Study to Evaluate Imetelstat in Patients With High-Risk MDS or AML Failing HMA-based Therapy

• Imetelstat sodium (Drug), also known as GRN163L: Intravenous injection

Primary outcomes

• Overall Hematological Response Rate of Participants After Treatment With Imetelstat [Up to Week 17 (Visit 9; approximately 17 weeks after first dose).]: The combined response assessment criteria for MDS and AML based on IWG (International Working Group) 2018 criteria (MDS) and the criteria of the European LeukemiaNet (AML) will be used to define responders. The response rate is calculated as number of responders divided by the number of all participants of the analysis set.

Secondary outcomes

• Toxicity Measured by NCI CTCAE v5.0 (National Cancer Institute - Common Terminology Criteria for Adverse Events Version 5.0) [From first dose of imetelstat through the last dose received, including follow-up to 28 ± 5 days after the last dose (duration varies by subject).]: Toxicity was assessed using the National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE) version 5.0. A treatment-emergent adverse event (TEAE) was defined as any adverse event arising or worsening after the first dose of study drug. The number of participants experiencing at least one TEAE was summarized in the Safety Evaluation Set.

Other outcomes

• Treatment Duration (Days) [From Treatment Start (Cycle 1 Day 1) to End of Treatment (EOT). Duration varies by subject.]: The number of days between the first and last doses of study treatment. Subjects who discontinued early have duration calculated to their final dose date.
• Treatment Compliance [From first dose of imetelstat through the last dose received, including follow-up to 28 ± 5 days after the last dose (duration varies by subject).]: Percentage of study-drug doses received relative to the number of doses planned per protocol. Computed as: Compliance (%) = (Actual doses received ÷ Planned doses) × 100. Missed or undocumented doses are counted as not received unless justified per protocol or Statistical Analysis Plan (SAP). Dose holds and reductions are included in compliance assessment.
• Cumulative Dose (mg) [From first dose of imetelstat through the last dose received, including follow-up to 28 ± 5 days after the last dose (duration varies by subject)]: Total amount of imetelstat (mg) received across all treatment administrations. Calculated as the sum of all administered doses documented in the dose-administration eCRF (electronic Case Report Form). Notes: Dose reductions, missed doses, and dose delays are captured in the calculation. Missing dose records default to "not administered" unless clarified.

Sex: All, ages: 18 Years to any

Inclusion Criteria:

* Signed written informed consent
* Male and female ≥ 18 years at the first screening
* Must be able to adhere to the study visit schedule and other protocol requirements
* Initial diagnosis of AML or MDS according to WHO (World Health Organization) 2016 classification
* At least one cytopenia
* Failure to achieve complete or partial response or hematological improvement observed after at least six azacitidine monotherapy or four decitabine monotherapy based 4-week treatment cycles administered during the past two years OR Failure to achieve complete or partial response or hematological improvement observed after at least two 4-week treatment cycles with azacitidine plus venetoclax or with decitabine plus venetoclax during the past two years OR Relapse after initial complete or partial response or hematological improvement observed after at least six (azacitidine) or four (decitabine) based 4-week treatment cycles administered during the past two years OR Relapse after initial complete or partial response or hematological improvement observed after at least two 4-week treatment cycles with azacitidine plus venetoclax or with decitabine plus venetoclax during the past two years OR Intolerance to treatment with HMA-based therapy during the past two years
* Not eligible for allogeneic stem cell transplantation
* ≥ 5% bone marrow blasts at screening
* Off all other treatments for AML/MDS for at least 14 days; granulocyte colony-stimulating factor (G-CSF) and erythropoietin are allowed before and during the study as clinically indicated
* Eastern Cooperative Oncology Group (ECOG) performance status of 0-2
* Biochemical laboratory test values must be within the defined limits.
* Availability of blood counts and transfusion events for previous 16 weeks
* Women of childbearing potential and practicing a highly effective method of birth control consistent with local regulations regarding the use of birth control methods for subjects participating in clinical studies. For females, these restrictions apply for 3 months after the end of dosing.
* A woman of childbearing potential must have a negative serum or urine pregnancy test at screening and agree to be tested on day 1 of every cycle and at End of Treatment (EOT)
* A man who is sexually active with a woman of childbearing potential and has not had a vasectomy must agree to use a barrier method of birth control. For males, these restrictions apply for 3 months after the end of dosing
* Patients who are relapsed or refractory to, or not eligible for, therapy with approved and available FLT3 (FMS-like tyrosine kinase 3) or IDH1/IDH2 (Isocitrate dehydrogenase) inhibitors or other approved targeted therapies.

Exclusion Criteria:

* Chemotherapy within the 14 days prior to the first dose of imetelstat being administered (other than hydroxyurea)
* Participant has known allergies, hypersensitivity, or intolerance to imetelstat or its excipients (refer to the Investigators Brochure (IB))
* Participant has received an experimental or investigational drug or used an invasive investigational medical device within 30 days prior to day 1 of Cycle 1
* Prior treatment with imetelstat
* Prior history of intensive chemotherapy or hematopoietic stem cell transplant
* Major surgery within 4 weeks prior to day 1 of Cycle 1 (excluding the placement of vascular access and other minor surgical procedures)
* Diagnosed or treated for malignancy other than MDS or AML, except:

Malignancy treated with curative intent and with no known active disease present for 3 years before day 1 of Cycle 1 Adequately treated non-melanoma skin cancer or lentigo maligna without evidence of disease Adequately treated cervical carcinoma in situ without evidence of disease

* Clinically significant cardiovascular disease such as uncontrolled or symptomatic arrhythmias, congestive heart failure, or myocardial infarction within 6 months of day 1 of Cycle 1, or any Class 3 (moderate) or Class 4 (severe) cardiac disease as defined by the New York Heart Association Functional Classification
* Known history of human immunodeficiency virus (HIV) or any uncontrolled active systemic infection requiring IV antibiotics
* Active systemic hepatitis infection requiring treatment (carriers of hepatitis virus are permitted to enter the study), or known acute or chronic liver disease including cirrhosis
* Any life-threatening illness, 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; Participant has any condition for which, in the opinion of the investigator, participation would not be in the best interest of the participant (eg, compromise the well-being) or that could prevent, limit, or confound the protocol-specified assessments
* Females who are pregnant or are currently breastfeeding or planning to become pregnant while enrolled in this study or within 3 months after the end of dosing
* Participant is a man who plans to father a child while enrolled in this study or within 3 months after the end of dosing
* Other:

Participant is in custody by order of an authority or a court of law Participation in another interventional clinical study within the last 3 months prior to signing the Informed consent form (ICF) or simultaneous participation in other interventional clinical studies Previous assignment to treatment during this study Close affiliation with the investigator (e.g., a close relative) or persons working at the study site Participant is an employee of the sponsor or involved Contract Research Organization (CRO) Criteria which in the opinion of the investigator preclude participation for scientific reasons, for reasons of compliance, or for reasons of the Participant's safety

Participant flow

Outcome results

• Overall Hematological Response Rate of Participants After Treatment With Imetelstat (Primary), Count of participants, Participants: Imetelstat Sodium (1 Treatment / Cycle) 0; Imetelstat Sodium (2 Treatments / Cycle) 1
• Toxicity Measured by NCI CTCAE v5.0 (National Cancer Institute - Common Terminology Criteria for Adverse Events Version 5.0) (Secondary), Number, participants: Imetelstat Sodium (1 Treatment / Cycle) 23; Imetelstat Sodium (2 Treatments / Cycle) 23
• Treatment Duration (Days) (Other pre specified), Mean, days: Imetelstat Sodium (1 Treatment / Cycle) 53.8 +/- 27.6; Imetelstat Sodium (2 Treatments / Cycle) 76.8 +/- 71.7
• Treatment Compliance (Other pre specified), Mean, percentage: Imetelstat Sodium (1 Treatment / Cycle) 70 +/- 20; Imetelstat Sodium (2 Treatments / Cycle) 60 +/- 30
• Cumulative Dose (mg) (Other pre specified), Mean, Milligrams: Imetelstat Sodium (1 Treatment / Cycle) 1502.32 +/- 511.08; Imetelstat Sodium (2 Treatments / Cycle) 2564.65 +/- 1290.84

Adverse events

Time frame: Adverse events were collected from informed consent until 28 (±5) days, up tp 1 month, after the last dose. Serious Adverse Events (SAEs) suspected to be related to imetelstat were collected at any time after discontinuation and documented without time limit.

Serious adverse events by term

Other adverse events by term

104 more terms not shown.

• Study Protocol (PDF, 2025-09-03)
• Statistical Analysis Plan (PDF, 2025-10-13)

• Uwe Platzbecker, MD, Principal investigator, Universitätsklinikum Leipzig