Azacitidine + Venetoclax for Acute Myeloid Leukemia

Age: 18+

Sex: Any

Trial Phase: Phase 2

Sponsor: University of Colorado, Denver

Must not be taking: CYP3A inhibitors, CYP3A inducers

Disqualifiers: HIV, Hepatitis B/C, CNS involvement, others

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

Prior Safety Data This treatment has passed at least one previous human trial

Approved in 5 Jurisdictions This treatment is already approved in other countries

Compensation: Varies

Number of Visits: Unknown

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial tests whether a combination of two drugs, azacitidine (Vidaza) and venetoclax, can effectively treat acute myeloid leukemia (AML) in older adults who haven't received prior treatment. The goal is to determine if these drugs can manage AML when standard treatments aren't viable due to other health issues. Suitable candidates for this trial are individuals aged 60 or older with AML who cannot or choose not to undergo standard aggressive treatments. As a Phase 2 trial, this research focuses on assessing the treatment's effectiveness in an initial, smaller group, offering a promising opportunity to advance AML treatment options.

Will I have to stop taking my current medications?

The trial protocol does not specify if you must stop taking your current medications. However, you cannot take certain medications like strong CYP3A inhibitors or inducers within 7 days before starting the study drugs.

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

Research has shown that the combination of azacitidine and venetoclax is generally well-tolerated by patients with acute myeloid leukemia (AML). Studies have found that common side effects include constipation and nausea, affecting about half of the patients. About 49% of patients experienced a decrease in neutrophils, a type of white blood cell, which can increase the risk of infections.

More seriously, about 23% of patients had severe reactions, with pneumonia being the most common. Despite these risks, the treatment's benefits, such as higher remission rates, are considered significant. These findings suggest that while side effects exist, many patients find the treatment manageable. ^{1 2 3 4 5}

Why do researchers think this study treatment might be promising for acute myeloid leukemia?

Researchers are excited about the combination of Azacitidine and Venetoclax for treating Acute Myeloid Leukemia (AML) because it offers a unique approach compared to traditional chemotherapy treatments. Unlike the standard of care, which typically involves intensive chemotherapy, this combination targets the cancer in a more targeted manner. Azacitidine is a hypomethylating agent that works by interfering with the DNA of cancer cells, while Venetoclax is a BCL-2 inhibitor that helps induce cancer cell death by disrupting a protein that prevents cell death. This dual-action approach not only targets the cancer cells more precisely but also has the potential to be less harsh on the body, offering hope for improved outcomes with potentially fewer side effects.

What evidence suggests that azacitidine and venetoclax could be effective for acute myeloid leukemia?

Research has shown that the combination of azacitidine and venetoclax, which participants in this trial will receive, holds promise for treating older patients with acute myeloid leukemia (AML). Studies have found that these drugs work well, particularly for older patients who might not tolerate stronger treatments. In one study with 654 patients, many responded positively to azacitidine and venetoclax. Another study noted that this combination caused fewer side effects compared to other treatments. Overall, this combination offers hope for those dealing with this challenging condition. ^{1 6 7 8 9}

Who Is on the Research Team?

Dan Pollyea

Principal Investigator

University of Colorado, Denver

Are You a Good Fit for This Trial?

This trial is for elderly patients (≥60 years old) with newly diagnosed acute myeloid leukemia (AML), who can't or won't undergo standard treatment due to health issues. They must have a life expectancy of at least 12 weeks, be able to perform daily activities with minimal assistance (ECOG ≤2), and have proper kidney and liver function. Men and postmenopausal or surgically sterile women must agree to use contraception.

Inclusion Criteria

My kidneys work well enough, with a creatinine clearance rate of at least 30 mL/min.

My liver functions within normal limits, except for conditions like Gilbert's syndrome.

I agree to use birth control and not donate sperm from the start of the study until 90 days after the last dose.

Exclusion Criteria

Subject is known to be positive for hepatitis B or C infection with the exception of those with an undetectable viral load. Hepatitis B or C testing is not required and subjects with serologic evidence of prior vaccination to HBV (i.e., HBs Ag, anti-HBs+ and anti-HBc-) may participate

My leukemia has spread to my brain or spinal cord.

I haven't taken steroids, certain medications, or consumed grapefruit and related products recently.

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Induction Treatment

Participants receive azacitidine and venetoclax until a minimal residual disease (MRD) negative response is achieved

4-8 weeks

Weekly visits for azacitidine administration

Maintenance Treatment

Participants continue with venetoclax alone at a maintenance dose after achieving MRD negative response

Up to 1 year

Monthly visits for monitoring

Follow-up

Participants are monitored for safety and effectiveness after treatment

1 year

What Are the Treatments Tested in This Trial?

Interventions

• Azacitidine
• Venetoclax

Trial Overview The study tests azacitidine combined with venetoclax as an initial ('induction') therapy followed by maintenance doses of venetoclax alone in elderly AML patients who respond well to the first phase. The goal is to see if this regimen is effective when standard treatments aren't suitable.

How Is the Trial Designed?

Group I: Azacitidine and Venetoclax Experimental Treatment 1 Intervention

On day 1 of cycle 1, Azacitidine 75 mg/m2 will be given by injection or infusion, and will continue for 7 days. Azacitidine doses will be given in subsequent cycles for patients who do not achieve response. Venetoclax will be administered orally once daily on days 2 through 28 in cycle 1. Beginning with cycle 2, and each subsequent cycle, venetoclax will be administered Days 1 through 28.

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?

University of Colorado, Denver

Lead Sponsor

Trials

1,842

Recruited

3,028,000+

Published Research Related to This Trial

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 50 adults with acute myeloid leukemia (AML) in Mexico and Peru, venetoclax-based therapy showed a high complete response rate of 78.6% in newly diagnosed patients and 45.5% in those with relapsed/refractory disease, indicating its efficacy in treating AML.

The median overall survival was 9.6 months for newly diagnosed patients and 8 months for relapsed/refractory patients, suggesting that venetoclax is a viable treatment option even in real-world settings, despite common hematologic toxicities and dose adjustments.

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]

In treatment-naïve patients with IDH1/2-mutant acute myeloid leukemia (AML), the combination of venetoclax and azacitidine resulted in a high composite complete remission rate of 79% and a median overall survival of 24.5 months, significantly outperforming the azacitidine-only group, which had an 11% remission rate and 6.2 months of survival.

The treatment was found to be safe, with no unexpected toxicities reported, and the favorable outcomes for patients with IDH1/2 mutations were consistent regardless of their cytogenetic risk, indicating a robust efficacy of this regimen.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Impact of Venetoclax and Azacitidine in Treatment-Naïve Patients with Acute Myeloid Leukemia and IDH1/2 Mutations. Pollyea, DA., DiNardo, CD., Arellano, ML., et al.[2023]

In a study of 20 elderly patients with relapsed refractory acute myeloid leukemia (AML), the combination of azacytidine and venetoclax showed a total treatment efficiency of 90%, significantly higher than the 40% efficiency observed with azacytidine alone.

The combination treatment improved hematological parameters, such as platelet and white blood cell counts, while maintaining a similar safety profile to azacytidine alone, indicating it is a promising option for enhancing treatment efficacy in this patient population.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Analysis of the Clinical Efficacy of Azacytidine + Venetoclax in the Treatment of Elderly Patients with Relapsed Refractory Acute Myeloid Leukemia. Wang, W., Luo, Q., Chen, Q., et al.[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 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 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]

Citations

1. nature.com nature.com/articles/s41375-025-02730-3

Outcomes of patients treated with venetoclax plus ... Overall survival for patients likely to benefit from IC (A), less likely to benefit from IC (B), and likely to benefit from palliative care or a ...

2. pubmed.ncbi.nlm.nih.gov pubmed.ncbi.nlm.nih.gov/40951718/

Real-world outcomes of azacitidine plus venetoclax in ... This real-world practice highlights the feasibility and effectiveness of AZA-VEN in combination with antifungal prophylaxis for elderly or ...

3. pubmed.ncbi.nlm.nih.gov pubmed.ncbi.nlm.nih.gov/40496033/

Outcomes of patients with Acute Myeloid Leukemia ... Our findings contribute to the growing evidence that venetoclax combined with azacitidine is an effective treatment option for elderly patients with AML.

4. sciencedirect.com sciencedirect.com/science/article/pii/S2950328024000177

Real-world outcomes of newly diagnosed AML treated with ... Here we report a large real-world cohort of 654 patients treated in 53 UK hospitals with either venetoclax and azacitidine (n=587) or LDAC (n=67).

5. ascopubs.org ascopubs.org/doi/10.1200/JCO.2025.43.16_suppl.e18509

Comparative safety and effectiveness of azacitidine plus ... In AML patients aged 60–75 years, HMA&Ven demonstrated comparable all-cause mortality to IC and significantly lower risk of several adverse events.

6. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC12135334/

Efficacy and safety of venetoclax and azacitidine for acute ... VEN-AZA demonstrated high efficacy and manageable toxicity in patients with AML. Following VEN-AZA failure, the combination of VEN-AZA with ...

7. 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 ... Adverse events reflected known safety profiles for venetoclax and azacitidine, including constipation (53.3%), nausea (49.5%), neutropenia (48.6%), ...

8. nejm.org nejm.org/doi/full/10.1056/NEJMoa2012971

Azacitidine and Venetoclax in Previously Untreated Acute ... In patients with composite complete remission, measurable residual disease negativity occurred in 23.4% (95% CI, 18.6 to 28.8) of the patients ...

9. venclextahcp.com venclextahcp.com/aml/efficacy/ven-aza/survival-results.html

VEN+AZA: Overall survival (OS) data from the VIALE-A trial Fatal adverse reactions occurred in 23% of patients who received VENCLEXTA in combination with azacitidine, with the most frequent (≥2%) being pneumonia (4%), ...