Phase II Study of Imetelstat Sodium in High‑Risk MDS and AML Patients Refractory to Hypomethylating Agent Therapy
- Trial ID
- 2022-500721-32-00
- Protocol
- IMpress_001
Trial statistics
Diseases & Conditions
Objectives
The primary objective of this phase II study is to assess the **efficacy** of Imetelstat in patients with acute myeloid leukemia (AML) and high-risk myelodysplastic syndromes (MDS) who have failed or are refractory to first-line hypomethylating agent (HMA)-based treatment. This evaluation is clinically relevant as it addresses the need for effective therapeutic options in a patient population with limited treatment alternatives and poor prognosis.
Secondary objectives include:
- Toxicity as measured by NCI CTCAE v5.0
- Overall survival
- Progression-free survival
- Duration of response
- Best overall response
- Quality of Life (EORTC QLQ-C30)
Participants
The clinical trial involves a total of **16 participants** diagnosed with **acute myeloid leukemia (AML)** or **myelodysplastic syndromes (MDS)** who have failed or are refractory to hypomethylating agent (HMA)-based treatment. The study population includes both male and female subjects aged 18 years and older. Participants were selected based on their ability to adhere to the study visit schedule and other protocol requirements, and they must have an initial diagnosis of AML or MDS according to the WHO 2016 classification. The trial does not include a vulnerable population. Participants are required to have at least one cytopenia and must not be eligible for allogeneic stem cell transplantation. Lifestyle considerations such as diet and physical activity are not specified. The selection criteria ensure that participants have a performance status of 0-2 on the ECOG scale and meet specific biochemical laboratory test values. The trial does not include individuals who are currently undergoing other treatments for AML/MDS, except for G-CSF and erythropoietin, which are allowed as clinically indicated.
Plans and Procedures
The clinical trial is designed to evaluate the efficacy and safety of **imetelstat** in patients with high-risk myelodysplastic syndromes (MDS) or acute myeloid leukemia (AML) who have failed or are refractory to hypomethylating agent (HMA)-based therapy. This is a phase II, randomized, double-blind, controlled trial. The trial is expected to last until June 2025, with recruitment having started in December 2022. Participants will be involved in the study for a maximum treatment period of 9 months, with the possibility of early termination if they experience significant adverse effects or if the disease progresses.
The study involves several key visits, beginning with an inclusion (screening) visit to assess eligibility based on criteria such as age, performance status, and laboratory test values. Participants must have an initial diagnosis of AML or MDS and meet specific hematological criteria. Following the screening, participants will undergo regular follow-up visits to monitor treatment response and safety. These visits will include assessments of overall response rate, toxicity, and survival outcomes. The end-of-study visit will occur after the completion of the treatment period or upon early termination.
Participants will receive **imetelstat** as a solution for infusion, administered intravenously. The trial will also involve auxiliary medications such as **diphenhydramine** and **hydrocortisone** to manage potential side effects. The primary endpoint is the overall response rate after 4 months of treatment, assessed using combined response criteria for MDS and AML. Secondary endpoints include toxicity, overall survival, progression-free survival, and quality of life scores. The trial aims to provide valuable insights into the potential benefits of **imetelstat** for patients with limited treatment options.
Treatment
The clinical trial involves the administration of **IMETELSTAT**, an experimental medication, which is a **solution for infusion**. The active substance in this medication is **imetelstat sodium**, classified as a nucleic acid. It is administered intravenously with a maximum daily dose of 7.5 mg/kg and a total maximum dose of 67.5 mg/kg over a treatment period of 9 weeks. IMETELSTAT functions as an oligonucleotide and telomerase inhibitor, and it is designated as an orphan drug. The sponsor of this product is Geron Corporation, and it is identified by the sponsor product code GRN163L.
In addition to the experimental treatment, the study includes the use of **DIPHENHYDRAMINE**, which serves as an auxiliary treatment. This medication is also administered intravenously and is available in the pharmaceutical form PHF00251MIG. The active substances in this formulation are **chlorhexidine dihydrochloride** and **diphenhydramine hydrochloride**, both of which are chemical in origin. The maximum daily dose for diphenhydramine is 50 mg, with a total maximum dose of 450 mg over the same 9-week treatment period. Diphenhydramine is classified as an antihistamine.
Another auxiliary treatment used in the study is **HYDROCORTISONE**, administered intravenously in the pharmaceutical form PHF00099MIG. The active substance is **hydrocortisone**, a chemical compound also known as cortisol. The maximum daily dose for hydrocortisone is 200 mg, with a total maximum dose of 1800 mg over the 9-week treatment period. Hydrocortisone is categorized as a corticosteroid. Both diphenhydramine and hydrocortisone are not designated as orphan drugs and are used to support the primary treatment with IMETELSTAT.
Efficacy
The efficacy of **Imetelstat** in the treatment of patients with high-risk myelodysplastic syndromes (MDS) or acute myeloid leukemia (AML) who have failed or are refractory to hypomethylating agent (HMA)-based therapy will be assessed in this clinical trial. The primary endpoint for evaluating efficacy is the overall response rate, which will be assessed after 4 months of treatment. This assessment will utilize combined response criteria for MDS and AML based on the International Working Group (IWG) 2018 criteria for MDS and the European LeukemiaNet criteria for AML.
Secondary endpoints include toxicity measured by the National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE) version 5.0, overall survival, progression-free survival, duration of best overall response, and best overall response. Additionally, patient-reported outcomes will be evaluated using the EORTC QLQ-C30 (version 3) questionnaire, which includes global health status, quality of life, functional scales, and symptom scales/items. These efficacy parameters will be collected and analyzed at specified timepoints throughout the trial to determine the therapeutic impact of Imetelstat on the target patient population.
Inclusion and Exclusion Criteria
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 2016 classification
- At least one cytopenia (ANC < 1800/μL or platelet count < 100,000/μL or hemoglobin < 10 g/dL)
- a. 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 b. 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 c. 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 d. 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 e. 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; G-CSF and erythropoietin are allowed before and during the study as clinically indicated
- ECOG performance status of 0-2
- Biochemical laboratory test values must be within the following limits: a. AST, ALT and ALP ≤2.5 times the upper limit of normal (x ULN) b. Serum creatinine ≤2.0 x ULN c. Total bilirubin ≤3 x ULN and direct bilirubin ≤2 x ULN (unless due to Gilbert’s syndrome, ineffective erythropoiesis due to MDS, or hemolysis due to RBC transfusion)
- Availability of blood counts and transfusion events for previous 16 weeks
- Women of childbearing potential and practicing a highly effective method of birth control according to the Clinical Trial Facilitation Coordination Group Recommendation (Version 1.1, 2020)28: - combined (estrogen and progestogen containing) hormonal contraception associated with inhibition of ovulation: o oral o intravaginal o transdermal - progestogen-only hormonal contraception associated with inhibition of ovulation: o oral o injectable o implantable - intrauterine device (IUD) - intrauterine hormone-releasing system ( IUS) - bilateral tubal occlusion - vasectomised partner - sexual abstinence For females, these restrictions apply for 3 months after the end of dosing. Note: If the childbearing potential changes after start of the study (e.g., woman who is not heterosexually active becomes active, premenarchal woman experiences menarche) a woman must begin a highly effective method of birth control, as described above
- A woman of childbearing potential must have a negative serum (ẞ-human chorionic gonadotropin [ẞ-hCG] pregnancy test at screening and agree to be tested (serum or urine) on day 1 of every cycle and at 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 eg, either condom with spermicidal foam/gel/film/cream/suppository or partner with occlusive cap (diaphragm or cervical/vault caps) with spermicidal foam/gel/film/cream/suppository, and all men must also not donate sperm during the study. For males, these restrictions apply for 3 months after the end of dosing
- France-specific inclusion criterion: Subjects participating at French sites must be covered by the French public welfare system.
Exclusion Criteria
- Chemotherapy within the 14 days prior to the first dose of imetelstat being administered (other than hydroxyurea)
- Subject has known allergies, hypersensitivity, or intolerance to imetelstat or its excipients (refer to the IB)
- Subject has received an experimental or investigational drug or used an invasive investigational medical device within 30 days prior to day 1 of C1
- Prior treatment with imetelstat
- Prior history of intensive chemotherapy or hematopoietic stem cell transplant
- Major surgery within 4 weeks prior to day 1 of C1 (excluding the placement of vascular access and other minor surgical procedures)
- Diagnosed or treated for malignancy other than MDS or AML, except: a. Malignancy treated with curative intent and with no known active disease present for 3 years before day 1 of C1 b. Adequately treated non-melanoma skin cancer or lentigo maligna without evidence of disease c. 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 C1, 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 subject’s safety, interfere with the imetelstat metabolism, or put the study outcomes at undue risk; Subject has any condition for which, in the opinion of the investigator, participation would not be in the best interest of the subject (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
- Subject is a man who plans to father a child while enrolled in this study or within 3 months after the end of dosing
Trial Status by Country
| Country | Status | Start of Recruitment | Planned Patients |
|---|---|---|---|
 France | Not Yet Recruiting | 31 Dec 2022 | 15 |
 Germany | Not Yet Recruiting | 31 Dec 2022 | 15 |
Sites & Investigators
Investigational Products
Details about the medicinal products being studied in this clinical trial.
| Product Name | Role in Trial | Formulation | Administration | Max Daily Dose | Treatment Duration | EU MP Number |
|---|---|---|---|---|---|---|
IMETELSTAT | Test | SOLUTION FOR INFUSION | INTRAVENOUS | 7.5 | 9 | PRD257254 |
DIPHENHYDRAMINE | Other | PHF00251MIG | INTRAVENOUS | 50 | 9 | SCP4359919 |
HYDROCORTISONE | Other | PHF00099MIG | INTRAVENOUS | 200 | 9 | SCP29190199 |