Venetoclax + HMA for Acute Myeloid Leukemia

Recruiting at 146 trial locations

Overseen by Jessica K Altman

Age: 18+

Sex: Any

Travel: May Be Covered

Time Reimbursement: Varies

Trial Phase: Phase 2

Recruiting

Sponsor: National Cancer Institute (NCI)

Must not be taking: Strong CYP3A4 inducers

Disqualifiers: Pregnancy, Breastfeeding, Uncontrolled infection, others

No Placebo Group

Prior Safety Data

Breakthrough Therapy

Trial Summary

What is the purpose of this trial?

This phase II MyeloMATCH treatment trial compares the usual treatment of azacitidine and venetoclax to the combination treatment of azacitidine, venetoclax and gilteritinib in treating older and unfit patients with acute myeloid leukemia and FLT3 mutations. Azacitidine is a drug that is absorbed into DNA and leads to the activation of cancer suppressor genes, which are genes that help control cell growth. Venetoclax is in a class of medications called B-cell lymphoma-2 (BCL-2) inhibitors. It may stop the growth of cancer cells by blocking Bcl-2, a protein needed for cancer cell survival. Gilteritinib is in a class of medications called kinase inhibitors. It works by blocking the action of a certain naturally occurring substance that may be needed to help cancer cells multiply. This study may help doctors find out if these different approaches are better than the usual approaches. To decide if they are better, the study doctors are looking to see if the study drugs lead to a higher percentage of patients achieving a deeper remission compared to the usual approach.

Will I have to stop taking my current medications?

The trial does not specify if you need to stop taking your current medications. However, you cannot be on a strong CYP3A4 inducing drug, as it may interfere with the trial medications.

What data supports the effectiveness of the drug combination Venetoclax and Azacitidine for treating acute myeloid leukemia?

Research shows that the combination of Venetoclax and Azacitidine improves remission rates and survival in older or unfit patients with acute myeloid leukemia compared to Azacitidine alone, with a high rate of complete remission. ^{1 2 3 4 5}

What makes the drug combination of Venetoclax, Azacitidine, and Gilteritinib unique for treating acute myeloid leukemia?

This drug combination is unique because it combines Venetoclax and Azacitidine, which are effective for older or unfit patients with acute myeloid leukemia, with Gilteritinib, potentially enhancing treatment outcomes. Venetoclax targets cancer cell survival mechanisms, while Azacitidine helps modify abnormal cell growth, making this combination a novel approach for those who cannot undergo standard chemotherapy. ^{1 2 3 4 5}

Research Team

Jessica K Altman

Principal Investigator

ECOG-ACRIN Cancer Research Group

Eligibility Criteria

This trial is for older adults or those unfit for intensive therapy, aged 60+ or younger with specific health considerations. Participants must have AML with FLT3 mutations, no prior treatment with hypomethylating agents or FLT3 inhibitors, and not be pregnant or breastfeeding. They should agree to use effective contraception.

Inclusion Criteria

I am HIV-positive, on treatment, and my viral load is undetectable.

My cancer has a specific genetic change known as FLT3-ITD or D835.

Patient must not breastfeed during treatment and for a specified period after treatment ends

Trial Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Induction

Patients receive azacitidine and venetoclax, with or without gilteritinib, for up to 2 cycles or until remission

8 weeks

Multiple visits for drug administration and monitoring

Consolidation

Patients continue treatment with azacitidine and venetoclax, with or without gilteritinib, for 2 years

2 years

Regular visits every 28 days for drug administration and monitoring

Follow-up

Participants are monitored for safety and effectiveness after treatment

Up to 10 years

Every 3 months if < 2 years from registration, every 6 months if 2-5 years from registration

Treatment Details

Interventions

• Azacitidine (Anti-tumor antibiotic)
• Gilteritinib (Kinase Inhibitor)
• Venetoclax (BCL-2 Inhibitor)

Trial Overview The study compares usual AML treatment (azacitidine + venetoclax) against a combination of azacitidine, venetoclax, and gilteritinib. It aims to see if adding gilteritinib increases the percentage of patients achieving deeper remission compared to the standard approach.

Participant Groups

Group I: Regimen 3 (azacitidine, venetoclax, gilteritinib) Experimental Treatment 6 Interventions

INDUCTION: Patients receive azacitidine IV or SC on days 1-7 and venetoclax PO on days 1-28, and gilteritinib PO on days 8-21 of each cycle. Treatment repeats every 28 days for up to 2 cycles or until patient achieves remission, whichever comes first, in the absence of disease progression or unacceptable toxicity. CONSOLIDATION: Patients receive azacitidine IV or SC on days 1-5, venetoclax PO on days 1-14 and gilteritinib PO on days 8-21 of each cycle. Cycles repeat every 28 days for 2 years in the absence of disease progression or unacceptable toxicity. Patients undergo bone marrow biopsy and aspiration as well as blood sample collection on the trial.

Group II: Regimen 2 (azacitidine, venetoclax, gilteritinib) Experimental Treatment 6 Interventions

INDUCTION: Patients receive azacitidine IV or SC on days 1-7 and venetoclax and gilteritinib PO on days 1-28 of each cycle. Treatment repeats every 28 days for up to 2 cycles or until patient achieves remission, whichever comes first, in the absence of disease progression or unacceptable toxicity. CONSOLIDATION: Patients receive azacitidine IV or SC on days 1-5, venetoclax PO on days 1-7 and gilteritinib PO on days 1-28 of each cycle. Cycles repeat every 28 days for 2 years in the absence of disease progression or unacceptable toxicity. Patients undergo bone marrow biopsy and aspiration as well as blood sample collection on the trial.

Group III: Regimen 1 (azacitidine, venetoclax) Experimental Treatment 5 Interventions

INDUCTION: Patients receive azacitidine IV or SC on days 1-7 of each cycle and venetoclax PO on days 1-28 of each cycle. Treatment repeats every 28 days for up to 2 cycles or until patient achieves remission, whichever comes first, in the absence of disease progression or unacceptable toxicity. CONSOLIDATION: Patients receive azacitidine IV or SC on days 1-7 and venetoclax PO on days 1-28 of each cycle. Cycles repeat every 28 days for 2 years in the absence of disease progression or unacceptable toxicity. Patients undergo bone marrow biopsy and aspiration as well as blood sample collection on the trial.

Azacitidine is already approved in Canada, Japan for the following indications:

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?

National Cancer Institute (NCI)

Lead Sponsor

Trials

14,080

Recruited

41,180,000+

Findings from Research

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 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 of 13 patients with acute leukemia treated with venetoclax and azacitidine, 46% developed COVID-19, highlighting a significant risk associated with this treatment during the pandemic.

The study found that 33% of those who contracted COVID-19 died from the virus, indicating that COVID-19 can lead to severe outcomes in patients receiving AZA-VEN therapy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

SARS-CoV-2 Infection in Patients Treated with Azacitidine and Venetoclax for Acute Leukemia: A Report of a Case Series Treated in a Single Institution. Drozd-Sokołowska, J., Mądry, K., Barankiewicz, J., 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 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]

References

1. 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]

2. England pubmed.ncbi.nlm.nih.gov

Venetoclax in combination with azacitidine in Japanese patients with acute myeloid leukaemia: phase 1 trial findings. [2021]

3. Switzerland pubmed.ncbi.nlm.nih.gov

SARS-CoV-2 Infection in Patients Treated with Azacitidine and Venetoclax for Acute Leukemia: A Report of a Case Series Treated in a Single Institution. [2023]

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

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

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

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