Venetoclax + Decitabine/Cedazuridine for Acute Myeloid Leukemia

Age: 18+

Sex: Any

Trial Phase: Phase 2

Sponsor: M.D. Anderson Cancer Center

Disqualifiers: Acute promyelocytic leukemia, Active GVHD, Uncontrolled infection, Uncontrolled hypertension, Congestive heart failure, 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 2 years

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial aims to evaluate the effectiveness of a combination of venetoclax, decitabine, and cedazuridine in treating acute myeloid leukemia (AML) that has returned or is unresponsive to other treatments. These drugs work together to stop cancer cells from growing and spreading. The trial targets individuals diagnosed with hard-to-treat AML or similar conditions who are not currently experiencing severe health issues like uncontrolled infections. For those with AML unresponsive to current treatments, this trial might be suitable. As a Phase 2 trial, the research focuses on assessing the treatment's effectiveness in an initial, smaller group of participants.

Will I have to stop taking my current medications?

The trial protocol does not specify if you need to stop taking your current medications. However, there is a requirement to wait at least 7 days after your last treatment before starting the trial, unless you have rapidly growing disease, in which case certain medications like hydroxyurea are allowed.

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

Research has shown that using venetoclax with decitabine and cedazuridine can pose some risks. In certain studies, patients in remission experienced serious side effects, including deaths from severe infections, bleeding in the stomach or intestines, and breathing problems. However, these events are uncommon, and many patients tolerate the treatment well.

In clinical trials, researchers study how these drugs work together to understand and manage any risks. Since this trial is in an early stage, it aims to gather more information about the treatment's safety and patient responses. The combination is under study because it might help treat challenging cases of acute myeloid leukemia, a type of blood cancer. Always consult a doctor about the possible risks and benefits before joining a trial. ^{1 2 3 4 5}

Why are researchers excited about this trial's treatments?

Researchers are excited about combining Venetoclax with Decitabine/Cedazuridine for treating Acute Myeloid Leukemia (AML) because it offers a novel approach compared to the standard chemotherapy options. Unlike traditional treatments, Venetoclax works by targeting and inhibiting a protein called BCL-2, which helps cancer cells survive. This unique mechanism can potentially lead to more effective elimination of cancer cells. Additionally, the combination with Decitabine/Cedazuridine, which provides an oral administration option, may enhance patient convenience and adherence compared to intravenous treatments. This innovative approach could offer new hope for patients with AML by tackling the disease from multiple angles.

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

This trial will evaluate the combination of three oral medications—venetoclax, decitabine, and cedazuridine—to treat acute myeloid leukemia (AML). Studies have shown promising results for this combination, demonstrating its effectiveness and safety, particularly for older patients or those in poor health. One study highlighted the success of a 10-day treatment plan, which showed positive outcomes for patients whose AML had returned or did not respond to previous treatments. The combination uses chemotherapy drugs to attack cancer cells in various ways, such as killing them or stopping their growth and spread. These early findings suggest this treatment might help manage AML, offering hope for those with difficult cases. ^{2 3 6 7 8}

Who Is on the Research Team?

Abhishek Maiti, MD

Principal Investigator

M.D. Anderson Cancer Center

Are You a Good Fit for This Trial?

Adults (18+) with relapsed or refractory Acute Myeloid Leukemia, including biphenotypic leukemia with a myeloid component. Participants must have adequate organ function and performance status, agree to use effective contraception, and be able to consent. Excluded are those with severe conditions affecting drug absorption, uncontrolled illnesses, active hepatitis B/C or HIV, high white cell count without hydroxyurea treatment, pregnant or nursing women not using contraception, certain genetic abnormalities in their leukemia cells (t(15;17)), symptomatic CNS leukemia or active graft-versus-host disease.

Inclusion Criteria

Willing and able to provide informed consent

I haven't had cancer treatment in the last 7 days, except for specific cases approved by my doctor.

Aspartate aminotransferase (AST) and/or alanine aminotransferase (ALT) < 3 x ULN unless considered due to leukemic involvement

Exclusion Criteria

I don't have severe stomach or metabolic issues affecting medication absorption.

My leukemia is of a specific type known as acute promyelocytic (M3-AML).

Any other medical, psychological, or social condition that may interfere with study participation or compliance, or compromise patient safety in the opinion of the investigator

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants receive decitabine and cedazuridine orally once daily on days 1-10 and venetoclax once daily on days 1-28 of cycle 1 and days 1-21 of subsequent cycles. Cycles repeat every 28 days.

Up to 2 years

Follow-up

Participants are monitored for safety and effectiveness after treatment completion

Every 3 months

What Are the Treatments Tested in This Trial?

Interventions

• Cedazuridine
• Decitabine
• Venetoclax

Trial Overview The trial is testing the combination of venetoclax with decitabine and cedazuridine for patients whose AML has returned after treatment or hasn't responded to other treatments. Venetoclax targets cancer cells' survival mechanisms while decitabine interferes with their DNA replication. Cedazuridine inhibits enzymes that could break down these drugs before they work.

How Is the Trial Designed?

Group I: Treatment (decitabine and cedazuridine, venetoclax) Experimental Treatment 2 Interventions

Patients receive decitabine and cedazuridine PO QD on days 1-10. Patients who achieve CR/CRi during consolidation/maintenance may receive decitabine and cedazuridine PO QD on days 1-5. Patients also receive venetoclax PO QD on days 1-28 of cycle 1 and days 1-21 of subsequent cycles. Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity.

Cedazuridine is already approved in United States for the following indications:

Approved in United States as ASTX727 for:

• Acute Myeloid Leukemia (AML)

Who Is Running the Clinical Trial?

M.D. Anderson Cancer Center

Lead Sponsor

Trials

3,107

Recruited

1,813,000+

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 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 involving 145 older patients (median age 74) with acute myeloid leukemia (AML) who were ineligible for intensive chemotherapy, the combination of venetoclax with decitabine or azacitidine resulted in a high complete remission (CR) rate of 67%, demonstrating its efficacy in this challenging population.

The treatment was well tolerated, with no cases of tumor lysis syndrome reported, and the median overall survival was 17.5 months, indicating that venetoclax combined with hypomethylating agents is a promising option for elderly patients with AML.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Venetoclax combined with decitabine or azacitidine in treatment-naive, elderly patients with acute myeloid leukemia. DiNardo, CD., Pratz, K., Pullarkat, V., et al.[2021]

In a study of 22 heavily pre-treated patients with relapsed or refractory acute myeloid leukaemia (RR-AML), the combination of venetoclax and decitabine resulted in a 45.5% overall response rate, with 40.9% achieving complete remission, demonstrating its efficacy in a real-world setting.

While the treatment was effective, it was associated with significant side effects, including grade IV neutropenia and thrombocytopenia in all patients, but no deaths were attributed to the treatment side effects, indicating that the adverse effects were manageable.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Efficacy of Venetoclax Combined with Decitabine-Based Treatment for Heavily Pre-Treated Relapsed or Refractory AML Patients in a Real-World Setting. Tong, J., Zhao, N., Hu, X., 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 phase 2 trial involving 168 patients with acute myeloid leukaemia (AML), the combination of venetoclax and a 10-day regimen of decitabine resulted in a high overall response rate of 74%, with particularly impressive results in newly diagnosed AML patients (89%).

The treatment demonstrated a manageable safety profile, with common adverse events including neutropenia and infections, and a 30-day mortality rate of only 3.6%, indicating that this combination therapy is both effective and relatively safe for older patients or those unfit for intensive chemotherapy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

10-day decitabine with venetoclax for newly diagnosed intensive chemotherapy ineligible, and relapsed or refractory acute myeloid leukaemia: a single-centre, phase 2 trial. DiNardo, CD., Maiti, A., Rausch, CR., et al.[2021]

In a study comparing older adults with newly diagnosed acute myeloid leukemia (AML), those treated with the combination of decitabine (DEC) and venetoclax (VEN) had a significantly longer median overall survival of 13.4 months compared to 8.3 months for those receiving DEC alone.

The combination therapy also resulted in a higher response rate of 70.3% versus 24.3% for DEC monotherapy, indicating that DEC+VEN is more effective in treating AML without increasing short-term mortality rates.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Venetoclax with decitabine versus decitabine monotherapy in elderly acute myeloid leukemia: a propensity score-matched analysis. Kwag, D., Cho, BS., Bang, SY., et al.[2022]

Venetoclax, a BCL-2 inhibitor, shows promise in combination therapies for newly diagnosed or relapsed acute myeloid leukemia (AML) and myelodysplastic syndrome (MDS), achieving high remission rates and deep molecular responses.

Despite these encouraging results, there are concerns about side effects such as incomplete blood count recovery and increased infection rates, particularly when used with chemotherapy, and more research is needed to understand the long-term effectiveness and durability of these treatments.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Venetoclax combination therapy in acute myeloid leukemia and myelodysplastic syndromes. Shimony, S., Stone, RM., Stahl, M.[2023]

The combination of venetoclax with hypomethylating agents (HMA) has significantly improved survival rates in patients with acute myeloid leukemia (AML), as demonstrated in a phase 3 study.

Venetoclax is also safe when added to standard intensive regimens, leading to high remission rates and measurable residual disease negativity in both newly diagnosed and relapsed/refractory AML patients.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Venetoclax in combination with nucleoside analogs in acute myelogenous leukemia. Ball, BJ., Koller, PB., Pullarkat, V.[2023]

Citations

1. clinicaltrials.gov clinicaltrials.gov/study/NCT04657081

Study Details | NCT04657081 | Pharmacokinetics, Safety, ... The primary purpose of the study is to rule out drug-drug interactions between ASTX727 and venetoclax combination therapy by evaluating area under the curve ( ...

2. pubmed.ncbi.nlm.nih.gov pubmed.ncbi.nlm.nih.gov/38452788/

Oral decitabine and cedazuridine plus venetoclax for older or ... ASTX727 plus venetoclax is an active fully oral regimen and safe in most older or unfit patients with acute myeloid leukaemia.

3. ascopubs.org ascopubs.org/doi/10.1200/JCO.2025.43.16_suppl.6551

Phase II trial of 10-day ASTX727 (decitabine/cedazuridine ... In this prospective clinical trial, we investigate the efficacy of a novel 10-day induction regimen with fully oral combination therapy for pts with R/R AML.

4. ashpublications.org ashpublications.org/blood/article/144/Supplement%201/2896/533121/Fully-Oral-Combination-of-Decitabine-Cedazuridine

Fully Oral Combination of Decitabine/Cedazuridine (ASTX727 ... We present here updated results of a phase 2 study evaluating ASTX727 plus venetoclax for patients with newly diagnosed AML. Methods: This was a ...

5. aml-hub.com aml-hub.com/medical-information/oral-decitabine-and-cedazuridine-venetoclax-for-the-treatment-of-older-patients-with-newly-diagnosed-aml

Oral decitabine and cedazuridine + venetoclax for the ... Here, we summarize a phase II study investigating the efficacy and safety of the oral decitabine and cedazuridine + venetoclax for the ...

6. clinicaltrials.gov clinicaltrials.gov/study/NCT04657081

Study Details | NCT04657081 | Pharmacokinetics, Safety, ... The primary purpose of the study is to rule out drug-drug interactions between ASTX727 and venetoclax combination therapy by evaluating area under the curve ( ...

7. ashpublications.org ashpublications.org/blood/article/142/Supplement%201/833/499481/A-Phase-2-Study-of-the-Fully-Oral-Combination-of

A Phase 2 Study of the Fully Oral Combination of ASTX727 ... We performed a phase 2 study to evaluate the efficacy and safety of ASTX727 plus venetoclax in the frontline (FL) and relapsed-refractory (R/R) ...

8. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC12268998/

Oral decitabine/cedazuridine plus venetoclax for older or ... Big data analysis of treatment patterns and outcomes among elderly acute myeloid leukemia patients in the United States. Ann Hematol 2015; 94: 1127–38. [DOI] ...