Trial Review

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Trial registered on ANZCTR


Registration number
ACTRN12625000964415p
Ethics application status
Not yet submitted
Date submitted
25/06/2025
Date registered
3/09/2025
Date last updated
3/09/2025
Date data sharing statement initially provided
3/09/2025
Type of registration
Prospectively registered

Titles & IDs
Public title
ALLG AMLM30/EVOLVE II: Randomised study to assess revumenib in combination with azacitidine + venetoclax in adult patients with newly diagnosed NPM1-mutated or KMT2A-rearranged Acute Myeloid Leukaemia (AML) ineligible for intensive chemotherapy
Scientific title
ALLG AMLM30/EVOLVE II: Randomised study to assess revumenib in combination with azacitidine + venetoclax in adult patients with newly diagnosed NPM1-mutated or KMT2A-rearranged AML ineligible for intensive chemotherapy
Secondary ID [1] 314588 0
EVOLVE II
Secondary ID [2] 314589 0
HOVON 177
Secondary ID [3] 315117 0
2024-512733-32-00
Universal Trial Number (UTN)
Trial acronym
Linked study record

Health condition
Health condition(s) or problem(s) studied:
Acute myeloid leukaemia (AML) 337703 0
Cancer 337704 0
Condition category
Condition code
Cancer 334038 334038 0 0
Leukaemia - Acute leukaemia

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
Patients will be randomised to Azacitidine and Venetoclax with Revumenib (Arm 1-Comparator) or placebo (Arm 2-Control).

Treatment cycles are 28 days long. Azacitidine is administered subcutaneous at a dose of 75 mg/m2/day continuously for 7 days (or over 9 days as per institutional standard) every 28 days starting on day 1. Dose banding is permitted for high-weight patients per local standard of care. In the first treatment cycle, Venetoclax is orally administered with a two-day ramp-up phase followed by a dose of 50 mg of Venetoclax combined with a strong cytochrome P450 (CYP)3A4 inhibitor.

Revumenib or placebo will be orally administered. Revumenib will be orally administered at a dose of 160mg twice daily in combination with a strong CYP3A4 inhibitor azole, which is given each cycle for 28 days. They will not be continued beyond day 28 if a next cycle is delayed.

The dosing schedule of subsequent cycles will be based on previous cycle, with the exception that there is no ramp-up phase of Venetoclax.

Bone marrow assessment will be performed after each cycle. Treatment will be continued until disease relapse, disease progression, death, development of unacceptable toxicity, withdrawal by subject, or other protocol defined criteria for discontinuation (whichever comes first).

All treatment will be administered by the study team. Drug accountability will be performed by the administering institutions to assess compliance.
Intervention code [1] 331214 0
Treatment: Drugs
Comparator / control treatment
Control Arm 2 patients will have placebo orally administered. Placebo will consist of inactive ingredients: microcrystalline cellulose, lactose, magnesium stearate, and coloring agents.
Control group
Placebo

Outcomes
Primary outcome [1] 341711 0
Overall survival in adult patients with newly diagnosed NPM1-mutated AML ineligible for intensive chemotherapy
Timepoint [1] 341711 0
Date of randomisation to the date of death from any cause. Up to 4 years after randomisation of the last patient.
Secondary outcome [1] 448457 0
Event free survival (EFS) in adult patients with newly diagnosed NPM1-mutated AML ineligible for intensive chemotherapy,
Timepoint [1] 448457 0
Date of randomisation to the date of treatment failure, hematologic relapse from complete remission (CR)/complete remission hematologic (CRh) response (i.e., not molecular relapse) or death from any cause, whichever occurs first. Up to 4 years after randomisation of the last patient. Treatment failure in this unfit AML population is defined as lack of obtaining either CR or CRh by week 24.
Secondary outcome [2] 448458 0
Rate of CR/CRh in adult patients with newly diagnosed NPM1-mutated AML ineligible for intensive chemotherapy,
Timepoint [2] 448458 0
Any time-point during therapy. Assessment will be performed at the end of each cycle.
Secondary outcome [3] 448459 0
Rate of complete remission (CR) in adult patients with newly diagnosed NPM1-mutated AML ineligible for intensive chemotherapy
Timepoint [3] 448459 0
Any time-point during therapy. Assessment will be performed at the end of each cycle.

Eligibility
Key inclusion criteria
In order to be eligible to participate in this study, a patient must meet all of the following criteria:
1. Patient with newly diagnosed NPM1-mutated AML, consistent with NPM1c, according to the 2022 International Consensus Classification (i.e. greater or equal to 10% blasts).
OR
Patient with newly diagnosed KMT2A-rearranged AML according to the 2022 International Consensus Classification (i.e. greater or equal to 10% blasts). KMT2A partial tandem duplications or deletions are NOT eligible.
2. Central confirmation of NPM1 mutation or KMT2A rearrangement in one of the dedicated central genetic laboratories.
3. Age greater or equal to 18 years, no upper age limit.
4. Patient is ineligible for intensive induction chemotherapy by meeting at least 1 of the following criteria:
• greater or equal to 75 years of age: ineligible for intensive chemotherapy per physician’s discretion (with an Eastern Cooperative Oncology Group (ECOG) performance status 0-2)
• 18-74 years: patient is not eligible for standard chemotherapy because any of the following co-morbidities:
o ECOG performance status 2 or 3
o Cardiac history of chronic heart failure requiring treatment; or with an ejection fraction less or equal to 50%; or chronic stable angina.
o Diffusing Capacity of Lung for Carbon Monoxide (DLCO) less or equal to 65% or Forced Expiratory Volume (in one second) (FEV1) less or equal to 65%.
o Creatinine clearance greater or equal to 30 mL per min to less than 45 ml per min calculated by the Cockcroft Gault formula.
o Moderate hepatic impairment with total bilirubin greater than 1.5 to less than 3.0 x upper limit of normal (ULN).
o Any other comorbidity that the local physician assesses to be incompatible with intensive chemotherapy.
5. Patient must have a projected life expectancy of at least 12 weeks (as assessed by the treating physician).
6. Patient must have a white cell blood (WBC) count of less than 25 x 109 per L. Hydroxyurea can be used prior to study enrolment to reduce the WBC count to meet this criterion.
7. Adequate renal function as evidenced by serum creatinine less or equal to 2.0 × upper limit of norm (ULN) or creatinine clearance greater than 30 mL per min based on the Cockcroft-Gault glomerular filtration rate (GFR).
8. Adequate hepatic function as evidenced by:
• Serum total bilirubin less or equal to 3.0 × ULN unless considered due to Gilbert’s disease, or leukemic involvement.
• Aspartate aminotransferase (AST), alanine aminotransferase (ALT), and alkaline phosphatase (ALP) less or equal to 3.0 × ULN, unless considered due to leukemic involvement.
9. Female patient must:
• be of nonchildbearing potential:
o postmenopausal (defined as at least 1 year without any menses).
o documented surgically sterile (e.g. documented hysterectomy, or bilateral oophorectomy, bilateral salpingectomy) or status post hysterectomy (at least 1 month prior to screening).
• or, if of childbearing potential (not surgically sterile and not postmenopausal)
agree to avoid pregnancy during the study and for 6 months after the final study drug administration.
o and have a negative urine or serum pregnancy test at screening.
o and, if heterosexually active, agree to consistently apply one highly effective* method of birth control in combination to a barrier method for the duration of the study and for 6 months after the final study drug administration.
*Highly effective forms of birth control include
- Consistent and correct usage of established hormonal contraceptives that inhibit ovulation for at least 1 month prior to taking study drug. (hormonal contraception is only a highly effective method of birth control, if a combined [estrogen and progestogen containing] hormonal contraception or a progestogen-only hormonal contraception – both associated with inhibition of ovulation - is used.
- Established intrauterine device (IUD) or intrauterine system (IUS)
- Bilateral tubal occlusion
- Vasectomy – a vasectomy is highly effective contraception method provided the absence of sperm has been confirmed. If not, an additional highly effective method of contraception should be used.
- Male is sterile due to a bilateral orchiectomy.
- Sexual abstinence is considered a highly effective method only if defined as refraining from heterosexual activity during the entire period of risk associated with the study drug. The reliability of sexual abstinence needs to be evaluated in relation to the duration of the clinical study and the preferred and usual lifestyle of the patient.
List is not all inclusive. Prior to enrolment, the investigator is responsible for confirming patient will utilize highly effective forms of birth control in combination with a barrier method according to locally accepted standards during the protocol defined period.
Note: A postmenopausal state is defined as no menses for 12 months without an alternative medical cause. A high follicle stimulating hormone (FSH) level in the postmenopausal range may be used to confirm a post-menopausal state in women not using hormonal contraception or hormonal replacement therapy. However in the absence of 12 months of amenorrhea, a single FSH measurement is insufficient.
• agree not to breastfeed starting at screening and throughout the study period.
• agree not to donate ova starting at screening and throughout the study period, and for 6 months after the final study drug administration.
10. Men must use a latex condom during any sexual contact with women of childbearing potential (WOCBP), even if they have undergone a successful vasectomy and must agree to avoid to father a child (while on therapy and for 6 months after the final study drug administration). In addition, their female partners of childbearing potential must use a highly effective method of birth control.
11. Male patient must not donate sperm starting at screening and throughout the study period and for 6 months after the final study drug administration.
12. Able to understand and willing to sign an informed consent form (ICF).
13. Institutional Review Board/Independent Ethics Committee-approved written informed consent as per national regulations must be obtained from the patient prior to any study-related procedures (including consent for withdrawal of prohibited medication, if applicable).
Minimum age
18 Years
Maximum age
No limit
Sex
Both males and females
Can healthy volunteers participate?
No
Key exclusion criteria
1. Subject has previously been treated for AML; a treatment period with hydroxyurea to control WBC counts is allowed; prior treatment with a hypomethylating agent for Myelodysplastic Syndrome with Excess Blasts (MDS-EB) is not allowed; prior treatment with erythropoiesis-stimulating agents or luspatercept for Myelodysplastic Syndrome (MDS) is allowed.
2. Acute promyelocytic leukemia (APL) with t(15;17)(q22;q12); PML-RARA; or one of the other pathognomonic variant chromosomal translocations / fusion genes.
3. AML with BCR-ABL1; or myeloid blast crisis of Chronic Myeloid Leukemia (CML).
4. Significant active cardiac disease within 3 months prior to the start of study treatment, including:
o New York Heart Association (NYHA) class III or IV congestive heart failure
o Myocardial infarction
o Unstable angina
o Severe cardiac arrhythmias
o Congenital long QT syndrome of family member with this condition
o Corrected QT interval by Fridericia (QTcF) greater than 450 msec on screening electrogram for males and greater than 470 msec on screening electrogram for females (mean of triplicate recordings; calculated using Fridericia’s correction).
5. Severe obstructive or restrictive ventilation disorder.
6. History of stroke or intracranial hemorrhage within 6 months prior to randomisation.
7. Clinical symptoms suggestive of active central nervous system (CNS) leukemia or known CNS leukemia. Evaluation of cerebrospinal fluid (CSF) during screening is only required if there is a clinical suspicion of CNS involvement by leukemia during screening.
8. Active infection, including hepatitis B or hepatitis C or Human Immunodeficiency Virus (HIV) infection, that is uncontrolled prior to first dose of study treatment and may interfere with the study objectives or which could expose the patient to undue risk through the participation in the clinical trial; an infection controlled with an approved antibiotic/ antiviral/ antifungal treatment that is not a strong or moderate CYP3A inducer is allowed. Patients with COVID-19 infection can be enrolled, if the patient has no symptoms and was tested negative twice by polymerase chain reaction (PCR) test prior to inclusion in the trial.
9. Immediate life-threatening, severe complications of leukemia such as uncontrolled bleeding and/or disseminated intravascular coagulation.
10. Conditions that limit the ingestion or gastrointestinal absorption of orally administered drugs.
11. Patient with a currently active second malignancy. Patients are not considered to have a currently active malignancy, if they have completed therapy and are considered by their physician to be at less than 30% risk of relapse within one year. However, patients with the following history/concurrent conditions are allowed:
o Basal or squamous cell carcinoma of the skin;
o Carcinoma in situ of the cervix;
o Carcinoma in situ of the breast;
o Incidental histologic finding of prostate cancer.
12. Receipt of live, attenuated vaccine within 30 days prior to the study inclusion (NOTE: patient, if enrolled, should not receive live vaccine during the study and until 6 months after the therapy).
13. Severe neurological or psychiatric disorder interfering with ability to give an informed consent.
14. Contraindication to azacitidine or venetoclax (as per Summary of Product Characteristics (SmPC).
15. Patient weighing less than 40 kg at registration.
16. Participation in other prospective studies with anti-leukemic and/or investigational agents.
17. Patient taking Dabigatran unless they can be transferred to other medications within greater than 5 half-lives prior to dosing. Patients taking other P-glycoprotein (P-gP) transporter-sensitive medications should be properly monitored during the study if they cannot be transferred to other medications.
18. Patients taking known strong cytochrome P450 (CYP) 3A4 inducers, unless they can be transferred to other medications within greater than 5 half-lives prior to dosing.
19. The patient is a pregnant or lactating woman, or plans to become pregnant during the study.
20. Patient who has once been screened and randomized into this trial but was considered ineligible cannot re-enter this trial at a later date.

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)
A block stratified randomisation method and stratification factors including patient age at randomization (younger than 75 years versus 75 years and older), genotype (NPM1-mutated vs. KMT2A-rearranged) and region (Europe vs. Australia vs. U.S.). Allocation concealment was maintained through an online registration database.


Methods used to generate the sequence in which subjects will be randomised (sequence generation)
Each patient will be given a unique patient study number (a sequence number by order of enrollment in the trial). Patient study number and result of randomisation will be given immediately by the online registration database or by phone and confirmed by email.
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
1/03/2026
Actual
Date of last participant enrolment
Anticipated
1/09/2027
Actual
Date of last data collection
Anticipated
1/03/2034
Actual
Sample size
Target
415
Accrual to date
Final
Recruitment in Australia
Recruitment state(s)
NSW,QLD,SA,WA,VIC
Recruitment outside Australia
Country [1] 27100 0
Germany
State/province [1] 27100 0
Country [2] 27101 0
Netherlands
State/province [2] 27101 0
Country [3] 27102 0
United Kingdom
State/province [3] 27102 0

Funding & Sponsors
Funding source category [1] 319135 0
Other Collaborative groups
Name [1] 319135 0
Australasian Leukaemia and Lymphoma Group
Country [1] 319135 0
Australia
Primary sponsor type
Other Collaborative groups
Name
Australasian Leukaemia and Lymphoma Group
Address
Country
Australia
Secondary sponsor category [1] 321602 0
None
Name [1] 321602 0
Address [1] 321602 0
Country [1] 321602 0

Ethics approval
Ethics application status
Not yet submitted
Ethics committee name [1] 317729 0
Northwell Health Clinical Ethics Collaborative
Ethics committee address [1] 317729 0
Ethics committee country [1] 317729 0
Australia
Date submitted for ethics approval [1] 317729 0
04/11/2025
Approval date [1] 317729 0
Ethics approval number [1] 317729 0

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

Contacts
Principal investigator
Name 141954 0
Dr Jad Othman
Address 141954 0
Department of Haematology and Transfusion Medicine on Level 5, Acute services Building. Royal North Shore Hospital. Reserve Road, St Leonards, NSW 2065
Country 141954 0
Australia
Phone 141954 0
+61 0400311174
Fax 141954 0
Email 141954 0
[email protected]
Contact person for public queries
Name 141955 0
Delaine Smith
Address 141955 0
ALLG 35 Elizabeth St Richmond Vic 3121
Country 141955 0
Australia
Phone 141955 0
+61 03 83739701
Fax 141955 0
Email 141955 0
[email protected]
Contact person for scientific queries
Name 141956 0
Delaine Smith
Address 141956 0
ALLG 35 Elizabeth St Richmond Vic 3121
Country 141956 0
Australia
Phone 141956 0
+61 03 83739701
Fax 141956 0
Email 141956 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
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)
• Assessed on a case-by-case basis

When can requests for individual participant data be made (start and end dates)?
From:
3 months following publication

To:
No end date
Where can requests to access individual participant data be made, or data be obtained directly?
• Data sharing request system: Health Data Australia catalogue

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

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

Documents added automatically
No additional documents have been identified.