Trial Review

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Trial registered on ANZCTR


Registration number
ACTRN12625000226404
Ethics application status
Approved
Date submitted
7/02/2025
Date registered
28/03/2025
Date last updated
28/03/2025
Date data sharing statement initially provided
28/03/2025
Type of registration
Retrospectively registered

Titles & IDs
Public title
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.
Scientific title
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.
Secondary ID [1] 307928 0
ALLG AMLM27: IMpress 001
Universal Trial Number (UTN)
Trial acronym
IMpress
Linked study record
registration record NCT05583552 - was created by the site in Germany and this registration was created by Australian sponsor for the same study.

Health condition
Health condition(s) or problem(s) studied:
Myelodysplastic Syndromes 327581 0
Acute Myeloid Leukaemia 327582 0
Condition category
Condition code
Blood 324668 324668 0 0
Haematological diseases
Cancer 324669 324669 0 0
Leukaemia - Acute leukaemia

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
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.
Intervention code [1] 324389 0
Treatment: Drugs
Comparator / control treatment
No control group
Control group
Uncontrolled

Outcomes
Primary outcome [1] 332529 0
To assess the efficacy of Imetelstat for the treatment of AML and MDS patients failing or being refractory to hypomethylating agent (HMA)-based treatment
Timepoint [1] 332529 0
Primary timepoint: Overall response rate assessed after 4 months of treatment. Using combined response assessment criteria for MDS and AML based on IWG 2018 criteria (MDS) and the criteria of the European LeukemiaNet (AML).
Secondary outcome [1] 413832 0
To further assess efficacy and safety of Imetelstat regarding Toxicity as measured by National Cancer Institute for Common Terminology Criteria for Adverse Events (NCI CTCAE) Version 5.0. (this will be assessed as a composite outcome)
Timepoint [1] 413832 0
All adverse events will be assessed ongoing from the commencement of the intervention until completion of study (within 2 weeks of last drug dose on trial), withdrawal, disease progression or death. Adverse events (AE) will be defined as treatment-emergent if they are newly occurring or worsen following treatment with imetelstat. For this trial, the only adverse events that will be counted will be treatment emergent AE's (TEAEs). TEAEs will be classified by system organ class and preferred term using the Medical Dictionary for Regulatory Activities (MedDRA). Tables for TEAEs will show the number and frequencies of incidences by severity and relation to IMP. Individual listings of AEs, SAEs and deaths within 30 days from last exposure to IMP will be generated. TEAEs leading to premature discontinuation of study drug or withdrawal from the study will be summarized and listed in the same manner. (this will be assessed as a composite outcome)
Secondary outcome [2] 413836 0
To assess overall survival (OS) outcomes to Imetelstat in this patient population. (this will be assessed as a composite outcome)
Timepoint [2] 413836 0
Overall Survival (OS) is defined as the time from the beginning of imetelstat treatment until death or censored at the date of the last follow-up visit. Overall Survival (OS) will be assessed using Kaplan-Meier method. The death of patient is regarded as the event of interest. The estimates obtained are invariably expressed in graphical form. Median survival time, the survival rate at week 17 (in Cycle 5, Visit 9) and more additional timepoints with two-sided 95% confidence intervals (CI) using the complementary log-log transformation method will be tabulated. (this will be assessed as a composite outcome)
Secondary outcome [3] 413837 0
To assess progression free survival (PFS) outcomes to Imetelstat in this patient population. (this will be assessed as a composite outcome)
Timepoint [3] 413837 0
Progression free survival will be defined as the duration of time from the time of imetelstat treatment to time of progression or death, whichever occurs first. A subject who has neither progressed nor died will be censored on the date of last follow-up visit. Kaplan-Meier method will be used to assess progression-free survival (PFS). Kaplan-Meier Curves depicting PFS will be generated. Additionally, median PFS, PFS rate at week 17 (in Cycle 5, Visit 9) and more additional timepoints of treatment with imetelstat will be reported. The two-sided 95% confidence intervals (CI) for the median, week 4, and week 17 will be calculated using the complementary log-log transformation method. (data is collected via linkage to medical records)
Secondary outcome [4] 413859 0
To assess duration of best overall response to imetelstat in this patient population.
Timepoint [4] 413859 0
Measured from the time measurement criteria are met for Complete Response (CR), Complete Response incomplete (CRi), Partial Recovery (PR) or stable disease (SD), (whichever is first recorded), until the first date at which recurrent or progressive disease is objectively documented. Median time and 95% confidence interval for duration of response will be summarized using Kaplan-Meier estimates, and the Kaplan-Meier survival curve will be provided. (data is collected via linkage to medical records)
Secondary outcome [5] 413860 0
To assess best overall response to imetelstat in this patient population
Timepoint [5] 413860 0
Defined as the best response recorded from the start of the imetelstat treatment until disease progression (taking as reference for progressive disease the smallest measurements recorded since the treatment started). Best overall response at the end of treatment will be summarised. The summary data will include counts and percentages for each response category (CR, PR, SD etc). Response based on IWG 2023 criteria (MDS population only) • assessed in week 17 (in C5, V9) of treatment with imetelstat
Secondary outcome [6] 413861 0
To assess Quality of Life. This is measured using a health-related quality of life tool (HRQoL). (only 1 assessment tool is mentioned in the next section)
Timepoint [6] 413861 0
Scores from the European Organisation for Research and Treatment of Cancer assessment of quality of life questionnaire C-30 (EORTC QLQ-C30 ) version 3 will be used to measure quality of life. Health-related Quality of Life (HRQoL) will be accessed using EORTC QLQ-C30, version 3. The raw score for global health status/QoL, functional scales and symptom scales/items will be summarised with descriptive statistics by visit. Moreover, the convert score will also be provided. Quality of life questionnaires will be administered on Day 1 of each treatment cycle until end of treatment (within 2 weeks of last drug dose on trial), withdrawal or disease progression.

Eligibility
Key inclusion criteria
1 Signed written informed consent
2 Male and female greater than or equal to 18 years at the first screening
3 Must be able to adhere to the study visit schedule and other protocol requirements
4 Initial diagnosis of AML or MDS according to World health organisation (WHO) 2016 classification.
5 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)
6 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.
7 Not eligible for allogeneic stem cell transplantation
8 Greater than or equal to 5% bone marrow blasts at screening
9 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
10 ECOG performance status of 0-2
11 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)
12 Availability of blood counts and transfusion events for previous 16 weeks
13 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.
14 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.
15 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
16 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.
Minimum age
18 Years
Maximum age
No limit
Sex
Both males and females
Can healthy volunteers participate?
No
Key exclusion criteria
1 Chemotherapy within the 14 days prior to the first dose of imetelstat being administered (other than hydroxyurea)
2 Subject has known allergies, hypersensitivity, or intolerance to imetelstat or its excipients (refer to the IB)
3 Subject has received an experimental or investigational drug or used an invasive investigational medical device within 30 days prior to day 1 of C1
4 Prior treatment with imetelstat
5 Prior history of intensive chemotherapy or hematopoietic stem cell transplant
6 Major surgery within 4 weeks prior to day 1 of C1 (excluding the placement of vascular access and other minor surgical procedures)
7 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
8 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
9 Known history of human immunodeficiency virus (HIV) or any uncontrolled active systemic infection requiring IV antibiotics
10 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
11 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
12 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
13 Subject is a man who plans to father a child while enrolled in this study or within 3 months after the end of dosing
14 Subject is in custody by order of an authority or a court of law
15 Previous assignment to treatment during this study
16 Close affiliation with the investigator (e.g., a close relative) or persons working at the study site
17 Subject is an employee of the sponsor or involved CRO
18 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

Study design
Purpose of the study
Treatment
Allocation to intervention
Non-randomised trial
Procedure for enrolling a subject and allocating the treatment (allocation concealment procedures)
allocation is not concealed.
Methods used to generate the sequence in which subjects will be randomised (sequence generation)
not applicable.
Masking / blinding
Open (masking not used)
Who is / are masked / blinded?



Intervention assignment
Single group
Other design features
Phase
Phase 2
Type of endpoint/s
Safety/efficacy
Statistical methods / analysis
The study was designed as single-arm phase II trial. The design of the trial focused on demonstrating that the efficacy is greater than an undesired level of efficacy (p0) which would indicate that the treatment is ineffective. A Simon’s two-stage design was used to allow for initial assessment of efficacy. The sample size calculation was based on the following assumptions.
• Given Null hypothesis H0: p =< p0
• Alternative hypothesis H1: p > p0
• Level of inefficacy p0 = 0.05
• Expected true response rate p1 = 0.2
• Type-1-error a = 0.05, one-sided
• Type-2-error ß = 0.1
The null hypothesis that the true response rate is 0.05 was planned to be tested against a one-sided alternative. In the first stage, 21 patients were accrued. If there were 1 or fewer responses in these 21 patients, the study should be stopped. Otherwise, it was planned to accrue 20 additional patients for a total of 41. The null hypothesis would be rejected in favor of the alternative hypothesis if 5 or more responses are observed in 41 patients. This design yielded a one-sided type I error rate of no more than 0.05 and power of at least 0.9 when the true response rate is 0.2. To account for a loss of follow up of ~10%, enrollment of up to 46 patients is expected. Similarly, a total of 23 patients were planned to be enrolled prior to the interim analysis to ensure 21 evaluable patients for the interim analysis.
After the interim analysis was conducted, no responder according to the primary endpoint definition was identified. Due to the transient improvement seen in WBC and peripheral blasts in patients early in treatment, the study will continue in an exploratory approach with a change in dose frequency.

Recruitment
Recruitment status
Active, not recruiting
Date of first participant enrolment
Anticipated
Actual
7/08/2023
Date of last participant enrolment
Anticipated
Actual
11/11/2024
Date of last data collection
Anticipated
1/06/2026
Actual
Sample size
Target
6
Accrual to date
Final
7
Recruitment in Australia
Recruitment state(s)
QLD,SA,WA
Recruitment hospital [1] 23160 0
Royal Brisbane & Womens Hospital - Herston
Recruitment hospital [2] 23162 0
The Royal Adelaide Hospital - Adelaide
Recruitment hospital [3] 27431 0
Linear Clinical Research - Nedlands
Recruitment postcode(s) [1] 38521 0
4029 - Herston
Recruitment postcode(s) [2] 38523 0
5000 - Adelaide
Recruitment postcode(s) [3] 43543 0
6009 - Nedlands
Recruitment outside Australia
Country [1] 26786 0
France
State/province [1] 26786 0
Country [2] 26787 0
Germany
State/province [2] 26787 0

Funding & Sponsors
Funding source category [1] 312201 0
Other Collaborative groups
Name [1] 312201 0
Australasian Leukaemia & Lymphoma Group
Country [1] 312201 0
Australia
Primary sponsor type
Other Collaborative groups
Name
Australasian Leukaemia & Lymphoma Group
Address
Ground Floor, 35 Elizabeth St, Richmond VIC 3121
Country
Australia
Secondary sponsor category [1] 313727 0
Other Collaborative groups
Name [1] 313727 0
GCP-Service International West GmBH
Address [1] 313727 0
GCP-Service International West GmbH Siegfeldstraße 1153721 Siegburg
Country [1] 313727 0
Germany

Ethics approval
Ethics application status
Approved
Ethics committee name [1] 311583 0
Metro North Health Human Research Ethics Committee A
Ethics committee address [1] 311583 0
Ethics committee country [1] 311583 0
Australia
Date submitted for ethics approval [1] 311583 0
27/10/2022
Approval date [1] 311583 0
14/11/2022
Ethics approval number [1] 311583 0
89416

Summary
Brief summary
Trial website
Trial related presentations / publications
Public notes

Contacts
Principal investigator
Name 121610 0
A/Prof Steven Lane
Address 121610 0
QIMR Berghofer Medical Research InstituteRoyal Brisbane and Women's Hospital 300 Herston Rd, Herston QLD 4006
Country 121610 0
Australia
Phone 121610 0
+61 7 3362 0222
Fax 121610 0
Email 121610 0
[email protected]
Contact person for public queries
Name 121611 0
Delaine Smith
Address 121611 0
Australasian Leukaemia & Lymphoma GroupGround Floor, 35 Elizabeth St, Richmond VIC 3121
Country 121611 0
Australia
Phone 121611 0
+61 3 8373 9701
Fax 121611 0
Email 121611 0
[email protected]
Contact person for scientific queries
Name 121612 0
Delaine Smith
Address 121612 0
Australasian Leukaemia & Lymphoma GroupGround Floor, 35 Elizabeth St, Richmond VIC 3121
Country 121612 0
Australia
Phone 121612 0
+61 3 8373 9701
Fax 121612 0
Email 121612 0
[email protected]

Data sharing statement
Will the study consider sharing individual participant data?
No
No IPD sharing reason/comment: Individual patient data will not be shared publicly. Aggregate patient data and final results will be presented in the final report



What supporting documents are/will be available?

No Supporting Document Provided



Results publications and other study-related documents

Documents added manually
No documents have been uploaded by study researchers.

Documents added automatically
No additional documents have been identified.