Triple-Drug Therapy for Acute Myeloid Leukemia

Recruiting at 20 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

Trial Summary

What is the purpose of this trial?

People with acute myeloid leukemia (AML) are usually treated with chemotherapy. Some people with AML have a changed FLT3 gene which causes leukemia cells to grow faster. Therefore, chemotherapy is less suitable to treat AML in people with the changed FLT3 gene. Gilteritinib, given with venetoclax and azacitidine, is a potential new treatment for people with AML with the changed FLT3 gene. They cannot have chemotherapy due to old age or other conditions. Before these combined 3 medicines are available as a treatment, the researchers need to understand how they are processed by and act upon the body when given together. In this study, they do this to find a suitable dose for venetoclax and to check for potential medical problems from the treatment. In this study, people newly diagnosed with AML who have the changed FLT3 gene and cannot have chemotherapy can take part. The main aims of this study are: to find suitable doses of gilteritinib, venetoclax and azacitidine as a combined treatment; to learn how they are processed by and act upon the body; to learn the remission rate; to check for medical problems during this treatment. In the study, people will visit the study clinic many times. The first visit is to check if they can take part. People will be asked about their medical history, have a medical examination, and have their vital signs checked. Also, they will have an ECG to check their heart rhythm and have some blood and urine samples taken for laboratory tests. They will have a chest X-ray and a bone marrow sample will be taken. The changed FLT3 gene will be confirmed, either by the bone marrow or a blood sample. This study will be in 2 phases. In Phase 1, different small groups of people will take venetoclax tablets containing lower to higher doses in the combined treatment. The doses of gilteritinib and azacytidine will be unchanged. This is done to find a suitable dose of venetoclax to use in phase 2 of the study. People will take tablets of gilteritinib and venetoclax once a day on a 28-day cycle. They will be given azacytidine as an infusion or an injection just under the skin. This will be for 7 days at the beginning of each 28-day cycle. They will continue cycles of treatment throughout this phase of the study. In Phase 2, more people newly diagnosed with AML with the changed FLT3 gene will take part. They will be treated with the suitable doses of the combined treatment worked out from Phase 1. Treatment will be on a 28-day cycle. People will continue on cycles of treatment throughout this phase of the study. Researchers will work out the remission rate from this phase of the study. In each phase of the study, people can continue with up to 12 cycles of treatment if they can manage any medical problems. People will visit the study clinic many times during their first treatment cycle, and less often during the next cycles. During these visits, medical problems will be recorded and some blood samples will be taken for laboratory tests. On some visits, people will also have their vital signs checked. Bone marrow samples will be taken during cycle 1, and at the beginning of cycle 3. More samples will be taken during the study from people who are not in remission. When people have finished treatment, those who have responded well to treatment and are in remission will be invited to continue with up to 24 more cycles of gilteritinib plus azacitidine. All people taking part in the study will visit the study clinic for an end-of-treatment visit. During this visit, medical problems will be recorded and some blood samples will be taken for laboratory tests. People will have a medical examination, an ECG, and will have their vital signs checked. Also, a bone marrow sample will be taken. There will be a follow-up visit 30 days later to check for medical problems. Then people will visit the clinic or get a phone call every 3 months for up to 3 years. This is to give an update on their current treatment for AML. Some people can have a stem cell transplant during the study if they meet certain study rules. They will pause their study treatment during the stem cell transplant process and continue study treatment afterwards.

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.

How is the triple-drug therapy for acute myeloid leukemia different from other treatments?

The triple-drug therapy for acute myeloid leukemia combines azacitidine, gilteritinib, and venetoclax, which is unique because it targets multiple pathways in cancer cells, potentially improving treatment effectiveness. This combination is novel as venetoclax and azacitidine are already known to improve remission rates, and adding gilteritinib may enhance outcomes further, especially for patients who are not eligible for intensive chemotherapy. ^{1 2 3 4 5}

Research Team

Medical Director

Principal Investigator

Astellas Pharma Global Development, Inc.

Eligibility Criteria

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

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

Treatment Details

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.

Participant Groups

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

Findings from Research

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]

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]

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 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]

References

1. England pubmed.ncbi.nlm.nih.gov

Not BCL2 mutation but dominant mutation conversation contributed to acquired venetoclax resistance in acute myeloid leukemia. [2022]

2. United States 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. [2023]

3. England 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. [2023]

4. Netherlands pubmed.ncbi.nlm.nih.gov

Single-institution experience of venetoclax combined with azacitidine in newly diagnosed acute myeloid leukemia patients. [2023]

5. England pubmed.ncbi.nlm.nih.gov

Venetoclax plus azacitidine in Japanese patients with untreated acute myeloid leukemia ineligible for intensive chemotherapy. [2023]