Azacitidine + Venetoclax + Pevonedistat for Acute Myeloid Leukemia

Overseen By Nicholas Short

Age: 18+

Sex: Any

Trial Phase: Phase 1 & 2

Sponsor: M.D. Anderson Cancer Center

Must not be taking: Strong CYP3A4 inducers

Disqualifiers: Uncontrolled infection, Cardiopulmonary disease, Hepatic impairment, others

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

Compensation: Varies

Number of Visits: 1

Duration: Up to 24 cycles (28 days each)

40 Participants Needed

Trial Summary

What is the purpose of this trial?

This phase I/II trial studies the best dose of venetoclax when given together with azacitidine and pevonedistat and to see how well it works in treating patients with newly diagnosed acute myeloid leukemia. Drugs used in chemotherapy, such as azacitidine, 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. Pevonedistat may stop the growth of cancer cells by blocking some of the enzymes needed for cell growth. Giving azacitidine, venetoclax, and pevonedistat may work better in treating patients with acute myeloid leukemia.

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

The trial does not specify if you need to stop taking your current medications. However, you cannot take strong CYP3A4 inducers within 14 days before starting the study drug, and certain other treatments are restricted. It's best to discuss your specific medications with the trial team.

What data supports the effectiveness of the drug combination Azacitidine, Venetoclax, and Pevonedistat for treating Acute Myeloid Leukemia?

Research shows that combining venetoclax with azacitidine improves remission rates and survival in older patients with acute myeloid leukemia compared to azacitidine alone. This suggests that adding venetoclax to treatments for this condition can be beneficial. ^{1 2 3 4 5}

Is the combination of Azacitidine, Venetoclax, and Pevonedistat safe for humans?

The combination of Azacitidine and Venetoclax has been studied in patients with acute myeloid leukemia and is generally considered safe, with common side effects including blood-related and digestive issues. However, specific safety data for the combination with Pevonedistat is not provided in the available research. ^{2 5 6 7 8}

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

This drug combination is unique because it includes Pevonedistat, which is not commonly used in standard treatments for acute myeloid leukemia. Pevonedistat works by inhibiting a specific protein that helps cancer cells survive, potentially offering a new approach to treatment when combined with Azacitidine and Venetoclax. ^{1 2 3 5 9}

Research Team

Nicholas Short

Principal Investigator

M.D. Anderson Cancer Center

Eligibility Criteria

This trial is for adults with newly diagnosed acute myeloid leukemia who have not received certain previous treatments and are not suitable for intensive chemotherapy. They should be in a relatively good physical state (ECOG 0-2), able to practice effective contraception, and have adequate organ function. Those with severe infections, heart conditions, or other serious health issues unrelated to cancer are excluded.

Inclusion Criteria

I have MDS or CMML and my treatment with azacitidine or decitabine did not work.

My blood disorder shows abnormal cell changes in at least half of certain blood cells, without specific genetic mutations.

Your bilirubin levels should not be too high, except if you have a condition called Gilbert's syndrome, or if the high levels are related to your leukemia. If you have Gilbert's syndrome or high levels due to leukemia, you may still be able to participate if your direct bilirubin levels are within a certain range.

Exclusion Criteria

I haven't had cancer treatment except for specific exceptions in the last 14 days.

My cancer is only present outside the bone marrow.

I am HIV positive with a CD4 count over 350, undetectable viral load, on specific HIV meds, and no severe infections.

Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants receive venetoclax orally once daily on days 1-28, azacitidine intravenously or subcutaneously on days 1-7, and pevonedistat intravenously on days 1, 3, and 5. Treatment repeats every 28 days for up to 24 cycles.

Up to 24 cycles (28 days each)

Follow-up

Participants are monitored for safety and effectiveness after treatment completion

30 days

1 visit (in-person), then every 6 months

Treatment Details

Interventions

• Azacitidine
• Pevonedistat
• Venetoclax

Trial Overview The study is testing the combination of three drugs: Azacitidine, Venetoclax, and Pevonedistat. It aims to find the best dose of Venetoclax alongside the other two drugs and evaluate how well this trio works together against acute myeloid leukemia by stopping cancer cells from growing.

Participant Groups

Group I: Treatment (venetoclax, azacitidine, pevonedistat) Experimental Treatment 3 Interventions

Patients receive venetoclax PO QD on days 1-28, azacitidine IV or SC on days 1-7, and pevonedistat IV over 60 minutes on days 1, 3, and 5. Treatment repeats every 28 days for up to 24 cycles in the absence of disease progression or unacceptable toxicity.

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?

M.D. Anderson Cancer Center

Lead Sponsor

Trials

3,107

Recruited

1,813,000+

National Cancer Institute (NCI)

Collaborator

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 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]

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]

Outpatient induction therapy using low-dose venetoclax combined with itraconazole and azacitidine is feasible and safe for newly diagnosed acute myeloid leukemia (ND-AML) patients, with 77.7% of participants completing the first treatment cycle as outpatients.

The treatment showed promising efficacy, with a composite complete response rate of 53.9% after the first cycle and 85.7% after the second cycle, indicating that this regimen could be a viable option for patients eligible for intensive chemotherapy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Low dose venetoclax plus itraconazole outpatient induction in newly diagnosed acute myeloid leukemia: A phase 2 study. De la Garza-Salazar, F., Colunga-Pedraza, PR., Gómez-Almaguer, D., 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 study of 60 patients with acute myeloid leukemia (AML), the combination of venetoclax and azacitidine (Ven+AZA) demonstrated a high response rate, with 70.8% of previously untreated patients unfit for standard chemotherapy achieving complete remission (CR) or CR with incomplete hematological recovery (CRi) after one cycle.

Ven+AZA was found to be safe and tolerable, with some patients achieving minimal residual disease (MRD) negativity, particularly in those with favorable genetic mutations like NPM1, IDH1/IDH2, and TP53, indicating its potential effectiveness in specific patient subgroups.

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]

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

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

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

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

5. 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]

6. England pubmed.ncbi.nlm.nih.gov

Low dose venetoclax plus itraconazole outpatient induction in newly diagnosed acute myeloid leukemia: A phase 2 study. [2023]

7. Netherlands pubmed.ncbi.nlm.nih.gov

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

8. China pubmed.ncbi.nlm.nih.gov

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

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

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