Venetoclax + Azacitidine for Acute Myeloid Leukemia

Recruiting at 8 trial locations

Overseen By Amir T Fathi, MD

Age: 18+

Sex: Any

Trial Phase: Phase 2

Sponsor: Massachusetts General Hospital

Must not be taking: CYP3A inducers

Disqualifiers: APL, FLT3-mutated AML, CML, 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

Compensation: Varies

Number of Visits: Unknown

Duration: Up to 3 years

172 Participants Needed

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial tests a new combination of drugs, azacitidine (a chemotherapy drug) and venetoclax (a targeted therapy), to determine if they outperform standard chemotherapy for people with newly diagnosed acute myeloid leukemia (AML). The goal is to identify which treatment more effectively reduces cancer cells. Participants will receive either the investigational treatment or the standard chemotherapy, which involves different drugs. This trial targets individuals diagnosed with AML who have not yet received treatment. As a Phase 2 trial, the research focuses on measuring the treatment's effectiveness in an initial, smaller group of people.

Will I have to stop taking my current medications?

The trial does not specify if you need to stop taking your current medications, but it does exclude patients who have taken strong or moderate CYP3A inducers within 7 days before starting the study treatment. It's best to discuss your current medications with the study team to see if any adjustments are needed.

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

Research shows that the combination of venetoclax and azacitidine is generally well-tolerated by patients with acute myeloid leukemia (AML). Studies found that patients experienced manageable side effects. Common side effects included low white blood cell counts and nausea, typical for many cancer treatments.

Evidence suggests that this treatment may be safer than traditional chemotherapy, especially for older patients who often struggle more with standard chemotherapy. The treatment aims to improve survival rates while helping patients maintain a better quality of life during treatment.

Although side effects occur, patients generally handle them well, according to available data. Always consult your healthcare team to determine if this treatment is suitable for you. ^{1 2 3 4 5}

Why are researchers excited about this trial's treatments?

Unlike the standard of care for acute myeloid leukemia, which typically involves chemotherapy drugs like cytarabine and daunorubicin, the investigational treatment of venetoclax and azacitidine offers a unique approach. Venetoclax works by targeting the BCL-2 protein, which helps cancer cells survive, thereby promoting their death and potentially increasing treatment effectiveness. Azacitidine, on the other hand, is a hypomethylating agent that can alter cancer cell DNA, making them more sensitive to treatment. Researchers are excited about this combination because it may enhance treatment responses and offer a promising option for patients who may not tolerate traditional chemotherapy well.

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

Research has shown that combining venetoclax and azacitidine may help treat acute myeloid leukemia (AML). Studies have demonstrated that this combination can extend the lives of older patients who haven't been treated before. Participants in this trial may receive this investigational combination, which has shown better results compared to some traditional treatments. A review of several studies found that this combination is effective and has manageable side effects. Overall, early evidence suggests that venetoclax and azacitidine could be an effective treatment for AML. ^{1 2 3 6 7}

Who Is on the Research Team?

Amir Fathi, MD

Principal Investigator

Massachusetts General Hospital

Are You a Good Fit for This Trial?

Adults diagnosed with newly confirmed acute myeloid leukemia (AML), either de novo or secondary, who are eligible for intensive chemotherapy. Participants must be over 18, have an ECOG performance status ≤2, adequate liver function and heart health, and not have received prior AML treatment except hydroxyurea for cytoreduction. They must agree to use contraception due to unknown effects of venetoclax on fetuses.

Inclusion Criteria

I haven't had cancer treatment for AML, except possibly hydroxyurea or ATRA.

Left ventricular ejection fraction > 50% as measured by echocardiogram or MUGA scan

Ability to understand and the willingness to sign a written informed consent document.

Exclusion Criteria

My AML is FLT3-mutated.

I am under 60 and have AML with an NPM1 mutation.

I refuse blood products or am allergic to them.

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants receive either the investigational combination of venetoclax and azacitidine or standard induction chemotherapy with cytarabine and idarubicin (or daunorubicin) or liposomal daunorubicin and cytarabine.

Up to 3 years

Regular visits as per protocol

Follow-up

Participants are monitored for safety and effectiveness after treatment, including assessments of event-free survival and overall survival.

3 years

Consolidation (if needed)

Participants may receive additional cycles of chemotherapy to consolidate response, depending on age and response to initial treatment.

Varies

What Are the Treatments Tested in This Trial?

Interventions

• Azacitidine
• Daunorubicin
• Idarubicin
• Liposomal daunorubicin and cytarabine
• Venetoclax

Trial Overview The trial is testing the effectiveness of a combination therapy using azacitidine and venetoclax against standard induction chemotherapy options like cytarabine with idarubicin or daunorubicin, or liposomal daunorubicin and cytarabine in patients with acute myeloid leukemia.

How Is the Trial Designed?

Group I: Standard of Care (Conventional Induction) Experimental Treatment 4 Interventions

Randomized participants will receive cytarabine and idarubicin \[or daunorubicin) per standard of care as follows: Induction: cytarabine on days 1-7 and idarubicin (or daunorubicin) on days 1-3 of induction. Second Induction (if needed): Cytarabine on days 1-5 and idarubicin (or daunorubicin) on days 1-2 of re-induction. Consolidation (if needed): If \< 60 years, cytarabine days 1,3,5 of consolidation cycles, and if ≥60 years, cytarabine days 1-5 of consolidation cycles Those with secondary or therapy-related AML can receive liposomal daunorubicin and cytarabine (Vyxeos) per standard of care as follows: Induction: Liposomal daunorubicin and cytarabine (Vyxeos) on Days 1,3, 5 of induction. Second Induction (if needed): Liposomal daunorubicin and cytarabine (Vyxeos) on days 1,3 of re-induction Consolidation (if needed): liposomal daunorubicin and cytarabine (Vyxeos) on days 1,3 of consolidation cycles

Group II: Investigational (Venetoclax and Azacitidine) Experimental Treatment 2 Interventions

Participants will receive azacitidine on days 1-7 and venetoclax daily for up to (3) three 28-day study cycles and evaluated for response or benefit. If benefit/response is achieved, azacitidine on days 1-7 and venetoclax on days 1-28 (or less if deemed necessary per protocol) will be given in repeating 28-day cycles until benefit/response is no longer achieved or until patient proceeds to transplantation.

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?

Massachusetts General Hospital

Lead Sponsor

Trials

3,066

Recruited

13,430,000+

AbbVie

Industry Sponsor

Trials

1,079

Recruited

535,000+

Founded

2013

Headquarters

North Chicago, USA

Known For

Immunology treatments

Top Products

Humira (adalimumab), Skyrizi (risankizumab), Rinvoq (upadacitinib)

Dr. Roopal Thakkar

AbbVie

Chief Medical Officer since 2023

MD from Wayne State University School of Medicine

Robert A. Michael

AbbVie

Chief Executive Officer

Bachelor's degree in Finance from the University of Illinois

Published Research Related to This Trial

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 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]

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 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 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 2 trial involving 33 adults with newly diagnosed acute myeloid leukaemia, the combination of venetoclax with daunorubicin and cytarabine (DAV regimen) achieved a remarkable composite complete remission rate of 91% after one cycle of treatment.

The treatment was found to be safe, with no treatment-related deaths reported, although all patients experienced grade 3 or worse adverse events, such as neutropenia and thrombocytopenia, highlighting the need for careful monitoring during therapy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Venetoclax plus 3 + 7 daunorubicin and cytarabine chemotherapy as first-line treatment for adults with acute myeloid leukaemia: a multicentre, single-arm, phase 2 trial. Wang, H., Mao, L., Yang, M., et al.[2022]

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]

Citations

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

Efficacy and safety of venetoclax and azacitidine for acute ... The salvage therapy outcomes in patients with treatment-naïve AML after AZA-VEN suggested best outcomes for VEN-AZA combined with a targeted ...

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

Azacitidine and Venetoclax in Previously Untreated Acute ... Older patients with acute myeloid leukemia (AML) have a dismal prognosis, even after treatment with a hypomethylating agent. Azacitidine ...

3. clinicaltrials.gov clinicaltrials.gov/study/NCT04161885

NCT04161885 | A Study Evaluating Safety and Efficacy of ... The main objective of this study is to evaluate the efficacy of venetoclax in combination with azacitidine to improve Overall Survival (OS) in Acute Myeloid ...

4. clinicaltrial.be clinicaltrial.be/en/details/13943?per_page=100&recruiting=1&enrolling_by_invitation=1&active_not_recruiting=1&not_yet_recruiting=0&completed=0&only_recruiting=0&only_eligible=0

A Study to Assess Change in Disease State in Adult Partic... This study will evaluate how well venetoclax in combination with azacitidine works to treat AML in adult participants in Colombia. Venetoclax in ...

5. eurjmedres.biomedcentral.com eurjmedres.biomedcentral.com/articles/10.1186/s40001-025-02571-x

Meta-analysis on the effectiveness and safety of venetoclax ... This meta-analysis focuses on evaluating the efficacy and adverse reactions of venetoclax in combination with HMAs in AML treatment.

6. sciencedirect.com sciencedirect.com/science/article/pii/S0006497118473065

A Phase 1b Study of Venetoclax (ABT-199/GDC-0199) in ... Elderly AML patients (pts) respond poorly to standard chemotherapy, with low overall survival and poor outcomes. Venetoclax (VEN) is a selective, potent, orally ...

7. link.springer.com link.springer.com/article/10.1007/s00277-025-06643-0

Efficacy and safety of venetoclax plus azacitidine based ... This meta-analysis aimed to evaluate the efficacy and safety of venetoclax plus azacitidine (VEN + AZA) regimens in patients with relapsed ...