Combination Therapies for Acute Myeloid Leukemia

Recruiting in Palo Alto (17 mi)

+117 other locations

Overseen by Mary L Savoie

Age: 18 - 65

Sex: Any

Travel: May Be Covered

Time Reimbursement: Varies

Trial Phase: Phase 2

Recruiting

Sponsor: National Cancer Institute (NCI)

Must not be taking: CYP3A inhibitors

Disqualifiers: Pregnancy, Myeloid sarcoma, Allergic reactions, 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 cytarabine with daunorubicin versus cytarabine with daunorubicin and venetoclax versus venetoclax with azacitidine for the treatment of younger patients with intermediate risk acute myeloid leukemia (AML). Cytarabine is a drug that inhibits some of the enzymes needed for deoxyribonucleic acid (DNA) replication and repair and can slow or stop the growth of cancer cells. Daunorubicin is a drug that blocks a certain enzyme needed for cell division and DNA repair, and it may kill cancer cells. 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. Azacitidine is a drug that interacts with DNA to activate tumor-suppressing genes, resulting in an anti-tumor effect. Adding venetoclax to cytarabine and daunorubicin, and adding venetoclax to azacitidine, may work better than the usual treatment of cytarabine with daunorubicin alone. To decide if they are better, the study doctors are looking to see if venetoclax increases the rate of elimination of AML in participants by 20% or more compared to the usual approach.

Do I need to stop my current medications to join the trial?

The trial requires participants to stop taking strong or moderate CYP3A inhibitors at least 48 hours before starting the study treatment if assigned to arm 1 or 2. Other medication requirements are not specified in the protocol.

What data supports the effectiveness of this drug combination for treating acute myeloid leukemia?

Research shows that combining venetoclax with azacitidine improves remission rates and survival in patients with acute myeloid leukemia, especially those who are older or not fit for intensive chemotherapy. This combination has been shown to significantly prolong overall survival compared to azacitidine alone. ^{1 2 3 4 5}

Is the combination therapy of Venetoclax and Azacitidine safe for treating acute myeloid leukemia?

The combination of Venetoclax and Azacitidine has been shown to be generally safe for treating acute myeloid leukemia, with common side effects including low blood cell counts (neutropenia, thrombocytopenia, and anemia). These side effects are considered tolerable, and the treatment is effective in achieving remission in many patients. ^{5 6 7 8 9}

What makes this drug combination unique for treating acute myeloid leukemia?

This drug combination is unique because it combines venetoclax with azacitidine, cytarabine, and daunorubicin, which is particularly beneficial for older or unfit patients with acute myeloid leukemia (AML) who are ineligible for intensive chemotherapy. The combination has shown improved remission rates and survival compared to azacitidine alone, offering a promising option for those who cannot undergo more aggressive treatments. ^{3 4 7 10 11}

Research Team

Mary L Savoie

Principal Investigator

Canadian Cancer Trials Group

Eligibility Criteria

This trial is for younger patients with intermediate risk acute myeloid leukemia (AML) who have specific genetic mutations or changes. They must be enrolled in the MyeloMATCH program, assigned to this study based on actionable mutations, and agree to submit specimens for research.

Inclusion Criteria

Participants must have been registered to master screening and re-assessment protocol (myeloMATCH MSRP) prior to consenting to this study

I am between 18 and 59 years old.

I am capable of limited self-care and spend more than half of my waking hours out of bed.

Exclusion Criteria

Patients who are receiving any other investigational agents

I have AML and have only been treated with hydroxyurea or leukapheresis.

Pregnant women

Trial Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants receive assigned treatment regimen based on randomization: daunorubicin, cytarabine, and venetoclax; azacitidine and venetoclax; or daunorubicin and cytarabine. Treatment cycles are 28 days.

Up to 56 days

Multiple visits for drug administration and assessments

Follow-up

Participants are monitored for safety and effectiveness after treatment completion, with follow-up assessments at 4 weeks, every 3 months for 1 year, every 6 months for the second year, and yearly thereafter.

Up to 10 years

Treatment Details

Interventions

• Azacitidine (DNA Methylation Inhibitor)
• Cytarabine (Anti-tumor antibiotic)
• Daunorubicin Hydrochloride (Anti-tumor antibiotic)
• Venetoclax (BCL-2 Inhibitor)

Trial Overview The trial compares three treatments: Cytarabine + Daunorubicin; Cytarabine + Daunorubicin + Venetoclax; and Venetoclax + Azacitidine. It aims to see if adding Venetoclax improves treatment effectiveness by at least 20% over standard therapy.

Participant Groups

Group I: ARM II (azacitidine, venetoclax) Experimental Treatment 4 Interventions

Patients receive azacitidine IV or SC on days 1-7 or days 1-5 and 8-9 and venetoclax PO on days 1-28 of each cycle. Cycles repeat every 28 days for a total of 2 cycles, in the absence of disease progression or unacceptable toxicity. Patients also undergo bone marrow aspiration and collection of blood samples on study and as clinically indicated.

Group II: ARM I (daunorubicin, cytarabine, venetoclax) Experimental Treatment 5 Interventions

Patients receive daunorubicin IV on days 2-4, cytarabine IV continuously on days 2-8, and venetoclax PO QD on days 1-11. Cycle is 28 days and treatment is given in the absence of disease progression or unacceptable toxicity. Based on a bone marrow aspiration assessment, patients may receive reinduction consisting of daunorubicin IV on days 2-3, cytarabine IV continuously on days 2-6, and venetoclax PO QD on days 1-8. Cycle is 28 days and treatment is given in the absence of disease progression or unacceptable toxicity. Patients also undergo bone marrow aspiration and collection of blood samples on study and as clinically indicated.

Group III: ARM III (daunorubicin, cytarabine) Active Control 4 Interventions

Patients receive daunorubicin IV on days 1-3 and cytarabine IV, continuously, on days 1-7. Cycle is 28 days and treatment is given in the absence of disease progression or unacceptable toxicity. Based on a bone marrow aspiration assessment, patients may receive reinduction consisting of cytarabine IV, continuously, on days 1-5 and daunorubicin IV on days 1-2. Cycle is 28 days and treatment is given in the absence of disease progression or unacceptable toxicity. Patients also undergo bone marrow aspiration and collection of blood samples on study and as clinically indicated.

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

Find a Clinic Near You

Research Locations Nearby Select from list below to view details:

Genesee Cancer and Blood Disease Treatment Center Flint, MI

Genesee Hematology Oncology PC Flint, MI

Genesys Hurley Cancer Institute Flint, MI

Hurley Medical Center Flint, MI

More Trial Locations

Who Is Running the Clinical Trial?

National Cancer Institute (NCI)

Lead Sponsor

Trials

14080

Patients Recruited

41,180,000+

Findings from Research

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]

Venetoclax (VEN) is FDA approved for treating newly diagnosed elderly or unfit patients with acute myeloid leukemia (AML) when combined with hypomethylating agents, showing complete remission rates of 28.3% and overall survival improvements in a phase-3 study.

While VEN has demonstrated effectiveness in various myeloid malignancies, including relapsed AML and high-risk myelodysplastic syndromes, remissions are often short-lived, typically lasting less than a year, but can facilitate transitions to allogeneic stem cell transplants.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Venetoclax-based chemotherapy in acute and chronic myeloid neoplasms: literature survey and practice points. Gangat, N., Tefferi, A.[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 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]

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]

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

[Short-term efficacy of venetoclax combined with azacitidine in acute myeloid leukemia: a single-institution experience]. Yu, WJ., Jia, JS., Wang, J., et al.[2022]

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Venetoclax-based combinations for acute myeloid leukemia: optimizing their use in Latin-America. Gómez-De León, A., Demichelis-Gómez, R., Pinedo-Rodríguez, A., et al.[2022]

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]

The VA regimen, combining venetoclax and azacitidine, demonstrated a high complete remission (cCR) rate of 78.8% after the first treatment cycle and 81.8% after prolonged treatment in 66 patients with newly diagnosed acute myeloid leukemia (AML) who were not suitable for conventional chemotherapy.

The treatment was generally safe, with manageable adverse effects, primarily neutropenia, thrombocytopenia, and anemia, and showed better outcomes in patients with specific gene mutations (IDH1/2 or NPM1) and those experiencing rebound thrombocytosis.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

[Efficacy of venetoclax combined azacitidine in newly diagnosed acute myeloid leukemia unfit for standard chemotherapy: a single center experience]. Sun, L., Ye, SJ., Zhou, N., et al.[2023]

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]

References

1. 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]

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

Venetoclax-based chemotherapy in acute and chronic myeloid neoplasms: literature survey and practice points. [2023]

3. 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]

4. England pubmed.ncbi.nlm.nih.gov

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

6. China pubmed.ncbi.nlm.nih.gov

[Short-term efficacy of venetoclax combined with azacitidine in acute myeloid leukemia: a single-institution experience]. [2022]

7. England pubmed.ncbi.nlm.nih.gov

Venetoclax-based combinations for acute myeloid leukemia: optimizing their use in Latin-America. [2022]

8. Netherlands pubmed.ncbi.nlm.nih.gov

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

9. China pubmed.ncbi.nlm.nih.gov

[Efficacy of venetoclax combined azacitidine in newly diagnosed acute myeloid leukemia unfit for standard chemotherapy: a single center experience]. [2023]

10. 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]

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

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