AMLM27/ IMpress_001: A phase II study evaluating the efficacy and safety of Imetelstat in Patients with high-risk (HR) myelodysplastic syndromes (MDS) or Acute Myeloid Leukaemia (AML) failing HMA-based therapy.
AMLM27/ IMpress_001: A phase II study evaluating the efficacy and safety of Imetelstat in Patients with HR myelodysplastic Syndromes (MDS) or AML failing HMA-based therapy.
Australasian Leukaemia & Lymphoma Group
6 participants
Aug 7, 2023
Interventional
Conditions
Summary
This is an open-label, phase II study for treatment of high-risk myelodysplastic syndromes (MDS) or Acute Myeloid Leukaemia (AML). The purpose of this study is to evaluate the safety, response and survival of Imetelstat treatment in patients that do not respond to Hypo-Methylating Agent (HMA)-based therapy. This multi-centre study will recruit participants across Australia, Germany and France. A total of up to 46 subjects will be recruited for this study. You may be eligible to join this study if you are aged 18 years or above and have been diagnosed with MDS or AML. People with high-risk myelodysplasia (MDS) currently have limited treatment options. This group of patients often rely on blood transfusions and unfortunately, some standard of care therapies are not often successful as a treatment option. Participants who meet the eligibility criteria for this study will receive 2-hour intravenous (IV) infusion with Imetelstat twice in a 28-day cycle (once every 14 days) for at least 4 cycles. After 4 treatment cycles (8 administrations of Imetelstat) response assessment will be performed on all patients. Non-responding patients will discontinue Imetelstat treatment, undergo End of Treatment and enter the follow-up phase of the trial. Patients who are categorized as responders according to the primary endpoint definition and have Bone Marrow blasts =>5% at the response assessment (Visit 9) will continue Imetelstat treatment every 14 days until loss of response/disease progression. Patients who are categorized as responders according to the primary endpoint definition and have Bone Marrow blasts <5% will continue Imetelstat treatment every 28 days until loss of response/disease progression. During and after completion of the treatment participants will be assessed for overall response using response assessment, safety and toxicity using adverse events, overall survival and progression free survival from medical records, and quality of life questionnaires. It is hoped that this research project will contribute to the field of Myelodysplastic Syndromes and that it may be used to improve health outcomes.
Eligibility
Inclusion Criteria32
- Signed written informed consent
- Male and female greater than or equal to 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 World health organisation (WHO) 2016 classification.
- At least one cytopenia (Absolute neutrophil count (ANC) less than 1800/µL or platelet count less than 100,000/µL or hemoglobin less than 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 haematological 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
- Greater than or equal to 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
- ECOG performance status of 0-2
- Biochemical laboratory test values must be within the following limits:
- a. Aspartate aminotransferase (AST), Alanine transaminase (ALT) and Alkanine phosphotase (ALP) less than or equal to 2.5 times the upper limit of normal (x ULN)
- b. Serum creatinine less than or equal to 2.0 x ULN
- c. Total bilirubin less than or equal to 3 x ULN and direct bilirubin less than or equal to 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 consistent with local regulations regarding the use of birth control methods for subjects participating in clinical studies: eg, established use of oral, injected or implanted
- hormonal methods of contraception; placement of an intrauterine device or intrauterine system; barrier methods: condom with spermicidal foam/gel/film/cream/suppository or occlusive cap (diaphragm or cervical/vault caps) with spermicidal foam/gel/film/cream/suppository; male partner sterilization (the vasectomized partner should be the sole partner for that subject); true abstinence (when this is in line with the preferred and usual lifestyle of the subject). 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 (Beta-human chorionic gonadotropin [B-hCG] or urine pregnancy test at screening and agree to be tested 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
- Patients who are relapsed or refractory to, or not eligible for, therapy with approved and available FLT3 or IDH1/IDH2 inhibitors or other approved targeted therapies.
Exclusion Criteria21
- 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
- Subject is in custody by order of an authority or a court of law
- Previous assignment to treatment during this study
- Close affiliation with the investigator (e.g., a close relative) or persons working at the study site
- Subject is an employee of the sponsor or involved CRO
- Criteria which in the opinion of the investigator preclude participation for scientific reasons, for reasons of compliance, or for reasons of the subject’s safety
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Interventions
This study is an open-label, single arm multicentre, phase 2 study assessing the efficacy of Imetelstat for the treatment of acute myeloid leukaemia (AML) and Myelodysplastic syndromes (MDS) participants failing or being refractory to the first line of hypomethylating agent (HMA) - based treatment. After undergoing screening procedures and meeting the eligibility criteria for this study, All patients will receive 7.5 mg/kg via a 2-hour intravenous (IV) infusion with Imetelstat twice in a 28-day cycle (once every 14 days) for at least 4 cycles. There is no planned breaks between cycles. After 4 treatment cycles (8 administrations of Imetelstat) response assessment will be performed on all patients. Non-responding patients will discontinue Imetelstat treatment, undergo End of Treatment (EOT) and enter the follow-up phase of the trial. Patients who are categorized as responders according to the primary endpoint definition and have BM blasts =>5% at the response assessment (Visit 9) will continue Imetelstat treatment every 14 days until loss of response/disease progression. Patients who are categorized as responders according to the primary endpoint definition and have BM blasts <5% will continue Imetelstat treatment every 28 days until loss of response/disease progression. Strict adherence to all specifications laid down in this protocol is required for all aspects of study conduct, i.e., the investigator is not allowed to modify the procedures described in this protocol.
Locations(5)
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ACTRN12625000226404