ASTX727 + Venetoclax + Gilteritinib for Acute Myeloid Leukemia

Age: 18+

Sex: Any

Trial Phase: Phase 1 & 2

Sponsor: M.D. Anderson Cancer Center

Must not be taking: CYP3A inducers

Disqualifiers: Active infection, Cardiac failure, Hepatitis, others

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

Compensation: Varies

Number of Visits: Unknown

42 Participants Needed

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial tests a new combination of treatments to evaluate their effectiveness against acute myeloid leukemia (AML) with the FLT3 mutation. Researchers aim to determine the optimal dose and assess how well these drugs control the disease when newly diagnosed, recurrent, or unresponsive to other treatments. The treatments under investigation include ASTX727 (a combination of Decitabine and Cedazuridine), Venetoclax, and Gilteritinib. Individuals with AML featuring the FLT3 mutation or a related condition who have tried at least one other treatment may qualify for this trial. Those interested should consider reaching out for more information. As a Phase 1, Phase 2 trial, this study seeks to understand the treatment's effects in participants and measure its effectiveness in an initial, smaller group, offering a chance to contribute to groundbreaking research.

Do I need to stop my current medications for this trial?

The trial protocol does not specify if you need to stop your current medications. However, you must not have taken strong inducers of CYP3A or p-glycoprotein within 3 days of enrollment, and you should not have had any investigational antileukemic agents or chemotherapy agents in the last 7 days before study entry unless you have fully recovered from side effects or have life-threatening disease. It's best to discuss your current medications with the trial team.

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

Research shows that combining ASTX727 and venetoclax is generally safe for most patients with acute myeloid leukemia. This fully oral treatment is usually well-tolerated, though rare cases of serious side effects like bleeding and infections have occurred.

Venetoclax, a key component of this treatment, has shown promise in treating leukemia with manageable safety concerns. Patients using venetoclax may experience some side effects, but these are common with cancer treatments and can be managed with medical care.

Gilteritinib, the final component, has FDA approval for certain leukemia patients, indicating thorough study. Some patients have experienced side effects like differentiation syndrome, infections, and heart issues, especially in the first year. However, its safety remains stable over time.

Overall, these treatments have been studied in various combinations and are considered manageable in terms of safety, but close monitoring by healthcare providers is essential. ^{1 2 3 4 5}

Why are researchers excited about this trial's treatments?

Researchers are excited about the combination of ASTX727, venetoclax, and gilteritinib for treating acute myeloid leukemia (AML) because it brings a novel approach compared to existing treatments. Unlike traditional chemotherapy, which can be harsh and non-specific, this combination targets leukemia cells more precisely, potentially leading to better outcomes with fewer side effects. ASTX727 combines decitabine with cedazuridine, enhancing the delivery and effectiveness of the drug. Venetoclax works by inhibiting BCL-2, a protein that helps cancer cells survive, while gilteritinib specifically targets FLT3 mutations, which are common in AML cases. This targeted therapy approach could mean more effective treatment and improved survival rates for patients with AML.

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

This trial will evaluate the combination of ASTX727, venetoclax, and gilteritinib for patients with acute myeloid leukemia (AML). Studies have shown that combining ASTX727 with venetoclax benefits AML patients who cannot undergo intensive chemotherapy, offering a safety and success rate similar to other AML treatments. Venetoclax alone effectively blocks Bcl-2, a protein that helps cancer cells survive. Research has shown that gilteritinib improves survival chances and response rates compared to standard chemotherapy for AML patients with the FLT3 mutation. Together, these treatments in this trial aim to control cancer growth by targeting different survival mechanisms of cancer cells. ^{1 2 6 7 8}

Who Is on the Research Team?

Farhad Ravandi-Kashani

Principal Investigator

M.D. Anderson Cancer Center

Are You a Good Fit for This Trial?

Adults aged 18+ with FLT3-mutated acute myeloid leukemia (AML) or high-risk myelodysplastic syndrome (MDS), either newly diagnosed, relapsed, or refractory. Participants must have adequate organ function and performance status <=3 on the ECOG scale. Exclusions include prior gilteritinib treatment, more than three lines of therapy for Phase II cohort B, serious infections, heart failure, CNS leukemia, HIV positivity, hepatitis B/C infection.

Inclusion Criteria

Total serum bilirubin =< 2.5 x upper limit of normal (ULN), unless due to Gilbert's syndrome, hemolysis or the underlying leukemia approved by the PI

I can swallow without any issues.

I am an adult with AML or MDS, my condition is high-risk, and I have a FLT3 mutation.

Exclusion Criteria

I do not have severe heart failure.

I am willing and able to undergo intensive chemotherapy.

I have hepatitis B or C but my viral load is undetectable.

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Induction

Patients receive decitabine and cedazuridine, venetoclax, and gilteritinib to establish the maximum tolerated dose

4 weeks

Daily oral administration

Consolidation

Patients continue treatment with decitabine and cedazuridine, gilteritinib, and venetoclax to maintain response

23 cycles of 4 weeks each

Daily oral administration

Maintenance

Patients receive gilteritinib to maintain remission

Ongoing 4-week cycles

Daily oral administration

Follow-up

Participants are monitored for safety and effectiveness after treatment

30 days post-treatment, then every 6 months

What Are the Treatments Tested in This Trial?

Interventions

• ASTX727
• Gilteritinib
• Venetoclax

Trial Overview The trial is testing a combination of ASTX727 (decitabine and cedazuridine), venetoclax, and gilteritinib to determine the best dose and effect on AML/MDS with FLT3 mutation. The study aims to see if these drugs can control cancer growth by killing cells or stopping them from dividing/spreading.

How Is the Trial Designed?

Group I: Treatment (decitabine, cedazuridine, venetoclax, gilteritib) Experimental Treatment 3 Interventions

INDUCTION (CYCLE 1): Patients receive decitabine and cedazuridine PO QD on days 1-5, venetoclax PO QD on days 1-28, and gilteritinib PO QD on days 1-28 in the absence of disease progression or unacceptable toxicity CONSOLIDATION (CYCLES 2-24): Patients receive decitabine and cedazuridine PO QD on days 1-5, gilteritinib PO QD on days 1-28, and venetoclax PO QD on days 1-14. Treatment repeats every 28 days. MAINTENANCE (CYCLES 24+): Patients receive gilteritinib PO QD on days 1-28. Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity.

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+

Published Research Related to This Trial

Gilteritinib has been approved in the EU as a monotherapy for adult patients with relapsed or refractory acute myeloid leukemia (AML) with a FLT3 mutation, showing a significant improvement in overall survival (9.3 months) compared to salvage chemotherapy (5.6 months) in a phase III study with 371 participants.

The safety profile of gilteritinib is considered manageable, with common side effects including increases in liver enzymes and creatine phosphokinase, as well as gastrointestinal and general symptoms like fatigue and nausea.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

The European Medicines Agency Review of Gilteritinib (Xospata) for the Treatment of Adult Patients with Relapsed or Refractory Acute Myeloid Leukemia with an FLT3 Mutation. Tzogani, K., Røshol, H., Olsen, HH., et al.[2021]

A study involving 31 primary high-risk AML samples identified gilteritinib as the most effective drug to combine with venetoclax, showing increased apoptosis and reduced cell viability, even in resistant cell lines.

The combination of gilteritinib and venetoclax works by inhibiting FLT3 and AXL signaling, leading to the degradation of the antiapoptotic protein MCL-1, suggesting this combination could be a promising treatment for patients with high-risk FLT3 wild-type AML.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Venetoclax synergizes with gilteritinib in FLT3 wild-type high-risk acute myeloid leukemia by suppressing MCL-1. Janssen, M., Schmidt, C., Bruch, PM., et al.[2023]

In patients with newly diagnosed unfit acute myeloid leukemia (AML), the combination of azacitidine and venetoclax is a standard first-line treatment.

However, patients with TP53-mutated AML and poor-risk cytogenetics do not benefit from adding venetoclax to azacitidine, suggesting that alternative treatment regimens should be considered for these individuals.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

TP53 or Not TP53: That Is the Question. Green, SD., Zeidner, JF.[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 27 older patients with acute myeloid leukemia (AML) and high-risk myelodysplastic syndromes (MDS), the combination of azacytidine and venetoclax resulted in a median overall survival of 22.3 months, significantly higher than the 14.7 months reported in phase III trials and 5.94 months in a historical cohort treated with azacytidine alone.

The combination therapy also improved progression-free survival compared to azacytidine alone, and the results suggest that administering azacytidine and venetoclax as upfront therapy may enhance clinical benefits, even in patients with negative prognostic markers.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Clinical efficacy of azacytidine and venetoclax and prognostic impact of Tim-3 and galectin-9 in acute myeloid leukemia and high-risk myelodysplastic syndromes: A single-center real-life experience. Giudice, V., Serio, B., Ferrara, I., 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]

The combination of venetoclax and gilteritinib showed a high modified composite complete response (mCRc) rate of 75% in patients with FLT3-mutated acute myeloid leukemia (AML), indicating strong efficacy regardless of prior FLT3 inhibitor treatment.

While the treatment was effective, it also led to significant side effects, particularly cytopenias, prompting dose interruptions in about half of the patients, highlighting the need for careful monitoring and management of adverse events.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Venetoclax Plus Gilteritinib for FLT3-Mutated Relapsed/Refractory Acute Myeloid Leukemia. Daver, N., Perl, AE., Maly, J., et al.[2023]

In a study of 86 patients with relapsed or refractory acute myeloid leukemia (RR-AML) treated with venetoclax combinations, the complete remission rate was 24%, and the overall response rate was 31%, indicating that venetoclax is an effective treatment option for this patient group.

Azacitidine combined with venetoclax showed significantly better outcomes than low-dose cytarabine with venetoclax, with median overall survival of 25 months compared to 3.9 months, highlighting the importance of treatment choice in improving survival in RR-AML.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Clinical and molecular predictors of response and survival following venetoclax therapy in relapsed/refractory AML. Stahl, M., Menghrajani, K., Derkach, A., et al.[2021]

The FDA has approved several new treatments for acute myeloid leukemia, including venetoclax and glasdegib, aimed at older patients who may not tolerate intensive therapies, but concerns exist about the criteria used to define patient fitness for these treatments.

The efficacy of venetoclax and glasdegib is questioned due to modest remission rates and the lack of randomized comparisons with more intensive treatments, suggesting that better outcomes might be achievable with alternative therapies.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Recent drug approvals for newly diagnosed acute myeloid leukemia: gifts or a Trojan horse? Estey, E., Karp, JE., Emadi, A., et al.[2022]

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]

The combination of venetoclax and hypomethylating agents (VEN+HMA) has shown promising efficacy in treating FLT3-mutated acute myeloid leukemia (AML), particularly in newly diagnosed and relapsed patients, but some patients with the FLT3-ITD mutation did not respond to this treatment.

This study is the first to explore the safety and effectiveness of combining gilteritinib, a targeted FLT3 inhibitor, with venetoclax in two AML patients who were unresponsive to the standard VEN+AZA therapy, suggesting a potential new treatment avenue for FLT3-ITD mutated patients.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Rapid and Efficient Response to Gilteritinib and Venetoclax-Based Therapy in Two AML Patients with FLT3-ITD Mutation Unresponsive to Venetoclax Plus Azacitidine. Zhang, LS., Wang, J., Xu, MZ., et al.[2022]

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. 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.

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. ashpublications.org ashpublications.org/blood/article/142/Supplement%201/833/499481/A-Phase-2-Study-of-the-Fully-Oral-Combination-of

A Phase 2 Study of the Fully Oral Combination of ASTX727 ... Conclusions: In this older and very high-risk population of pts with AML, an entirely oral regimen consisting of ASTX727 and venetoclax was ...

8. sciencedirect.com sciencedirect.com/science/article/abs/pii/S0006497124056489

Fully Oral Combination of Decitabine/Cedazuridine ... 3 deaths occurred on study treatment in patients in remission and were potentially treatment-related (1 from bleeding and 2 from infections). Conclusions: ...