Revumenib in Combination With Azacitidine + Venetoclax in Patients NPM1-mutated or KMT2A-rearranged AML
Randomized 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
2 other identifiers
interventional
415
3 countries
67
Brief Summary
Treatment of patients with newly diagnosed AML who are not eligible for intensive chemotherapy has remained an area of high unmet medical need. The combination therapy with two medicines, azacitidine and venetoclax, is the usual plan of action. This has brought significant progress in the treatment, but it nevertheless is not curative and the disease does relapse over time. Revumenib blocks a specific molecule called menin in the cell nucleus. Some types of AML are reliant on menin working properly. These are leukemia cells with a change in the DNA, i.e. a mutation in the NPM1 or KMT2A gene. Revumenib can prevent the production of these types of leukemia cells by disrupting the production of this menin. The current study investigates whether adding revumenib to the combination therapy improves the prognosis for AML patients with a mutation in the NPM1 or KMT2A gene. This is a randomized, double-blind, placebo-controlled clinical study where subjects will be treated until disease progression, or development of side effects or death. From the moment of inclusion of the last patient, there will be a 4-year observational follow-up study in order to register survival duration and follow-up visits. Approximately 415 previously untreated patients with a mutation in the NPM1 or KMT2A gene and with newly diagnosed AML, who are not eligible for intensive chemotherapy. Patients must be ≥18 years of age.
Trial Health
Trial Health Score
Automated assessment based on enrollment pace, timeline, and geographic reach
participants targeted
Target at P50-P75 for phase_3
Started Mar 2025
Longer than P75 for phase_3
67 active sites
Health score is calculated from publicly available data and should be used for screening purposes only.
Trial Relationships
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Study Timeline
Key milestones and dates
First Submitted
Initial submission to the registry
October 2, 2024
CompletedFirst Posted
Study publicly available on registry
October 22, 2024
CompletedStudy Start
First participant enrolled
March 31, 2025
CompletedPrimary Completion
Last participant's last visit for primary outcome
December 13, 2029
ExpectedStudy Completion
Last participant's last visit for all outcomes
July 10, 2031
April 4, 2025
March 1, 2025
4.7 years
October 2, 2024
April 3, 2025
Conditions
Keywords
Outcome Measures
Primary Outcomes (1)
Overall survival (OS) in adult patients with newly diagnosed NPM1-mutated AML ineligible for intensive chemotherapy.
To assess if treatment with revumenib, in combination with azacitidine and venetoclax, prolongs overall survival (OS) measured from the date of randomization to the date of death from any cause; patients not known to have died at last follow-up are censored on the date they were last known to be alive.
58 months after last patient inclusion
Secondary Outcomes (7)
Event-free survival (EFS) in adult patients with newly diagnosed NPM1-mutated AML ineligible for intensive chemotherapy.
58 months after the first NPM1-mutated AML patient has been randomized
Rate of CR/CRh in adult patients with newly diagnosed NPM1mutated AML ineligible for intensive chemotherapy,
58 months after the first randomized NPM1-mutated AML patient
Rate of CR in adult patients with newly diagnosed NPM1-mutated AML ineligible for intensive chemotherapy
58 months after the first randomized NPM1-mutated AML patient
Rate of response (CRh and CR/CRi) in adult patients with newly diagnosed NPM1-mutated AML ineligible for intensive chemotherapy
58 months after the first randomized NPM1-mutated AML patient
Rates of CR, CR/CRh and CR/CRi without measurable residual disease (CRMRD-, CR/CRhMRD- and CR/CRiMRD-)
58 months after the first randomized NPM1-mutated AML patient
- +2 more secondary outcomes
Study Arms (2)
Revumenib-placebo
PLACEBO COMPARATORday 1-28 Placebo Treatment will be on a continuous 28-day cycle schedule and continued until disease progression, development of unacceptable toxicity, death, withdrawal by subject or other protocol defined criteria for discontinuation (whichever comes first).
Revumenib
EXPERIMENTALday 1-28 Revumenib Treatment will be on a continuous 28-day cycle schedule and continued until disease progression, development of unacceptable toxicity, death, withdrawal by subject or other protocol defined criteria for discontinuation (whichever comes first).
Interventions
Eligibility Criteria
You may qualify if:
- In order to be eligible to participate in this study, a patient must meet all of the following criteria:
- Patient with newly diagnosed NPM1-mutated AML, consistent with NPM1c, according to the 2022 International Consensus Classification (i.e. ≥ 10% blasts).
- OR Patient with newly diagnosed KMT2A-rearranged AML according to the 2022 International Consensus Classification (i.e. ≥ 10% blasts). KMT2A partial tandem duplications or deletions are NOT eligible.
- Central confirmation of NPM1 mutation or KMT2A rearrangement in one of the dedicated central genetic laboratories.
- Age ≥ 18 years, no upper age limit.
- Patient is ineligible for intensive induction chemotherapy by meeting at least 1 of the following criteria:
- ≥ 75 years of age: ineligible for intensive chemotherapy per physician's discretion (with an ECOG performance status 0-2) .
- years: patient is not eligible for standard chemotherapy because any of the following co-morbidities: o ECOG performance status 2 or 3 .
- Cardiac history of chronic heart failure requiring treatment; or with an ejection fraction ≤50%; or chronic stable angina.
- DLCO ≤ 65% or FEV1 ≤ 65%.
- Creatinine clearance ≥ 30 mL/min to \<45 ml/min calculated by the Cockcroft Gault formula.
- Moderate hepatic impairment with total bilirubin \> 1.5 to \< 3.0 x upper limit of normal (ULN).
- Any other comorbidity that the local physician assesses to be incompatible with intensive chemotherapy must be reviewed and approved by the Sponsor's (co-) Principal Investigator (written approval must be sent to HO177@erasmusmc.nl before study enrolment).
- Patient must have a projected life expectancy of at least 12 weeks (as assessed by the treating physician).
- Patient must have a white cell blood (WBC) count of \< 25 x 109/L. Hydroxyurea can be used prior to study enrolment to reduce the WBC count to meet this criterion.
- +25 more criteria
You may not qualify if:
- 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 MDS-EB is not allowed; prior treatment with erythropoiesis-stimulating agents or luspatercept for MDS is allowed.
- \. Acute promyelocytic leukemia (APL) with t(15;17)(q24.1;q21.2); PML-RARA; or one of the other pathognomonic variant chromosomal translocations / fusion genes. 3. AML with BCR-ABL1; or myeloid blast crisis of CML. 4. Significant active cardiac disease within 3 months prior to the start of study treatment, including:
- New York Heart Association (NYHA) class III or IV congestive heart failure
- Myocardial infarction
- Unstable angina
- Severe cardiac arrhythmias
- Congenital long QT syndrome of family member with this condition QTcF \>450 msec on screening electrogram for males and \>470msec 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 randomization.
- \. 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 \< 30% risk of relapse within one year. However, patients with the following history/concurrent conditions are allowed:
- Basal or squamous cell carcinoma of the skin;
- Carcinoma in situ of the cervix;
- Carcinoma in situ of the breast;
- \. Severe neurological or psychiatric disorder interfering with ability to give an informed consent.
- \. Known or suspected hypersensitivity to any of the anti-leukemic agents used.
- \. Participation in other prospective studies with anti-leukemic and/or investigational agents.
- \. Patient taking Dabigatran unless they can be transferred to other medications within ≥5 half-lives prior to dosing. Patients taking other P-gP transporter-sensitive medications (see Appendix H) should be properly monitored during the study if they cannot be transferred to other medications.
- +2 more criteria
Contact the study team to confirm eligibility.
Sponsors & Collaborators
Study Sites (67)
DE-Berlin-CAMPUSBENFRANKLIN
Berlin, Germany
DE-Berlin-CAMPUSVIRCHOW
Berlin, Germany
DE-Berlin-VIVANTESNEUKOLLN
Berlin, Germany
DE-Bochum-RUB
Bochum, Germany
DE-Bonn-UNIBONN
Bonn, Germany
DE-Braunschweig-KLINIKUMBRAUNSCHWEIG
Braunschweig, Germany
DE-Bremen-KBM
Bremen, Germany
DE-Darmstadt-KLINIKUMDARMSTADT
Darmstadt, Germany
DE-Essen-KEM
Essen, Germany
DE-Flensburg-MALTESER
Flensburg, Germany
DE-Frankfurt-KLINIKUMFRANKFURT
Frankfurt, Germany
DE-Freiburg-UNIKLINIKFREIBURG
Freiburg im Breisgau, Germany
DE-Greifswald-UNIGREIFSWALD
Greifswald, Germany
DE-Hamburg-ASKLEPIOSSTGEORG
Hamburg, Germany
DE-Hamburg-UKE
Hamburg, Germany
DE-Hannover-MHHANNOVER
Hanover, Germany
DE-Hannover-SILOAHKRH
Hanover, Germany
DE-Heilbronn-SLK General Information
Heilbronn, Germany
DE-Herne-MARIENHOSPITALHERNE
Herne, Germany
DE-Karlsruhe-KLINIKUMKARLSRUHE
Karlsruhe, Germany
DE-Mainz-UNIMEDIZINMAINZ
Mainz, Germany
DE-Minden-MUEHLENKREISKLINKEN
Minden, Germany
DE-München-IRZTUM
München, Germany
DE-Oldenburg-KLINIKUMOLDENBURG
Oldenburg, Germany
DE-Potsdam-BERGMANN
Potsdam, Germany
DE-Stuttgart-KLINIKUMSTUTTGART
Stuttgart, Germany
DE-Tübingen-MEDUNITUEBINGEN
Tübingen, Germany
DE-Ulm-UNIKLINKULM
Ulm, Germany
DE-Wuppertal-HELIOSGESUNDHEIT
Wuppertal, Germany
NL-Den Bosch-JBZ
's-Hertogenbosch, Netherlands
NL-Amersfoort-MEANDERMC
Amersfoort, Netherlands
NL-Amsterdam-OLVG
Amsterdam, Netherlands
NL-Amsterdam-VUMC
Amsterdam, Netherlands
NL-Arnhem-RIJNSTATE
Arnhem, Netherlands
NL-Breda-AMPHIA
Breda, Netherlands
NL-Delft-RDGG
Delft, Netherlands
NL-Eindhoven-MAXIMAMC
Eindhoven, Netherlands
NL-Enschede-MST
Enschede, Netherlands
NL-Goes-ADRZ
Goes, Netherlands
NL-Groningen-UMCG
Groningen, Netherlands
NL-Leeuwarden-MCL
Leeuwarden, Netherlands
NL-Leiden-LUMC
Leiden, Netherlands
NL-Maastricht-MUMC
Maastricht, Netherlands
NL-Nieuwegein-ANTONIUS
Nieuwegein, Netherlands
NL-Nijmegen-RADBOUDUMC
Nijmegen, Netherlands
NL-Rotterdam-ERASMUSMC
Rotterdam, Netherlands
NL-Den Haag-HAGA
The Hague, Netherlands
NL-Utrecht-UMCUTRECHT
Utrecht, Netherlands
NL-Zwolle-ISALA
Zwolle, Netherlands
Belfasttrust
Belfast, United Kingdom
Birmingham-QE
Birmingham, United Kingdom
Blackpool Victoria
Blackpool, United Kingdom
UH Bristol
Bristol, United Kingdom
University Hospital of Wales
Cardiff, United Kingdom
Beatson West of Scotland Cancer Centre
Glasgow, United Kingdom
St. James UH
Leeds, United Kingdom
University Hospitals of Leicester NHS Trust
Leicester, United Kingdom
University of Liverpool
Liverpool, United Kingdom
King's College Hospital
London, United Kingdom
St Bartholomew's Hospital
London, United Kingdom
Christie NHS Foundation Trust
Manchester, United Kingdom
The Newcastle upon Tyne Hospitals NHS Foundation Trust
Newcastle, United Kingdom
Nottingham University Hospitals NHS Trust
Nottingham, United Kingdom
Churchill Hospital, Oxford
Oxford, United Kingdom
Southampton General Hospital
Southampton, United Kingdom
The Royal Marsden NHSFT
Sutton, United Kingdom
New cross hospital wolverhampton
Wolverhampton, United Kingdom
Related Links
MeSH Terms
Conditions
Interventions
Condition Hierarchy (Ancestors)
Study Officials
- PRINCIPAL INVESTIGATOR
Gerwin Huls, MD
UMCG/ HOVON
Central Study Contacts
Study Design
- Study Type
- interventional
- Phase
- phase 3
- Allocation
- RANDOMIZED
- Masking
- SINGLE
- Who Masked
- INVESTIGATOR
- Purpose
- TREATMENT
- Intervention Model
- SINGLE GROUP
- Sponsor Type
- OTHER
- Responsible Party
- SPONSOR
Study Record Dates
First Submitted
October 2, 2024
First Posted
October 22, 2024
Study Start
March 31, 2025
Primary Completion (Estimated)
December 13, 2029
Study Completion (Estimated)
July 10, 2031
Last Updated
April 4, 2025
Record last verified: 2025-03
Data Sharing
- IPD Sharing
- Will share
- Shared Documents
- STUDY PROTOCOL, SAP
- Time Frame
- After the publication of primary endpoint analysis
According to the current publication policy the protocol and Statistical Analysis Plan ( SAP) will be shared. The principal Investigators can be contacted for IPD sharing after the publication of the study results. According to 'HOVON sample and/or Data request Form' the HOVON director; chair of the HOVON Acute Myeloid Leukemic working group, the study PI and Coordinating Investigator should approve data/sample sharing.