Novel Therapies for Acute Myeloid Leukemia

Recruiting at 199 trial locations

Age: 18 - 65

Sex: Any

Trial Phase: Phase 2

Sponsor: National Cancer Institute (NCI)

Must not be taking: Investigational agents

Disqualifiers: Acute promyelocytic leukemia, FLT3 mutations, t(9;22) translocation, Wilson's disease, 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: 1

Duration: 4-8 weeks

335 Participants Needed

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial aims to determine if new treatment combinations can more effectively shrink cancer in individuals with high-risk acute myeloid leukemia (AML), a challenging type of blood cancer. The study compares the standard chemotherapy approach to several experimental regimens, which include various pairings of drugs such as venetoclax (a targeted therapy), azacitidine, and liposomal forms of daunorubicin and cytarabine. It seeks participants who have been newly diagnosed with high-risk AML and have not yet begun treatment. Individuals experiencing challenging symptoms or conditions related to AML may be suitable candidates for this trial. 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 does not specify if you need to stop taking your current medications. However, you must not have received or be currently receiving any prior therapy for acute myeloid leukemia, except for certain allowed medications like hydroxyurea and all trans retinoic acid (ATRA).

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

Research has shown that the treatments tested in this trial have been safe in earlier studies. For the combination of daunorubicin, cytarabine liposome, and venetoclax, studies found it was tolerated by adults with high-risk acute myeloid leukemia (AML), suggesting it could be a safe option for those unable to undergo intense chemotherapy.

For the combination of cytarabine, daunorubicin, and venetoclax, research found it was safe for patients with newly diagnosed AML. Adding venetoclax to standard chemotherapy yielded good results without unexpected safety issues.

The azacitidine and venetoclax combination also has a known safety profile. Common side effects included constipation and nausea, typical for these medications. This combination has been used safely in real-world settings, even with dosage adjustments.

Lastly, the daunorubicin and cytarabine liposome treatment had side effects similar to regular chemotherapy, indicating it was about as safe as standard treatments, with some patients going into remission.

Overall, these treatments have been fairly well-tolerated in past studies, with side effects similar to those expected from cancer therapies. ^{1 2 3 4 5}

Why are researchers excited about this trial's treatments?

Researchers are excited about these treatments for acute myeloid leukemia (AML) because they offer promising new approaches beyond traditional chemotherapy. Unlike the standard of care, which primarily involves cytarabine and daunorubicin, these investigational treatments include venetoclax, a drug that targets cancer cells' ability to survive by inhibiting BCL-2, a protein that helps cancer cells avoid death. Additionally, the use of liposomal formulations of daunorubicin and cytarabine in some arms enhances drug delivery and potentially reduces side effects. These novel combinations and delivery methods aim to improve treatment effectiveness and patient outcomes by offering more targeted and potentially less toxic options.

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

Research has shown that combining daunorubicin and cytarabine liposome with venetoclax, as studied in Arm V of this trial, is promising for treating acute myeloid leukemia (AML). Studies have found that using CPX-351 (a special form of daunorubicin and cytarabine) leads to complete remission rates of 41%–58%, higher than the usual treatment rates of 14%–40%. Adding venetoclax, which helps stop cancer cells from surviving, has shown positive results and is generally safe for hard-to-treat AML cases.

Similarly, Arm II of this trial, which uses cytarabine, daunorubicin, and venetoclax together, has been effective, with some studies showing a two-year survival rate of 72%. Meanwhile, Arm III, which combines azacitidine and venetoclax, also appears promising, especially for older patients, by improving survival rates and causing fewer side effects compared to other treatments. Each of these experimental treatments offers unique potential benefits for high-risk AML patients. ^{1 6 7 8 9}

Who Is on the Research Team?

Paul J Shami

Principal Investigator

SWOG Cancer Research Network

Are You a Good Fit for This Trial?

This trial is for adults aged 18-59 with newly diagnosed, untreated high-risk acute myeloid leukemia (AML) as defined by specific criteria. Eligible participants must not have had previous AML treatment, except hydroxyurea or a single dose of intrathecal chemotherapy. Prior limited anthracycline therapy and exposure to hypomethylating agents for non-AML conditions are permitted.

Inclusion Criteria

Participants must not be receiving or planning to receive any other investigational agents before completing protocol therapy

The following tests must be performed within 14 days prior to registration to establish baseline values: Complete blood count (CBC)/differential/platelets, Total bilirubin, Lactate dehydrogenase (LDH), Albumin, Glucose, Fibrinogen

Total bilirubin =< 2.0 x ULN (or 5.0 x ULN if the participant has a history of Gilbert's disease) within 28 days prior to registration

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

1 visit (in-person)

Treatment

Participants receive assigned treatment regimen based on randomization, with cycles repeating every 28 days

4-8 weeks

Multiple visits for treatment administration and monitoring

Follow-up

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

Up to 5 years

Monthly visits for the first year, then decreasing frequency

What Are the Treatments Tested in This Trial?

Interventions

• Azacitidine
• Cytarabine
• Daunorubicin Hydrochloride
• Venetoclax

Trial Overview The study compares standard cytarabine and daunorubicin treatments against four experimental regimens: liposome-encapsulated versions alone; combined with venetoclax; azacitidine with venetoclax; and the combination of all three drugs. These new approaches may be more effective in treating high-risk AML.

How Is the Trial Designed?

Group I: Arm V (daunorubicin and cytarabine liposome, venetoclax) Experimental Treatment 6 Interventions

Patients receive daunorubicin and cytarabine liposome IV over 90 minutes on days 1, 3, and 5 and venetoclax PO on days 1-14 of each cycle. Cycles repeat every 28 days for 1 cycle in the absence of disease progression or unacceptable toxicity. Patients may receive an additional cycle of daunorubicin and cytarabine liposome IV over 90 minutes on days 1 and 3 and venetoclax PO on days 1-7. Patients undergo ECHO or MUGA scan during screening. Patients also undergo a bone marrow aspiration and collection of blood throughout the trial.

Group II: Arm IV (daunorubicin and cytarabine liposome) Experimental Treatment 5 Interventions

Patients receive daunorubicin and cytarabine liposome IV over 90 minutes on days 1, 3, and 5 of each cycle. Cycles repeat every 28 days for 1 cycle in the absence of disease progression or unacceptable toxicity. Patients may receive an additional cycle of daunorubicin and cytarabine liposome IV over 90 minutes on days 1 and 3. Patients undergo ECHO or MUGA scan during screening. Patients also undergo a bone marrow aspiration and collection of blood throughout the trial.

Group III: Arm III (azacitidine, venetoclax) Experimental Treatment 5 Interventions

Patients receive azacitidine SC or IV on days 1-7 and venetoclax PO on days 1-28 of each cycle. Cycles repeat every 28 days for 2 cycles in the absence of disease progression or unacceptable toxicity. Patients undergo ECHO or MUGA scan during screening. Patients also undergo a bone marrow aspiration and collection of blood throughout the trial.

Group IV: Arm II (cytarabine, daunorubicin, venetoclax) Experimental Treatment 7 Interventions

Patients receive cytarabine IV continuously on days 2-8 and daunorubicin IV on days 2-4 with venetoclax PO on days 1-11 of each cycle. Cycles repeat every 28 days for 1 cycle in the absence of disease progression or unacceptable toxicity. Patients may receive an additional cycle of cytarabine IV continuously on days 2-6 and daunorubicin IV on days 2-3 with venetoclax PO on days 1-8. Patients undergo ECHO or MUGA scan during screening. Patients also undergo a bone marrow aspiration and collection of blood throughout the trial.

Group V: Arm I (cytarabine, daunorubicin) Active Control 6 Interventions

Patients receive cytarabine IV continuously on days 1-7 and daunorubicin IV on days 1-3 per standard approach of each cycle. Cycles repeat every 28 days for 1 cycle in the absence of disease progression or unacceptable toxicity. Patients may receive an additional cycle of cytarabine IV continuously on days 1-5 and daunorubicin IV on days 1-2. Patients undergo ECHO or MUGA scan during screening. Patients also undergo a bone marrow aspiration and collection of blood throughout the trial.

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?

National Cancer Institute (NCI)

Lead Sponsor

Trials

14,080

Recruited

41,180,000+

Published Research Related to This Trial

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]

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]

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]

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 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 network meta-analysis of 1140 patients with untreated acute myeloid leukemia, the combination of venetoclax (VEN) with low-dose cytarabine (LDAC) and with azacitidine (AZA) showed significantly higher response rates and overall survival compared to standard therapies like AZA, LDAC, and best supportive care.

VEN + AZA was particularly effective, achieving a 95.2% likelihood of improving overall survival, while VEN + LDAC had a 91.4% likelihood of achieving complete remission, indicating these combinations are superior treatment options for patients ineligible for intensive chemotherapy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Comparative Efficacy of Venetoclax-Based Combination Therapies and Other Therapies in Treatment-Naive Patients With Acute Myeloid Leukemia Ineligible for Intensive Chemotherapy: A Network Meta-Analysis. Li, X., Suh, HS., Lachaine, J., et al.[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 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 study of nine AML patients with acquired resistance to venetoclax, the typical BCL2 mutation associated with resistance was not found, suggesting that this mutation is not necessary for developing resistance in AML.

The study identified that existing mutations, particularly the expansion of FLT3-ITD, were primarily responsible for venetoclax resistance, indicating that monitoring these mutations could help in developing strategies to prevent or overcome resistance.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Not BCL2 mutation but dominant mutation conversation contributed to acquired venetoclax resistance in acute myeloid leukemia. Zhang, X., Qian, J., Wang, H., et al.[2022]

In a phase 2 trial involving 33 adults with newly diagnosed acute myeloid leukaemia, the combination of venetoclax with daunorubicin and cytarabine (DAV regimen) achieved a remarkable composite complete remission rate of 91% after one cycle of treatment.

The treatment was found to be safe, with no treatment-related deaths reported, although all patients experienced grade 3 or worse adverse events, such as neutropenia and thrombocytopenia, highlighting the need for careful monitoring during therapy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Venetoclax plus 3 + 7 daunorubicin and cytarabine chemotherapy as first-line treatment for adults with acute myeloid leukaemia: a multicentre, single-arm, phase 2 trial. Wang, H., Mao, L., Yang, M., et al.[2022]

Citations

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

Outcomes of patients treated with venetoclax plus ... The 5-year relative survival of patients with AML is ~32%, and survival rates are dependent on age at diagnosis. Patients <50 years of age have ...

2. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC12422247/

Efficacy of Venetoclax Combined with Azacitidine in Elderly ... Venetoclax combined with azacitidine has shown promising activity in newly diagnosed or relapsed/refractory AML, but real-world data on older ...

3. hematologyadvisor.com hematologyadvisor.com/news/combination-azacitidine-venetoclax-acute-myeloid-leukemia-aml-treatment-risk/

Combination Azacitidine, Venetoclax Effective in AML ... Analysis showed that the overall response rates in the azacitidine plus venetoclax, chemotherapy, and azacitidine monotherapy groups were 38.5%, ...

4. pubmed.ncbi.nlm.nih.gov pubmed.ncbi.nlm.nih.gov/40496033/

Outcomes of patients with Acute Myeloid Leukemia ... Our findings contribute to the growing evidence that venetoclax combined with azacitidine is an effective treatment option for elderly patients with AML.

5. ascopubs.org ascopubs.org/doi/10.1200/JCO.2025.43.16_suppl.e18509

Comparative safety and effectiveness of azacitidine plus ... In AML patients aged 60–75 years, HMA&Ven demonstrated comparable all-cause mortality to IC and significantly lower risk of several adverse events.

6. pubmed.ncbi.nlm.nih.gov pubmed.ncbi.nlm.nih.gov/40951718/

Real-world outcomes of azacitidine plus venetoclax in ... This study shows that azacitidine and venetoclax can be used safely and effectively in Thai hospitals, even when lower medicine doses are used ...

7. 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 ...

8. 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 ... Adverse events reflected known safety profiles for venetoclax and azacitidine, including constipation (53.3%), nausea (49.5%), neutropenia (48. ...

9. nature.com nature.com/articles/s41408-025-01389-4

Granulocyte colony-stimulating factor plus venetoclax and ... Real-world data suggests that compared with conventional intensive chemotherapy, venetoclax plus azacitidine has similar outcomes in AML ...