Combination Chemotherapy for Acute Myeloid Leukemia

Overseen By Tapan Kadia

Age: 18+

Sex: Any

Trial Phase: Phase 2

Sponsor: M.D. Anderson Cancer Center

Disqualifiers: Pregnancy, Uncontrolled illness, Hypersensitivity, 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

508 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 chemotherapy drugs—cladribine, idarubicin, cytarabine, and venetoclax—for individuals with certain blood cancers, such as acute myeloid leukemia (AML) and high-risk myelodysplastic syndrome (MDS). These drugs work by stopping cancer cells from growing, dividing, or spreading. The trial suits individuals diagnosed with AML, MDS, or similar conditions who have not previously received potentially curative treatment. 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 information does not specify if you need to stop taking your current medications. However, it allows prior use of certain drugs like hydroxyurea and azacytidine, suggesting some medications might be continued. 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 has shown that combining cladribine, idarubicin, and venetoclax is generally safe for people with acute myeloid leukemia (AML). Studies indicate that most patients tolerate this treatment well. While some side effects have been reported, they are usually manageable. Common side effects include low blood cell counts, nausea, and tiredness, similar to those from other chemotherapy treatments. It is important to remember that researchers are still studying this treatment to confirm its safety and effectiveness. Always consult a healthcare provider about the potential risks and benefits before joining a clinical trial. ^{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 introduces venetoclax, a BCL-2 inhibitor, which works to promote cancer cell death, making it a potential game-changer when paired with traditional chemotherapy agents. Unlike standard treatments that often revolve around the drugs cytarabine and anthracyclines, this regimen adds a targeted therapy component that can enhance effectiveness, especially in patients with specific genetic mutations like FLT3. The inclusion of venetoclax, along with the possibility of using midostaurin or gilteritinib for patients with FLT3 mutations, offers a more tailored approach that aims to improve outcomes and reduce resistance.

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

In this trial, participants will receive a combination of four drugs—cladribine, idarubicin, cytarabine, and venetoclax—to treat acute myeloid leukemia (AML). Studies have shown that this combination can be very effective, with venetoclax enhancing the effectiveness of these chemotherapy drugs by stopping cancer cells from surviving. This combination has led to strong and lasting remissions in newly diagnosed AML patients. Specifically, patients who previously received this treatment experienced significant improvements, indicating that this drug mix can effectively stop cancer cells from growing and dividing. Overall, this treatment shows promise for those fighting AML and similar conditions. ^{1 3 4 5 6}

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 with acute myeloid leukemia, high-risk myelodysplastic syndrome, or blastic phase chronic myeloid leukemia. Eligible participants must have certain levels of liver and kidney function, a heart ejection fraction >= 45%, an ECOG performance status of =< 2 (which means they can do some activities), and no severe allergies to the drugs used. Pregnant or breastfeeding women cannot join, and participants must agree to use contraception.

Inclusion Criteria

I have been diagnosed with AML, acute biphenotypic leukemia, high risk MDS, or CML in myeloid blast phase.

A negative urine pregnancy test is required within 1 week for all women of childbearing potential prior to enrolling on this trial

I can take care of myself but might not be able to do heavy physical work.

Exclusion Criteria

Pregnant women are excluded from this study due to potential teratogenic or abortifacient effects; breastfeeding should also be avoided

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

I am using contraception or agree to use it during the study.

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 idarubicin intravenously, with additional treatments for specific mutations, repeated every 28 days for up to 2 cycles

8 weeks

Multiple visits for IV administration

Consolidation

Patients receive cladribine, cytarabine, and idarubicin intravenously, with additional treatments for specific mutations, repeated every 28 days for up to 5 cycles

20 weeks

Multiple visits for IV administration

Follow-up

Participants are monitored for safety and effectiveness after treatment

6-12 months

What Are the Treatments Tested in This Trial?

Interventions

• Cladribine
• Idarubicin
• Venetoclax

Trial Overview The study tests how well a combination of chemotherapy drugs—cladribine, idarubicin, cytarabine—and venetoclax work in treating specific blood cancers. It's designed to see if these drugs can stop cancer cells from growing by killing them or preventing their division and spread.

How Is the Trial Designed?

Group I: Treatment (cladribine, cytarabine, idarubicin) Experimental Treatment 7 Interventions

INDUCTION: Patients receive cladribine IV and cytarabine IV over 1-2 hours on days 1-5 and idarubicin IV over 30-60 minutes on days 1-3. Patients with untreated AML and MDS also receive venetoclax PO on days 2-8. AML patients with known FLT3-ITD or FLT3 kinase domain mutations may receive midostaurin PO BID on days 6-19 or gilteritinib PO QD on days 1-14. Treatment repeats every 28 days for up to 2 cycles in the absence of disease progression or unacceptable toxicity. CONSOLIDATION: Patients receive cladribine IV and cytarabine IV over 1-2 hours on days 1-3 and idarubicin IV over 30-60 minutes on days 1-2. Patients with untreated AML and MDS also receive venetoclax PO on days 2-8. AML patients with known FLT3-ITD or FLT3 kinase domain mutations may receive midostaurin PO BID on days 6-19 or gilteritinib PO QD. Treatment repeats every 28 days for up to 5 cycles in the absence of disease progression or unacceptable toxicity.

Cladribine is already approved in United States, European Union for the following indications:

Approved in United States as Leustatin for:

• Hairy cell leukemia
• Chronic lymphocytic leukemia (CLL)
• Non-Hodgkin's lymphoma
• Multiple sclerosis

Approved in European Union as Litak for:

• Hairy cell leukemia
• Chronic lymphocytic leukemia (CLL)
• Non-Hodgkin's lymphoma

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

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]

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 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 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 comparison of two combination therapies for acute myeloid leukemia—glasdegib+low-dose cytarabine (LDAC) and venetoclax+LDAC—no statistically significant differences in overall survival or complete remission rates were found, suggesting similar efficacy.

When choosing between these treatments, factors like safety profiles, ease of administration, and patient preferences will be important since both therapies appear equally effective.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Comparative effectiveness of glasdegib versus venetoclax combined with low-dose cytarabine in acute myeloid leukemia. Tremblay, G., Daniele, P., Bell, T., et al.[2021]

In a study of 118 patients with relapsed and refractory acute myeloid leukemia (R/R AML), the combination of fludarabine, cytarabine, and idarubicin with venetoclax (FLAVIDA) resulted in a significantly higher overall response rate (78%) compared to the standard FLA-IDA treatment (47%).

Both treatment regimens led to similar rates of measurable residual disease negativity and event-free survival, but FLAVIDA was effective in quickly identifying chemosensitive patients, making it a promising option for inducing remission in R/R AML.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Fludarabine, cytarabine, and idarubicin with or without venetoclax in patients with relapsed/refractory acute myeloid leukemia. Shahswar, R., Beutel, G., Gabdoulline, R., et al.[2023]

In a phase Ib trial, the combination of the BCL2 inhibitor venetoclax and the MDM2 inhibitor idasanutlin showed a response rate of 35.9% in patients with relapsed or refractory acute myeloid leukemia, indicating potential efficacy in this difficult-to-treat population.

The side effects of this combination therapy were reported to be manageable, suggesting a favorable safety profile for patients undergoing treatment.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

BCL2/MDM2 Inhibitor Combo Effective in AML. [2019]

In a study comparing treatment regimens for relapsed/refractory acute myeloid leukemia (R/R AML), the venetoclax (VEN) combination therapy showed a comparable overall response rate (59.3%) to intensive chemotherapy (IC) (44.0%), suggesting it is an effective alternative for patients who have failed previous treatments.

Patients receiving the VEN combination had a significantly higher percentage of successful stem cell transplants at blast clearance (86.5% vs. 62.3% for IC), indicating better disease control and potentially lower treatment-related mortality.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

A retrospective comparison of salvage intensive chemotherapy versus venetoclax-combined regimen in patients with relapsed/refractory acute myeloid leukemia (AML). Park, S., Kwag, D., Kim, TY., et al.[2022]

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 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 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 3 trial involving 211 adults with acute myeloid leukemia (AML) who were not eligible for intensive chemotherapy, the combination of venetoclax and low-dose cytarabine (LDAC) showed a clinically meaningful improvement in overall survival, with a median survival of 8.4 months compared to 4.1 months for LDAC alone.

The treatment also resulted in higher remission rates, with 48% of patients achieving complete remission or complete remission with incomplete blood count recovery, while maintaining a manageable safety profile, despite some significant adverse events.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Venetoclax plus LDAC for newly diagnosed AML ineligible for intensive chemotherapy: a phase 3 randomized placebo-controlled trial. Wei, AH., Montesinos, P., Ivanov, V., et al.[2021]

Citations

1. clinicaltrials.gov clinicaltrials.gov/study/NCT02115295

NCT02115295 | Cladribine, Idarubicin, Cytarabine, and ... This phase II trial studies how well cladribine, idarubicin, cytarabine, and venetoclax work in patients with acute myeloid leukemia, ...

2. 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 ...

3. ash.confex.com ash.confex.com/ash/2024/webprogram/Paper203459.html

Paper: A Phase II Trial of Venetoclax in Combination with ... CLIA-venetoclax is a highly effective regimen, producing deep and durable remissions in patients with newly diagnosed AML. Disclosures: ...

4. clinicaltrials.gov clinicaltrials.gov/study/NCT07053020

A Phase 1b/2 Open-label, Dose-ranging Safety and ... The goal of Part 2 of this clinical research study is to learn if the dose of cladribine found in Part 1, when combined with LDAC and venetoclax ...

5. trialx.com trialx.com/clinical-trials/listings/266701/cladribine-idarubicin-cytarabine-and-venetoclax-in-treating-patients-with-acute-myeloid-leukemia-high-risk-myelodysplastic-syndrome-or-blastic-phase-chronic-myeloid-leukemia/

Cladribine, Idarubicin, Cytarabine, and Venetoclax in ... This phase II trial studies how well cladribine, idarubicin, cytarabine, and venetoclax work in patients with acute myeloid leukemia, high-risk ...

6. pubmed.ncbi.nlm.nih.gov pubmed.ncbi.nlm.nih.gov/40389725/

Efficacy and safety of cladribine, low-dose cytarabine and ... The aim of this study was to assess the safety, response, and survival outcomes of cladribine (CLAD) + low-dose cytarabine (LDAC) + venetoclax ( ...