Decitabine + Cedazuridine + Venetoclax for Acute Myeloid Leukemia

Overseen By Vanderbilt-Ingram Services for Timely Access

Age: 18+

Sex: Any

Trial Phase: Phase 2

Sponsor: Sanjay Mohan

Must not be taking: BCL-2 inhibitors

Disqualifiers: GVHD, CNS leukemia, cardiovascular, 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: 28 days per cycle

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial tests a combination of medications to evaluate their effectiveness against acute myeloid leukemia (AML) that has returned after a stem cell transplant. The study combines decitabine and cedazuridine to prolong decitabine's activity in the body, along with venetoclax, which targets a specific protein essential for cancer cell survival. Suitable participants have experienced a return of AML post-stem cell transplant and are not currently facing uncontrolled infections or certain other illnesses. As a Phase 2 trial, this research focuses on assessing the treatment's effectiveness in an initial, smaller group of people.

Will I have to stop taking my current medications?

The trial protocol does not specify if you must stop taking your current medications, but it mentions that concurrent treatment with a non-permitted medication is not allowed. It's best to discuss your current medications with the trial 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 decitabine, cedazuridine, and venetoclax is generally safe for patients. Studies have found that this treatment is well-tolerated by people with certain blood cancers, such as myelodysplastic syndromes and chronic myelomonocytic leukemia.

Participants in these studies experienced some side effects, but they were mostly manageable. Common issues included low blood counts, which are expected with these treatments. More serious side effects were rare.

This treatment is currently in phase 2 trials, indicating it has already passed initial safety tests. Researchers are now studying its effectiveness and monitoring any side effects. This stage helps researchers better understand the balance between benefits and risks. ^{1 2 3 4 5}

Why are researchers excited about this trial's treatments?

Researchers are excited about the combination of Decitabine, Cedazuridine, and Venetoclax for treating Acute Myeloid Leukemia (AML) because it introduces a fresh approach to tackling the disease. Unlike traditional chemotherapy, which broadly targets rapidly dividing cells, Venetoclax works by specifically inhibiting BCL-2, a protein that helps cancer cells survive. Cedazuridine and Decitabine are delivered orally, making treatment more convenient compared to the standard intravenous administration. This combination not only promises a targeted attack on cancer cells but also offers a potentially more patient-friendly treatment regimen.

What evidence suggests that this treatment might be an effective treatment for acute myeloid leukemia?

Research has shown that the combination of decitabine and cedazuridine (DEC-C) holds promise for treating acute myeloid leukemia (AML). One study reported a 67% overall response rate, indicating that many patients experienced improvement in their cancer. In this trial, participants will receive DEC-C along with venetoclax. This combination is considered effective and safe for older or less fit patients with AML. Venetoclax, when combined with other treatments, has helped about 75% of patients achieve remission. Together, these drugs attack cancer cells in different ways, potentially leading to better outcomes for those with relapsed AML. ^{1 6 7 8 9}

Who Is on the Research Team?

Sanjay R. Mohan

Principal Investigator

Vanderbilt University/Ingram Cancer Center

Are You a Good Fit for This Trial?

This trial is for adults over 18 with relapsed Acute Myeloid Leukemia (AML) after a donor stem cell transplant. Participants must have adequate organ function, not be pregnant or breastfeeding, and cannot have active graft versus host disease or other uncontrolled conditions. They should not have received certain treatments recently and must be able to take oral medication.

Inclusion Criteria

Total bilirubin < 1.5 x ULN (Patients with Gilbert's syndrome must have a total bilirubin of < 3 x ULN)

My AML has returned after a stem cell transplant.

I have had a bone marrow biopsy to collect tissue for this trial.

Exclusion Criteria

Pregnancy or breastfeeding females

I currently have an infection that isn't under control.

I cannot take pills or have severe stomach/intestine problems.

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants receive venetoclax orally daily for 28 days in a 28-day cycle and DEC-C orally daily on days 1-5 of a 28-day cycle. Bone marrow biopsy, aspiration, and blood sample collection are conducted throughout the study.

28 days per cycle

Follow-up

Participants are monitored for safety, effectiveness, and survival outcomes after treatment

Up to 24 months post-treatment

What Are the Treatments Tested in This Trial?

Interventions

• Cedazuridine
• Decitabine
• Venetoclax

Trial Overview The trial tests a combination of decitabine and cedazuridine (DEC-C) with venetoclax in patients whose AML has returned post-transplant. DEC-C may help the bone marrow produce healthy cells and kill cancer cells, while venetoclax targets proteins essential for cancer cell survival.

How Is the Trial Designed?

Group I: Treatment (Venetoclax, DEC-C) Experimental Treatment 5 Interventions

Patients receive venetoclax PO daily for 28 days in a 28-day cycle. Patients receive DEC-C PO daily on days 1-5 of a 28-day cycle. Patients undergo bone marrow biopsy and aspiration and blood sample collection throughout the study.

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?

Sanjay Mohan

Lead Sponsor

Trials

2

Recruited

130+

Taiho Oncology, Inc.

Industry Sponsor

Trials

79

Recruited

12,700+

Tim Whitten

Taiho Oncology, Inc.

Chief Executive Officer since 2018

MBA and Pharmacy degree

Harold Keer

Taiho Oncology, Inc.

Chief Medical Officer

MD, PhD

National Comprehensive Cancer Network

Collaborator

Trials

121

Recruited

7,400+

Published Research Related to This Trial

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]

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 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]

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]

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 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 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 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 81 patients with acute myeloid leukemia (AML) receiving venetoclax with decitabine or azacitidine, 72.8% experienced infections, with the most common pathogens being Candida albicans and Klebsiella pneumonia.

The study found that the incidence of infectious complications was lower with this treatment compared to conventional chemotherapy, and high leukemia burden and fever were identified as significant risk factors for developing infections.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

A real-world study of infectious complications of venetoclax combined with decitabine or azacitidine in adult acute myeloid leukemia. Zhu, LX., Chen, RR., Wang, LL., et al.[2022]

Citations

1. 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.

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

Fully Oral Combination of Decitabine/Cedazuridine (ASTX727 ... The median follow-up time was 20 months. The ORR was 40/60 (67%), including 24 (40%) complete remission (CR), 13 (22%) CR with incomplete count ...

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. 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 ...

5. cancertherapyadvisor.com cancertherapyadvisor.com/news/decitabine-cedazuridine-plus-venetoclax-under-review-for-aml/

Decitabine/Cedazuridine Plus Venetoclax Under Review ... The median overall survival was 15.5 months. The most common grade 3 or higher adverse events were febrile neutropenia, anemia, and neutropenia.

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

Oral decitabine plus cedazuridine and venetoclax in ... The combination of oral decitabine plus cedazuridine with venetoclax for higher-risk-myelodysplastic syndromes and chronic myelomonocytic leukaemia is safe in ...

7. 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.

8. 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 ...

9. ash.confex.com ash.confex.com/ash/2023/webprogram/Paper172658.html

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) settings.