SNDX-5613 + ASTX727 + Venetoclax for Acute Myeloid Leukemia

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: Menin inhibitors

Disqualifiers: Uncontrolled conditions, Active infection, others

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

Compensation: Varies

Number of Visits: Unknown

43 Participants Needed

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial explores the optimal dose of a new treatment mix for individuals with acute myeloid leukemia (AML) or mixed phenotype acute leukemia with a myeloid type (MPAL). The goal is to determine if a combination of three drugs—SNDX-5613 (Revumenib or Revuforj), ASTX727 (Decitabine/Cedazuridine), and Venetoclax—can effectively manage these conditions. Eligible participants should have newly diagnosed or recurring AML or MPAL that is unresponsive to treatment and be unable to tolerate intense chemotherapy. 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 new treatment.

Will I have to stop taking my current medications?

The trial does not specify if you must stop all current medications, but it does not allow other chemotherapeutic or anti-leukemic agents during the study, except for certain cases like intrathecal chemotherapy or hydroxyurea. You should discuss your current medications with the study team to see if they are allowed.

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

Research has shown that SNDX-5613, also known as revumenib, has a manageable safety profile. Patients with certain genetic mutations in acute myeloid leukemia (AML) responded well, and the side effects were manageable. The FDA has approved the drug for specific AML cases, indicating confidence in its safety.

Venetoclax, another treatment in this study, is FDA-approved for AML and is generally well-tolerated, according to studies. However, serious side effects like febrile neutropenia (a low white blood cell count with fever) occurred in about 30% of patients in some studies.

ASTX727 combines decitabine and cedazuridine. Research has shown it is safe for most patients, especially when used with venetoclax. The safety of this combination is similar to other treatments.

Overall, these treatments have demonstrated a good safety profile in past studies. However, like any medication, side effects can occur. Discuss any concerns with a healthcare provider. ^{1 2 3 4 5}

Why are researchers excited about this trial's treatments?

Researchers are excited about these treatments for acute myeloid leukemia (AML) because they offer a fresh approach compared to standard chemotherapy. SNDX-5613 is particularly interesting as it targets specific proteins involved in cancer cell growth, potentially offering a more precise treatment option. Venetoclax works by inducing cancer cell death by targeting a key protein that helps cancer cells survive, which could lead to better outcomes when combined with other therapies. Lastly, ASTX727, an oral form of azacitidine, simplifies treatment by allowing patients to take it at home, which is a major convenience advantage over traditional intravenous therapies. Together, these drugs could provide a more targeted and convenient approach to treating AML.

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

Research has shown that SNDX-5613, one of the treatments in this trial, may help treat acute myeloid leukemia (AML). In studies, 40% of patients with specific genetic mutations responded to it, and 35% achieved complete remission. Venetoclax, another treatment option in this trial, has proven effective when combined with other treatments, with 75% of older AML patients going into remission. The combination of decitabine/cedazuridine (ASTX727) with venetoclax, also under study in this trial, has shown a 67% response rate, with 40% achieving complete remission. These findings suggest that using SNDX-5613, venetoclax, and ASTX727 in separate arms of this trial might better control AML by leveraging their individual strengths. ^{1 2 4 6 7}

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 and older, weighing at least 40kg, with relapsed/refractory acute myeloid leukemia (AML) or mixed phenotype acute leukemia with a myeloid phenotype. Participants must have an ECOG performance status of ≤2, be on certain antifungal medications, and not be taking other strong CYP3A4 inhibitors/inducers. They should agree to contraception use during the study and for three months after. Exclusions include active malignancy under treatment, severe gastrointestinal/metabolic conditions affecting drug absorption, recent significant cardiovascular events, uncontrolled medical conditions or infections.

Inclusion Criteria

I am a male who is sterile or will use contraception during and 3 months after the study.

I am taking certain antifungal medications and no other strong medications that affect drug metabolism.

My leukemia has returned or is not responding to treatment.

Exclusion Criteria

I have severe acute or chronic graft-versus-host disease.

I am currently being treated for another cancer.

I haven't had a heart attack, severe heart issues, or a stroke in the last 6 months.

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Dose Finding (Part 1b)

Determine the highest tolerable dose of SNDX-5613 in combination with ASTX727 and venetoclax

Varies

Frequent visits for dose escalation and monitoring

Treatment (Part 2)

Assess the efficacy of the determined dose of SNDX-5613 in combination with ASTX727 and venetoclax

Multiple cycles, each cycle is 28 days

Regular visits for drug administration and monitoring

Follow-up

Participants are monitored for safety and effectiveness after treatment

6 months

What Are the Treatments Tested in This Trial?

Interventions

• ASTX727
• SNDX-5613
• Venetoclax

Trial Overview The trial is testing the highest tolerable dose of SNDX-5613 in combination with ASTX727 (decitabine/cedazuridine) and venetoclax in patients with AML or MPAL. The goal is to determine if this oral drug combination can control these types of leukemia effectively.

How Is the Trial Designed?

Group I: Venetoclax Experimental Treatment 1 Intervention

Tablets by mouth on Days 1-14 of each cycle.

Group II: SNDX-5613 Experimental Treatment 1 Intervention

Capsules by mouth 2 times every day (about 12 hours apart).

Group III: ASTX727 Experimental Treatment 1 Intervention

Tablets by mouth on Days 1-5 of each cycle.

ASTX727 is already approved in United States, European Union for the following indications:

Approved in United States as Inqovi for:

• Myelodysplastic Syndromes (MDS)

Approved in European Union as Inqovi for:

• Myelodysplastic Syndromes (MDS)

Who Is Running the Clinical Trial?

M.D. Anderson Cancer Center

Lead Sponsor

Trials

3,107

Recruited

1,813,000+

Syndax Pharmaceuticals, Inc.

Collaborator

Trials

5

Recruited

220+

Astex Pharmaceuticals, Inc.

Industry Sponsor

Trials

97

Recruited

7,400+

Dr. Harren Jhoti

Astex Pharmaceuticals, Inc.

Chief Executive Officer since 2007

PhD in Biochemistry from Birkbeck College, London

Dr. Harold N. Keer

Astex Pharmaceuticals, Inc.

Chief Medical Officer since 2020

MD

Syndax Pharmaceuticals

Industry Sponsor

Trials

49

Recruited

2,700+

Published Research Related to This Trial

In a study of 22 heavily pre-treated patients with relapsed or refractory acute myeloid leukaemia (RR-AML), the combination of venetoclax and decitabine resulted in a 45.5% overall response rate, with 40.9% achieving complete remission, demonstrating its efficacy in a real-world setting.

While the treatment was effective, it was associated with significant side effects, including grade IV neutropenia and thrombocytopenia in all patients, but no deaths were attributed to the treatment side effects, indicating that the adverse effects were manageable.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Efficacy of Venetoclax Combined with Decitabine-Based Treatment for Heavily Pre-Treated Relapsed or Refractory AML Patients in a Real-World Setting. Tong, J., Zhao, N., Hu, X., et al.[2022]

Venetoclax combined with azacitidine or low-dose cytarabine (LDAC) is associated with significantly lower costs per patient achieving complete remission (CR) or complete remission with incomplete blood count recovery (CRi) compared to other treatments for newly diagnosed acute myeloid leukemia (AML) patients who cannot undergo intensive chemotherapy.

The estimated costs per patient achieving CR + CRi were $473,960 for venetoclax + azacitidine and $428,071 for venetoclax + LDAC, which are substantially lower than the costs for azacitidine ($1,197,438) and other therapies, indicating a more cost-effective treatment option.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Costs per patient achieving remission with venetoclax-based combinations in newly diagnosed patients with acute myeloid leukemia ineligible for intensive induction chemotherapy. Choi, M., Song, J., Bui, CN., et al.[2022]

In a phase 1/2 study involving six Japanese patients aged 60 and older with acute myeloid leukaemia, the combination of venetoclax and azacitidine demonstrated a high response rate, with 83% of patients achieving a response, including three complete remissions.

The treatment was generally well tolerated, with a median overall survival of 15.7 months, although some patients experienced serious adverse events, including grade 3 fungal pneumonia, which required treatment adjustments.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Venetoclax in combination with azacitidine in Japanese patients with acute myeloid leukaemia: phase 1 trial findings. Taniguchi, S., Yamauchi, T., Choi, I., et al.[2021]

In a study involving 145 older patients (median age 74) with acute myeloid leukemia (AML) who were ineligible for intensive chemotherapy, the combination of venetoclax with decitabine or azacitidine resulted in a high complete remission (CR) rate of 67%, demonstrating its efficacy in this challenging population.

The treatment was well tolerated, with no cases of tumor lysis syndrome reported, and the median overall survival was 17.5 months, indicating that venetoclax combined with hypomethylating agents is a promising option for elderly patients with AML.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Venetoclax combined with decitabine or azacitidine in treatment-naive, elderly patients with acute myeloid leukemia. DiNardo, CD., Pratz, K., Pullarkat, V., et al.[2021]

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 phase 2 trial involving 168 patients with acute myeloid leukaemia (AML), the combination of venetoclax and a 10-day regimen of decitabine resulted in a high overall response rate of 74%, with particularly impressive results in newly diagnosed AML patients (89%).

The treatment demonstrated a manageable safety profile, with common adverse events including neutropenia and infections, and a 30-day mortality rate of only 3.6%, indicating that this combination therapy is both effective and relatively safe for older patients or those unfit for intensive chemotherapy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

10-day decitabine with venetoclax for newly diagnosed intensive chemotherapy ineligible, and relapsed or refractory acute myeloid leukaemia: a single-centre, phase 2 trial. DiNardo, CD., Maiti, A., Rausch, CR., et al.[2021]

In a phase 1 study involving 38 pediatric patients aged 3-22 with relapsed or refractory acute myeloid leukemia, the combination of venetoclax and high-dose cytarabine showed promising efficacy, with 70% of patients achieving complete remission at the recommended phase 2 dose.

The study identified 360 mg/m2 of venetoclax as the recommended dose, but also reported significant safety concerns, including a 66% incidence of febrile neutropenia and one treatment-related death, highlighting the need for careful monitoring in future trials.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Venetoclax in combination with cytarabine with or without idarubicin in children with relapsed or refractory acute myeloid leukaemia: a phase 1, dose-escalation study. Karol, SE., Alexander, TB., Budhraja, A., et al.[2021]

The combination of venetoclax with hypomethylating agents (HMA) has significantly improved survival rates in patients with acute myeloid leukemia (AML), as demonstrated in a phase 3 study.

Venetoclax is also safe when added to standard intensive regimens, leading to high remission rates and measurable residual disease negativity in both newly diagnosed and relapsed/refractory AML patients.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Venetoclax in combination with nucleoside analogs in acute myelogenous leukemia. Ball, BJ., Koller, PB., Pullarkat, V.[2023]

A case of early-relapsed high-risk T-cell acute lymphoblastic leukemia (T-ALL) with high BCL-2 expression was successfully treated with a combination of decitabine and venetoclax, leading to complete remission (CR).

The results suggest that decitabine and venetoclax may work synergistically in treating BCL-2 positive acute lymphoblastic leukemia, indicating a potential new therapeutic strategy for this high-risk group.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Venetoclax in association with decitabine as effective bridge to transplant in a case of relapsed early T-cell lymphoblastic leukemia. Zappone, E., Cencini, E., Defina, M., et al.[2020]

Citations

1. ascopubs.org ascopubs.org/doi/10.1200/JCO.2025.43.16_suppl.6551

Phase II trial of 10-day ASTX727 (decitabine/cedazuridine ... Conclusions: The 10-day ASTX727-VEN combination showed safety profile comparable to other HMA-VEN regimens in salvage setting. TP53 wild type, ...

2. ashpublications.org ashpublications.org/blood/article/144/Supplement%201/2896/533121/Fully-Oral-Combination-of-Decitabine-Cedazuridine

Fully Oral Combination of Decitabine/Cedazuridine (ASTX727 ... The median follow-up time was 20 months. The ORR was 40/60 (67%), including 24 (40%) complete remission (CR), 13 (22%) CR with incomplete count ...

3. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC12268998/

Oral decitabine/cedazuridine plus venetoclax for older or ... Hypomethylating agents combined with venetoclax are effective regimens in patients with acute myeloid leukaemia who are ineligible for intensive chemotherapy. ...

4. clinicaltrials.gov clinicaltrials.gov/study/NCT04657081

Study Details | NCT04657081 | Pharmacokinetics, Safety, ... The primary purpose of the study is to rule out drug-drug interactions between ASTX727 and venetoclax combination therapy by evaluating area under the curve ( ...

5. onclive.com onclive.com/view/venetoclax-dec-c-is-potential-new-soc-in-newly-diagnosed-aml-ineligible-for-intensive-chemo

Venetoclax/DEC-C Is Potential New SOC in Newly ... Venetoclax and decitabine-cedazuridine demonstrated complete responses and encouraging survival outcomes in newly diagnosed AML.

6. pubmed.ncbi.nlm.nih.gov pubmed.ncbi.nlm.nih.gov/38452788/

Oral decitabine and cedazuridine plus venetoclax for older or ... ASTX727 plus venetoclax is an active fully oral regimen and safe in most older or unfit patients with acute myeloid leukaemia.

7. ascopubs.org ascopubs.org/doi/10.1200/JCO.2025.43.16_suppl.6504

An all-oral regimen of decitabine-cedazuridine (DEC-C) ... The all-oral regimen of DEC-C plus VEN resulted in comparable safety, response, and survival rates to parenteral AZA plus VEN in pts with newly diagnosed AML.