Venetoclax + ASTX727 for Acute Myeloid Leukemia

Overseen By Ravandi-Kashani Farhad, MD

Age: 18+

Sex: Any

Trial Phase: Phase 2

Sponsor: M.D. Anderson Cancer Center

Must not be taking: BCL2 inhibitors

Disqualifiers: Acute promyelocytic leukemia, CNS leukemia, 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: 3

Duration: Up to 24 months

85 Participants Needed

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial tests the combination of venetoclax and ASTX727 to determine if they can better control acute myeloid leukemia (AML), particularly in cases where the cancer has returned or resisted other treatments. Venetoclax may prevent cancer cell growth, while ASTX727 (a combination of decitabine and cedazuridine) aims to stop cancer cells from spreading. The trial seeks participants whose AML has relapsed, not responded to other treatments, or who are elderly with newly diagnosed AML and unable to undergo aggressive chemotherapy. Participants should have AML that has returned, not improved with past treatments, or be newly diagnosed and unable to undergo intensive chemotherapy. 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. However, oral hydroxyurea is allowed before and during the study for certain patients, and other medications may be permitted after discussion with the study's principal investigator.

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

Research has shown that the combination of decitabine and cedazuridine, known as ASTX727, is generally safe for most patients. Studies have found that this treatment, particularly when combined with venetoclax, is well-tolerated by many older or less fit patients with acute myeloid leukemia (AML). Some side effects occur, but they are usually manageable.

For venetoclax, research indicates it is typically safe for patients with AML. Some individuals experience side effects, but these are often not severe. A meta-analysis, which combines results from multiple studies, found that venetoclax is generally effective, with side effects similar to other AML treatments.

Both treatments have shown promise in treating AML while maintaining a safety profile acceptable for many patients. ^{1 2 3 4 5}

Why are researchers excited about this trial's treatments?

Researchers are excited about this treatment combination for acute myeloid leukemia (AML) because it targets cancer cells more precisely. Unlike traditional chemotherapy that indiscriminately attacks rapidly dividing cells, venetoclax selectively inhibits a protein called BCL-2, which helps cancer cells survive. Additionally, decitabine and cedazuridine make DNA in cancer cells behave abnormally, slowing their growth. This targeted approach not only holds promise for being more effective but also potentially offers fewer side effects compared to conventional treatments.

What evidence suggests that venetoclax and ASTX727 might be an effective treatment for acute myeloid leukemia?

This trial will evaluate the combination of decitabine, cedazuridine, and venetoclax for managing acute myeloid leukemia (AML), particularly in older patients or those unable to undergo strong chemotherapy. Studies have shown that this treatment stops cancer cells from growing. Research indicates that taking these drugs in pill form is effective and safe for most patients. Early results suggest that this combination might also benefit patients whose AML has returned or is not responding to other treatments. Overall, this drug combination shows promise in controlling AML by targeting cancer cell growth. ^{3 5 6 7 8}

Who Is on the Research Team?

Farhad Ravandi-Kashani

Principal Investigator

M.D. Anderson Cancer Center

Are You a Good Fit for This Trial?

This trial is for adults with Acute Myeloid Leukemia (AML) that's resistant to treatment, has returned after treatment, or newly diagnosed in elderly patients unfit for intensive chemotherapy. Participants must be over 18, have a performance status indicating they can care for themselves with varying degrees of assistance, and meet specific health criteria related to liver and kidney function.

Inclusion Criteria

Able to give written informed consent

I am 75 years old or older.

I agree to use birth control during and for 3 months after the study ends.

Exclusion Criteria

Pregnant or breastfeeding

I have been treated with a BCL2 inhibitor before.

I have symptoms or uncontrolled leukemia in my brain or spinal cord.

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 daily on days 1-5 and venetoclax orally daily on days 1-28 of the first cycle and on days 1-21 of subsequent cycles. Treatment repeats every 28 days for up to 24 cycles.

Up to 24 months

Monthly visits for each cycle

Follow-up

Participants with an objective response are monitored every 3-6 months for up to 5 years to assess overall survival and disease-free survival.

Up to 5 years

Every 3-6 months

What Are the Treatments Tested in This Trial?

Interventions

• Decitabine and Cedazuridine
• Venetoclax

Trial Overview The trial is testing the combination of Venetoclax and ASTX727 (a fixed-dose combo of cedazuridine and decitabine) on AML. Venetoclax aims to prevent cancer growths while ASTX727 may slow down cell growth by making decitabine last longer in the body before it breaks down.

How Is the Trial Designed?

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

Patients receive decitabine and cedazuridine PO daily on days 1-5 and venetoclax PO daily on days 1-28 of the first cycle and on days 1-21 of subsequent cycles. Treatment repeats every 28 days for up to 24 cycles in the absence of disease progression or unacceptable toxicity.

Decitabine and Cedazuridine is already approved in European Union, United States for the following indications:

Approved in European Union as Inaqovi for:

• Acute myeloid leukemia (AML) in adults who are ineligible for standard induction chemotherapy

Approved in United States as ASTX727 for:

• Adult patients with newly diagnosed acute myeloid leukemia (AML) who are 75 years or older, or who have comorbidities precluding intensive induction chemotherapy

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

A 50-year-old male with relapsed acute myeloid leukemia (AML) achieved complete remission after being treated with decitabine and venetoclax as a fifth-line therapy, demonstrating the potential efficacy of this combination in difficult-to-treat cases.

Following remission, the patient successfully underwent a haploidentical transplant, resulting in an overall survival of 48.6 months, suggesting that this treatment approach may serve as a viable bridge to transplant for patients with multiresistant AML.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Efficacy of Decitabine and Venetoclax as Salvage and Bridge Therapy to Haploidentical Hematopoietic Stem Cell Transplantation in a Multiresistant Acute Myeloid Leukemia Patient. Serio, B., Giudice, V., Morini, D., et al.[2022]

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]

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]

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]

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 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]

The study evaluates the safety and efficacy of venetoclax combined with oral azacitidine as maintenance therapy for patients with acute myeloid leukemia (AML) who are in complete remission but have incomplete blood count recovery after intensive treatment.

The primary goal of the trial is to assess relapse-free survival, with secondary outcomes including overall survival and quality of life, highlighting the potential of this combination therapy to prevent relapse in AML patients.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Design of the VIALE-M phase III trial of venetoclax and oral azacitidine maintenance therapy in acute myeloid leukemia. Ivanov, V., Yeh, SP., Mayer, J., et al.[2022]

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]

Citations

1. clinicaltrials.gov clinicaltrials.gov/study/NCT04817241

Testing Oral Decitabine and Cedazuridine (ASTX727) in ... This phase Ib/II trial studies the effects of ASTX727 (decitabine and cedazuridine) in combination with venetoclax in treating patients with higher-risk ...

2. clinicaltrials.gov clinicaltrials.gov/study/NCT04774393

NCT04774393 | Decitabine/Cedazuridine and Venetoclax ... Giving decitabine/cedazuridine and venetoclax in combination with ivosidenib or enasidenib may help control acute myeloid leukemia. Detailed Description.

3. 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.

4. pubmed.ncbi.nlm.nih.gov pubmed.ncbi.nlm.nih.gov/38316133/

Oral decitabine plus cedazuridine and venetoclax in ... We investigated the safety and activity of the first totally oral combination of decitabine plus cedazuridine and venetoclax in patients with higher-risk- ...

5. thelancet.com thelancet.com/cms/10.1016/S2352-3026(24)00033-4/attachment/be77ea53-9ca7-40e2-ba6a-3b576d4a3301/mmc1.pdf

Supplementary appendix Oral decitabine and cedazuridine plus venetoclax for older or unfit patients with acute myeloid leukaemia: a phase 2 study. Lancet Haematol 2024 ...

6. 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.

7. 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 ...

8. cancer.gov cancer.gov/research/participate/clinical-trials/intervention/decitabine-and-cedazuridine?pn=1

Clinical Trials Using Decitabine and Cedazuridine - NCI Review the clinical trials studying decitabine and cedazuridine on this list and use the filters to refine the results by age and location.