Clinical Trials Register

Summary
EudraCT Number:	2020-003288-24
Sponsor's Protocol Code Number:	GRN163LMYF3001
National Competent Authority:	Hungary - National Institute of Pharmacy
Clinical Trial Type:	EEA CTA
Trial Status:	Trial now transitioned
Date on which this record was first entered in the EudraCT database:	2020-12-22
Trial results

Index
A. PROTOCOL INFORMATION
B. SPONSOR INFORMATION
C. APPLICANT IDENTIFICATION
D. IMP IDENTIFICATION
D.8 INFORMATION ON PLACEBO
E. GENERAL INFORMATION ON THE TRIAL
F. POPULATION OF TRIAL SUBJECTS
G. INVESTIGATOR NETWORKS TO BE INVOLVED IN THE TRIAL
N. REVIEW BY THE COMPETENT AUTHORITY OR ETHICS COMMITTEE IN THE COUNTRY CONCERNED
P. END OF TRIAL

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A. Protocol Information

A.1

Member State Concerned

Hungary - National Institute of Pharmacy

A.2

EudraCT number

2020-003288-24

A.3

Full title of the trial

A Randomized Open-Label, Phase 3 Study to Evaluate Imetelstat (GRN163L) Versus Best Available Therapy (BAT) in Patients with Intermediate-2 or High-risk Myelofibrosis (MF) Relapsed / Refractory (R/R) to Janus Kinase (JAK)-Inhibitor

Randomizált, nyílt címkés, III. fázisú vizsgálat a legjobb rendelkezésre álló
terápiával (BAT) szemben alkalmazott imetelsztát (GRN163L) értékelésére
közepes-2 vagy magas kockázatú, Janus-kináz (JAK)-gátlóval szemben
ellenálló myelofibrosisban (MF) szenvedő betegeknél

A.3.1

Title of the trial for lay people, in easily understood, i.e. non-technical, language

A study comparing current available therapies with imetelstat for the treatment of intermediate-2 or high-risk MF who are not responding to JAK-inhibitor treatment

Vizsgálat a jelenleg rendelkezésre álló terápiákkal szembeni imetelsztát
összehasonlítására közepes-2 vagy magas kockázatú MF-ben szenvedő
betegeknél, akik nem reagálnak a JAK-gátló kezelésre

A.4.1

Sponsor's protocol code number

GRN163LMYF3001

A.7

Trial is part of a Paediatric Investigation Plan

A.8

EMA Decision number of Paediatric Investigation Plan

B. Sponsor Information
B.Sponsor: 1
B.1.1	Name of Sponsor	Geron Corporation
B.1.3.4	Country	United States
B.3.1 and B.3.2	Status of the sponsor	Commercial
B.4 Source(s) of Monetary or Material Support for the clinical trial:
B.4.1	Name of organisation providing support	Geron Corporation
B.4.2	Country	United States
B.5 Contact point designated by the sponsor for further information on the trial
B.5.1	Name of organisation	Geron Corporation
B.5.2	Functional name of contact point	Clinical Trial Enquiries
B.5.3	Address:
B.5.3.1	Street Address	919 E. Hillsdale Blvd.
B.5.3.2	Town/ city	Foster City, CA
B.5.3.3	Post code	94404
B.5.3.4	Country	United States
B.5.6	E-mail	myf3001-info@Geron.com

D. IMP Identification
D.IMP: 1
D.1.2 and D.1.3	IMP Role	Test
D.2	Status of the IMP to be used in the clinical trial
D.2.1	IMP to be used in the trial has a marketing authorisation	No
D.2.5	The IMP has been designated in this indication as an orphan drug in the Community	Yes
D.2.5.1	Orphan drug designation number	EU/3/15/1593
D.3 Description of the IMP
D.3.1	Product name	Imetelstat sodium
D.3.2	Product code	GRN163L
D.3.4	Pharmaceutical form	Lyophilisate for solution for infusion
D.3.4.1	Specific paediatric formulation	No
D.3.7	Routes of administration for this IMP	Intravenous use
D.3.8 to D.3.10 IMP Identification Details (Active Substances)
D.3.8	INN - Proposed INN	Imetelstat sodium
D.3.9.1	CAS number	1007380-31-5
D.3.9.2	Current sponsor code	GRN163L
D.3.9.3	Other descriptive name	IMETELSTAT SODIUM
D.3.9.4	EV Substance Code	SUB174121
D.3.10	Strength
D.3.10.1	Concentration unit	mg milligram(s)
D.3.10.2	Concentration type	equal
D.3.10.3	Concentration number	210
D.3.11 The IMP contains an:
D.3.11.1	Active substance of chemical origin	Yes
D.3.11.2	Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP)	No
	The IMP is a:
D.3.11.3	Advanced Therapy IMP (ATIMP)	No
D.3.11.3.1	Somatic cell therapy medicinal product	No
D.3.11.3.2	Gene therapy medical product	No
D.3.11.3.3	Tissue Engineered Product	No
D.3.11.3.4	Combination ATIMP (i.e. one involving a medical device)	No
D.3.11.3.5	Committee on Advanced therapies (CAT) has issued a classification for this product	No
D.3.11.4	Combination product that includes a device, but does not involve an Advanced Therapy	No
D.3.11.5	Radiopharmaceutical medicinal product	No
D.3.11.6	Immunological medicinal product (such as vaccine, allergen, immune serum)	No
D.3.11.7	Plasma derived medicinal product	No
D.3.11.8	Extractive medicinal product	No
D.3.11.9	Recombinant medicinal product	No
D.3.11.10	Medicinal product containing genetically modified organisms	No
D.3.11.11	Herbal medicinal product	No
D.3.11.12	Homeopathic medicinal product	No
D.3.11.13	Another type of medicinal product	No

D.8 Information on Placebo

E. General Information on the Trial

E.1 Medical condition or disease under investigation

E.1.1

Medical condition(s) being investigated

Myelofibrosis

E.1.1.1

Medical condition in easily understood language

Myelofibrosis

E.1.1.2

Therapeutic area

Diseases [C] - Cancer [C04]

MedDRA Classification

E.1.2 Medical condition or disease under investigation

E.1.2	Version	20.0
E.1.2	Level	PT
E.1.2	Classification code	10028537
E.1.2	Term	Myelofibrosis
E.1.2	System Organ Class	10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps)

E.1.3

Condition being studied is a rare disease

Yes

E.2 Objective of the trial

E.2.1

Main objective of the trial

The primary objective of this study is to compare the overall survival (OS) of participants, treated with imetelstat versus BAT, with intermediate-2 or high-risk Myelofibrosis (MF) whose disease is relapsed / refractory to JAK-inhibitor treatment.

E.2.2

Secondary objectives of the trial

to evaluate imetelstat versus BAT with respect to:
• Symptom response rate at Week 24, defined as the proportion of participants who have ≥ 50% reduction in total symptom score (TSS) at Week 24 from baseline as measured by the Myelofibrosis Symptom Assessment Form (MFSAF) v4.0 e-diary questionnaire
• Progression-free survival, defined as the time interval from randomization date to the first date of disease progression or death from any cause, whichever occurs first
• Spleen response rate at Week 24, defined as the proportion of participants who achieve ≥ 35% spleen volume reduction (SVR) at Week 24 from baseline as measured by magnetic resonance imaging (MRI) or computed tomography scan and assessed by Central Radiology Review. Additionally, SVR of ≥ 20% and ≥ 10% at Week 24 will be assessed.
• Complete remission, partial remission, clinical improvement, spleen response, symptoms response, and anemia response per modified 2013 IWG MRT criteria

see Protocol

E.2.3

Trial contains a sub-study

E.3

Principal inclusion criteria

1. ≥18 years of age.
2. Diagnosis of primary MF (PMF) according to the revised WHO criteria (Section 18.2); or PET-MF or PPV-MF according to the IWG-MRT criteria (Section 18.3) confirmed by local pathology report.
3. Dynamic International Prognostic Scoring System intermediate-2 or high-risk MF.
4. Relapsed / Refractory to JAK-inhibitor treatment as defined in either inclusion 4.1, 4.2 or 4.3 and not eligible for ASCT at screening:
4.1: Treatment with JAK-inhibitor for ≥ 6 months duration, including at least 2 months at an optimal dose as assessed by the investigator for that participant and at least ONE of the following:
a) no decrease in spleen volume (< 10% by MRI or CT) from the start of treatment with JAK-inhibitor.
b) no decrease in spleen size (< 30% by palpation or length by imaging) from start of treatment with JAK-inhibitor
c) no decrease in symptoms (< 20% by MFSAF or myeloproliferative neoplasm SAF) from start of treatment with JAK-inhibitor.
d) a score of at least 15 on TSS assessed using the MFSAF v4.0 (adapted as the MF Symptom Recall Form, Section 18.6) during screening.
4.2: Treatment with JAK-inhibitor for ≥ 3 months duration with maximal doses for that participant (e.g. 20-25 mg twice daily ruxolitinib) without a spleen or symptom response as defined in inclusion criterion 4.1 (a, b, or c) and would not benefit from remaining on treatment for 6 months.
4.3: Following maximum tolerated doses of JAK inhibitor therapy for ≥3 months duration, having documented relapsed disease defined as either:
•Increase in spleen volume from time of best response by 25% measured by MRI or CT, or
•Increase in spleen size by palpation, CT, or ultrasound
- For splenomegaly of 5-10 cm at the start of JAK inhibitor treatment, at least 100% increase in palpable spleen size from time of best response;
- For splenomegaly of > 10 cm at the start of JAK inhibitor treatment, at least 50% increase in palpable spleen size from time of best response;
AND not a candidate for further JAK inhibitor at screening per investigator.

5. Measurable splenomegaly demonstrated by a palpable spleen measuring ≥ 5 cm below the left costal margin or a spleen volume ≥ 450 cm3 by MRI or CT.
6. Active symptoms of MF on the MFSAF v4.0 (adapted as the MF Symptom Recall Form, Section 18.6) demonstrated by a symptom score of at least 5 points (on a 0 to 10 scale) on at least 1 of the symptoms or a score of 3 or greater on at least 2 of the following symptoms: fatigue, night sweats, itchiness, abdominal discomfort, pain under ribs on left side, early satiety, and bone pain.
7. Hematology laboratory test values within the following limits:
• absolute neutrophil count (ANC) ≥ 1.5 x 10^9/L independent of growth factor support, AND
• platelets ≥ 75 x 10^9/L independent of platelet transfusion support
8. Biochemical laboratory test values must be within the following limits:
• Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) ≤ 2.5 x upper limit of normal (ULN);
• Alkaline phosphatase (ALP) ≤ 5 x ULN;
• Serum creatinine ≤ 2 x ULN;
• Total bilirubin ≤ 3 x ULN; and direct bilirubin ≤ 2 x ULN (unless due to Gilbert’s syndrome or underlying MF).
9. Eastern Cooperative Oncology Group Performance Status score of 0, 1, or 2
10. Women of childbearing potential and men who are sexually active must use a highly effective method of birth control during and after the study consistent with local regulations regarding the use of birth control methods for participants participating in clinical trials. Men must use a highly effective method of birth control and agree not to father a child or donate sperm during and after the study. For females, these restrictions apply for 1 month after the last dose of study drug. For males, these restrictions apply for 3 months after the last dose of study drug.
11. A woman of childbearing potential must have a negative serum or urine pregnancy test at screening.
12. Each participant (or their legally acceptable representative) must sign an informed consent form (ICF) indicating the participant understands the purpose of and procedures required for the study and are willing to participate in the study.

E.4

Principal exclusion criteria

1. Peripheral blood blast count of ≥ 10% or bone marrow blast count of ≥ 10%.
2. Known allergies, hypersensitivity, or intolerance to imetelstat or its excipients.
3. Prior treatment with imetelstat.
4. Any chemotherapy or MF directed therapy, including investigational drug regardless of class or mechanism of action, immunomodulatory or immunosuppressive therapy, corticosteroids > 30 mg/day prednisone or equivalent, and JAK-inhibitor treatment ≤ 14 days prior to randomization.
5. Persistent unresolved toxicity from prior treatment, i.e., has not returned to Grade ≤1 or pre-treatment baseline.
6. Diagnosis or treatment for malignancy other than MF except:
• Malignancy treated with curative intent and with no known active disease present for ≥ 3 years before randomization.
• Adequately treated non-melanoma skin cancer or lentigo maligna without
evidence of disease.
• Adequately treated cervical carcinoma in situ without evidence of disease.
7. Clinically significant cardiovascular disease such as uncontrolled or symptomatic arrhythmias, congestive heart failure, or myocardial infarction within 6 months of screening, or any Class 3 (moderate) or Class 4 (severe) cardiac disease as defined by the New York Heart Association Functional Classification.
8. Known history of human immunodeficiency virus or any uncontrolled active systemic infection requiring IV antibiotics.
9. Active systemic hepatitis infection requiring treatment (carriers of hepatitis virus are permitted to enter the study), or any known acute or chronic liver disease requiring treatment unless related to underlying hepatosplenomegaly due to MF.
10. Major surgery within 28 days prior to randomization.
11. Female participants who are pregnant or are currently breastfeeding or planning to become pregnant while enrolled in this study or within 30 days after the end of dosing.
12. Male participants who plan to father a child while enrolled in this study or within 90 days after the end of dosing.
13. Any life-threatening illness (e.g., COVID-19), medical condition, or organ system dysfunction which, in the investigator’s opinion, could compromise the participant’s safety, interfere with the imetelstat metabolism, or put the study outcomes at undue risk; if participant has any condition for which, in the opinion of the investigator, participation would not be in the best interest of the participant (e.g., compromise the well- being) or that could prevent, limit, or confound the protocol-specified assessments.

E.5 End points

E.5.1

Primary end point(s)

The primary endpoint of overall survival (OS) is defined as the time interval from randomization date to date of death from any cause.

E.5.1.1

Timepoint(s) of evaluation of this end point

date of death from any cause

E.5.2

Secondary end point(s)

- symptom response rate at Week 24 (defined as the proportion of patients who have ≥ 50% reduction in TSS at Week 24 from baseline as measured by the MFSAF v4.0),
- spleen response rate at Week 24 (defined as the proportion of patients who achieve ≥ 35% reduction in spleen volume at Week 24 from baseline as measured by imaging scans).

See Protocol

E.5.2.1

Timepoint(s) of evaluation of this end point

Week 24
See Protocol

E.6 and E.7 Scope of the trial

E.6

Scope of the trial

E.6.1

Diagnosis

E.6.2

Prophylaxis

E.6.3

Therapy

Yes

E.6.4

Safety

Yes

E.6.5

Efficacy

Yes

E.6.6

Pharmacokinetic

Yes

E.6.7

Pharmacodynamic

E.6.8

Bioequivalence

E.6.9

Dose response

E.6.10

Pharmacogenetic

E.6.11

Pharmacogenomic

E.6.12

Pharmacoeconomic

E.6.13

Others

Yes

E.6.13.1

Other scope of the trial description

Immunogenicity
Biomarker

E.7

Trial type and phase

E.7.1

Human pharmacology (Phase I)

E.7.1.1

First administration to humans

E.7.1.2

Bioequivalence study

E.7.1.3

Other

E.7.1.3.1

Other trial type description

E.7.2

Therapeutic exploratory (Phase II)

E.7.3

Therapeutic confirmatory (Phase III)

Yes

E.7.4

Therapeutic use (Phase IV)

E.8 Design of the trial

E.8.1

Controlled

Yes

E.8.1.1

Randomised

Yes

E.8.1.2

Open

Yes

E.8.1.3

Single blind

E.8.1.4

Double blind

E.8.1.5

Parallel group

E.8.1.6

Cross over

E.8.1.7

Other

E.8.2

Comparator of controlled trial

E.8.2.1

Other medicinal product(s)

Yes

E.8.2.2

Placebo

E.8.2.3

Other

Yes

E.8.2.3.1

Comparator description

Best Available Therapy (BAT)

E.8.2.4

Number of treatment arms in the trial

E.8.3

The trial involves single site in the Member State concerned

E.8.4

The trial involves multiple sites in the Member State concerned

Yes

E.8.4.1

Number of sites anticipated in Member State concerned

E.8.5

The trial involves multiple Member States

Yes

E.8.5.1

Number of sites anticipated in the EEA

E.8.6 Trial involving sites outside the EEA

E.8.6.1

Trial being conducted both within and outside the EEA

Yes

E.8.6.2

Trial being conducted completely outside of the EEA

E.8.6.3

If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned

Argentina

Colombia

Singapore

Switzerland

Taiwan

Australia

Austria

Belgium

Brazil

Bulgaria

Denmark

France

Georgia

Germany

Hungary

India

Israel

Italy

Korea, Republic of

Poland

Portugal

Russian Federation

Spain

Turkey

United Kingdom

United States

E.8.7

Trial has a data monitoring committee

Yes

E.8.8

Definition of the end of the trial and justification where it is not the last visit of the last subject undergoing the trial

LVLS

E.8.9 Initial estimate of the duration of the trial

E.8.9.1

In the Member State concerned years

E.8.9.1

In the Member State concerned months

E.8.9.1

In the Member State concerned days

E.8.9.2

In all countries concerned by the trial years

E.8.9.2

In all countries concerned by the trial months

F. Population of Trial Subjects

F.1 Age Range

F.1.1

Trial has subjects under 18

F.1.1.1

In Utero

F.1.1.2

Preterm newborn infants (up to gestational age < 37 weeks)

F.1.1.3

Newborns (0-27 days)

F.1.1.4

Infants and toddlers (28 days-23 months)

F.1.1.5

Children (2-11years)

F.1.1.6

Adolescents (12-17 years)

F.1.2

Adults (18-64 years)

Yes

F.1.2.1

Number of subjects for this age range:

220

F.1.3

Elderly (>=65 years)

Yes

F.1.3.1

Number of subjects for this age range:

100

F.2 Gender

F.2.1

Female

Yes

F.2.2

Male

Yes

F.3 Group of trial subjects

F.3.1

Healthy volunteers

F.3.2

Patients

Yes

F.3.3

Specific vulnerable populations

Yes

F.3.3.1

Women of childbearing potential not using contraception

F.3.3.2

Women of child-bearing potential using contraception

Yes

F.3.3.3

Pregnant women

F.3.3.4

Nursing women

F.3.3.5

Emergency situation

F.3.3.6

Subjects incapable of giving consent personally

F.3.3.7

Others

F.4 Planned number of subjects to be included

F.4.1

In the member state

F.4.2

For a multinational trial

F.4.2.1

In the EEA

160

F.4.2.2

In the whole clinical trial

320

F.5

Plans for treatment or care after the subject has ended the participation in the trial (if it is different from the expected normal treatment of that condition)

The sponsor will ensure that subjects benefiting from treatment with imetelstat will be able to continue treatment after the End of the Study.

G. Investigator Networks to be involved in the Trial

N. Review by the Competent Authority or Ethics Committee in the country concerned

Competent Authority Decision

Authorised

Date of Competent Authority Decision

2021-02-25

Ethics Committee Opinion of the trial application

Favourable

Ethics Committee Opinion: Reason(s) for unfavourable opinion

Date of Ethics Committee Opinion

2021-02-15

P. End of Trial
P.	End of Trial Status	Trial now transitioned

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IMP with orphan designation in the indication
Orphan Designation Number:
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