Combination Chemotherapy for Acute Myeloid Leukemia

Overseen By Tapan Kadia

Age: 18+

Sex: Any

Trial Phase: Phase 2

Sponsor: M.D. Anderson Cancer Center

Must not be taking: Venetoclax

Disqualifiers: Pregnancy, Uncontrolled illness, APL, 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

145 Participants Needed

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 four drugs—venetoclax, cladribine, low-dose cytarabine, and azacitidine—in halting the growth of cancer cells in individuals with untreated acute myeloid leukemia (AML). These drugs function in various ways, such as killing cancer cells or preventing their growth and spread. This trial may suit individuals with AML who have not received certain treatments and can meet the study's requirements. Participants should have stable organ function and be capable of providing informed consent. 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, prior therapy with certain drugs like hydroxyurea and cytarabine is allowed, so it's best to discuss your specific medications with the trial team.

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

Research shows that a combination of four drugs—venetoclax, cladribine, low-dose cytarabine, and azacitidine—is being tested to treat acute myeloid leukemia (AML). Earlier studies suggest this combination can be effective for newly diagnosed AML patients, especially older or less fit individuals, indicating that these drugs are generally well-tolerated.

Regarding safety, previous studies found that patients can manage this treatment. However, as this is a Phase 2 trial, the treatment is still under careful study to ensure safety and effectiveness. Phase 2 trials are designed to assess a treatment's safety and efficacy, so ongoing monitoring remains important.

Prospective participants should discuss with their doctor to understand the potential risks and benefits based on the latest research. ^{1 2 3 4 5}

Why are researchers excited about this trial's treatments?

Researchers are excited about this combination chemotherapy treatment for acute myeloid leukemia (AML) because it integrates several drugs, each with a unique mechanism of action, to tackle the cancer more effectively. Azacitidine and Venetoclax work together to disrupt the leukemia cells' survival pathways, increasing the cancer cells' vulnerability. Cladribine and Cytarabine, on the other hand, directly target and destroy rapidly dividing cells. This multi-pronged approach is different from standard treatments like intensive chemotherapy alone, as it aims to improve outcomes by attacking the cancer on multiple fronts simultaneously.

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

Research has shown that a combination of four drugs—venetoclax, cladribine, low-dose cytarabine, and azacitidine—holds promise for treating acute myeloid leukemia (AML). Participants in this trial will receive this combination treatment. Studies have found that this mix effectively kills cancer cells in newly diagnosed AML patients. Specifically, using venetoclax with cladribine and low-dose cytarabine has proven very successful. Substituting azacitidine in this regimen has also yielded good results, particularly for older or less fit patients. Overall, this combination effectively targets cancer cells, offering hope for those with untreated AML. ^{1 2 3 6 7}

Who Is on the Research Team?

Tapan Kadia, MD

Principal Investigator

M.D. Anderson Cancer Center

Are You a Good Fit for This Trial?

This trial is for adults under 50 with untreated acute myeloid leukemia (AML), who can't have standard therapy. They must have normal liver and kidney function, be physically stable enough to participate, not pregnant or breastfeeding, willing to use contraception, and able to consent.

Inclusion Criteria

I understand the study's requirements and have signed the consent form.

I have AML and may have had only specific minor treatments.

I am 50 years or older, or under 50 but considered unsuitable for standard treatment.

Exclusion Criteria

I am of childbearing age and do not use birth control.

Participants with documented hypersensitivity to any of the components of the chemotherapy program

I have been diagnosed with acute promyelocytic leukemia.

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Induction

Patients receive cladribine, cytarabine, and venetoclax for 28 days. A second induction cycle may be given if CR or CRi is not achieved.

4 weeks

Daily visits for drug administration

Consolidation/Maintenance

Patients receive cladribine, cytarabine, venetoclax, and azacitidine in cycles, repeating every 28 days for up to 18 cycles.

Up to 18 months

Regular visits for each cycle

Follow-up

Participants are monitored for safety and effectiveness after treatment completion.

Every 6-12 months for 5 years

What Are the Treatments Tested in This Trial?

Interventions

• Azacitidine
• Cladribine
• Cytarabine
• Venetoclax

Trial Overview The study tests a combination of chemotherapy drugs: Venetoclax, Cladribine, low dose Cytarabine, and Azacitidine in two phases—induction followed by consolidation—to see if they're more effective together in treating AML.

How Is the Trial Designed?

Group I: Treatment (cladribine, cytarabine, venetoclax, azacitidine) Experimental Treatment 4 Interventions

See Detailed Description.

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?

M.D. Anderson Cancer Center

Lead Sponsor

Trials

3,107

Recruited

1,813,000+

Published Research Related to This Trial

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 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 study of 60 patients with acute myeloid leukemia (AML), the combination of venetoclax and azacitidine (Ven+AZA) demonstrated a high response rate, with 70.8% of previously untreated patients unfit for standard chemotherapy achieving complete remission (CR) or CR with incomplete hematological recovery (CRi) after one cycle.

Ven+AZA was found to be safe and tolerable, with some patients achieving minimal residual disease (MRD) negativity, particularly in those with favorable genetic mutations like NPM1, IDH1/IDH2, and TP53, indicating its potential effectiveness in specific patient subgroups.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

[Short-term efficacy of venetoclax combined with azacitidine in acute myeloid leukemia: a single-institution experience]. Yu, WJ., Jia, JS., Wang, J., et al.[2022]

In a study of 6 children with refractory or relapsed acute myeloid leukemia (AML), the combination of venetoclax, azacitidine, and cladribine (VAC regimen) resulted in significant treatment responses, with 4 achieving complete remission and 1 showing partial remission.

Despite severe side effects like grade IV neutropenia and thrombocytopenia, there were no treatment-related deaths or infections, indicating that the VAC regimen is both effective and safe for this vulnerable patient group.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

[Safety and the Short-Term Efficacy of Venetoclax Combined with Azacitidine Followed by Cladribine in Children with Refractory/Relapsed Acute Myeloid Leukemia]. DU, WW., Liu, SX., Wang, Y., et al.[2023]

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]

The combination of venetoclax (Ven) and azacitidine (AZA) shows a high efficacy in treating acute myeloid leukemia (AML) and myelodysplastic syndrome (MDS), with an overall complete response rate of 57.9% across 19 studies involving 1615 patients.

This treatment is particularly effective for newly diagnosed AML patients, achieving a complete response rate of 67.5%, although it is less effective for those with relapsed or refractory AML, which had a response rate of only 30%.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

The efficacy and safety of venetoclax and azacytidine combination treatment in patients with acute myeloid leukemia and myelodysplastic syndrome: systematic review and meta-analysis. Du, Y., Li, C., Yan, J.[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 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]

Citations

1. clinicaltrials.gov clinicaltrials.gov/study/NCT03586609

NCT03586609 | Venetoclax, Cladribine, Low Dose ... This phase II trial studies how well venetoclax, cladribine, low dose cytarabine, and azacitidine work in treating patients with acute myeloid leukemia that ...

2. clinicaltrials.gov clinicaltrials.gov/study/NCT06504459

Study Details | NCT06504459 | Venetoclax in Combination ... Giving venetoclax with cladribine and cytarabine alternating with azacitidine and venetoclax may kill more cancer cells in patients with newly diagnosed ...

3. pubmed.ncbi.nlm.nih.gov pubmed.ncbi.nlm.nih.gov/35704787/

Phase II Study of Venetoclax Added to Cladribine Plus Low ... Venetoclax and CLAD/LDAC alternating with venetoclax and 5-AZA is an effective regimen among older or unfit patients with newly diagnosed ...

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

Evaluating venetoclax and its potential in treatment-naïve ... Relapsed acute myeloid leukemia is less sensitive to venetoclax + azacitidine due to leukemia stem cell resistance driven by fatty acid metabolism and can ...

5. ash.confex.com ash.confex.com/ash/2024/webprogram/Paper202620.html

56 Phase II Study of Cladribine with Low Dose Cytarabine ... The addition of cladribine (CLAD) and LDAC with VEN has been shown to be highly effective in newly diagnosed AML.

6. careacross.com careacross.com/clinical-trials/trial/NCT06504459

Venetoclax in Combination With Cladribine and Cytarabine ... Giving venetoclax with cladribine and cytarabine alternating with azacitidine and venetoclax may kill more cancer cells in patients with newly diagnosed ...

7. library.ehaweb.org library.ehaweb.org/eha/2025/eha2025-congress/4160556/alex.bataller.phase.ii.study.of.cladribine.with.low.dose.cytarabine.and.html

PHASE II STUDY OF CLADRIBINE WITH LOW DOSE ... Cladribine (CLAD) added to LDAC with VEN is effective in newly diagnosed AML. Aims: We report a cohort update and subgroup analysis of pts ...