lee Moffitt Cancer Center
Franciscan Health
St. Agnes Healthcare, Inc
Center for Cancer and Blood Disorders
Washington University School of Medicine
University of New Mexico Cancer Center
Icahn School of Medicine at Mount Sinai Program for the Protection of Human Subjects
Columbia Presbyterian
Columbia University Medical Center
Weill Cornell Medical College-New York Presbyterian Hospital
Cleveland Clinic Taussig Cancer
The Ohio State Comprehensive Cancer Center
Prairie lakes Healthcare system, Inc
Vanderbilt University Medical - Hematology-Oncology
Texas Oncology/Methodist Charlton Cancer Center
Simmons Comprehensive Cancer Center
Fred Hutchinson Cancer Research Center (FHCRC)
GZA Ziekenhuizen - Campus Sint
AZ Sint-Jan Burgge-Oostende
Az Groeninge
ZNA Middelheim
ZNA Stuyvenberg Antwerpen
AZ Klina
Universitair Ziekenhuis Gent
UZ Leuven - Campus Gasthuisberg
Tom Baker Cancer Centre
University of Alberta Hospital - Hematology Research
The Ottawa Hospital
Sunnybrook Health Sciences Centre
Princess Margaret Hospital
Jewish General Hospital
Fakultni nemocnice Brno
FN Hradec Kralove
FN Kralovske Vinohrady
Vseobecna fakultni nemocnice v Praze
Hopital de l'Archet
CHU Tours
CHU de Limoges, Hopital Dupuytren
CHU de Grenoble - Hôpital Albe
CHRU Nancy Brabois
CH Le Mans - HAEMATOLOGY
CHU de Poitiers
Centre Hospitalier Universitai
CHRU de Lille - Hopital Claude Huriez - Maladies du Sang
CHU - HÃ´pital Saint Louis - H
University Hospital Freiburg
Fachärztliche Gemeinschaftspraxis mit Schwerpunkt
University Hospital Leipzig
Studienzentrum für Hämatologie, Onkologie,Diabetologie, Endoskopie und Fußambulanz
University Hospital Bonn
Universitatsklinikum Carl Gustav Carcus Dresden
Universitätsklinikum Düsseldorf
Johannes Gutenberg Universität
Kaplan Medical Center
The Edith Wolfson Medical Center
Meir Medical Center
Ha'Emek Medical Center
Tel Aviv Sourasky Medical Center
The Chaim Sheba Medical Center
Carmel MC
Hadassah Medical Organization
Rabin Medical Center, Beilinson Hospital
A.O. Ospedale Niguarda Ca' Granda
Istituto Clinico Humanitas Rozzano, IRCCS
Irccs Crob
AOU Ospedali Riuniti Umberto I G.M. Lancisi G. Salesi
AOU di Bologna Policlinico S. Orsola Malpighi
Azienda Ospedaliera Universitaria Careggi di Firenze
Grande Ospedale Metropolitano 'Bianchi-Melacrino-Morelli' Reggio Calabria
A.O. Universitaria Policlinico Tor Vergata
AO S. Andrea, Università degli Studi di Roma La Sapienza
Ospedale di Circolo, PO Varese
Gachon University Gil Medical Center - oncology
Pusan National University Hospital - Hematology and Oncology
Seoul National University Hospital
Chonnam National University Hwasun Hospital
Asan Medical Center
Samsung Medical Center
The Catholic University of Korea Seoul St. Mary's Hospital
Severance Hospital, Yonsei Uni
Radboud Umcn
Meander Medisch Centrum
VU Medisch Centrum
Universitair Medisch Centrum Groningen
Uniwersytecki Szpital Kliniczny im. J. Mikulicza-Radeckiego
Centrum Medyczne Pratia Poznan
Wojewódzki Szpital Specjalistyczny sp.z o.o.
SPZOZ MSWiA z Warminsko - Mazurskim Centrum Onkologii
Ars Medical sp. z o.o.
Clinics of Samarskiy GMU
Emergency Hospital of Dzerzhinsk
City Clinical Hospital
Nizhniy Novgorod Region Clinical Hospital
Ryazan Regional Clinical Hospital
FGU-Russian Research Institut
Oncologic Dispensary No.2
H.U.Pta.del Mar
Hospital Universitario Puerta de Hierro Majadahonda
Hospital de Cruces
Hosp. Univ. Germans Trias I Pujol
Hosp. Univ. Vall D Hebron
Hosp. Gral. Univ. Gregorio Maranon
Hosp. Univ. La Paz
Hosp. Clinico Univ. de Salamanca
Hospital Universitario Nuestra Señora de Valme
Hospital Universitario Doctor
Hospital Universitari i Politecnic La Fe
University Hospital in Basel
Kantonsspital St. Gallen - Onkologie/Hämatologie
Inselspital - Universitätsspital Bern
Universitaetsspital Zuerich
Ankara University Medical Faculty - Hematology
Cukurova University Medical Faculty
Ege Universitesi Tip Fakultesi - Hematology
KZ "Miska bahatoprofilna klinichna likarnia No4", hematolohi
Instytut patolohii krovi ta transfusiynoi medytsyny NAMN Ukr
KNP "Cherkaskyi oblasnyi onkolohichnyi dyspanser Cherkaskoi
Nottingham City Hospital - Clinical Haematology
Aberdeen Royal Infirmary
The Leeds Teaching Hospitals NHS Trust
Southampton University Hospital

Arms of the Study

Arm 1

Arm 2

Arm 3

Arm 4

Arm 5

Arm Type

Experimental

Placebo Comparator

Experimental

Placebo Comparator

Arm Label

Part 1: Imetelstat

Part 2 (Main Study): Imetelstat

Part 2 (Main Study): Placebo

Part 2 (Ventricular Repolarization Substudy): Imetelstat

Part 2 (Ventricular Repolarization Substudy): Placebo

Arm Description

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.

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.

Matching Placebo to Imetelstat will be administered.

Outcomes

Primary Outcome Measures

Part 1 and Part 2 (Main Study): Percentage of Participants Without any Red Blood Cell (RBC) Transfusion During any Consecutive 8-Week Period

Secondary Outcome Measures

Part 1 and Part 2: Number of Participants with Adverse Events (AEs)

Part 1 and Part 2: Percentage of Participants Without any RBC Transfusion During any Consecutive 24-Week Period

Part 1 and Part 2: Time to the 8-Week RBC Transfusion Independence (TI)

Part 1 and Part 2: Duration of RBC TI

Part 1 and Part 2: Percentage of Participants with Hematologic Improvement

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

Part 1 and Part 2: Overall Survival

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.

Part 1 and Part 2: Time to Progression to Acute Myeloid Leukemia

Part 1 and Part 2: Amount of RBC Transfusions

Part 1 and Part 2: Relative Change in RBC Transfusions

Part 1 and Part 2: Percentage of Participants Receiving any Myeloid Growth Factors

Part 1 and Part 2: Maximum Observed Plasma Concentration (Cmax)

Part 1 and Part 2: Area Under the Drug Concentration-Plasma Time Curve From Time Zero to Last Measurable Concentration (AUC0-t)

Part 1 and Part 2: Percentage of Participants with Antibodies to Imetelstat

Part 2 (Main Study): Medical Resource Utilization Data

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.

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).

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.

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".

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.

Extension Phase: Number of Participants with Adverse Events (AEs)

Extension Phase: Overall Survival

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.

Full Information

NCT ID

NCT02598661

First Posted

October 27, 2015

Last Updated

September 28, 2023

Sponsor

Geron Corporation

1. Study Identification

Unique Protocol Identification Number

NCT02598661

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

Study Type

Interventional

2. Study Status

Record Verification Date

September 2023

Overall Recruitment Status

Active, not recruiting

Study Start Date

November 24, 2015 (Actual)

Primary Completion Date

November 23, 2022 (Actual)

Study Completion Date

October 13, 2026 (Anticipated)

3. Sponsor/Collaborators

Responsible Party, by Official Title

Sponsor

Name of the Sponsor

Geron Corporation

4. Oversight

Studies a U.S. FDA-regulated Drug Product

Yes

Studies a U.S. FDA-regulated Device Product

Data Monitoring Committee

Yes

5. Study Description

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).

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study

Myelodysplastic Syndromes

Keywords

Myelodysplastic Syndromes, Imetelstat, GRN163L, Relapsed/refractory to ESAs, Transfusion dependent, IMerge

7. Study Design

Primary Purpose

Treatment

Study Phase

Phase 2, Phase 3

Interventional Study Model

Parallel Assignment

Masking

ParticipantInvestigator

Allocation

Randomized

Enrollment

289 (Actual)

8. Arms, Groups, and Interventions

Arm Title

Part 1: Imetelstat

Arm Type

Experimental

Arm Description

Arm Title

Part 2 (Main Study): Imetelstat

Arm Type

Experimental

Arm Description

Arm Title

Part 2 (Main Study): Placebo

Arm Type

Placebo Comparator

Arm Description

Matching Placebo to Imetelstat will be administered.

Arm Title

Part 2 (Ventricular Repolarization Substudy): Imetelstat

Arm Type

Experimental

Arm Description

Arm Title

Part 2 (Ventricular Repolarization Substudy): Placebo

Arm Type

Placebo Comparator

Arm Description

Matching Placebo to Imetelstat will be administered.

Intervention Type

Drug

Intervention Name(s)

Imetelstat

Other Intervention Name(s)

GRN163L

Intervention Description

Intravenous injection.

Intervention Type

Drug

Intervention Name(s)

Placebo

Intervention Description

Matching Placebo to Imetelstat will be administered.

Primary Outcome Measure Information:

Title

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

Secondary Outcome Measure Information:

Title

Part 1 and Part 2: Number of Participants with Adverse Events (AEs)

Time Frame