Trial Review

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Trial registered on ANZCTR


Registration number
ACTRN12625000995471p
Ethics application status
Not yet submitted
Date submitted
14/08/2025
Date registered
9/09/2025
Date last updated
9/09/2025
Date data sharing statement initially provided
9/09/2025
Type of registration
Prospectively registered

Titles & IDs
Public title
ALLG AMLM30: Bleximenib or Placebo in Combination with Standard Induction and Consolidation Therapy followed by Maintenance for the Treatment of Patients with Newly Diagnosed KMT2A-rearranged or NPM1-mutant Acute Myeloid Leukemia Eligible for Intensive Chemotherapy: a double-blind phase 3 study.
Scientific title
ALLG AMLM30: Bleximenib or Placebo in Combination with Standard Induction and Consolidation Therapy followed by Maintenance for the Treatment of Patients with Newly Diagnosed KMT2A-rearranged or NPM1-mutant Acute Myeloid Leukemia Eligible for Intensive Chemotherapy: a double-blind phase 3 study.
Secondary ID [1] 315128 0
2025-522767-15
Secondary ID [2] 315129 0
HOVON 181 AML
Secondary ID [3] 315130 0
AMLSG 37-25
Universal Trial Number (UTN)
Trial acronym
Linked study record

Health condition
Health condition(s) or problem(s) studied:
Acute myeloid leukaemia (AML) 338545 0
Cancer 338546 0
Condition category
Condition code
Cancer 334849 334849 0 0
Leukaemia - Acute leukaemia

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
The intervention is Bleximenib in combination with standard induction, consolidation, and maintenance therapy. Bleximenib is supplied as an oral tablet, 50 or 100mg tablets and administered over a period of 28 days (with the exception of induction cycle 1 where it is administered for 24 days).

Standard Induction Therapy consists of two cycles:
-Cytarabine: 300 mg/m²/day administered via continuous intravenous infusion (CIV) on Days 1–7.
-Either Daunorubicin 60 mg/m² IV or Idarubicin 12 mg/m² IV on Days 1–3.

Standard Consolidation Therapy is administered in up to three cycles:
-Cytarabine (IDAC): 1500 mg/m² IV twice daily on Days 1–3 (reduced to 1000 mg/m² for patients aged =61 years).

There are two interventional arms in this study.

Interventional Arm 1: Bleximenib + standard induction and consolidation chemotherapy, followed by up to 24 cycles of Bleximenib maintenance.
Interventional Arm 2: Bleximenib + standard induction and consolidation chemotherapy, followed by up to 24 cycles of placebo maintenance. Day 1 to Day 672: A placebo will be orally administered twice a day.

Induction Therapy-Cycle 1:
Day 4 to Day 28: 100 mg of Bleximenib will be orally administered twice a day.
In addition to standard of care induction therapy.

Induction Therapy-Cycle 2.
Day 1 to Day 28: 100 mg of Bleximenib will be orally administered twice a day.
In addition to standard of care induction therapy.

Consolidation therapy (3 cycles):
Day 1 to Day 3: 1500 mg/m2 of intermediate dose of cytarabine (IDAC) administered intravenous (IV) twice a day. (Patients 61 years of age or older will receive 1000 mg/m2 of IDAC twice a day).
Day 1 to Day 28: 100 mg of Bleximenib will be orally administered twice a day.

Maintenance therapy (24 cycles):
Day 1 to Day 672: 100 mg of Bleximenib will be orally administered twice a day.

All treatment will be administered by the study team. Drug accountability will be performed by the administering institutions to assess compliance.
Intervention code [1] 331752 0
Treatment: Drugs
Comparator / control treatment
Control Arm 3: Placebo + standard induction and consolidation chemotherapy, followed by up to 24 cycles of placebo maintenance. Placebo will consist of inactive ingredients: microcrystalline cellulose, lactose, magnesium stearate, and coloring agents.

Induction Therapy-Cycle 1:
Day 4 to Day 28: A placebo will be orally administered twice a day.
Day 1 to Day 7: Cytarabine will be administered 300mg/m^2/day with continuous IV (CIV).
Day 1 to Day 3: Daunorubicin will be administered 60 mg/m^2 with IV.
or Idarubicin will be administered 12 mg/m^2 with IV.

Induction Therapy-Cycle 2.
Day 1 to Day 28: A placebo will be orally administered twice a day.
Day 1 to Day 7: Cytarabine will be administered 300mg/m^2/day with continuous IV (CIV).
Day 1 to Day 3: Daunorubicin will be administered 60 mg/m^2 with IV.
or Idarubicin will be administered 12 mg/m^2 with IV.

Consolidation therapy:
1) For patients who are KMT2A-rearranged or present with minimal residual disease (MRD) positivity after induction cycle 2 will proceed to all allogeneic stem cell transplant.

2) Day 1 to Day 3: 1500 mg/m2 of intermediate dose of cytarabine (IDAC) administered intravenous (IV) twice a day. (Patients 61 years of age or older will receive 1000 mg/m2 of IDAC twice a day).
Day 1 to Day 28: A placebo will be orally administered twice a day.
Up to 3 cycles.

Maintenance therapy (24 cycles):
Day 1 to Day 672: A placebo will be orally administered twice a day.

All treatment will be administered by the study team. Drug accountability will be performed by the administering institutions to assess compliance.
Control group
Placebo

Outcomes
Primary outcome [1] 342482 0
Event Free Survival (EFS) (Arm 1 vs Arm 3)
Timepoint [1] 342482 0
Time from randomization to failure to achieve complete remission (CR) after remission induction, hematologic relapse after achieving CR or death, whichever occurs first. Until 4 years post treatment.
Secondary outcome [1] 450993 0
Overall survival (OS)
Timepoint [1] 450993 0
Time from randomisation to the date of death from any cause. Until 4 years post treatment.
Secondary outcome [2] 450994 0
modified EFS (Arm 1 vs Arm 3)
Timepoint [2] 450994 0
Time from randomization to failure to achieve CR, CR with partial hematologic recovery (CRh) or CR with incomplete hematologic recovery (CRi), within 60 days following the start of the last induction cycle, hematologic relapse after achieving CR/CRh/CRi, or death, whichever occurs first,
Secondary outcome [3] 450995 0
Response (Arm 1 vs Arm 3)
Timepoint [3] 450995 0
Time from randomization to failure to achieve CR, CRh, or CRi within 60 days following the start of the last induction cycle, hematologic relapse after achieving CR/CRh/CRi or death, whichever occurs first.
Secondary outcome [4] 450996 0
Proportion of patients undergoing allogeneic stem cell transplant. (Arm 1 vs Arm 3).
Timepoint [4] 450996 0
Time from randomization up to 4 years after treatment has stopped.
Secondary outcome [5] 450997 0
Health-related quality of life. (Arm 1 vs Arm 3)
Timepoint [5] 450997 0
Time of randomisation, after each induction cycle, day 1 of maintenance therapy, every 12 weeks on maintenance therapy, and at the end of treatment.
Secondary outcome [6] 450998 0
Pharmacokinetics
Timepoint [6] 450998 0
2 hours post-dose on day 4 of induction treatment cycle 1, end of Induction Cycle 1, pre-dose and 2 hours post-dose on day 1 of induction treatment cycle 2, end of induction treatment cycle 2, pre-dose on the 1st day of the second consolidation treatment cycle, 2 hours post-dose on the 1st day of the first Maintenance cycle, and pre-dose on the 1st day of the second Maintenance cycle.
Secondary outcome [7] 450999 0
Relapsed Free Survival (RFS) of Bleximenib in maintenance therapy. (Arm 1 vs Arm 2)
Timepoint [7] 450999 0
From start of maintenance among participants who achieved CR during remission induction, defined as the time from start of maintenance until relapse or death, whichever occurs first. Until 4 years post treatment.
Secondary outcome [8] 451000 0
EFS (Arm 2 vs Arm 3)
Timepoint [8] 451000 0
Time from randomization to failure to achieve complete remission (CR) after remission induction, hematologic relapse after achieving CR or death, whichever occurs first. Until 4 years post treatment.

Eligibility
Key inclusion criteria
1. 18 years of age or older (or the legal age of majority in the jurisdiction in which the study is taking place, whichever is greater) at the time of informed consent.
2. New diagnosis of acute myeloid leukaemia (AML) (equal or greater than 10% blasts in bone marrow (BM) or peripheral blood) with mutated Nucleophosmin 1 (NPM1) or with recurring rearrangements involving Lysine Methyltransferase 2A (KMT2A) according to International Consensus Clarification (ICC) 2022 criteria.
• Eligibility will be determined as follows:
o AML with mutated NPM1 on a BM or peripheral blood sample tested in a dedicated central laboratory.
o AML with rearrangements involving KMT2A, on a BM or peripheral blood sample tested in a dedicated central laboratory or by local assessment by Fluorescence In Situ Hybridization (FISH)/cytogenetics.
o Absence of FMS-like Tyrosine Kinase 3 – Internal Tandem Duplication (FLT3-ITD) or Tyrosine Kinase Domain (TKD) mutations based on a BM or peripheral blood sample tested in a dedicated central laboratory unless participant is ineligible for, or has refused, targeted FLT3-inhibition therapies or if targeted FLT3 therapies are not available/reimbursed at participating sites/countries.
• Previously untreated AML
• AML may be secondary to prior hematological disorders, including myelodysplastic syndrome (MDS), and/or therapy-related. Participants may have had previous treatment for an antecedent phase of MDS with agents such as erythropoiesis stimulating agents, Luspatercept, Imetelstat or hypomethylating agents. These agents are allowed if administered more than 5 half-lives prior to the first dose of study treatment.
• Emergency leukapheresis or cytoreductive therapy with hydroxyurea (See Inclusion Criterion #6) is permitted prior to first dose of study treatment.
3. Considered eligible for intensive chemotherapy.
4. WHO/ECOG performance status equal or less than 2.
5. Adequate renal and hepatic functions prior to randomization:
• Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) less than 3 × upper limit of normal (ULN); for participants with leukemic organ involvement (documented by biopsy or imaging) AST and ALT less than 5 × ULN is permitted.
• Total bilirubin less than 3 × ULN, unless bilirubin rise is considered due to leukemic organ involvement (documented by biopsy or imaging), congenital nonhemolytic hyperbilirubinemia such as Gilbert’s syndrome, or of non-hepatic origin.
• Renal impairment defined as estimated glomerular filtration rate (eGFR) equal or greater than 30 mL/min based on Modification of Diet in Renal Disease (MDRD) formula (KDIGO 2024).
6. White blood cell (WBC) count less than 25 × 109/L. Use of hydroxyurea (equal or greater than 2 g divided into 2 to 3-times-daily dosing) is allowed for the control of peripheral leukemic blasts in participants with leukocytosis.
7. While on study treatment and for at least 6 months after the last dose of study treatment,
a female participant:
• of nonchildbearing potential must be:
o postmenopausal (defined as at least 1 year without any menses).
o documented surgically sterile (e.g. documented hysterectomy, bilateral oophorectomy or bilateral salpingectomy) or status post hysterectomy (at least 1 month prior to screening).
• of childbearing potential (not surgically sterile and not postmenopausal) must agree to avoid pregnancy starting at screening and throughout the study period and for 6 months after the final study drug administration
o and have a negative highly sensitive pregnancy test at screening and within 48 hours of the first dose of study treatment.
o and, if heterosexually active, agree to consistently apply one highly effective method of birth control for the duration of the study and for 6 months after the final study drug administration, in addition to a barrier method.
• must agree not to breastfeed starting at screening and throughout the study period, and for 1 month after the final study drug administration.
• must agree not to donate ova starting at screening and throughout the study period, and for 6 months after the final study drug administration.
a male participant
• must use a latex condom during any sexual contact with a partner childbearing potential, even if they have undergone a successful vasectomy and must agree to avoid to father a child for at least 90 days after the last dose of Bleximenib/placebo and 6 months after the final dose of chemotherapy. In addition, their partners of childbearing potential must use a highly effective method of birth control.
• must not donate sperm starting at screening and throughout the study period and for at least 90 days after the last dose of Bleximenib/placebo or 6 months after the final dose of chemotherapy.
8. Must be capable of signing an informed consent form (ICF) indicating that the participant understands the purpose of, and procedures required for, the study and is willing to participate in the study.
Minimum age
18 Years
Maximum age
No limit
Sex
Both males and females
Can healthy volunteers participate?
No
Key exclusion criteria
1. Diagnosis of acute promyelocytic leukemia with PML-RARA or one of the other pathognomonic variant fusion genes/chromosome translocations
2. AML with t(9;22)(q34.1;q11.2); BCR::ABL1, or myeloid blast crisis of chronic myeloid leukemia.
3. Prior (chemo-)therapy for AML, including prior treatment with hypomethylating agents (prior treatment of antecedent MDS with hypomethylating agents is allowed; see Inclusion Criterion #2)
4. Known active leukemic involvement of the central nervous system (CNS). Evaluation of cerebrospinal fluid during screening is only required if there is a clinical suspicion of CNS involvement by leukemia during screening.
5. Recipient of solid organ transplant.
6. Cardiac disease:
a. Any of the following within 6 months of randomization: myocardial infarction, uncontrolled/unstable angina, congestive heart failure (New York Heart Association (NYHA) Class III or IV), uncontrolled or symptomatic arrhythmias, stroke, or transient ischemic attack.
b. QTc interval using Fridericia’s formula (QTcF) equal or greater than 470 ms. Prolonged QTc interval associated with bundle branch block or pacemaking is permitted.
c. Left ventricular ejection fraction (LVEF) less than 40% by ECHO or MUGA scan obtained within 28 days prior to the start of study treatment.
d. Previously received cumulative dose of any combination of anthracyclines or anthracenediones of equal or greater than 500 mg/m2.
7 Chronic respiratory disease requiring supplemental oxygen.
8. Active infection, including hepatitis B or C or human immunodeficiency virus (HIV) infection that is uncontrolled at randomization. An infection controlled with an approved or closely monitored antibiotic/antiviral/antifungal treatment is allowed.
• Known to be positive or tests positive at screening for HIV. HIV positive participants with undetectable viral load, CD4 count over 200 cell/mm^3, and on stable highly active antiretroviral therapy that are not strong cytochrome P450 (CYP)3A4 inhibitors, which are contraindicated, are permitted.
• Active hepatitis of infectious origin:
a. Seropositive for hepatitis B: defined by a positive test for hepatitis B surface antigen (HBsAg). Participants with resolved infection (i.e., participants with a history of hepatitis B virus (HBV) infections or who are HBsAg negative with positive antibodies to total hepatitis B core antigen [anti-HBc] must be screened using Reverse Transcription Polymerase Chain Reaction (RT-PCR) measurement of HBV Deoxyribonucleic Acid (DNA) levels. Those who are RT-PCR positive will be excluded. Participants with serologic findings suggestive of HBV vaccination (anti-HBs positivity as the only serologic marker) AND a known history of prior HBV vaccination, do not need to be tested for HBV DNA by RT-PCR.
b. Known hepatitis C infection or positive serologic testing for hepatitis C virus (anti-HCV) antibody. Participants with positive hepatitis C antibody due to prior resolved disease can be enrolled only if a confirmatory negative hepatitis C Ribonucleic Acid (RNA) test is obtained at screening or within 3 months prior to first dose of study treatment.
c. Other clinically active liver disease of infectious origin.
9. Concurrent enrollment in another anticancer therapeutic investigational clinical study.

Study design
Purpose of the study
Treatment
Allocation to intervention
Randomised controlled trial
Procedure for enrolling a subject and allocating the treatment (allocation concealment procedures)
Allocation is concealed until after registration through a central software system, with randomisation details provided by the Clinical Research Associate (CRA) via secure communication. This process ensures that treatment allocation is not known to investigators or patients prior to enrolment, maintaining allocation concealment integrity.
Methods used to generate the sequence in which subjects will be randomised (sequence generation)
Participants will be randomized using a stratified block randomization method and stratification factors including participant age at randomization (=60 years of age vs. =61 years of age), genetic status (NPM1m vs. KMT2Ar) and geographic region (U.S. vs. Europe vs. Asia-Pacific).

Each participant will be given a unique participant study number (a sequence number by order of enrollment in the trial). Participant study number will be given immediately by the randomization system.
Masking / blinding
Who is / are masked / blinded?



Intervention assignment
Other design features
Phase
Phase 3
Type of endpoint/s
Statistical methods / analysis

Recruitment
Recruitment status
Not yet recruiting
Date of first participant enrolment
Anticipated
1/12/2025
Actual
Date of last participant enrolment
Anticipated
1/06/2028
Actual
Date of last data collection
Anticipated
1/06/2032
Actual
Sample size
Target
45
Accrual to date
Final
Recruitment in Australia
Recruitment state(s)
NSW,QLD,SA,WA,VIC
Recruitment outside Australia
Country [1] 27281 0
Netherlands
State/province [1] 27281 0
Country [2] 27282 0
Germany
State/province [2] 27282 0
Country [3] 27283 0
Austria
State/province [3] 27283 0
Country [4] 27284 0
Poland
State/province [4] 27284 0
Country [5] 27285 0
Japan
State/province [5] 27285 0
Country [6] 27286 0
Poland
State/province [6] 27286 0
Country [7] 27287 0
Norway
State/province [7] 27287 0
Country [8] 27288 0
Sweden
State/province [8] 27288 0
Country [9] 27289 0
Denmark
State/province [9] 27289 0
Country [10] 27290 0
Iceland
State/province [10] 27290 0
Country [11] 27291 0
Spain
State/province [11] 27291 0
Country [12] 27292 0
Finland
State/province [12] 27292 0
Country [13] 27293 0
Italy
State/province [13] 27293 0
Country [14] 27294 0
China
State/province [14] 27294 0
Country [15] 27295 0
United States of America
State/province [15] 27295 0
Country [16] 27296 0
Korea, Republic Of
State/province [16] 27296 0

Funding & Sponsors
Funding source category [1] 319706 0
Other Collaborative groups
Name [1] 319706 0
Australasian Leukaemia and Lymphoma Group
Country [1] 319706 0
Australia
Primary sponsor type
Other Collaborative groups
Name
Australasian Leukaemia and Lymphoma Group
Address
Country
Australia
Secondary sponsor category [1] 322216 0
Other Collaborative groups
Name [1] 322216 0
HOVON
Address [1] 322216 0
Country [1] 322216 0
Netherlands

Ethics approval
Ethics application status
Not yet submitted
Ethics committee name [1] 318260 0
Peter MacCallum Cancer Centre Human Research Ethics Committee
Ethics committee address [1] 318260 0
Ethics committee country [1] 318260 0
Australia
Date submitted for ethics approval [1] 318260 0
03/11/2025
Approval date [1] 318260 0
Ethics approval number [1] 318260 0

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

Contacts
Principal investigator
Name 143614 0
A/Prof Andrew Wei
Address 143614 0
Peter MacCallum Cancer Centre 305 Grattan St, Melbourne, Victoria 3000
Country 143614 0
Australia
Phone 143614 0
+61 3 9345 2555
Fax 143614 0
Email 143614 0
[email protected]
Contact person for public queries
Name 143615 0
Delaine Smith
Address 143615 0
Australasian Leukaemia & Lymphoma Group. 35 Elizabeth St Richmond Vic 3121
Country 143615 0
Australia
Phone 143615 0
+61 03 83739701
Fax 143615 0
Email 143615 0
[email protected]
Contact person for scientific queries
Name 143616 0
Delaine Smith
Address 143616 0
Australasian Leukaemia & Lymphoma Group. 35 Elizabeth St Richmond Vic 3121
Country 143616 0
Australia
Phone 143616 0
+61 03 83739701
Fax 143616 0
Email 143616 0
[email protected]

Data sharing statement
Will the study consider sharing individual participant data?
Yes
Will there be any conditions when requesting access to individual participant data?
Persons/groups eligible to request access:
• Researchers
Conditions for requesting access:
• Yes, conditions apply:
• Requires review on a case-by-case basis by the trial custodian, sponsor or data sharing committee
• Requires a scientifically sound proposal or protocol
What individual participant data might be shared?
• All de-identified individual participant data
What types of analyses could be done with individual participant data?
• Any type of analysis (i.e. no restrictions on data re-use)
When can requests for individual participant data be made (start and end dates)?
From:
3 months after publication

To:
No end date
Where can requests to access individual participant data be made, or data be obtained directly?
• Data sharing request system: Access can be requested via the Health Data Australia catalogue (https://researchdata.edu.au/health/). Search for the ACTRN number in the catalogue to find datasets associated with this trial

Are there extra considerations when requesting access to individual participant data?
No


What supporting documents are/will be available?

TypeCitationLinkEmailOther DetailsAttachment
Study protocol  [email protected] Access can be requested via the Health Data Austra... [More Details]


Results publications and other study-related documents

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