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

Trial Summary

What is the purpose of this trial?

This phase I/II trial studies the best dose of gilteritinib given together with ASTX727 and venetoclax and the effect of ASTX727, venetoclax, and gilteritinib in treating patients with FLT3-mutated acute myeloid leukemia that is newly diagnosed, has come back (relapsed) or does not respond to treatment (refractory) or high-risk myelodysplastic syndrome. Chemotherapy drugs, such as ASTX727, work in different ways to stop the growth of cancer cells, either by killing the cells, by stopping them from dividing, or by stopping them from spreading. Venetoclax may stop the growth of cancer cells by blocking Bcl-2, a protein needed for cancer cell survival. Gilteritinib may stop the growth of cancer cells by blocking some of the enzymes needed for cell growth. Giving ASTX727, venetoclax, and gilteritinib may help to control the disease.

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.

What data supports the idea that ASTX727 + Venetoclax + Gilteritinib for Acute Myeloid Leukemia is an effective drug?

The available research shows that combining Venetoclax with Gilteritinib is effective for certain types of Acute Myeloid Leukemia (AML), especially those with specific genetic mutations. For example, one study found that Gilteritinib and Venetoclax together increased the death of cancer cells and reduced the disease in patients who had not responded to other treatments. Another study showed that Venetoclax combined with Decitabine, a component of ASTX727, improved survival rates and response rates in older patients with AML compared to Decitabine alone. These findings suggest that the combination of ASTX727, Venetoclax, and Gilteritinib could be a promising option for treating AML. ^{1 2 3 4 5}

What safety data is available for the treatment of ASTX727, Venetoclax, and Gilteritinib in Acute Myeloid Leukemia?

The safety data for the treatment involving ASTX727 (Decitabine/Cedazuridine), Venetoclax, and Gilteritinib in Acute Myeloid Leukemia (AML) can be summarized as follows: Venetoclax has been shown to be safe in combination with azacytidine for high-risk myeloid diseases, with appropriate management and dose adjustments for toxicities. Gilteritinib, approved for relapsed or refractory AML with FLT3 mutation, has a manageable safety profile with common adverse reactions including increased liver enzymes, gastrointestinal symptoms, and fatigue. The combination of Venetoclax and Gilteritinib has shown promising efficacy in preclinical models and early clinical reports, suggesting a potential for safe use in FLT3-mutated AML patients, although specific safety data for the triple combination with ASTX727 is not detailed in the provided research. ^{1 3 6 7 8}

Is the drug combination of ASTX727, Gilteritinib, and Venetoclax promising for treating acute myeloid leukemia?

Yes, the combination of these drugs is promising for treating acute myeloid leukemia. Gilteritinib and Venetoclax work well together, especially in cases with specific genetic mutations, to reduce cancer cell survival and increase the effectiveness of treatment. This combination has shown potential in overcoming resistance to other treatments and reducing the leukemia burden in patients. ^{1 2 9 10 11}

Research Team

Farhad Ravandi-Kashani

Principal Investigator

M.D. Anderson Cancer Center

Eligibility Criteria

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

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

Treatment Details

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.

Participant Groups

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+

Findings from Research

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]

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 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]

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]

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]

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]

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]

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]

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 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]

References

1. United States pubmed.ncbi.nlm.nih.gov

Venetoclax Plus Gilteritinib for FLT3-Mutated Relapsed/Refractory Acute Myeloid Leukemia. [2023]

2. United States pubmed.ncbi.nlm.nih.gov

Venetoclax synergizes with gilteritinib in FLT3 wild-type high-risk acute myeloid leukemia by suppressing MCL-1. [2023]

3. New Zealand 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. [2022]

4. United States pubmed.ncbi.nlm.nih.gov

Clinical and molecular predictors of response and survival following venetoclax therapy in relapsed/refractory AML. [2021]

5. United States pubmed.ncbi.nlm.nih.gov

Venetoclax with decitabine versus decitabine monotherapy in elderly acute myeloid leukemia: a propensity score-matched analysis. [2022]

6. Switzerland 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. [2023]

7. England 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. [2021]

8. New Zealand 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. [2022]

9. United States pubmed.ncbi.nlm.nih.gov

TP53 or Not TP53: That Is the Question. [2023]

10. United States pubmed.ncbi.nlm.nih.gov

225Ac-labeled CD33-targeting antibody reverses resistance to Bcl-2 inhibitor venetoclax in acute myeloid leukemia models. [2021]

11. England pubmed.ncbi.nlm.nih.gov

Recent drug approvals for newly diagnosed acute myeloid leukemia: gifts or a Trojan horse? [2022]