Venetoclax + Azacitidine for Myelodysplastic Syndrome

Not currently recruiting at 2 trial locations

Overseen By The Ohio State University Comprehensive Cancer Center

Age: 18+

Sex: Any

Trial Phase: Phase 2

Sponsor: Uma Borate

Must not be taking: CYP3A inducers, CYP3A inhibitors

Disqualifiers: HIV, Hepatitis B, Hepatitis C, 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: 58

Duration: Up to 12 months

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial tests a combination of two drugs, venetoclax and azacitidine, to determine their effectiveness in treating myelodysplastic syndrome (MDS), which can develop after other cancer treatments. Venetoclax may inhibit cancer cell growth by blocking a protein essential for their survival, while azacitidine can kill cancer cells or prevent their spread. Individuals with myelodysplastic syndrome that developed after previous cancer treatment and who have not yet received treatment for MDS might be suitable candidates for this trial. As a Phase 2 trial, this research measures the treatment's effectiveness in an initial, smaller group, allowing participants to contribute to significant advancements in MDS treatment.

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, but you should avoid certain substances like grapefruit and some medications that affect liver enzymes within a week before starting the trial. It's best to discuss your current medications with the trial team to ensure they don't interfere with the study.

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 tested for safety in treating blood cancers. One study found that patients generally tolerated this combination well. However, common side effects included low blood counts, nausea, and tiredness, which are typical for cancer treatments.

When used together, venetoclax and azacitidine may help stop cancer cells from growing. Venetoclax blocks a protein that cancer cells need to survive, while azacitidine, a chemotherapy drug, kills cancer cells or prevents their spread.

This combination has been used in other trials for similar conditions and shows promise. However, like all treatments, it may have side effects. Patients should always consult their doctor to understand the risks and benefits based on their health. ^{1 2 3 4 5}

Why are researchers excited about this study treatment for myelodysplastic syndrome?

Researchers are excited about the combination of venetoclax and azacitidine for treating Myelodysplastic Syndrome because it introduces a unique dual-action approach. Unlike traditional treatments, venetoclax targets and inhibits the BCL-2 protein, which helps cancer cells survive, while azacitidine is known for its ability to modify the DNA of cancer cells to prevent their growth. This combination could potentially lead to more effective results by simultaneously promoting cancer cell death and inhibiting their proliferation. Additionally, the oral administration of venetoclax offers a more convenient option compared to treatments that require more frequent hospital visits.

What evidence suggests that venetoclax and azacitidine might be an effective treatment for myelodysplastic syndrome?

Research has shown that using venetoclax with azacitidine may help treat myelodysplastic syndromes (MDS). Studies have found that this combination improves patient response to treatment and increases overall survival. In this trial, participants will receive venetoclax and azacitidine together. This treatment blocks proteins that cancer cells need to survive, while the chemotherapy directly attacks the cancer cells. Early results suggest this method could be more effective than current treatments for patients with high-risk MDS. ^{6 7 8 9 10}

Who Is on the Research Team?

Uma M Borate, MD

Principal Investigator

Ohio State University Comprehensive Cancer Center

Are You a Good Fit for This Trial?

Adults with untreated therapy-related myelodysplastic syndrome (t-MDS) and a specific risk score, who can consent to the study. They must have good organ function, not be pregnant or breastfeeding, agree to contraception if of childbearing potential, and not have certain heart conditions or uncontrolled illnesses. Prior cancer treatments are allowed except for venetoclax.

Inclusion Criteria

I agree to use or have my partner use two forms of birth control and not donate sperm until 90 days after my last treatment dose.

Aspartate aminotransferase (AST) < 3.0 x upper limit of normal (ULN) x upper limit of normal (ULN; local laboratory)

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

Exclusion Criteria

I have been treated with venetoclax or similar drugs before.

Subject has consumed one or more of the following within 3 days prior to the first dose of study drug: Grapefruit or grapefruit products, Seville oranges (including marmalade containing Seville oranges), Star fruit (carambola)

Subject has history of a cardiovascular, endocrinologic, hepatic, immunologic metabolic, neurologic, psychiatric, pulmonary, renal disease, or any other condition that in the opinion of the investigator would adversely affect his/her participation in this study or interpretation of study results

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 1-14 and azacitidine intravenously on days 1-7 or days 1-5 of week 1 and days 1 and 2 of week 2. Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity.

Up to 12 months

Visits at the start of each 28-day cycle

Follow-up

Participants are monitored for safety and effectiveness after treatment

24 months

Follow-up at 30 days post-treatment and every 6 months

What Are the Treatments Tested in This Trial?

Interventions

• Azacitidine
• Venetoclax

Trial Overview The trial is testing the combination of Venetoclax and Azacitidine in patients with t-MDS. Venetoclax targets proteins that help cancer cells survive while Azacitidine interferes with cell growth. The trial includes questionnaires and quality-of-life assessments to evaluate effectiveness.

How Is the Trial Designed?

Group I: Treatment (venetoclax, azacitidine) Experimental Treatment 4 Interventions

Patients receive venetoclax PO QD on days 1-14 and azacitidine IV over 10-40 minutes on days 1-7 or days 1-5 of week 1 and days 1 and 2 of week 2. Cycles repeat every 28 days 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?

Uma Borate

Lead Sponsor

Trials

7

Recruited

310+

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]

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 phase 1b study involving 44 patients with relapsed/refractory higher-risk myelodysplastic syndromes (MDS), the combination of venetoclax and azacitidine demonstrated significant activity, with a median overall survival of 12.6 months after prior treatment failure with hypomethylating agents.

The treatment resulted in hematological improvements, including complete remission in 7% of patients and transfusion independence in 36%, indicating that venetoclax plus azacitidine can provide meaningful clinical benefits for patients with limited options.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

A phase 1b study of venetoclax and azacitidine combination in patients with relapsed or refractory myelodysplastic syndromes. Zeidan, AM., Borate, U., Pollyea, DA., et al.[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 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 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 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. 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 ...

2. pubmed.ncbi.nlm.nih.gov pubmed.ncbi.nlm.nih.gov/39652823/

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

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

Outcomes of patients treated with venetoclax plus ... Efficacy, including composite complete remission and overall survival, were improved with venetoclax plus azacitidine vs. placebo plus ...

4. hematologyadvisor.com hematologyadvisor.com/news/myelodysplastic-syndrome-mds-venetoclax-azacitidine-shows-efficacy/

Venetoclax Plus Azacitidine Shows Promising Efficacy as ... First-line treatment of high-risk myelodysplastic syndromes (MDS) with venetoclax plus azacitidine resulted in promising response rates and reduced the rates ...

5. clinicaltrials.gov clinicaltrials.gov/study/NCT04401748

NCT04401748 | Study Of Venetoclax Tablet With ... The purpose of this study is to see how safe and effective venetoclax and azacitidine (AZA) combination are when compared to AZA and a placebo (contains no ...

6. clinicaltrials.gov clinicaltrials.gov/study/NCT02203773

NCT02203773 | Study of ABT-199 (GDC-0199) in ... This is a Phase 1b, open-label, non-randomized, multicenter study to evaluate the safety and pharmacokinetics of orally administered venetoclax (ABT-199) ...

7. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC10100228/

A phase 1b study of venetoclax and azacitidine ... In this phase‐1b study, we evaluated the safety of venetoclax either alone or in combination with azacitidine therapy after HMA failure. Due to the limited ...

8. 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 ...

9. ashpublications.org ashpublications.org/bloodadvances/article/8/13/3583/516002/Venetoclax-a-new-player-in-the-treatment-of

Venetoclax: a new player in the treatment of children with high ... This review summarizes the available current knowledge about venetoclax use in childhood high-risk myeloid neoplasms and discusses the possible integration of ...

10. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC6499443/

Evaluating venetoclax and its potential in treatment-naïve ... Study of ABT-199 (GDC-0199) in combination with azacitidine or decitabine (chemo combo) in subjects with AML, Active, not recruiting, AML, Venetoclax,