Study to Evaluate Imetelstat (GRN163L) in Subjects with IPSS Low or Intermediate-1 Risk Myelodysplastic Syndrome (MDS)

Overview

Sponsor-declared trial summary

Key facts

Sponsor

Geron Corp.

Participant type

Patients

Age range

18-64 years, 65+ years

Gender

Male and Female

Therapeutic area

Diseases [C] - Neoplasms [C04]

Trial duration

11 Dec 2015 → ongoing

Decision date (initial)

2024-05-24

Transition trial

Yes

Low-intervention

No

Rare-disease indication

Yes

Vulnerable population

Yes

Funding sources

Geron Corporation

External identifiers

EU CT number

2024-511348-25-00

EudraCT number

2015-002874-19

ClinicalTrials.gov

NCT02598661

Trial design

CTIS Part I — objectives, methods, condition coding

Main objective

Scope: Others, Efficacy, Pharmacodynamic, Safety, Pharmacokinetic

Part 1: To evaluate the efficacy and safety of imetelstat in transfusion
dependent subjects with low or intermediate-1 risk MDS that is
relapsed/refractory to ESA treatment.

Part 2: To compare the efficacy, in terms of RBC TI, of imetelstat to
placebo in transfusion dependent subjects with low or intermediate-1
risk MDS that is relapsed/refractory to ESA treatment.

Extension Phase: To evaluate the long-term safety, overall survival (OS),
and disease progression, including progression to acute myeloid
leukemia (AML) in transfusion dependent subjects with low or
immediate-1 risk to MDS that is relapsed/refractory to ESA treatment
receiving imetelstat.

Secondary objectives 1

1. For Part 1 and Part 2: To assess the safety of imetelstat in subjects with MDS ; To assess the time to RBC TI and duration of RBC TI ; To assess the rate of hematologic improvement ; To assess the rates of CR, PR or marrow complete remission (mCR) ; To assess OS ; To assess progression free survival (PFS) ; To assess time to progression to AML ; To assess the rate and amount of supportive care, including transfusions and myeloid growth factors (Part 2 only) ; To evaluate the pharmacokinetics and immunogenicity of imetelstat in subjects with MDS ; To assess the effect of imetelstat treatment on patient reported outcomes (PROs) ; To assess the effect of treatment on medical resource utilization (Part 2 only) ; To assess the effect of imetelstat on corrected QT (QTc) interval in subjects in the Ventricular Repolarization substudy (to be reported separately from Part 2)

Conditions and MedDRA coding

Myelodysplastic syndromes (MDS)

Regulatory references

Scientific advice from competent authorities

European Medicines Agency

Plan to share IPD

No

Eligibility criteria

Principal inclusion / exclusion criteria as submitted by sponsor

Inclusion criteria 6

1. Man or woman ≥18 years of age (or the legal age of consent in the jurisdiction in which the study is taking place)
2. In Part 1, diagnosis of myelodysplastic syndromes (MDS) according to WHO criteria confirmed by bone marrow aspirate and biopsy within 12 weeks prior to C1D1. A local laboratory report from this diagnostic bone marrow aspirate and biopsy must be reviewed and approved by the sponsor. In Part 2, diagnosis of MDS according to WHO criteria confirmed by bone marrow aspirate and biopsy within 12 weeks prior to Randomization. A sample of the baseline bone marrow aspirate and biopsy must be submitted to the Independent Central Pathology Reviewer for diagnostic confirmation. Central laboratory review is required to confirm diagnosis prior to Randomization.
3. International Prognostic Scoring System (IPSS) low or intermediate-1 risk MDS.
4. 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 C1D1 (Part 1) or Randomization (Part 2); pre-transfusion Hb should be ≤9.0 g/dL to count towards the 4 units total.
5. Has MDS that is relapsed/refractory to ESA treatment; as defined by meeting any one of the criteria below: - Received at least 8 weeks of treatment with a minimum weekly dose of epoetin alfa 40,000 U, epoetin beta 30,000 U or darbepoetin alfa 150 mcg (or equivalent agent/dose), without having achieved a Hb rise ≥1.5 g/dL or decreased RBC transfusion requirement by at least 4 units over 8 weeks - Transfusion dependence or reduction in Hb by ≥1.5 g/dL after hematologic improvement from at least 8 weeks of treatment with therapies outlined in the above inclusion criteria, in the absence of another explanation. - Endogenous serum EPO level >500 mU/mL
6. Eastern Cooperative Oncology Group (ECOG) performance status 0, 1 or 2.

Exclusion criteria 5

1. Subject has known allergies, hypersensitivity, or intolerance to imetelstat or its excipients.
2. Subject has received an experimental or investigational drug or used an invasive investigational medical device within 30 days prior to C1D1 (Part 1) or Randomization (Part 2) or is currently enrolled in an investigational study.
3. Prior treatment with imetelstat.
4. Have received corticosteroids >30 mg/day prednisone or equivalent, or growth factor treatment within 4 weeks prior to C1D1 (Part 1) or Randomization (Part 2).
5. a) Prior treatment with a hypomethylating agent (eg, azacitidine, decitabine); b) Prior treatment with lenalidomide, thalidomide, or other thalidomide analogues; c) Has received an ESA or any anti-MDS therapy, chemotherapy, immunomodulatory, or immunosuppressive therapy within 4 weeks prior to C1D1 (Part 1) or Randomization (Part 2) (8 weeks for long-acting ESAs).

Endpoints

Primary and secondary outcome measures (English text)

Primary endpoints 1

1. The primary efficacy endpoint of this study is the rate of RBC TI lasting at least 8 weeks. The 8-week RBC TI rate is defined as the proportion of subjects without any RBC transfusion during any consecutive 8 weeks (56 days) starting from Study Day 1. Study Day 1 is defined as the day of the first dose for subjects enrolled in Part 1 and the day of randomization for subjects enrolled in Part 2.

Secondary endpoints 15

1. Safety of imetelstat in subjects with MDS (eg, incidence, intensity, and type of adverse events, vital signs measurements, clinical laboratory values, ECGs changes, and deaths)
2. 24-week RBC TI rate, defined as the proportion of subjects without any RBC transfusion during any consecutive 24 weeks (168 days) starting from Study Day 1
3. Time to the 8-week (24 week) RBC TI, defined as the interval from Study Day 1 to the first day of the first 8-week (24 week) RBC TI period
4. Duration of RBC TI, defined as the first day of the longest RBC TI period to the date of the first RBC transfusion after the TI period starts
5. Rate of hematologic improvement, including HI-E, per modified IWG 2006
6. Rates of CR, PR, or mCR per modified IWG 2006
7. OS, defined as the interval from Study Day 1 to death from any cause. Survival time of living subjects will be censored on the last date a subject is known to be alive or lost to follow-up
8. Progression free survival, defined as the time interval from Study Day 1 to the first date of disease progression or death from any cause, whichever occurs first. For subjects who do not have documented disease progression and who are still alive at the end of the study or clinical cutoff will be censored at the last disease evaluation date.
9. Time to progression to AML, defined as the interval from Study Day 1 to the date of AML diagnosis. For subjects who have not progressed to AML and are still alive at the cutoff date for the analysis or who withdraw from the study (withdrawal of consent or lost to follow-up), data will be censored at the date of the last disease evaluation
10. Amount and relative change in RBC transfusions
11. Rate of myeloid growth factors usage, defined as the proportion of subjects receive any myeloid growth factors starting from Study Day 1; duration of myeloid growth factor administered starting from Study Day 1
12. Assessment of QUALMS, FACT-An, and EQ-5D-5L
13. Pharmacokinetic parameters (eg, Cmax, AUC0-t), and immunogenicity of imetelstat (eg, antibodies to imetelstat)
14. Medical resource utilization data including hospitalization, emergency room visits, and hematology specialist visits
15. ECG parameters including change in QT interval by Fridericia's correction method (ΔQTcF) in the Ventricular Repolarization substudy (Part 2 only)

Investigational products

Investigational medicinal products (IMPs), comparators, placebo, auxiliary

Test 1

Placebo 1

Auxiliary 2

Sponsors and contacts

Sponsor organisations, regulatory contacts, third parties

Geron Corp.

Sponsor organisation

Geron Corp.

Address

919 East Hillsdale Boulevard Suite 250

City

Foster City

Postcode

94404-3296

Country

United States

Scientific contact point

Organisation

Geron Corp.

Contact name

Clinical Trial Enquiries

Public contact point

Organisation

Geron Corp.

Contact name

Clinical Trial Enquiries

Third parties 7

Locations

8 EU/EEA countries · 36 investigational sites

By country

Investigational sites

Country notifications

Trial-start, recruitment-start, end and early-termination notifications submitted per Member State

Results and documents

Annex IV summary of results, Annex V layperson summary, and all documents registered in CTIS for this trial

Documents 46 files

Public protocol annexes, IB summaries, regulatory submissions and post-authorisation documents registered in CTIS.

Application history

5 submissions — initial application plus substantial / non-substantial modifications