A study investigating the effect of adding revumenib to treatment with venetoclax + azacitidine in patients with acute myeloid leukemia (AML) with a specific gene abnormality and who have not been treated before and who are not eligible for intensive chemotherapy.

Overview

Sponsor-declared trial summary

Key facts

Sponsor

Hemato-Oncologie voor Volwassenen Nederland (Hovon) Stichting

Participant type

Patients

Age range

18-64 years, 65+ years

Gender

Male and Female

Therapeutic area

Diseases [C] - Neoplasms [C04]

Trial duration

31 Mar 2025 → ongoing

Decision date (initial)

2025-07-14

Transition trial

No

Low-intervention

No

Rare-disease indication

No

Vulnerable population

Yes

Funding sources

Syndax

External identifiers

EU CT number

2024-512733-32-00

ClinicalTrials.gov

NCT06652438

Trial design

CTIS Part I — objectives, methods, condition coding

Main objective

Scope: Therapy, Pharmacokinetic, Safety, Efficacy

To assess if treatment with revumenib, in combination with azacitidine and venetoclax, improves 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, increases the combined rate of complete remission (CR) in adult patients with newly diagnosed NPM1-mutated AML ineligible for intensive chemotherapy.

Secondary objectives 18

1. To assess if treatment with revumenib, in combination with azacitidine and venetoclax, prolongs event-free survival (EFS) in adult patients with newly diagnosed NPM1-mutated AML ineligible for intensive chemotherapy
2. To assess if treatment with revumenib, in combination with azacitidine and venetoclax, increases the rate of CRMRD-, CR/CRhMRD- and CR/CRiMRD- assessed by quantitative PCR of peripheral blood in adult patients with newly diagnosed NPM1-mutated AML ineligible for intensive chemotherapy.
3. To assess if treatment with revumenib, in combination with azacitidine and venetoclax, increases the rate of CR in adult patients with newly diagnosed NPM1-mutated AML ineligible for intensive chemotherapy.
4. To assess if treatment with revumenib, in combination with azacitidine and venetoclax, increases the rate of CRh in adult patients with newly diagnosed NPM1-mutated AML ineligible for intensive chemotherapy.
5. To assess if treatment with revumenib, in combination with azacitidine and venetoclax, increases the combined rate of CR and CR with incomplete hematologic recovery (CRi) (CR/CRi) in adult patients with newly diagnosed NPM1-mutated AML ineligible for intensive chemotherapy.
6. To assess if treatment with revumenib, in combination with azacitidine and venetoclax, increases the rate of CR, CR/CRh and CR/CRi without measurable residual disease (CRMRD-, CR/CRhMRD- and CR/CRiMRD-) assessed by quantitative PCR in bone marrow in adult patients with newly diagnosed NPM1-mutated AML ineligible for intensive chemotherapy.
7. To assess if treatment with revumenib, in combination with azacitidine and venetoclax, shortens the time to response (CR, CR/CRh and CR/CRi) in adult patients with newly diagnosed NPM1-mutated AML ineligible for intensive chemotherapy.
8. To assess if treatment with revumenib, in combination with azacitidine and venetoclax, prolongs duration of response (CR, CR/CRh and CR/CRi; DoR) in adult patients with newly diagnosed NPM1-mutated AML ineligible for intensive chemotherapy.
9. To evaluate OS, CR rate, EFS, rates of CR/CRh, CR/CRi and DoR by prognostic variables, including clinical variables (e.g., age at randomization, sex, ECOG performance status, white blood cell count), 2022 European LeukemiaNet (ELN) risk groups, geographical region and by specific AML genotypes in adult patients with newly diagnosed NPM1-mutated AML ineligible for intensive chemotherapy.
10. To assess if treatment with revumenib, in combination with azacitidine and venetoclax, increases the rate of CRMRD-, CR/CRhMRD- and CR/CRiMRD- assessed by multiparameter flowcytometry of bone marrow in adult patients with newly diagnosed NPM1-mutated AML ineligible for intensive chemotherapy.
11. To evaluate resistance mechanisms after combined treatment with azacitidine/venetoclax/revumenib (e.g. MEN1 mutations, RAS mutations, FLT3 mutations, TP53 mutations).
12. To evaluate the impact of revumenib, in combination with azacitidine and venetoclax, on quality of life (QoL), using EORTC QLQ-C30 and EQ-5D-5 in adult patients with newly diagnosed NPM1-mutated AML ineligible for intensive chemotherapy.
13. To evaluate OS, CR rate, EFS, rates of CR/CRh, CR/CRi, CRMRD-, CR/CRhMRD-, CR/CRiMRD, time to response, DoR and QoL in adult patients with newly diagnosed KMT2A-rearranged AML ineligible for intensive chemotherapy.
14. To characterize PK parameters and assess the exposure-response relationships of revumenib and primary metabolite in combination with azacitidine and venetoclax.
15. To evaluate revumenib pharmacodynamic relationship with safety, efficacy and correlative biomarkers, which may include immunophenotyping of circulating peripheral blood mononuclear cells (PBMC) and/or bone marrow, gene expression, mutational analysis, and minimal residual disease (MRD).
16. To evaluate the incidence and severity of adverse events (AEs) according to Common Terminology Criteria for Adverse Events (CTCAE) version v5.0.
17. To assess time to hematopoietic recovery (absolute neutrophil counts [ANC] ≥0.5 and ≥ 1.0 x 109/L; platelet counts ≥ 50 and ≥ 100 x 109/L) after each cycle (but at least for each of the first 6 cycles).
18. To assess the need for blood transfusions (platelet and RBC) and the lenght of hospital stay.

Conditions and MedDRA coding

Acute Myeloid Leukemia (AML)

Eligibility criteria

Principal inclusion / exclusion criteria as submitted by sponsor

Inclusion criteria 13

1. 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. Of note: in case both NPM1 and IDH1 are mutated and both EVOLVE-1 (HO173) and EVOLVE-2 (HO177) are open for inclusion at your site, then patients can only be included in the EVOLVE-1 trial (HO173)
2. Central confirmation of NPM1 mutation or KMT2A rearrangement in one of the dedicated central genetic laboratories.
3. Age ≥ 18 years, no upper age limit.
4. 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) 18-74 years: patient is not eligible for standard chemotherapy because any of the following co-morbidities: 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.
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 < 25 x 109/L. Hydroxyurea can be used prior to study enrollment to reduce the WBC count to meet this criterion.
7. Adequate renal function as evidenced by serum creatinine ≤ 2.0 × upper limit of norm (ULN) or creatinine clearance >30 mL/min based on the Cockcroft-Gault glomerular filtration rate (GFR).
8. Adequate hepatic function as evidenced by: Serum total bilirubin ≤ 3.0 × ULN unless considered due to Gilbert’s disease, or leukemic involvement; Aspartate aminotransferase (AST), alanine aminotransferase (ALT), and alkaline phosphatase (ALP) ≤ 3.0 × ULN, unless considered due to leukemic involvement.
9. Female patient must: be of nonchildbearing potential: 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; and have a negative urine or serum pregnancy test at screening; 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; agree not to breastfeed starting at screening and throughout the study period, and for 1 week after the final study drug administration; 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).

Exclusion criteria 20

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 MDS-EB is not allowed; prior treatment with erythropoiesis-stimulating agents or luspatercept for MDS is allowed.
2. Conditions that limit the ingestion or gastrointestinal absorption of orally administered drugs.
3. 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; Incidental histologic finding of prostate cancer.
4. 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).
5. Severe neurological or psychiatric disorder interfering with ability to give an informed consent.
6. Contraindication to azacitidine or venetoclax
7. Participation in other prospective studies with anti-leukemic and/or investigational agents.
8. 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 should be properly monitored during the study if they cannot be transferred to other medications
9. Patients taking known strong cytochrome P450 (CYP) 3A4 inducers, unless they can be transferred to other medications within ≥5 half-lives prior to dosing.
10. The patient is a pregnant or lactating woman, or plans to become pregnant during the study.
11. Patient who has once been screened and randomized into this HO177 trial but was considered ineligible cannot re-enter this trial at a later date.
12. 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.
13. AML with BCR-ABL1; or myeloid blast crisis of CML.
14. 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).
15. Severe obstructive or restrictive ventilation disorder.
16. History of stroke or intracranial hemorrhage within 6 months prior to randomization.
17. 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.
18. 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.
19. Immediate life-threatening, severe complications of leukemia such as uncontrolled bleeding and/or disseminated intravascular coagulation.
20. Patient weighing <40 kg at registration.

Endpoints

Primary and secondary outcome measures (English text)

Primary endpoints 1

1. OS in adult patients with newly diagnosed NPM1-mutated AML ineligible for intensive chemotherapy, measured from the date of randomization to the date of death from any cause; Rate of CR in adult patients with newly diagnosed NPM1-mutated AML ineligible for intensive chemotherapy, defined as the proportion of NPM1-mutated AML patients who achieve CR at any time-point during protocol therapy.

Secondary endpoints 17

1. EFS in adult patients with newly diagnosed NPM1-mutated AML ineligible for intensive chemotherapy, measured from the date of randomization to the date of treatment failure, hematologic relapse from CR/CRh or death from any cause, whichever occurs first. Treatment failure is defined as lack of obtaining either CR or CRh by week 24
2. Rate of CR/CRh in adult patients with newly diagnosed NPM1-mutated AML ineligible for intensive chemotherapy, defined as the proportion of NPM1-mutated AML patients who achieve CR or CRh at any time-point during protocol therapy.
3. Rate of response (CRh and CR/CRi) in adult patients with newly diagnosed NPM1-mutated AML ineligible for intensive chemotherapy, defined as the proportion of NPM1-mutated AML patients with response at any time-point during protocol therapy.
4. Rates of CRMRD-, CR/CRhMRD- and CR/CRiMRD- assessed by quantitative PCR of bone marrow in adult patients with newly diagnosed NPM1-mutated AML ineligible for intensive chemotherapy, defined as the proportion of NPM1-mutated AML patients with CRMRD-, CR/CRhMRD- and CR/CRiMRD- by PCR in bone marrow, respectively, at any time-point during protocol therapy.
5. Time to achievement of response (CR, CR/CRh and CR/CRi) in adult patients with newly diagnosed NPM1-mutated AML ineligible for intensive chemotherapy, defined as time from the date of randomization to until the 1st occurrence of the response.
6. Duration of response (CR, CR/CRh and CR/CRi; DoR) in adult patients with newly diagnosed NPM1-mutated AML ineligible for intensive chemotherapy, measured from the date of achievement of response until the date of hematologic relapse or death from any cause; patients without any of these events will be censored on the date of the last clinical assessment.
7. OS, CR rate, EFS, rates of CR, CR/CRh, CR/CRi, and DoR across different patient subgroups in adult patients with newly diagnosed NPM1-mutated AML ineligible for intensive chemotherapy, where the groups are defined based on prognostic variables including clinical variables (e.g., age at randomization, sex, ECOG performance status, white blood cell count), risk category, geographical region as well as specific AML genotypes.
8. Rates of CRMRD, CR/CRhMRD- and CR/CRiMRD- assessed by multiparameter flowcytometry of bone marrow at any time-point during protocol therapy in adult patients with newly diagnosed NPM1-mutated AML ineligible for intensive chemotherapy, defined as the proportion of NPM1-mutated AML patients with CRMRD-, CR/CRhMRD- and CR/CRiMRD- by multiparameter flowcytometry, respectively, at any time-point during protocol therapy.
9. Resistance mechanisms after combined treatment with azacitidine/venetoclax/revumenib (e.g. MEN1 mutations, RAS mutations, TP53 mutations, FLT3 mutations).
10. Quality of life (QoL) in adult patients with newly diagnosed NPM1-mutated AML ineligible for intensive chemotherapy as assessed by EORTC QLC-C30 and EQ-5D-5L questionnaires.
11. OS, CR rate, EFS, rates of CR/CRh, CR/CRi, CRMRD-, CR/CRhMRD-, CR/CRiMRD-, time to response, DoR and QoL as assessed by EORTC QLQ-C30 and EQ-5D-5L questionnairesas defined above in adult patients with newly diagnosed KMT2A-rearranged AML ineligible for intensive chemotherapy.
12. Descriptive summary of plasma concentrations and PK parameters of revumenib and the primary metabolites.
13. Descriptive summary of revumenib pharmacodynamics in relation to safety, efficacy and correlative biomarkers, which may include immunophenotyping of circulating peripheral blood mononuclear cells (PBMC) and/or bone marrow, gene expression, mutational analysis, and minimal residual disease (MRD).
14. Frequency and severity of AE according to CTCAE version 5.0.
15. Time to hematopoietic recovery (absolute neutrophil counts ≥0.5 and ≥1.0 x 109/L; platelets ≥50 and ≥100 x 109/L) after each treatment cycle (but at least for each of the first 6 cycles), defined as the time from the start of the cycle until recovery.
16. Number of patients requiring transfusions (platelet and RBC) and number of units transfused, rate and duration of transfusion independence, length of hospital stay, where transfusion independence is defined as a period of at least 56 days with no transfusion between the first dose of study drug and the last dose of study drug + 30 days.
17. Rates of CRMRD-, CR/CRhMRD-, and CR/CRiMRD- assessed by quantitative PCR of peripheral blood in adult patients with newly diagnosed NPM1-mutated AML ineligible for intensive chemotherapy, defined as the proportion of NPM1-mutated AML patients with CRMRD-, CR/CRhMRD- and CR/CRiMRD- by PCR in peripheral blood, respectively, at any time-point during protocol therapy.

Investigational products

Investigational medicinal products (IMPs), comparators, placebo, auxiliary

Test 7

Placebo 3

Sponsors and contacts

Sponsor organisations, regulatory contacts, third parties

Hemato-Oncologie voor Volwassenen Nederland (Hovon) Stichting

Sponsor organisation

Hemato-Oncologie voor Volwassenen Nederland (Hovon) Stichting

Address

Dr. Molewaterplein 40

City

Rotterdam

Postcode

3015 GD

Country

Netherlands

Scientific contact point

Organisation

Hemato-Oncologie voor Volwassenen Nederland (Hovon) Stichting

Contact name

Dr. G. Huls

Public contact point

Organisation

Hemato-Oncologie voor Volwassenen Nederland (Hovon) Stichting

Contact name

HOVON

Third parties 8

Locations

14 EU/EEA countries · 139 investigational sites

By country

Investigational sites

Country notifications

Trial-start, recruitment-start, end and early-termination notifications submitted per Member State

Results and documents

Annex IV summary of results, Annex V layperson summary, and all documents registered in CTIS for this trial

Documents 145 files

Public protocol annexes, IB summaries, regulatory submissions and post-authorisation documents registered in CTIS.

Application history

21 submissions — initial application plus substantial / non-substantial modifications