Revumenib + Chemotherapy for Acute Myeloid Leukemia

Recruiting at 6 trial locations

Overseen By Jeffrey E. Rubnitz, MD, PhD

Age: < 65

Sex: Any

Trial Phase: Phase 1

Sponsor: St. Jude Children's Research Hospital

Must be taking: Posaconazole, Voriconazole

Disqualifiers: Pregnancy, Down syndrome, Uncontrolled infection, others

No Placebo Group All trial participants will receive the active study treatment (no placebo)

Compensation: Varies

Number of Visits: Unknown

Duration: 6 weeks

24 Participants Needed

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial aims to determine if a new drug, revumenib, combined with standard chemotherapy drugs, is safe and effective for treating certain types of leukemia. It focuses on patients whose acute myeloid leukemia (AML) or acute leukemia of ambiguous lineage (ALAL) has not responded to initial treatments or has returned after treatment. Participants should have specific genetic markers related to their leukemia and be able to take medication by mouth. The trial will help establish the safest dose and observe patient responses to the treatment. As a Phase 1 trial, participants will be among the first to receive this new treatment, aiding researchers in understanding how the drug works in people.

Will I have to stop taking my current medications?

The trial protocol does not specify if you need to stop taking your current medications, but you must be taking either posaconazole or voriconazole at least 24 hours before starting the trial therapy.

Is there any evidence suggesting that this trial's treatments are likely to be safe?

A previous study found revumenib to be safe and effective for patients with relapsed or hard-to-treat acute myeloid leukemia (AML). The FDA has approved this treatment for certain types of AML, indicating it is generally well-tolerated. Research shows promising results with high response rates and manageable side effects.

Venetoclax, when combined with azacitidine, also has FDA approval for AML. Common serious side effects include febrile neutropenia (a fever with a low white blood cell count) and pneumonia, but these are known and managed in clinical settings.

The safety of azacitidine is well-understood, though most side effects are serious, necessitating close monitoring. Despite this, it remains a standard treatment due to its effectiveness.

This trial explores the combined use of these three drugs. While each drug carries its own risks, their approval and existing safety data support their use under careful supervision. ^{1 2 3 4 5}

Why do researchers think this study treatment might be promising?

Researchers are excited about these treatments because they combine innovative drugs like Revumenib and Venetoclax with established chemotherapy agents Azacitidine and Cytarabine to tackle acute myeloid leukemia (AML). Revumenib is particularly notable for its novel mechanism targeting specific proteins involved in cancer cell survival, potentially making it more effective against certain AML types. Venetoclax, on the other hand, disrupts cancer cell energy processes, adding another layer of attack. This multi-pronged approach aims to enhance treatment efficacy and overcome resistance seen with traditional chemotherapy alone.

What evidence suggests that this trial's treatments could be effective for acute myeloid leukemia?

Research has shown that the drug revumenib, which participants in this trial will receive, may help treat acute myeloid leukemia (AML). In studies, 21% of patients achieved complete remission, meaning their leukemia signs disappeared after treatment. Similarly, venetoclax, another drug included in this trial, demonstrated a 75% remission rate in older AML patients when combined with chemotherapy. Azacitidine, also part of the treatment regimen in this trial, helps people with AML live longer, with research showing it significantly improves survival rates. These drugs work well individually, and using them together in this trial might enhance treatment results for leukemia that has returned or is difficult to treat. ^{3 4 5 6 7}

Who Is on the Research Team?

Hiroto Inaba, MD, PhD

Principal Investigator

St. Jude Children's Research Hospital

Are You a Good Fit for This Trial?

This trial is for young patients with a type of blood cancer called acute myeloid leukemia (AML) or ambiguous lineage leukemia that hasn't responded to treatment or has returned. Participants must be able to take an anti-fungal drug alongside the study medications.

Inclusion Criteria

QTcF < 480 msec

My liver, kidneys, and heart are functioning within normal ranges.

My cancer has a specific genetic change.

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants receive revumenib, azacitidine, and venetoclax in a dose-escalation fashion to determine safety and tolerability

6 weeks

Weekly visits for dose adjustments and monitoring

Follow-up

Participants are monitored for safety and effectiveness after treatment

4 weeks

Extension

Participants may continue to receive revumenib, venetoclax, and azacitidine if beneficial and without unacceptable side effects

What Are the Treatments Tested in This Trial?

Interventions

• Azacitidine
• Cytarabine
• Revumenib
• Venetoclax

Trial Overview The study is testing the combination of a new drug, Revumenib, with Azacitidine and Venetoclax in children and young adults. It aims to find out if this mix is safe and effective against relapsed or stubborn AML when taken with an anti-fungal medication.

How Is the Trial Designed?

Group I: All Eligible Participants Experimental Treatment 6 Interventions

All eligible patients receive the following intervention: Revumenib, Venetoclax, Azacitidine, Intrathecal chemotherapy

Azacitidine is already approved in European Union, United States, Canada, Japan for the following indications:

Approved in European Union as Vidaza for:

• Acute myeloid leukemia
• Chronic myelomonocytic leukemia
• Myelodysplastic syndromes

Approved in United States as Vidaza for:

• Myelodysplastic syndromes
• Chronic myelomonocytic leukemia

Approved in Canada as Vidaza for:

• Myelodysplastic syndromes
• Acute myeloid leukemia

Approved in Japan as Vidaza for:

• Myelodysplastic syndromes
• Acute myeloid leukemia

Who Is Running the Clinical Trial?

St. Jude Children's Research Hospital

Lead Sponsor

Trials

451

Recruited

5,326,000+

Syndax Pharmaceuticals

Industry Sponsor

Trials

49

Recruited

2,700+

Published Research Related to This Trial

In a study of 35 patients with relapsed or refractory acute myeloid leukaemia (R/R AML) treated with venetoclax-azacitidine (VEN-AZA), the complete remission rate was significantly higher at 48.6% compared to 15% in a historical cohort treated with azacitidine (AZA).

Patients receiving VEN-AZA also showed a trend towards longer overall survival (12.8 months) compared to those treated with AZA (7.3 months), indicating that VEN-AZA may offer a more effective treatment option for R/R AML.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Azacitidine-venetoclax versus azacitidine salvage treatment for primary induction failure or first relapsed acute myeloid leukaemia patients. Petit, C., Saillard, C., Mohty, B., et al.[2023]

The VA regimen, combining venetoclax and azacitidine, demonstrated a high complete remission (cCR) rate of 78.8% after the first treatment cycle and 81.8% after prolonged treatment in 66 patients with newly diagnosed acute myeloid leukemia (AML) who were not suitable for conventional chemotherapy.

The treatment was generally safe, with manageable adverse effects, primarily neutropenia, thrombocytopenia, and anemia, and showed better outcomes in patients with specific gene mutations (IDH1/2 or NPM1) and those experiencing rebound thrombocytosis.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

[Efficacy of venetoclax combined azacitidine in newly diagnosed acute myeloid leukemia unfit for standard chemotherapy: a single center experience]. Sun, L., Ye, SJ., Zhou, N., et al.[2023]

In a study of 51 patients with relapsed or refractory acute myeloid leukemia (RR-AML), venetoclax (VEN) showed a low complete remission (CR) rate of 12.4%, indicating limited effectiveness in this heavily pretreated population.

The median overall survival (OS) for patients treated with VEN was only 104 days, with 28% of patients experiencing treatment interruptions due to toxicity, highlighting the challenges and risks associated with this therapy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Use of Venetoclax in Patients with Relapsed or Refractory Acute Myeloid Leukemia: The PETHEMA Registry Experience. Labrador, J., Saiz-Rodríguez, M., de Miguel, D., et al.[2022]

In a network meta-analysis of 1140 patients with untreated acute myeloid leukemia, the combination of venetoclax (VEN) with low-dose cytarabine (LDAC) and with azacitidine (AZA) showed significantly higher response rates and overall survival compared to standard therapies like AZA, LDAC, and best supportive care.

VEN + AZA was particularly effective, achieving a 95.2% likelihood of improving overall survival, while VEN + LDAC had a 91.4% likelihood of achieving complete remission, indicating these combinations are superior treatment options for patients ineligible for intensive chemotherapy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Comparative Efficacy of Venetoclax-Based Combination Therapies and Other Therapies in Treatment-Naive Patients With Acute Myeloid Leukemia Ineligible for Intensive Chemotherapy: A Network Meta-Analysis. Li, X., Suh, HS., Lachaine, J., et al.[2023]

In a phase II study involving 60 older or unfit patients with newly diagnosed acute myeloid leukemia (AML), the combination of venetoclax with cladribine and low-dose cytarabine alternating with venetoclax and 5-azacitidine resulted in a high composite complete response rate of 93%.

The treatment showed promising overall survival and disease-free survival rates, with only one death occurring within 4 weeks, indicating that this regimen is effective and has a favorable safety profile for this patient population.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Phase II Study of Venetoclax Added to Cladribine Plus Low-Dose Cytarabine Alternating With 5-Azacitidine in Older Patients With Newly Diagnosed Acute Myeloid Leukemia. Kadia, TM., Reville, PK., Wang, X., et al.[2023]

In a study comparing older adults with newly diagnosed acute myeloid leukemia (AML), those treated with the combination of decitabine (DEC) and venetoclax (VEN) had a significantly longer median overall survival of 13.4 months compared to 8.3 months for those receiving DEC alone.

The combination therapy also resulted in a higher response rate of 70.3% versus 24.3% for DEC monotherapy, indicating that DEC+VEN is more effective in treating AML without increasing short-term mortality rates.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Venetoclax with decitabine versus decitabine monotherapy in elderly acute myeloid leukemia: a propensity score-matched analysis. Kwag, D., Cho, BS., Bang, SY., et al.[2022]

In a study of nine AML patients with acquired resistance to venetoclax, the typical BCL2 mutation associated with resistance was not found, suggesting that this mutation is not necessary for developing resistance in AML.

The study identified that existing mutations, particularly the expansion of FLT3-ITD, were primarily responsible for venetoclax resistance, indicating that monitoring these mutations could help in developing strategies to prevent or overcome resistance.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Not BCL2 mutation but dominant mutation conversation contributed to acquired venetoclax resistance in acute myeloid leukemia. Zhang, X., Qian, J., Wang, H., et al.[2022]

In a study of 60 patients with acute myeloid leukemia (AML), the combination of venetoclax and azacitidine (Ven+AZA) demonstrated a high response rate, with 70.8% of previously untreated patients unfit for standard chemotherapy achieving complete remission (CR) or CR with incomplete hematological recovery (CRi) after one cycle.

Ven+AZA was found to be safe and tolerable, with some patients achieving minimal residual disease (MRD) negativity, particularly in those with favorable genetic mutations like NPM1, IDH1/IDH2, and TP53, indicating its potential effectiveness in specific patient subgroups.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

[Short-term efficacy of venetoclax combined with azacitidine in acute myeloid leukemia: a single-institution experience]. Yu, WJ., Jia, JS., Wang, J., et al.[2022]

Venetoclax (VEN) is FDA approved for treating newly diagnosed elderly or unfit patients with acute myeloid leukemia (AML) when combined with hypomethylating agents, showing complete remission rates of 28.3% and overall survival improvements in a phase-3 study.

While VEN has demonstrated effectiveness in various myeloid malignancies, including relapsed AML and high-risk myelodysplastic syndromes, remissions are often short-lived, typically lasting less than a year, but can facilitate transitions to allogeneic stem cell transplants.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Venetoclax-based chemotherapy in acute and chronic myeloid neoplasms: literature survey and practice points. Gangat, N., Tefferi, A.[2023]

In a retrospective analysis of patients with acute myeloid leukemia, intensive chemotherapy (IC) resulted in higher rates of complete remission (60.9% vs. 44.2%) and hematopoietic stem cell transplant (18.1% vs. 8.0%) compared to the combination of venetoclax and azacitidine (VEN-AZA).

While median overall survival was longer for IC (17.7 months) compared to VEN-AZA (11.3 months), these differences were not statistically significant, indicating that further randomized controlled trials are needed to better understand the efficacy of these treatments.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Venetoclax plus azacitidine compared with intensive chemotherapy as induction for patients with acute myeloid leukemia: retrospective analysis of an electronic medical record database in the United States. Zeidan, AM., Pollyea, DA., Borate, U., et al.[2023]

Citations

1. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC9793740/

Clinical Utility of Azacitidine in the Management of Acute ... The data suggest that oral AZA maintenance is an effective maintenance strategy to prolong survival in high-risk as well as favorable-risk AML ...

2. sciencedirect.com sciencedirect.com/science/article/pii/S2213048916300486

Clinical outcomes of AML patients treated with Azacitidine ... Median OS was 10.6 months in those receiving AZA as 1st line. Response (overall response rate 44%) had a significant impact on overall survival (p=<0.0001).

3. ashpublications.org ashpublications.org/blood/article/144/Supplement%201/2425/531542/Real-World-Treatment-Patterns-and-Outcomes-with

Real-World Treatment Patterns and Outcomes with Oral ... At 12 mo, estimated OS and rwRFS rates from Oral-AZA initiation were 88.2% (standard error [SE], 2.3) and 85.5% (SE, 2.5), respectively. Median ...

4. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC2817034/

5-azacitidine prolongs overall survival in patients with ... Patients with intermediate-2 and high-risk myelodysplastic syndrome (MDS) have a survival rate of 0.4 to 1.2 years as well as a high risk of their disease ...

5. nature.com nature.com/articles/s41375-025-02730-3

Outcomes of patients treated with venetoclax plus ... The 5-year relative survival of patients with AML is ~32%, and survival rates are dependent on age at diagnosis. Patients <50 years of age have ...

6. pubmed.ncbi.nlm.nih.gov pubmed.ncbi.nlm.nih.gov/40233158/

Real-world treatment patterns and outcomes with oral ... Rates of real-world relapse-free survival and overall survival at 12 months from oral-AZA initiation were 66.9% and 74.5%, respectively. During ...

7. hematologyadvisor.com hematologyadvisor.com/news/azacitidine-myelodysplastic-syndrome-mds-adverse-events-safety-concerns/

New Adverse Events Highlight Safety Concerns With ... Most AEs (95.78%) were classified as serious, and 40.87% resulted in death. Health professionals submitted nearly 90% of the reports, with the ...