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

Myelodysplastic Syndromes Clinical Trial

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

Clinical Trial Details — Status: Active, not recruiting

Administrative data

• NCT number: NCT02598661
• Other study ID #: CR107947
• Secondary ID: 63935937MDS30012
• Status: Active, not recruiting
• Phase: Phase 2/Phase 3
• Start date: November 24, 2015
• Est. completion date: October 13, 2026

Study information

• Verified date: May 2024
• Source: Geron Corporation
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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.

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).

Recruitment information / eligibility

• Status: Active, not recruiting
• Enrollment: 289
• Est. completion date: October 13, 2026
• Est. primary completion date: October 13, 2023
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years and older

Eligibility

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

Related Conditions & MeSH terms

• Myelodysplastic Syndromes
• Preleukemia
• Syndrome

Intervention

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

Locations

Country	Name	City	State
Belgium	ZNA Middelheim	Antwerpen
Belgium	ZNA Stuyvenberg Antwerpen	Antwerpen
Belgium	AZ Klina	Brasschaat
Belgium	AZ Sint-Jan Burgge-Oostende	Brugge	West-Vlaanderen
Belgium	Universitair Ziekenhuis Gent	Gent
Belgium	Az Groeninge	Kortrijk	West-Vlaanderen
Belgium	UZ Leuven - Campus Gasthuisberg	Leuven
Belgium	GZA Ziekenhuizen - Campus Sint	Wilrijk	Antwerpen
Canada	Tom Baker Cancer Centre	Calgary	Alberta
Canada	University of Alberta Hospital - Hematology Research	Edmonton	Alberta
Canada	Jewish General Hospital	Montréal	Quebec
Canada	The Ottawa Hospital	Ottawa	Ontario
Canada	Princess Margaret Hospital	Toronto	Ontario
Canada	Sunnybrook Health Sciences Centre	Toronto	Ontario
Czechia	Fakultni nemocnice Brno	Brno	Brno-mesto
Czechia	FN Hradec Kralove	Hradec Králové
Czechia	FN Kralovske Vinohrady	Praha 10
Czechia	Vseobecna fakultni nemocnice v Praze	Praha 2
France	Centre Hospitalier Universitai	Angers
France	CHU de Grenoble - Hôpital Albe	La Tronche	Isère
France	CH Le Mans - HAEMATOLOGY	Le Mans	Sarthe
France	CHRU de Lille - Hopital Claude Huriez - Maladies du Sang	Lille
France	CHU de Limoges, Hopital Dupuytren	Limoges	Haute-Vienne
France	Hopital de l'Archet	Nice	Alpes-Maritimes
France	CHU - Hôpital Saint Louis - H	Paris	Île-de-France
France	CHU de Poitiers	Poitiers	Vienne
France	CHU Tours	Tours	Centre
France	CHRU Nancy Brabois	Vandœuvre-lès-Nancy	Meurthe-et-Moselle
Germany	Studienzentrum für Hämatologie, Onkologie,Diabetologie, Endoskopie und Fußambulanz	Aschaffenburg
Germany	University Hospital Bonn	Bonn
Germany	Fachärztliche Gemeinschaftspraxis mit Schwerpunkt	Dresden	Sachsen
Germany	Universitatsklinikum Carl Gustav Carcus Dresden	Dresden
Germany	Universitätsklinikum Düsseldorf	Duesseldorf
Germany	University Hospital Freiburg	Freiburg	Baden-Württemberg
Germany	University Hospital Leipzig	Leipzig	Sachsen
Germany	Johannes Gutenberg Universität	Mainz
Israel	Ha'Emek Medical Center	Afula	HaZafon
Israel	The Edith Wolfson Medical Center	H_olon	HaMerkaz
Israel	Carmel MC	Haifa
Israel	Hadassah Medical Organization	Jerusalem
Israel	Meir Medical Center	Kfar Saba	HaMerkaz
Israel	Rabin Medical Center, Beilinson Hospital	Petah Tikva
Israel	Kaplan Medical Center	Re?ovot	Hagalil Saint
Israel	Tel Aviv Sourasky Medical Center	Tel Aviv	Tel-Aviv
Israel	The Chaim Sheba Medical Center	Tel HaShomer	Tel-Aviv
Italy	AOU Ospedali Riuniti Umberto I G.M. Lancisi G. Salesi	Ancona
Italy	AOU di Bologna Policlinico S. Orsola Malpighi	Bologna
Italy	Azienda Ospedaliera Universitaria Careggi di Firenze	Firenze
Italy	A.O. Ospedale Niguarda Ca' Granda	Milano	Lombardia
Italy	Grande Ospedale Metropolitano 'Bianchi-Melacrino-Morelli' Reggio Calabria	Reggio Calabria
Italy	Irccs Crob	Rionero In Vulture	Potenza
Italy	A.O. Universitaria Policlinico Tor Vergata	Roma
Italy	AO S. Andrea, Università degli Studi di Roma La Sapienza	Roma
Italy	Istituto Clinico Humanitas Rozzano, IRCCS	Rozzano	Milano
Italy	Ospedale di Circolo, PO Varese	Varese
Korea, Republic of	Chonnam National University Hwasun Hospital	Hwasun	South Jeolla
Korea, Republic of	Gachon University Gil Medical Center - oncology	Incheon	Incheon Gwang'yeogsi
Korea, Republic of	Pusan National University Hospital - Hematology and Oncology	Seogu	Incheon
Korea, Republic of	Asan Medical Center	Seoul
Korea, Republic of	Samsung Medical Center	Seoul
Korea, Republic of	Seoul National University Hospital	Seoul	Seoul Teugbyeolsi
Korea, Republic of	Severance Hospital, Yonsei Uni	Seoul
Korea, Republic of	The Catholic University of Korea Seoul St. Mary's Hospital	Seoul
Netherlands	Meander Medisch Centrum	Amersfoort
Netherlands	VU Medisch Centrum	Amsterdam
Netherlands	Universitair Medisch Centrum Groningen	Groningen
Netherlands	Radboud Umcn	Nijmegen	Gelderland
Poland	SPZOZ MSWiA z Warminsko - Mazurskim Centrum Onkologii	Olsztyn	Warminsko-mazurskie
Poland	Ars Medical sp. z o.o.	Pila	Wielkopolskie Województwo
Poland	Centrum Medyczne Pratia Poznan	Skorzewo	Koscierzyna
Poland	Wojewódzki Szpital Specjalistyczny sp.z o.o.	Slupsk	Pomorskie
Poland	Uniwersytecki Szpital Kliniczny im. J. Mikulicza-Radeckiego	Wroclaw	Dolnoslaskie
Russian Federation	Emergency Hospital of Dzerzhinsk	Dzerzhinsk
Russian Federation	City Clinical Hospital	Moscow
Russian Federation	Nizhniy Novgorod Region Clinical Hospital	Nizhny Novgorod
Russian Federation	Ryazan Regional Clinical Hospital	Ryazan
Russian Federation	FGU-Russian Research Institut	Saint Petersburg
Russian Federation	Clinics of Samarskiy GMU	Samara	Volga
Russian Federation	Oncologic Dispensary No.2	Sochi
Spain	Hosp. Univ. Germans Trias I Pujol	Badalona
Spain	Hospital de Cruces	Baracaldo	Vizcaya
Spain	Hosp. Univ. Vall D Hebron	Barcelona
Spain	H.U.Pta.del Mar	Cadiz	Cádiz
Spain	Hosp. Gral. Univ. Gregorio Maranon	Madrid
Spain	Hosp. Univ. La Paz	Madrid
Spain	Hospital Universitario Puerta de Hierro Majadahonda	Majadahonda	Madrid
Spain	Hosp. Clinico Univ. de Salamanca	Salamanca
Spain	Hospital Universitario Nuestra Señora de Valme	Sevilla
Spain	Hospital Universitari i Politecnic La Fe	Valencia
Spain	Hospital Universitario Doctor	Valencia
Switzerland	University Hospital in Basel	Basel	Basel-Stadt (de)
Switzerland	Inselspital - Universitätsspital Bern	Bern
Switzerland	Kantonsspital St. Gallen - Onkologie/Hämatologie	Saint Gallen	Sankt Gallen
Switzerland	Universitaetsspital Zuerich	Zuerich
Turkey	Cukurova University Medical Faculty	Adana
Turkey	Ankara University Medical Faculty - Hematology	Ankara	Anatolia
Turkey	Ege Universitesi Tip Fakultesi - Hematology	Izmir
Ukraine	KNP "Cherkaskyi oblasnyi onkolohichnyi dyspanser Cherkaskoi	Cherkasy
Ukraine	KZ "Miska bahatoprofilna klinichna likarnia No4", hematolohi	Dnipropetrovs'k	Dnipropetrovs'ka Oblast'
Ukraine	Instytut patolohii krovi ta transfusiynoi medytsyny NAMN Ukr	Lviv	L'vivs'ka Oblast'
United Kingdom	Aberdeen Royal Infirmary	Aberdeen
United Kingdom	The Leeds Teaching Hospitals NHS Trust	Leeds
United Kingdom	Nottingham City Hospital - Clinical Haematology	Nottingham	Nottinghamshire
United Kingdom	Southampton University Hospital	Southampton
United States	University of New Mexico Cancer Center	Albuquerque	New Mexico
United States	CBCC Global Research, Inc.	Bakersfield	California
United States	St. Agnes Healthcare, Inc	Baltimore	Maryland
United States	Center for Cancer and Blood Disorders	Bethesda	Maryland
United States	UAB Comprehensive Cancer Center	Birmingham	Alabama
United States	Cleveland Clinic Taussig Cancer	Cleveland	Ohio
United States	The Ohio State Comprehensive Cancer Center	Columbus	Ohio
United States	Simmons Comprehensive Cancer Center	Dallas	Texas
United States	Texas Oncology/Methodist Charlton Cancer Center	Dallas	Texas
United States	Franciscan Health	Indianapolis	Indiana
United States	UCLA Ronald Regan Medical Center	Los Angeles	California
United States	Vanderbilt University Medical - Hematology-Oncology	Nashville	Tennessee
United States	Yale-New Haven Hospital (YNHH) - Smilow Cancer Hospital	New Haven	Connecticut
United States	Columbia Presbyterian	New York	New York
United States	Columbia University Medical Center	New York	New York
United States	Icahn School of Medicine at Mount Sinai Program for the Protection of Human Subjects	New York	New York
United States	Weill Cornell Medical College-New York Presbyterian Hospital	New York	New York
United States	BRCR Medical Center	Plantation	Florida
United States	Washington University School of Medicine	Saint Louis	Missouri
United States	Fred Hutchinson Cancer Research Center (FHCRC)	Seattle	Washington
United States	University of South Florida (USF) - H. Lee Moffitt Cancer Center	Tampa	Florida
United States	Acrc/Arizona Clinical Research, Inc.	Tucson	Arizona
United States	Prairie lakes Healthcare system, Inc	Watertown	South Dakota

Sponsors (1)

Lead Sponsor	Collaborator
Geron Corporation

Countries where clinical trial is conducted

United States,  Belgium,  Canada,  Czechia,  France,  Germany,  Israel,  Italy,  Korea, Republic of,  Netherlands,  Poland,  Russian Federation,  Spain,  Switzerland,  Turkey,  Ukraine,  United Kingdom, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	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	Part 1 and Part 2: Number of Participants with Adverse Events (AEs)		During study (approximately 2 years)
Secondary	Part 1 and Part 2: Percentage of Participants Without any RBC Transfusion During any Consecutive 24-Week Period		During study (approximately 2 years)
Secondary	Part 1 and Part 2: Time to the 8-Week RBC Transfusion Independence (TI)		During study (approximately 2 years)
Secondary	Part 1 and Part 2: Duration of RBC TI		During study (approximately 2 years)
Secondary	Part 1 and Part 2: Percentage of Participants with Hematologic Improvement		During study (approximately 2 years)
Secondary	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)
Secondary	Part 1 and Part 2: Overall Survival		During study (approximately 2 years)
Secondary	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)
Secondary	Part 1 and Part 2: Time to Progression to Acute Myeloid Leukemia		During study (approximately 2 years)
Secondary	Part 1 and Part 2: Amount of RBC Transfusions		During study (approximately 2 years)
Secondary	Part 1 and Part 2: Relative Change in RBC Transfusions		During study (approximately 2 years)
Secondary	Part 1 and Part 2: Percentage of Participants Receiving any Myeloid Growth Factors		During study (approximately 2 years)
Secondary	Part 1 and Part 2: Maximum Observed Plasma Concentration (Cmax)		During study (approximately 2 years)
Secondary	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)
Secondary	Part 1 and Part 2: Percentage of Participants with Antibodies to Imetelstat		During study (approximately 2 years)
Secondary	Part 2 (Main Study): Medical Resource Utilization Data		During study (approximately 2 years)
Secondary	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)
Secondary	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)
Secondary	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)
Secondary	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)
Secondary	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 (?QTcF) will be assessed in participants in the Ventricular Repolarization substudy.	Baseline and Day 1
Secondary	Extension Phase: Number of Participants with Adverse Events (AEs)		During extension (up to approximately 3 years)
Secondary	Extension Phase: Overall Survival		During extension (up to approximately 3 years)
Secondary	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)