Triple-Drug Therapy for Acute Myeloid Leukemia

Recruiting at 21 trial locations

Overseen By Astellas Pharma Global Development, Inc.

Age: 18+

Sex: Any

Trial Phase: Phase 1 & 2

Sponsor: Astellas Pharma Global Development, Inc.

Must be taking: Gilteritinib, Venetoclax, Azacitidine

Must not be taking: CYP3A inducers, P-gp inducers

Disqualifiers: APL, CNS involvement, MPN, others

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

Compensation: Varies

Number of Visits: 2

70 Participants Needed

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial seeks a new treatment option for individuals diagnosed with acute myeloid leukemia (AML) who have a specific altered FLT3 gene and cannot undergo traditional chemotherapy. Researchers are testing a combination of three drugs—gilteritinib (a targeted therapy), venetoclax, and azacitidine—to determine optimal doses, assess their interaction in the body, and evaluate their potential to induce remission. Individuals recently diagnosed with AML, possessing the altered FLT3 gene, and unable to receive chemotherapy due to age or other health conditions may be suitable candidates for this trial. Participants will receive treatment in cycles and attend regular clinic visits to monitor progress and any side effects. 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 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 taking your current medications. However, you cannot take drugs that strongly affect certain liver enzymes (CYP3A or P-gp) during the study. It's best to discuss your current medications with the study team to see if any adjustments are needed.

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

Research has shown that combining gilteritinib, venetoclax, and azacitidine might effectively treat acute myeloid leukemia (AML) with a specific FLT3 gene mutation. Earlier studies found that venetoclax with azacitidine was generally well-tolerated by older patients unable to undergo standard chemotherapy. While side effects can occur, they are usually manageable.

Gilteritinib has been tested with azacitidine and venetoclax in other research settings. Patients have generally tolerated this combination well, but the safety of using all three drugs together is still under study. The goal is to find the optimal dose that maximizes benefits while minimizing side effects.

Participants in the trial will receive close monitoring to manage any health issues, with efforts to minimize side effects. ^{1 2 3 4 5}

Why are researchers excited about this trial's treatments?

Researchers are excited about this triple-drug therapy for acute myeloid leukemia (AML) because it combines azacitidine, gilteritinib, and venetoclax, offering a novel approach to tackling this aggressive cancer. Unlike traditional treatments, which often use single agents like chemotherapy, this combination targets multiple pathways that leukemia cells use to survive and grow. Gilteritinib specifically inhibits the FLT3 gene mutation, which is common in AML, while venetoclax targets the BCL-2 protein that helps cancer cells resist death. Azacitidine, an epigenetic modifier, further disrupts the cancer cell cycle, enhancing the overall effectiveness of the treatment. This multi-pronged attack could potentially lead to better outcomes for patients, particularly those with resistant forms of AML.

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

Research shows that a combination of three drugs—gilteritinib, venetoclax, and azacitidine—may be promising for treating acute myeloid leukemia (AML) with a changed FLT3 gene. This trial will evaluate this combination, with participants receiving gilteritinib, venetoclax, and azacitidine in both the Dose Ranging Cohort (Phase 1) and the Dose Expansion Cohort (Phase 2). Studies suggest this combination might work better than using venetoclax and azacitidine alone. Gilteritinib specifically targets the FLT3 gene, potentially slowing the growth of leukemia cells. Venetoclax and azacitidine are already known to be effective in some AML cases because they work together to kill cancer cells. Early results indicate that adding gilteritinib could increase the chances of remission, meaning more people might see their cancer disappear temporarily. Overall, this three-drug approach aims to treat AML more effectively than any of the drugs alone. ^{2 3 5 6 7}

Who Is on the Research Team?

Medical Director

Principal Investigator

Astellas Pharma Global Development, Inc.

Are You a Good Fit for This Trial?

This trial is for adults with newly diagnosed Acute Myeloid Leukemia (AML) who have a specific FLT3 gene change and can't have standard chemotherapy due to age or other health issues. They must be able to take oral medication, not be pregnant or breastfeeding, agree to use contraception, and not participate in another study.

Inclusion Criteria

I agree not to breastfeed during and for 60 days after the study.

Participant must have a projected life expectancy of at least 12 weeks

I have been diagnosed with Acute Myeloid Leukemia for the first time.

Exclusion Criteria

I need to take medication that strongly affects liver enzymes or drug transporters during the study.

I have serious heart condition limitations.

Participant has a known or suspected hypersensitivity to gilteritinib, azacitidine or venetoclax or any components of the formulations used

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

1 visit (in-person)

Phase 1 Treatment

Participants receive gilteritinib, venetoclax, and azacitidine to determine suitable venetoclax dose

Up to 12 cycles of 28 days each

Many visits during first cycle, less often in subsequent cycles

Phase 2 Treatment

Participants receive optimized doses of gilteritinib, venetoclax, and azacitidine

Up to 12 cycles of 28 days each

Many visits during first cycle, less often in subsequent cycles

Follow-up

Participants are monitored for safety and effectiveness after treatment

3 years

1 visit 30 days post-treatment, then every 3 months

Open-label extension (optional)

Participants in remission may continue with up to 24 more cycles of gilteritinib plus azacitidine

Up to 24 cycles of 28 days each

What Are the Treatments Tested in This Trial?

Interventions

• Azacitidine
• Gilteritinib
• Venetoclax

Trial Overview The trial tests a combination of Gilteritinib, Venetoclax, and Azacitidine in patients with AML who have the FLT3 mutation. It aims to find suitable doses and assess how these drugs work together in the body over two phases involving different dosages on a 28-day cycle.

How Is the Trial Designed?

Group I: Dose Ranging Cohort (Phase 1) Experimental Treatment 3 Interventions

Participants will receive daily dose of gilteritinib and venetoclax for 28 days, and azacitidine for 7 days in each 28-day cycle.

Group II: Dose Expansion Cohort (Phase 2) Experimental Treatment 3 Interventions

Participants will receive daily dose of gilteritinib, venetoclax, and azacitidine at an optimized dose established from dose ranging cohort (Phase 1)

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?

Astellas Pharma Global Development, Inc.

Lead Sponsor

Trials

204

Recruited

123,000+

Tadaaki Taniguchi

Astellas Pharma Global Development, Inc.

Chief Medical Officer

M.D., Ph.D.

Naoki Okamura

Astellas Pharma Global Development, Inc.

Chief Executive Officer

Not available

Published Research Related to This Trial

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]

The combination of venetoclax (Ven) and azacitidine (AZA) shows a high efficacy in treating acute myeloid leukemia (AML) and myelodysplastic syndrome (MDS), with an overall complete response rate of 57.9% across 19 studies involving 1615 patients.

This treatment is particularly effective for newly diagnosed AML patients, achieving a complete response rate of 67.5%, although it is less effective for those with relapsed or refractory AML, which had a response rate of only 30%.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

The efficacy and safety of venetoclax and azacytidine combination treatment in patients with acute myeloid leukemia and myelodysplastic syndrome: systematic review and meta-analysis. Du, Y., Li, C., Yan, J.[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 of 57 elderly patients (average age 69.9 years) with acute myeloid leukemia, the combination of venetoclax and azacitidine (VEN + AZA) showed a high overall response rate of 87.5% and a complete remission (CR) rate of 68.8%, indicating strong efficacy in this population.

The treatment was associated with a median overall survival (OS) of 11.5 months, and achieving minimal residual disease (MRD) negativity (<0.1%) was more common with VEN + AZA compared to traditional chemotherapy, although older patients (≥75 years) and those with higher ECOG scores faced more challenges in achieving MRD negativity.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Single-institution experience of venetoclax combined with azacitidine in newly diagnosed acute myeloid leukemia patients. Yu, H., Wang, C., Lei, Y., et al.[2023]

In a Japanese subgroup of the phase 3 VIALE-A trial, venetoclax-azacitidine significantly improved overall survival rates compared to placebo-azacitidine, with 67% of patients alive at 12 months versus 46% in the placebo group.

The treatment also resulted in a high complete response (CR) and CR with incomplete hematologic recovery (CRi) rate of 67%, while maintaining a safety profile similar to the global study, indicating it is a viable first-line treatment for Japanese patients with acute myeloid leukemia ineligible for intensive chemotherapy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Venetoclax plus azacitidine in Japanese patients with untreated acute myeloid leukemia ineligible for intensive chemotherapy. Yamamoto, K., Shinagawa, A., DiNardo, CD., et al.[2023]

Citations

1. clinicaltrials.gov clinicaltrials.gov/study/NCT06317649

NCT06317649 | Venetoclax and HMA Treatment of Older ... This phase II MyeloMATCH treatment trial compares the usual treatment of azacitidine and venetoclax to the combination treatment of azacitidine, venetoclax ...

2. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC6499443/

Evaluating venetoclax and its potential in treatment-naïve ... Relapsed acute myeloid leukemia is less sensitive to venetoclax + azacitidine due to leukemia stem cell resistance driven by fatty acid metabolism and can ...

3. link.springer.com link.springer.com/article/10.1007/s00277-025-06643-0

Efficacy and safety of venetoclax plus azacitidine based ... This meta-analysis aimed to evaluate the efficacy and safety of venetoclax plus azacitidine (VEN + AZA) regimens in patients with relapsed ...

4. clinicaltrials.gov clinicaltrials.gov/study/NCT04140487

NCT04140487 | Azacitidine, Venetoclax, and Gilteritinib in ... Giving azacitidine, venetoclax, and gilteritinib may work better compared to azacitidine and venetoclax alone in treating patients with acute myeloid leukemia ...

5. jcto.weill.cornell.edu jcto.weill.cornell.edu/open_clinical_trials/a-phase-12-multicenter-open-label-randomized-dose-ranging-and-expansion-study-of-the-combination-of-gilteritinib-venetoclax-azacitidine-in-patients-with-newly-diagnosed-flt3-mutated-acute-myeloid-leukemia-not-eligible-for-intensive

A Phase 1/2, Multicenter, Open-Label, Randomized Dose ... The purpose of this research is to gather information on the safety and effectiveness of Gilteritinib (sold under the brand name XOSPATA®) in newly diagnosed ...

6. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC11095865/

Azacitidine, Venetoclax, and Gilteritinib in Newly ... The addition of gilteritinib, an oral FLT3 inhibitor, to azacitidine and venetoclax may improve outcomes in patients with FLT3-mutated AML.

7. ashpublications.org ashpublications.org/blood/article/145/12/1237/517960/How-I-treat-patients-with-AML-using-azacitidine

How I treat patients with AML using azacitidine and venetoclax Venetoclax (VEN) received full approval in October 2020 for use in older patients who are unfit with acute myeloid leukemia (AML) combined with either ...