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)

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial aims to determine the optimal dose of venetoclax when combined with azacitidine and pevonedistat for treating acute myeloid leukemia (AML). These medicines work together to stop cancer cells from growing and spreading. Participants should have a new diagnosis of AML and may have previously experienced conditions like myelodysplastic syndrome (MDS) or exposure to chemotherapy. 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 combination therapy.

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.

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

Research has shown that the combination of azacitidine, venetoclax, and pevonedistat is generally safe for patients with acute myeloid leukemia (AML). Studies have indicated promising results, particularly for patients previously treated for AML. However, some serious side effects have been reported. For example, in one study involving the venetoclax and azacitidine mix, 2 out of 10 patients developed fatal sepsis, a severe blood infection, prompting changes in the study.

These findings suggest that while the treatment has potential, risks are involved. The current phase of the study involves determining the best dose and assessing patient tolerance. Participants should consult their healthcare provider to understand the possible benefits and risks. ^{1 2 3 4 5}

Why are researchers excited about this trial's treatments?

Researchers are excited about the combination of azacitidine, venetoclax, and pevonedistat for treating Acute Myeloid Leukemia (AML) because it offers a novel approach compared to standard treatments like chemotherapy. Azacitidine and venetoclax work together to disrupt cancer cell growth, while pevonedistat adds a unique mechanism by inhibiting a protein that helps cancer cells survive, potentially enhancing the treatment's effectiveness. This combination targets multiple pathways simultaneously, which might lead to better outcomes and offer hope for patients with limited options.

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

This trial will evaluate the combination of azacitidine, venetoclax, and pevonedistat for treating acute myeloid leukemia (AML). Studies have shown that these three drugs together can effectively treat AML, with promising results suggesting they might help stop cancer growth. Azacitidine prevents cancer cells from multiplying and spreading. Venetoclax targets a protein called Bcl-2, which cancer cells need to survive. Pevonedistat inhibits enzymes that aid cancer cell growth. Research suggests that adding pevonedistat may lead to better outcomes than using only azacitidine and venetoclax. Overall, this combination shows early signs of being a strong treatment option for AML. ^{1 2 3 4 6}

Who Is on the Research Team?

Nicholas Short

Principal Investigator

M.D. Anderson Cancer Center

Are You a Good Fit for This Trial?

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 for a Trial Participant

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

What Are the Treatments Tested in This Trial?

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.

How Is the Trial Designed?

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+

Published Research Related to This Trial

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 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]

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 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 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]

Citations

1. pubmed.ncbi.nlm.nih.gov pubmed.ncbi.nlm.nih.gov/38572562/

A phase I study of pevonedistat, azacitidine, and ... To assess the tolerability and efficacy of adding pevonedistat to azacitidine/ venetoclax in relapsed/refractory AML, we conducted a phase I, ...

2. clinicaltrials.gov clinicaltrials.gov/study/NCT04266795

NCT04266795 | A Study of Pevonedistat and Venetoclax ... Pevonedistat is being tested to treat people who have AML. This study will compare the improvement in EFS in Arm A: Pevonedistat + Venetoclax + Azacitidine ...

3. tandfonline.com tandfonline.com/doi/full/10.1080/10428194.2024.2431878

Azacitidine and venetoclax with or without pevonedistat in ... This phase 2 study investigated pevonedistat + azacitidine + venetoclax (n = 83) versus azacitidine + venetoclax (n = 81) in patients with newly diagnosed ...

4. ashpublications.org ashpublications.org/blood/article/145/11/1126/534406/Efficacy-and-safety-of-venetoclax-plus-azacitidine

Efficacy and safety of venetoclax plus azacitidine for patients ... Outcomes are poor in patients with higher-risk myelodysplastic syndromes (HR MDS) and frontline treatment options are limited. This phase 1b study ...

5. haematologica.org haematologica.org/article/view/haematol.2024.285014

A phase I study of pevonedistat, azacitidine, and ... The combination of azacitidine, venetoclax and pevonedistat is safe and shows encouraging preliminary activity in patients with relapsed/refractory AML.

6. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC11367232/

A phase I study of pevonedistat, azacitidine, and venetoclax in ... The combination of azacitidine, venetoclax and pevonedistat is safe and shows encouraging preliminary activity in patients with relapsed/refractory AML. ( ...