Venetoclax + Decitabine for Acute Myeloid Leukemia

Overseen By Abhishek Maiti, MBBS

Age: 18+

Sex: Any

Trial Phase: Phase 2

Sponsor: M.D. Anderson Cancer Center

Must not be taking: BCL2 inhibitors

Disqualifiers: CNS leukemia, Uncontrolled infection, HIV, 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 24 cycles (approximately 2 years)

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial tests two drugs, venetoclax and decitabine, to evaluate their combined effectiveness in treating certain blood cancers, such as acute myeloid leukemia (AML) and high-risk myelodysplastic syndrome (MDS). These cancers may have returned or not responded to previous treatments. The goal is to determine if this combination can halt or slow the cancer by killing cancer cells or stopping their growth. Suitable participants have AML or high-risk MDS that hasn't responded to other treatments or has returned. As a Phase 2 trial, this 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 protocol does not specify if you need to stop taking your current medications. However, oral hydroxyurea and one dose of cytarabine are allowed before and during the study, and you should discuss any other medications with the principal investigator.

Is there any evidence suggesting that venetoclax and decitabine are likely to be safe for humans?

Research has shown that the combination of venetoclax and decitabine is usually well-tolerated by patients with acute myeloid leukemia (AML). Studies have found this treatment effective and free of severe side effects for most individuals. Specifically, older patients with AML found this combination both effective and manageable.

Another study examined venetoclax with either decitabine or a similar drug, azacitidine, and found it safe for use outside of the hospital. Patients did not need to stay in the hospital for treatment, and serious side effects were rare.

In summary, earlier research indicates that the venetoclax and decitabine combination has a good safety record. While every treatment carries risks, these findings suggest that this combination is generally safe for many people. ^{1 2 3 4}

Why do researchers think this study treatment might be promising?

Researchers are excited about the combination of venetoclax and decitabine for treating Acute Myeloid Leukemia (AML) because it targets cancer cells in a novel way. Unlike traditional chemotherapy, which attacks all rapidly dividing cells, venetoclax specifically targets and inhibits a protein called BCL-2. This protein helps leukemia cells survive, so blocking it can lead to the death of cancer cells while sparing more healthy cells. Additionally, combining venetoclax with decitabine, which alters the DNA of cancer cells to stop their growth, offers a two-pronged attack that could improve outcomes for patients with AML. This combination is promising because it may provide faster and more effective results compared to existing treatment options.

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

Research has shown that using venetoclax with decitabine, the combination under study in this trial, may help treat acute myeloid leukemia (AML). Studies have found that this combination can slow or stop the growth of cancer cells. One analysis found positive results for AML patients, especially when these drugs are used together. Venetoclax blocks a protein called BCL-2, which helps cancer cells survive, while decitabine stops cancer cells from growing and dividing. These promising results suggest this combination could be effective for those whose cancer has returned or is resistant to other treatments. ^{1 3 4 5 6}

Who Is on the Research Team?

Abhishek Maiti, MD

Principal Investigator

M.D. Anderson Cancer Center

Are You a Good Fit for This Trial?

This trial is for adults under 60 with newly diagnosed AML or high-risk MDS, not responding to treatment or relapsed. Participants must have adequate liver and kidney function, not be pregnant or breastfeeding, agree to use contraception if of childbearing potential, and cannot have certain blood cancers (like acute promyelocytic leukemia) or uncontrolled medical conditions.

Inclusion Criteria

I am 60 or younger with a specific type of aggressive AML.

Alanine aminotransferase (ALT) < 3 x ULN unless considered due to leukemic involvement

My kidney function is normal, with creatinine levels below 2.

Exclusion Criteria

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

I have leukemia in my brain that is causing symptoms or is not well-controlled.

I do not have any severe ongoing health issues like uncontrolled infections, high blood pressure, heart failure, or irregular heartbeats.

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants receive decitabine IV over 1 hour on days 1-10 and venetoclax PO daily on days 1-28 of cycle 1 and on days 1-21 of subsequent cycles. Treatment repeats every 28 days for up to 24 cycles.

Up to 24 cycles (approximately 2 years)

Follow-up

Participants are monitored for safety and effectiveness after treatment completion

Every 3 to 6 months for up to 5 years

What Are the Treatments Tested in This Trial?

Interventions

• Decitabine
• Venetoclax

Trial Overview The study tests how well venetoclax combined with decitabine works in treating relapsed/refractory acute myeloid leukemia (AML) or high-risk myelodysplastic syndrome (MDS). It's a phase II trial focusing on the effectiveness of these chemotherapy drugs in stopping cancer cell growth.

How Is the Trial Designed?

Group I: Treatment (decitabine, venetoclax) Experimental Treatment 3 Interventions

Participants receive decitabine IV over 1 hour on days 1-10 and may also receive decitabine on days 1-5 after achieving complete remission/complete remission with incomplete count recovery during consolidation/maintenance. Participants also receive venetoclax PO daily on days 1-28 of cycle 1 and on days 1-21 of subsequent cycles. Treatment repeat every 28 days for up to 24 cycles in the absence of disease progression or unacceptable toxicity.

Decitabine is already approved in European Union, United States, Canada, Japan for the following indications:

Approved in European Union as Dacogen for:

• Acute myeloid leukemia
• Myelodysplastic syndromes

Approved in United States as Dacogen for:

• Myelodysplastic syndromes
• Acute myeloid leukemia

Approved in Canada as Dacogen for:

• Myelodysplastic syndromes
• Acute myeloid leukemia

Approved in Japan as Dacogen for:

• Myelodysplastic syndromes
• Acute myeloid leukemia

Who Is Running the Clinical Trial?

M.D. Anderson Cancer Center

Lead Sponsor

Trials

3,107

Recruited

1,813,000+

National Cancer Institute (NCI)

Collaborator

Trials

14,080

Recruited

41,180,000+

Published Research Related to This Trial

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]

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 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]

A once-weekly low-dose decitabine (LDDec) combined with venetoclax (VEN) showed high efficacy in treating elderly patients with acute myeloid leukemia (AML) and myelodysplastic syndrome (MDS), achieving an overall response rate of 88% for AML and 64% for MDS in a retrospective study of 39 patients.

Patients receiving the LDDec/VEN regimen experienced longer treatment durations and a trend towards higher transfusion independence compared to those on standard dosing, suggesting that this approach may reduce severe myelosuppression while maintaining effectiveness.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

A Metabolically Optimized, Noncytotoxic Low-Dose Weekly Decitabine/Venetoclax in MDS and AML. Levitz, D., Saunthararajah, Y., Fedorov, K., et al.[2023]

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 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]

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 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 VA regimen, combining venetoclax and azacitidine, demonstrated a high complete remission (cCR) rate of 78.8% after the first treatment cycle and 81.8% after prolonged treatment in 66 patients with newly diagnosed acute myeloid leukemia (AML) who were not suitable for conventional chemotherapy.

The treatment was generally safe, with manageable adverse effects, primarily neutropenia, thrombocytopenia, and anemia, and showed better outcomes in patients with specific gene mutations (IDH1/2 or NPM1) and those experiencing rebound thrombocytosis.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

[Efficacy of venetoclax combined azacitidine in newly diagnosed acute myeloid leukemia unfit for standard chemotherapy: a single center experience]. Sun, L., Ye, SJ., Zhou, N., et al.[2023]

Citations

1. clinicaltrials.gov clinicaltrials.gov/study/NCT03941964

NCT03941964 | A Study of the Effectiveness of Venetoclax ... A study evaluating the effectiveness and safety of venetoclax, in combination with azacitidine or decitabine, in an outpatient setting for treatment-naïve ...

2. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC12032727/

Meta-analysis on the effectiveness and safety of venetoclax ... The combined therapy strategy of venetoclax with hypomethylating agents (HMAs) has demonstrated encouraging efficacy in the treatment of acute myeloid leukemia ...

3. sciencedirect.com sciencedirect.com/science/article/pii/S0006497118473065

A Phase 1b Study of Venetoclax (ABT-199/GDC-0199) in ... Elderly AML patients (pts) respond poorly to standard chemotherapy, with low overall survival and poor outcomes. Venetoclax (VEN) is a selective, potent, orally ...

4. 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) ...

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

Evaluating venetoclax and its potential in treatment-naïve ... Venetoclax (ABT-199), a BH3-mimetic and selective BCL-2 inhibitor, was recently approved by the US Food and Drug Administration (FDA) for the treatment of acute ...

6. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC6318429/

Venetoclax combined with decitabine or azacitidine in ... The novel combination of venetoclax with decitabine or azacitidine was effective and well tolerated in elderly patients with AML.