Venetoclax + Chemotherapy for Acute Myeloid Leukemia

Overseen by Courtney DiNardo, MD

Age: 18+

Sex: Any

Travel: May Be Covered

Time Reimbursement: Varies

Trial Phase: Phase 1 & 2

Recruiting

Sponsor: M.D. Anderson Cancer Center

Must not be taking: BCL2 inhibitors

Disqualifiers: CNS involvement, Heart failure, HIV, others

No Placebo Group

Breakthrough Therapy

Trial Summary

What is the purpose of this trial?

This trial is testing venetoclax with chemotherapy drugs to treat patients with acute myeloid leukemia (AML). Venetoclax blocks enzymes needed for cancer cell growth, while the chemotherapy drugs kill or stop the spread of cancer cells. Venetoclax is a selective Bcl-2 inhibitor used for treating lymphomas and leukemias, including AML, and has shown improved outcomes when combined with other treatments.

Do I need to stop my current medications for the trial?

The trial information does not specify if you need to stop taking your current medications. It's best to discuss this with the trial team or your doctor.

What data supports the effectiveness of the drug combination Venetoclax and Chemotherapy for Acute Myeloid Leukemia?

Research shows that adding Venetoclax to chemotherapy significantly increased the overall response rate in patients with relapsed or refractory acute myeloid leukemia compared to chemotherapy alone. Additionally, Venetoclax combined with low-dose cytarabine has shown to prolong overall survival in patients with newly diagnosed acute myeloid leukemia who are ineligible for intensive chemotherapy. ^{1 2 3 4 5}

Is the combination of Venetoclax and chemotherapy safe for treating acute myeloid leukemia?

The combination of Venetoclax with chemotherapy for acute myeloid leukemia has shown a manageable safety profile, with common side effects including low blood cell counts (neutropenia, thrombocytopenia, and anemia) and some non-blood-related effects like low potassium levels, vomiting, and constipation. These side effects are generally considered tolerable, and the treatment has been effective in achieving remission in many patients. ^{1 3 5 6 7}

What makes the drug combination of Venetoclax, Cytarabine, Fludarabine, and Idarubicin unique for treating acute myeloid leukemia?

This drug combination is unique because Venetoclax, a BCL-2 inhibitor, is added to traditional chemotherapy drugs, potentially improving response rates in relapsed or refractory acute myeloid leukemia (AML) patients. Venetoclax can also penetrate the cerebrospinal fluid, offering a novel approach for AML with central nervous system involvement. ^{1 2 3 8 9}

Research Team

Courtney DiNardo, MD

Principal Investigator

M.D. Anderson Cancer Center

Eligibility Criteria

This trial is for adults with newly diagnosed or stubborn acute myeloid leukemia (AML) who can perform daily activities with ease to moderate difficulty. They must have acceptable liver and kidney function, understand the study, and use effective contraception if needed. It's not for those with severe heart issues, trouble swallowing, prior BCL2 inhibitor therapy, certain genetic abnormalities in their leukemia, active infections like HIV or hepatitis B/C, or a very high white blood cell count.

Inclusion Criteria

Creatinine clearance >= 30 mL/min based on the Cockcroft-Gault equation

Total bilirubin < 1.5 x upper limit of normal (ULN) unless increase is due to Gilbert's disease or leukemic involvement

Ability to understand and provide signed informed consent

Exclusion Criteria

I have a condition that affects my ability to swallow or absorb pills.

My leukemia is of a specific type known as acute promyelocytic leukemia.

I have previously received BCL2 inhibitor therapy.

Trial Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Induction Therapy

Patients receive venetoclax and combination chemotherapy including fludarabine, cytarabine, idarubicin, and filgrastim or pegfilgrastim. Treatment repeats every 28 days for up to 2 cycles.

8 weeks

Multiple visits for drug administration

Consolidation Therapy

Patients receive venetoclax and combination chemotherapy including fludarabine, cytarabine, and filgrastim or pegfilgrastim. Treatment repeats every 28 days for up to 6 cycles.

24 weeks

Multiple visits for drug administration

Maintenance Therapy

Patients receive venetoclax continuously. Cycles repeat every 28 days for up to 1 year.

12 months

Monthly visits for monitoring

Follow-up

Participants are monitored for safety and effectiveness after treatment completion.

4 weeks

1 visit (in-person)

Treatment Details

Interventions

• Cytarabine (Antimetabolite)
• Filgrastim (Granulocyte Colony-Stimulating Factor (G-CSF))
• Fludarabine (Purine Analog)
• Idarubicin (Topoisomerase II inhibitor)
• Venetoclax (B-cell lymphoma-2 (BCL-2) inhibitor)

Trial Overview The trial is testing the effectiveness of Venetoclax combined with chemotherapy drugs (fludarabine, cytarabine, filgrastim and idarubicin) on AML patients. The goal is to find the best dose that works well together while monitoring side effects. This combination may be more effective than current treatments by blocking enzymes cancer cells need to grow.

Participant Groups

Group I: Treatment (venetoclax, FLAG-IDA) Experimental Treatment 6 Interventions

See detailed description.

Cytarabine is already approved in Canada for the following indications:

Approved in Canada as Cytosar-U for:

• Acute myeloid leukemia
• Acute lymphocytic leukemia
• Chronic myeloid leukemia

Who Is Running the Clinical Trial?

M.D. Anderson Cancer Center

Lead Sponsor

Trials

3,107

Recruited

1,813,000+

Dr. Peter WT Pisters

M.D. Anderson Cancer Center

Chief Executive Officer since 2017

MD from University of Western Ontario

Dr. Jeffrey E. Lee

M.D. Anderson Cancer Center

Chief Medical Officer

MD from Stanford University School of Medicine

National Cancer Institute (NCI)

Collaborator

Trials

14,080

Recruited

41,180,000+

Dr. Douglas R. Lowy

National Cancer Institute (NCI)

Chief Executive Officer since 2023

MD from New York University School of Medicine

Dr. Monica Bertagnolli

National Cancer Institute (NCI)

Chief Medical Officer since 2022

MD from Harvard Medical School

Findings from Research

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 subgroup of 27 Japanese patients with newly diagnosed acute myeloid leukaemia, venetoclax combined with low-dose cytarabine showed a higher complete remission rate (44.4%) compared to placebo (11.1%), indicating potential efficacy in this population.

Despite the higher remission rate, the median overall survival was similar between the venetoclax (4.7 months) and placebo (8.1 months) groups, suggesting limited survival benefit, which may be influenced by small sample size and baseline health differences among patients.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Venetoclax plus low-dose cytarabine in Japanese patients with untreated acute myeloid leukaemia ineligible for intensive chemotherapy. Yamauchi, T., Yoshida, C., Usuki, K., 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 pooled analysis of treatment-naïve patients with FLT3-mutant acute myeloid leukemia, the combination of venetoclax and azacitidine resulted in a significantly higher composite complete remission rate (67%) compared to azacitidine alone (36%), with a median overall survival of 12.5 months versus 8.6 months.

The treatment was found to be safe, with no unexpected toxicities reported, indicating that venetoclax + azacitidine is a promising option for older patients or those with comorbidities who are ineligible for intensive therapy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Impact of FLT3 Mutation on Outcomes after Venetoclax and Azacitidine for Patients with Treatment-Naïve Acute Myeloid Leukemia. Konopleva, M., Thirman, MJ., Pratz, KW., et al.[2023]

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]

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]

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]

A 52-year-old patient with acute myeloid leukemia (AML) relapsed in the central nervous system (CNS) after a bone marrow transplant was treated with venetoclax, a drug recently approved for AML.

The study found that venetoclax penetrated the cerebrospinal fluid (CSF) effectively, achieving concentrations similar to the in vitro IC50, suggesting potential efficacy in treating CNS involvement in AML.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Venetoclax penetrates in cerebrospinal fluid of an acute myeloid leukemia patient with leptomeningeal involvement. Condorelli, A., Matteo, C., Leotta, S., et al.[2022]

References

1. Italy pubmed.ncbi.nlm.nih.gov

Fludarabine, cytarabine, and idarubicin with or without venetoclax in patients with relapsed/refractory acute myeloid leukemia. [2023]

2. England pubmed.ncbi.nlm.nih.gov

Venetoclax plus low-dose cytarabine in Japanese patients with untreated acute myeloid leukaemia ineligible for intensive chemotherapy. [2022]

3. England pubmed.ncbi.nlm.nih.gov

Venetoclax-based combinations for acute myeloid leukemia: optimizing their use in Latin-America. [2022]

4. United States pubmed.ncbi.nlm.nih.gov

Impact of FLT3 Mutation on Outcomes after Venetoclax and Azacitidine for Patients with Treatment-Naïve Acute Myeloid Leukemia. [2023]

5. England 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. [2022]

6. China pubmed.ncbi.nlm.nih.gov

[Venetoclax with low-dose cytarabine for patients with untreated acute myeloid leukemia ineligible for intensive chemotherapy: results from the Chinese cohort of a phase three randomized placebo-controlled trial]. [2021]

7. China pubmed.ncbi.nlm.nih.gov

[Efficacy of venetoclax combined azacitidine in newly diagnosed acute myeloid leukemia unfit for standard chemotherapy: a single center experience]. [2023]

8. United States pubmed.ncbi.nlm.nih.gov

Venetoclax combination therapy in acute myeloid leukemia and myelodysplastic syndromes. [2023]

9. Germany pubmed.ncbi.nlm.nih.gov

Venetoclax penetrates in cerebrospinal fluid of an acute myeloid leukemia patient with leptomeningeal involvement. [2022]