Phase 3 Study of Revumenib in Combination with Intensive Chemotherapy in Newly Diagnosed NPM1-mutated AML

Overview

Sponsor-declared trial summary

Key facts

Sponsor

Syndax Pharmaceuticals Inc.

Participant type

Pediatric, Patients

Age range

0-17 years, 18-64 years, 65+ years

Gender

Male and Female

Therapeutic area

Diseases [C] - Neoplasms [C04]

Trial duration

2 Apr 2026 → ongoing

Decision date (initial)

2026-02-16

Transition trial

No

Low-intervention

No

Rare-disease indication

Yes

Vulnerable population

Yes

Funding sources

Syndax Pharmaceuticals Inc.

External identifiers

EU CT number

2025-522279-27-00

ClinicalTrials.gov

NCT07211958

Trial design

CTIS Part I — objectives, methods, condition coding

Main objective

Scope: Pharmacokinetic, Efficacy, Therapy, Safety, Pharmacodynamic

- To evaluate if revumenib + IC (intensive chemotherapy) improves EFS (event-free survival) compared to placebo + IC.
- To evaluate if revumenib + IC improves MRDBM (-) (Measurable Residual Disease in Bone Marrow) CR (complete remission) rate, compared to placebo + IC.

Secondary objectives 13

1. To evaluate if revumenib + IC improves OS (overall survival) compared to placebo + IC.
2. To evaluate if revumenib + IC improves EFS compared to placebo + IC.
3. To evaluate if revumenib + IC improves MRDBM (-) CR rate compared to placebo + IC.
4. To evaluate the MRDPB (-) CR rate for revumenib + IC compared to placebo + IC
5. To evaluate the MRDBM (-) CR rate for revumenib + IC compared to placebo + IC.
6. To evaluate if revumenib in combination with IC improves CR rate compared to placebo + IC.
7. To evaluate CRc (composite complete remission) rate for revumenib + IC compared to placebo + IC.
8. To evaluate ORR (overall response rate) in revumenib + IC compared to placebo + IC.
9. To evaluate Duration of CR for revumenib + IC compared to placebo + IC.
10. To evaluate Duration of CRc for revumenib + IC compared to placebo + IC
11. To evaluate DOR (duration of response) for revumenib + IC compared to placebo + IC.
12. To evaluate the safety and tolerability of revumenib + IC compared to placebo + IC.
13. To evaluate patient-reported fatigue for revumenib + IC compared to placebo + IC.

Conditions and MedDRA coding

Newly Diagnosed AML with an NPM1 mutation

Eligibility criteria

Principal inclusion / exclusion criteria as submitted by sponsor

Inclusion criteria 12

1. Participants must be ≥12 years of age and weigh ≥40 kg at the time of signing the informed consent form (ICF).
2. Participants must have newly diagnosed and previously untreated AML and be candidates for intensive chemotherapy. The International Consensus Classification AML classification system will be used for this study
3. Presence of an NPM1 mutation consistent with an NPM1c variant. Local mutation testing will be used to determine participant eligibility. Mutation status will subsequently be confirmed centrally.
4. White blood cell (WBC) ≤25 × 109 /L by the time of the start of revumenib/placebo at Cycle 1 Day 8 (C1D8). Cytoreduction with hydroxyurea, leukapheresis or a single dose of cytarabine is allowed up to and including Induction C1D1.
5. Have a life expectancy of ≥3 months as judged by the Investigator.
6. Eastern Cooperative Oncology Group (ECOG) performance status score 0 to 2 if 18 to 65 years or 0 to 1 if aged ≥65 years; Karnofsky Performance Scale of ≥40 (if aged ≥16 years and <18 years); Lansky Performance Score of ≥40 (if aged <16 years)
7. Creatinine Clearance (CLCr) ≥30 mL/min. CLCr calculation should be based on local institutional practice for age-appropriate determination (Cockcroft Gault formula for adults). A 24-hour urine collection may also be used to CLCr.
8. Adequate liver function defined as: • Total bilirubin <1.5 × the upper limit of normal (ULN) for age or normal conjugated bilirubin (unless attributed to leukemic involvement or Gilbert’s syndrome). • Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) <3 × ULN (unless attributed to leukemic involvement).
9. Adequate cardiac function defined as ejection fraction of ≥50% by echocardiogram or multigated acquisition (MUGA) scan.
10. Females of childbearing potential must have a negative serum pregnancy test at Screening and a negative urine or serum pregnancy test within 72 hours before the initiation of protocol therapy. If the urine test is positive or cannot be confirmed as negative, a serum pregnancy test will be obtained. Participants are considered to be not of childbearing potential if they are considered to be post-menopausal or surgically sterilized. Females who have been amenorrheic for at least 12 or more months are still considered to be of childbearing potential if the amenorrhea is possibly due to prior chemotherapy, anti-estrogens, ovarian suppression or any other reversible reason.
11. a. Females of childbearing potential must be willing to use a highly effective method of contraception from the time of first study intervention dose through the required contraceptive period and must be willing to refrain from in vitro fertilization and egg donation during the required contraceptive period. b. Males must be surgically sterile (eg. bilateral orchiectomy or vasectomy) or agree to use barrier contraception (male condoms) from the time of first study intervention dose through the required contraceptive period. Males must be willing to refrain from sperm donation during the required contraceptive period.
12. Participant or participant’s health care proxy is able and willing to provide written informed consent or assent and able to follow study instructions.

Exclusion criteria 23

1. Not a candidate for anthracycline-based therapy for Induction.
2. Cardiac Disease: • Any of the following within the 6 months before study entry: myocardial infarction, uncontrolled/unstable angina, congestive heart failure (New York Heart Association Classification Class ≥II), life-threatening, uncontrolled arrhythmia, cerebrovascular accident, or transient ischemic attack. Participants with controlled atrial fibrillation are allowed to enroll. • QTcF (Fridericia’s corrected QT interval) >450 msec at Screening. • Diagnosis or suspicion of Long QT syndrome or family history of Long QT syndrome.
3. Gastrointestinal Disease (GI): • Any GI issue of the upper GI tract likely to affect oral drug absorption or ingestion (eg, gastric bypass, gastroparesis). • Cirrhosis with a Child-Pugh score of B or C, or National Cancer Institute (NCI) Organ Dysfunction Working Group category of Severe Dysfunction. • Inability to swallow oral medications
4. Any concurrent malignancy requiring active therapy (except breast or prostate cancer stable on or responding to endocrine therapy). For participants with therapy-related leukemia, primary disease must be in remission.
5. Participants known to have 1 of the following genetic syndromes: Down syndrome, Bloom syndrome, ataxia-telangiectasia, Fanconi anemia, Kostmann syndrome, Shwachman syndrome, or any other known genetic bone marrow failure syndrome.
6. History of or any concurrent condition, therapy, laboratory abnormality, or allergy to excipients that in the Investigator’s opinion might confound the results of the study, interfere with the participant’s participation for the full duration of the study, or is not in the best interest of the participant to participate.
7. If the participant is known to be human immunodeficiency virus (HIV)-positive, the participant must have an undetectable HIV viral load within the previous 6 months. If viral load testing has not been performed within the previous 6 months, it must be performed during Screening.
8. Participant has known active or chronic hepatitis B or active hepatitis C (HCV) infection. Participants with a history of HCV infection who have completed curative therapy for HCVat least 12 weeks before the Screening Visit and have a documented undetectable viral load at the Screening Visit are eligible for randomization.
9. Uncontrolled active infection of any type. Infections under control with antibiotic treatment are acceptable for study entry.
10. Pregnant or nursing females.
11. Participants may not have received AML-directed therapy before randomization, with the following exceptions: hydroxyurea, leukapheresis for the acute management of hyperleukocytosis and Days 1 to 7 of protocol-defined Induction chemotherapy
12. Not a candidate for continuous infusion cytarabine during Induction or intermediate dose cytarabine for Consolidation.
13. The following exclusions apply related to concomitant use of CYP3A4 inhibitors: • Participants who will not receive revumenib with coadministration of a strong CYP3A4i (eg, itraconazole, ketoconazole, posaconazole, or voriconazole) must discontinue all strong CYP3A4 inhibitors at least 7 days before the first dose of revumenib or placebo. They will receive the revumenib or placebo and they may continue to receive moderate or weak CYP3A4 inhibitors, including fluconazole and isavuconazole. • Participants who will receive revumenib or placebo with coadministration of a strong CYP3A4i (eg, itraconazole, ketoconazole, posaconazole, or voriconazole) must have started the treatment at least 24 hours before the first dose of revumenib or placebo.
14. Participants requiring the concurrent use of medications known or suspected to prolong the QT/QTc interval, with the exception of drugs with low risk of QT/QTc prolongation that are used as standard supportive therapies (eg, diphenhydramine, famotidine, ondansetron, sulfamethoxazole and trimethoprim) and the azoles permitted.
15. Current or future participation in another investigational drug study, scheduled to occur during this study, or has received an investigational agent within 14 days or 5 half-lives of the study intervention, whichever is longer) before dosing on C1D1 (Cycle 1 Day 1).
16. Presence of FLT3 (FMS-like tyrosine kinase 3) mutation (either internal tandem duplication or tyrosine kinase domain) with a VAF ≥5%.
17. Clinical signs/symptoms of hyperleukocytosis/leukostasis that have failed therapy including hydroxyurea or leukapheresis (of at least 3 days duration).
18. History of prior allogeneic stem cell transplant for another malignancy or solid organ transplant.
19. Diagnosis of active acute promyelocytic leukemia.
20. Isolated extramedullary disease.
21. Presence of life-threatening bleeding or thrombosis.
22. Active central nervous system (CNS) disease (cytologic, eg, any blasts on cytospin or radiographic). Participants who have cleared CNS disease by at least one negative tap before dosing may be randomized, and prophylactic intrathecal chemotherapy may be continued while on study.
23. [EU only] Otherwise considered to be inappropriate for the study by the investigator including where other treatment options, such as gemtuzumab ozogamicin, are preferred according to local institutional practice and prescribing guidelines.

Endpoints

Primary and secondary outcome measures (English text)

Primary endpoints 1

1. EFS: Defined as the time from the date of randomization to the date of Induction treatment failure, relapse or death due to any cause, whichever occurs first. MRDBM (-) CR rate: Defined as the percentage of participants with CR

Secondary endpoints 12

1. OS: Defined as the time from the date of randomization to the date of death from any cause.
2. EFS (Investigator-assessed): Defined as the time from the date of randomization to the date of Induction treatment failure, relapse or death due to any cause, whichever occurs first.
3. MRDBM (-) CR rate: Defined as the percentage of participants with CR (Investigator-assessed) who achieve MRDBM (-) status by molecular assay
4. MRDPB (-) CR rate: Defined as the percent of participants with CR (Investigator assessed) who achieve MRDPB (-) status by molecular assay
5. MRDBM (-) CR rate: Defined as the percent of participants with CR who achieve MRDBM (-) status.
6. CR rate (Investigator-assessed): Defined as the percentage of participants who achieve CR
7. CRc rate (Investigator-assessed): Defined as the rate of CR + CRh (complete remission with partial hematologic recovery) + Cri (complete remission with incomplete hematologic recovery).
8. ORR (Investigator-assessed): Defined as the rate of CR + CRh + CRi + MLFS (morphologic leukemia-free state) + PR (partial response).
9. Duration of CR: Defined as time from first date of first CR to relapse or death.
10. Duration of CRc: Defined as time from first date of first CRc to relapse or death.
11. DOR: Defined as time from date of first documented response (CR, CRh, CRi, PR, or MLFS) to the first documented relapse or death.
12. • Frequency, duration, and severity of TEAEs (treatment-emergent adverse events), TRAEs (treatment-related adverse event), and SAEs. • Incidence and shifts from baseline of clinically significant clinical laboratory abnormalities. • Change from baseline in other observations related to safety, including ECGs, vital signs, and performance status.

Investigational products

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

Test 3

Placebo 1

Auxiliary 3

Sponsors and contacts

Sponsor organisations, regulatory contacts, third parties

Syndax Pharmaceuticals Inc.

Sponsor organisation

Syndax Pharmaceuticals Inc.

Address

730 3rd Avenue Floor 9

City

New York

Postcode

10017-3206

Country

United States

Scientific contact point

Organisation

Syndax Pharmaceuticals Inc.

Contact name

Angie Smith, MD, Executive Medical Director

Public contact point

Organisation

Syndax Pharmaceuticals Inc.

Contact name

Angie Smith, MD, Executive Medical Director

Third parties 17

Locations

13 EU/EEA countries · 94 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 108 files

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

Application history

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