Venetoclax + Revumenib for Acute Myeloid Leukemia

Recruiting at 3 trial locations

Overseen By Ghayas Issa, MD

Age: Any Age

Sex: Any

Trial Phase: Phase 1 & 2

Sponsor: M.D. Anderson Cancer Center

Must not be taking: Chemotherapeutics, Antileukemics

Disqualifiers: Uncontrolled infection, Active malignancy, HIV, others

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

Compensation: Varies

Number of Visits: 1

Duration: 2 years

8 Participants Needed

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial aims to determine if combining venetoclax and revumenib (also known as Revuforj or SNDX-5613) can control a type of acute myeloid leukemia (AML) with minimal residual disease (MRD), where some cancer cells remain after treatment. Participants will take both medications for up to a year and then continue with just venetoclax if the disease remains stable. The study seeks individuals with AML who have previously undergone specific treatments and currently show some remaining disease, but no visible leukemia in bone marrow. As a Phase 1 trial, the research focuses on understanding how the treatment works in people, offering participants the opportunity to be among the first to receive this novel combination therapy.

Do I need to stop my current medications to join the trial?

The trial protocol does not specify if you need to stop your current medications, but it does not allow other chemotherapeutic or anti-leukemic agents during the study, except for certain cases like CNS prophylaxis or controlled CNS disease. It's best to discuss your specific medications with the trial team.

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

Research has shown that using venetoclax and revumenib together is generally safe for patients with acute leukemia. Studies have found positive results with this combination, and most patients tolerate the treatment well without serious issues.

Some patients might experience side effects, but these are usually manageable. Common side effects include mild to moderate symptoms like tiredness or nausea. Importantly, revumenib has been tested both alone and with other drugs, demonstrating promising safety results.

Overall, research supports the safety of combining venetoclax and revumenib, with careful monitoring for any side effects. ^{1 2 3 4 5}

Why are researchers excited about this study treatment for AML?

Researchers are excited about the combination of Venetoclax and Revumenib for treating Acute Myeloid Leukemia (AML) because it offers a novel approach compared to current options. While traditional treatments often involve chemotherapy and stem cell transplants, Venetoclax targets a protein called BCL-2, which helps cancer cells survive, thereby prompting cancer cell death. Revumenib, on the other hand, inhibits the menin-MLL interaction, potentially disrupting the cancer's ability to grow. This dual-action approach not only targets the leukemia cells more precisely but also offers the potential for improved outcomes with potentially fewer side effects.

What evidence suggests that the combination of venetoclax and revumenib could be effective for acute myeloid leukemia?

Participants in this trial may receive a combination of revumenib and venetoclax, which previous studies have shown to be promising for treating acute myeloid leukemia (AML). Early findings suggest this treatment is safe and effective for certain types of AML, particularly those with specific genetic changes. Research indicates that revumenib, which blocks a protein called Menin, works well with venetoclax, a drug that targets proteins that help cancer cells survive. In trials, this combination has demonstrated positive results in controlling the disease. This treatment offers hope for AML patients, especially those who haven't responded well to other therapies. ^{4 6 7 8 9}

Who Is on the Research Team?

Ghayas Issa, MD

Principal Investigator

M.D. Anderson Cancer Center

Are You a Good Fit for This Trial?

This trial is for individuals aged 12 or older, weighing at least 45Kg, with MRD-positive AML in remission but still showing signs of cancer cells. They must have proper kidney and liver function, no severe heart issues, and not be pregnant or breastfeeding. Participants should agree to use contraception and not have any active infections or other health conditions that could interfere with the study.

Inclusion Criteria

I can swallow pills.

Participants or parent/guardian is willing and able to provide informed consent

Women of childbearing potential must agree to adequate methods of contraception during the study and at least 3 months after the last treatment

Exclusion Criteria

QTc >450 msec for males and QTc >470 msec for females using the Fridericia Formula

History of or any concurrent condition, therapy, or laboratory abnormality that in the Investigator's opinion might confound the results of the study, interfere with the participants's participation for the full duration of the study, or is not in the best interest of the patient to participate

I've been off all immunosuppression drugs for 2 weeks and calcineurin inhibitors for 4 weeks, except for low-dose steroids or topical treatments.

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants receive the combination of venetoclax and revumenib for up to 1 year, followed by venetoclax alone for an additional year

2 years

Daily oral administration on Days 1-14 of each cycle

Follow-up

Participants are monitored for safety and effectiveness after treatment

1 year

What Are the Treatments Tested in This Trial?

Interventions

• Revumenib
• Venetoclax

Trial Overview The trial is testing a combination of two drugs, Venetoclax and Revumenib, to see if they can control Acute Myeloid Leukemia (AML) when there's minimal residual disease (MRD). It involves patients who've had some treatment but still have traces of leukemia despite appearing in remission.

How Is the Trial Designed?

Group I: Venetoclax + Revumenib Experimental Treatment 2 Interventions

Participants may receive the combination of venetoclax and revumenib for up to 1 year, and then 1 more year of venetoclax alone. You will no longer be able to take the study drug(s) if the disease gets worse or if intolerable side effects occur. Participants will take venetoclax by mouth on 1 time a day at about the same time each day, on Days 1-14 of each cycle. Take each dose with about 1 cup of water within 30 minutes after a meal, preferably breakfast.

Revumenib is already approved in United States for the following indications:

Approved in United States as Revuforj for:

• Relapsed or refractory acute leukemia with a lysine methyltransferase 2A gene (KMT2A) translocation in adult and pediatric patients aged 1 year and older

Who Is Running the Clinical Trial?

M.D. Anderson Cancer Center

Lead Sponsor

Trials

3,107

Recruited

1,813,000+

Break Through Cancer

Collaborator

Trials

2

Recruited

120+

Syndax Pharmaceuticals

Industry Sponsor

Trials

49

Recruited

2,700+

AbbVie

Industry Sponsor

Trials

1,079

Recruited

535,000+

Founded

2013

Headquarters

North Chicago, USA

Known For

Immunology treatments

Top Products

Humira (adalimumab), Skyrizi (risankizumab), Rinvoq (upadacitinib)

Dr. Roopal Thakkar

AbbVie

Chief Medical Officer since 2023

MD from Wayne State University School of Medicine

Robert A. Michael

AbbVie

Chief Executive Officer

Bachelor's degree in Finance from the University of Illinois

Published Research Related to This Trial

In a study of 82 adult patients with acute myeloid leukemia (AML), 57% were able to start venetoclax treatment safely in an outpatient setting, demonstrating its feasibility outside of the hospital.

The risk of tumor lysis syndrome (TLS) was very low, with only 2.1% of patients experiencing TLS after starting venetoclax, and 98% of patients did not require hospitalization for TLS within the first week of treatment.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Outpatient initiation of venetoclax in patients with acute myeloid leukemia. Palmer, S., Patel, A., Wang, C., 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 study of 26 adult patients with relapsed/refractory acute myeloid leukemia (R/R AML), the combination of venetoclax (VEN) with demethylating agents (azacitidine or decitabine) resulted in a 57.7% overall response rate, including 13 complete responses, indicating its efficacy as a salvage therapy.

Patients who achieved minimal residual disease negativity had significantly better overall survival and event-free survival, highlighting the importance of this outcome in improving long-term prognosis for R/R AML patients.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

[Clinical Observation of Venetoclax Combined with Demethylating Agents on the Treatment of Relapsed/Refractory Acute Myeloid Leukemia]. Wang, Y., Huang, SL., Zhang, XX., et al.[2023]

A study analyzing 19,107 adverse event reports related to venetoclax (VEN) identified significant unexpected serious adverse events, including pleural effusion and atrial fibrillation, highlighting the need for careful monitoring of patients.

The median time for these adverse events to occur was 31 days after starting VEN treatment, with many events happening within the first month, indicating that early detection and management of side effects are crucial for patient safety.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

A real-world pharmacovigilance study of FDA Adverse Event Reporting System (FAERS) events for venetoclax. Yang, Y., Shu, Y., Chen, G., et al.[2023]

Venetoclax is a highly effective treatment for relapsed or refractory chronic lymphocytic leukemia (CLL), achieving response rates of about 80% in clinical trials involving 240 patients from 2011 to 2016.

While venetoclax has an acceptable safety profile, common side effects include neutropenia and diarrhea, and there is a risk of tumor lysis syndrome (TLS), which can be managed through careful dose ramp-up and patient education, leading to no reported TLS events in ongoing trials.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Venetoclax: Management and Care for Patients With Relapsed or Refractory Chronic Lymphocytic Leukemia . Brumbaugh Paradis, H., Alter, D., Llerandi, D.[2018]

In a study comparing treatment regimens for relapsed/refractory acute myeloid leukemia (R/R AML), the venetoclax (VEN) combination therapy showed a comparable overall response rate (59.3%) to intensive chemotherapy (IC) (44.0%), suggesting it is an effective alternative for patients who have failed previous treatments.

Patients receiving the VEN combination had a significantly higher percentage of successful stem cell transplants at blast clearance (86.5% vs. 62.3% for IC), indicating better disease control and potentially lower treatment-related mortality.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

A retrospective comparison of salvage intensive chemotherapy versus venetoclax-combined regimen in patients with relapsed/refractory acute myeloid leukemia (AML). Park, S., Kwag, D., Kim, TY., et al.[2022]

In the phase III CLL14 trial, a 12-month treatment with venetoclax combined with obinutuzumab significantly improved progression-free survival and rates of undetectable minimal residual disease compared to traditional chemoimmunotherapy with chlorambucil and obinutuzumab in patients with untreated chronic lymphocytic leukaemia.

Venetoclax + obinutuzumab is a well-tolerated, chemotherapy-free treatment option for CLL, with manageable side effects like neutropenia, making it suitable for patients who cannot undergo intensive chemotherapy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Venetoclax: A Review in Previously Untreated Chronic Lymphocytic Leukaemia. Blair, HA.[2021]

The combination of venetoclax and alvocidib was found to be safe and tolerable in patients with relapsed/refractory Acute Myeloid Leukemia (AML), with no maximum tolerated dose reached, although significant gastrointestinal side effects were common.

The overall response rate to this treatment was modest, with only 11.4% achieving complete or incomplete remission, indicating that while the combination is safe, it may not significantly enhance efficacy compared to using each drug alone.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

A phase 1b study of venetoclax and alvocidib in patients with relapsed/refractory acute myeloid leukemia. Jonas, BA., Hou, JZ., Roboz, GJ., et al.[2023]

The combination of 225 Ac-lintuzumab and venetoclax showed a synergistic effect in killing tumor cells in venetoclax-resistant acute myeloid leukemia (AML) models, indicating a potential new treatment strategy.

This combination therapy not only induced DNA damage but also reduced MCL-1 protein levels, which is linked to resistance against venetoclax, leading to better tumor control and prolonged survival in preclinical studies.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

225Ac-labeled CD33-targeting antibody reverses resistance to Bcl-2 inhibitor venetoclax in acute myeloid leukemia models. Garg, R., Allen, KJH., Dawicki, W., et al.[2021]

Citations

1. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC12316144/

Azacitidine, Venetoclax, and Revumenib for Newly Diagnosed ... Azacitidine and venetoclax is a standard frontline treatment regimen for newly diagnosed older adults with AML; however, long-term outcomes remain poor.

2. ashpublications.org ashpublications.org/blood/article/142/Supplement%201/58/502145/Early-Results-of-the-Phase-I-II-Study

Early Results of the Phase I/II Study Investigating the All-Oral ... The Phase I/II study investigating the all-oral combination of the Menin inhibitor Revumenib (SNDX-5613) with Decitabine/Cedazuridine (ASTX727) and Venetoclax ...

3. ir.syndax.com ir.syndax.com/news-releases/news-release-details/syndax-presents-positive-revuforjr-revumenib-data-acute

Syndax Presents Positive Revuforj® (revumenib) Data in ... Positive data from multiple trials of Revuforj® (revumenib) as a single-agent and in combination with standard of care agents in patients with acute leukemias.

4. clinicaltrials.gov clinicaltrials.gov/study/NCT05360160

NCT05360160 | A Phase I-II Study Investigating the All- ... To assess the efficacy of SNDX-5613 in combination with ASTX727 and venetoclax for patients with AML. Secondary Objectives. • To assess overall survival, event- ...

5. sciencedirect.com sciencedirect.com/science/article/abs/pii/S0006497123046621

Early Results of the Phase I/II Study Investigating the All ... Early results indicate acceptable safety and high efficacy of this combination in R/R myeloid leukemias with either KMT2Ar or NPM1mt or NUP98r.

6. ascopubs.org ascopubs.org/doi/10.1200/JCO-25-00914

Azacitidine, Venetoclax, and Revumenib for Newly ... Revumenib is a first-in-class menin inhibitor approved for R/R KMT2Ar acute leukemia with overall response rates (ORRs), CR, and median OS of ...

7. ashpublications.org ashpublications.org/blood/article/144/Supplement%201/216/530724/Phase-I-II-Study-of-the-All-Oral-Combination-of

Phase I/II Study of the All-Oral Combination of Revumenib ... Phase I/II study of the all-oral combination of Revumenib (SNDX-5613) with Decitabine/Cedazuridine (ASTX727) and Venetoclax (SAVE) in R/R AML.

8. clinicaltrials.gov clinicaltrials.gov/study/NCT06177067

NCT06177067 | Study of Revumenib, Azacitidine, and ... This is a research study to find out if adding a new study drug called revumenib to commonly used chemotherapy drugs is safe and if they have beneficial ...

9. cancer.gov cancer.gov/research/participate/clinical-trials-search/v?id=NCI-2022-03312

SNDX-5613 with Decitabine/Cedazuridine, and Venetoclax ... This phase I/II trial studies the side effects and best dose of SNDX-5613 and and to see how well it works in combination with decitabine/cedazuridine and ...