Venetoclax + Azacitidine and DLI for Acute Myeloid Leukemia

Overseen By Antonio M Jimenez Jimenez, MD

Age: 18+

Sex: Any

Trial Phase: Phase 1

Sponsor: Antonio M Jimenez Jimenez

Disqualifiers: Active disease, Active GVHD, Uncontrolled infection, Active viral infection, Significant cardiac disease, Recent malignancy, others

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

Compensation: Varies

Number of Visits: Unknown

Duration: 12 months

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial tests a new combination of treatments: venetoclax (a targeted therapy), azacitidine (a chemotherapy drug), and donor lymphocyte infusion (DLI) for individuals with acute myeloid leukemia (AML) at high risk of relapse after a stem cell transplant. The goal is to determine if this combination is safe and effective in preventing leukemia recurrence. Suitable candidates have AML in remission, face a high risk of relapse, and have already undergone a stem cell transplant. 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 new combination therapy.

Will I have to stop taking my current medications?

The trial information does not specify whether you need to stop taking your current medications. It's best to discuss this with the trial coordinators or your doctor.

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

Research has shown that the combination of venetoclax and azacitidine has been studied for treating acute myeloid leukemia (AML). These studies indicate it can be quite effective, though some side effects may occur. Common issues include low blood cell counts, nausea, and infections, which are often manageable with medical care.

The FDA has already approved venetoclax for use in certain AML patients, indicating its safety is well understood. Azacitidine is also a recognized treatment for AML. When used together, this combination has been tested in other studies, and patients generally tolerated it well. However, since this trial is in the early stages, researchers are closely monitoring the safety of using it with donor lymphocyte infusion (DLI). Participants in this trial will be observed carefully to manage any side effects. ^{1 2 3 4 5}

Why are researchers excited about this trial's treatments?

Researchers are excited about Venetoclax and Azacitidine for treating Acute Myeloid Leukemia (AML) because they offer a novel approach compared to standard chemotherapy and targeted therapies. Venetoclax works by inhibiting the BCL-2 protein, which helps cancer cells survive, thereby promoting their death. This mechanism is uniquely effective in disrupting leukemia cell survival. Additionally, the combination with Azacitidine may enhance the treatment's efficacy by further targeting the leukemia cells' growth and survival processes. These therapies, particularly when used together, offer a promising alternative that could potentially improve outcomes for patients with AML.

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

Research has shown that using venetoclax and azacitidine together may help treat acute myeloid leukemia (AML). In one study with 107 patients, nearly 30% achieved complete remission, meaning their cancer was no longer detectable. Another study found that 38.5% of patients responded well to this treatment, experiencing significant reductions in cancer signs. In this trial, participants will receive the combination of venetoclax and azacitidine in different cohorts, with some potentially receiving donor lymphocyte infusions (DLI) based on specific criteria. These findings suggest that the combination of venetoclax and azacitidine can effectively fight AML. ^{6 7 8 9 10}

Who Is on the Research Team?

Antonio M Jimenez Jimenez, MD

Principal Investigator

University of Miami

Are You a Good Fit for This Trial?

This trial is for adults aged 18-75 with high-risk AML in remission, who've had a cell transplant and are at risk of relapse. They must have stable blood counts, good organ function, and no active infections or severe heart issues. Women must not be pregnant, and there should be no recent other cancers.

Inclusion Criteria

Adequate hematopoietic recovery after HCT, defined as: Absolute neutrophil count (ANC) >= 1 x 10^9/L without daily use of myeloid growth factors, Platelet count >= 50 x 10^9/L without platelet transfusion within 1 week, Eastern Cooperative Oncology Group (ECOG) performance status of 0, 1, or 2, Serum creatinine =< 1.5 mg/dL or creatinine clearance greater or equal than 40 cc/min, Serum bilirubin =< 1.5 x upper limit of normal (ULN), Aspartate transaminase (AST) or alanine transaminase (ALT) =< 2.5 x ULN, Alkaline phosphatase =< 2.5 x UL, Negative serum or urine pregnancy test for women with reproductive potential, A negative donor-specific antibody (DSA) assay (i.e., Micro-Flow Imaging (MFI) <m3000) for recipients of any mismatched graft (including haploidentical) HCT

I have AML in remission with a high risk of relapse and less than 5% bone marrow blasts.

Exclusion Criteria

I do not have any ongoing serious infections.

I haven't had cancer in the last 2 years, except for certain skin cancers or cancers that were fully treated.

I am currently on medication for ongoing chronic GVHD.

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants receive Venetoclax and Azacitidine (VEN/AZA) combination therapy, followed by optional donor lymphocyte infusions (DLI). Treatment includes up to 12 cycles over one year.

12 months

Follow-up

Participants are monitored for safety, effectiveness, and disease relapse prevention after treatment. Follow-up includes monitoring for chronic and acute GVHD.

12 months

What Are the Treatments Tested in This Trial?

Interventions

• Azacitidine
• Donor Lymphocyte Infusion
• Venetoclax

Trial Overview The study tests a combination treatment using venetoclax, azacitidine, and donor lymphocyte infusion (DLI) on patients with high-risk AML post-cell transplant to see if it's safe and can prevent the cancer from coming back.

How Is the Trial Designed?

Group I: VEN/AZA Expansion Cohort Experimental Treatment 3 Interventions

Participants in this group will receive VEN/AZA therapy at the most appropriate dose determined in Part 1. Participants may also receive donor lymphocyte infusions (DLI) at the discretion of the treating physician, if certain criteria are met. Participants will receive up to one year (12 cycles) of study therapy, followed by up to one year of follow-up. Total participation duration is up to two years.

Group II: VEN/AZA Dose Escalation/De-Escalation Cohort Experimental Treatment 3 Interventions

Participants in this group will begin Venetoclax and Azacitidine (VEN/AZA) combination therapy between day +42 and day +100 following hematopoietic cell transplant (HCT) infusion. VEN/AZA combination therapy will be administered for up to six (6) cycles, followed by up to six (6) additional cycles of Venetoclax monotherapy in the absence of disease progression or unacceptable toxicity. Each cycle is 28 days. Participants may also receive donor lymphocyte infusions (DLI) at the discretion of the treating physician, if certain criteria are met. Participants will receive up to one year (12 cycles) of study therapy, followed by up to one year of follow-up. Total participation duration is up to two years.

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?

Antonio M Jimenez Jimenez

Lead Sponsor

Trials

1

Recruited

30+

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]

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]

The combination of venetoclax, azacitidine, and homoharringtonine (VAH) resulted in a high composite complete remission rate of 70.8% in patients with relapsed or refractory acute myeloid leukemia (R/R AML), indicating strong efficacy of this treatment regimen.

Patients treated with VAH had a median overall survival of 22.1 months and a 1-year overall survival rate of 61.5%, suggesting that this regimen not only effectively induces remission but also improves survival outcomes in this challenging patient population.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Venetoclax Combined with Azacitidine and Homoharringtonine in Relapsed/Refractory AML: A Multicenter, Phase 2 Trial. Jin, H., Zhang, Y., Yu, S., 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 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 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 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 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]

Citations

1. 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 ... Among 107 patients treated with venetoclax plus azacitidine at the RP2D, 29.9% (n = 32; 95% CI, 21.4-39.5) achieved a best response of CR, and ...

2. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC12320475/

Reduced-dose azacitidine plus venetoclax as maintenance ... The combination of azacitidine and venetoclax (in full doses) has already proved highly effective in AML in the phase 3 VIALE-A study and ...

3. clinicaltrials.gov clinicaltrials.gov/study/NCT06158100

Venetoclax in Combination With Azacitidine (VEN/AZA ... The purpose of this study is to see the effects of an investigational combination treatment of venetoclax, azacitidine, and donor lymphocyte infusion (DLI) ...

4. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC12552324/

a meta-analysis of clinical trials and Real-World outcomes This meta-analysis, comprising 24 studies, evaluated the efficacy of venetoclax (VEN) in combination with hypomethylating agents (HMAs), ...

5. hematologyadvisor.com hematologyadvisor.com/news/combination-azacitidine-venetoclax-acute-myeloid-leukemia-aml-treatment-risk/

Combination Azacitidine, Venetoclax Effective in AML ... Analysis showed that the overall response rates in the azacitidine plus venetoclax, chemotherapy, and azacitidine monotherapy groups were 38.5%, ...

6. 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 ...

7. 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 ...

8. 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.

9. ashpublications.org ashpublications.org/blood/article/145/12/1237/517960/How-I-treat-patients-with-AML-using-azacitidine

How I treat patients with AML using azacitidine and venetoclax Venetoclax (VEN) received full approval in October 2020 for use in older patients who are unfit with acute myeloid leukemia (AML) combined with either ...

10. 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 ...