Venetoclax + Chemotherapy for Acute Myeloid Leukemia

Overseen By DiNardo, MD

Age: 18+

Sex: Any

Trial Phase: Phase 1 & 2

Sponsor: M.D. Anderson Cancer Center

Must not be taking: BCL2 inhibitors

Disqualifiers: CNS involvement, Heart failure, HIV, others

No Placebo Group All trial participants will receive the active study treatment (no placebo)

Compensation: Varies

Number of Visits: 1

116 Participants Needed

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial explores the effectiveness of combining venetoclax with chemotherapy to treat acute myeloid leukemia (AML), a type of blood cancer. Researchers aim to determine the optimal dose and monitor side effects to assess whether this combination can more effectively halt cancer cell growth. The trial seeks participants whose AML is newly diagnosed, has returned, or has not responded to treatment. Individuals diagnosed with AML or a related condition with 10% or more abnormal blood cells may be suitable candidates. As a Phase 1 trial, the research focuses on understanding how the treatment works in people, offering participants the opportunity to be among the first to receive this new combination therapy.

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.

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

Research has shown that venetoclax, when combined with certain chemotherapy drugs, is generally well-tolerated by patients with acute myeloid leukemia (AML). In studies where venetoclax was paired with chemotherapy drugs like idarubicin and cytarabine, a 14-day venetoclax treatment provided the same cancer-fighting benefits with fewer side effects, making it safer for patients.

Additionally, using a lower-dose version of the chemotherapy treatment called FLA-IDA with venetoclax improved patient response without increasing harmful side effects. This resulted in better outcomes without added risks.

These findings are important because they demonstrate that while the treatments are still under investigation, previous patients have tolerated them well. The combination appears promising for treating AML with manageable safety. ^{1 2 3 4 5}

Why are researchers excited about this study treatment for acute myeloid leukemia?

Venetoclax is unique because it targets a specific protein called BCL-2, which helps cancer cells survive. This is different from most standard treatments for acute myeloid leukemia (AML), which typically focus on killing rapidly dividing cells. Researchers are excited about venetoclax because it can potentially make cancer cells more vulnerable to chemotherapy, like cytarabine, fludarabine, and idarubicin, thereby enhancing their effectiveness. This combination approach could lead to better outcomes for patients with AML, offering hope for those who might not respond well to traditional therapies alone.

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

Studies have shown that venetoclax can effectively treat acute myeloid leukemia (AML). One study demonstrated that using venetoclax in various ways led to a good response, with 72% of patients achieving complete response or remission. Although the average survival time was about 11 months, the results offer promise for improving outcomes in AML patients. In this trial, participants will receive a combination of venetoclax with the FLAG-IDA treatment, which includes the drugs fludarabine, cytarabine, and idarubicin. The FLAG-IDA regimen has proven effective on its own, resulting in complete remission in about 63% of patients and showing strong activity against leukemia. Combining venetoclax with this chemotherapy treatment may enhance its effectiveness for AML. ^{6 7 8 9 10}

Who Is on the Research Team?

Courtney DiNardo, MD

Principal Investigator

M.D. Anderson Cancer Center

Are You a Good Fit for This Trial?

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.

Timeline for a Trial Participant

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)

What Are the Treatments Tested in This Trial?

Interventions

• Cytarabine
• Filgrastim
• Fludarabine
• Idarubicin
• Venetoclax

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.

How Is the Trial Designed?

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

See detailed description.

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

Approved in United States as Cytosar-U for:

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

Approved in European Union as Depocyt for:

• Lymphomatous meningitis

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+

National Cancer Institute (NCI)

Collaborator

Trials

14,080

Recruited

41,180,000+

Published Research Related to This Trial

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 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 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]

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]

In a study involving 15 Chinese patients with acute myeloid leukemia (AML) who could not tolerate intensive chemotherapy, venetoclax combined with low-dose cytarabine (LDAC) showed a 38% reduction in the risk of death compared to placebo, with a median overall survival of 9.0 months versus 4.1 months for the placebo group.

The treatment resulted in a complete remission rate of 33% among those receiving venetoclax, while no patients in the placebo group achieved remission, indicating that venetoclax with LDAC is an effective option for this patient population.

NCBI (Pubmed)

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]. Hu, Y., Jin, J., Zhang, Y., 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]

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]

Citations

1. pubmed.ncbi.nlm.nih.gov pubmed.ncbi.nlm.nih.gov/12191567/

FLAG-IDA Regimen (Fludarabine, Cytarabine, Idarubicin ... Overall survival (OS) at 12 months was 40%. The FLAG-IDA regimen shows evident antileukemic activity in patients with high-risk myeloid malignancies with ...

2. ascopubs.org ascopubs.org/doi/10.1200/JCO.23.00943

Fludarabine, Cytarabine, Granulocyte Colony-Stimulating ... Overall, FLAG-Ida + GO significantly reduced relapse without improving OS. However, exploratory analyses show that patients with NPM1 and FLT3 ...

3. sciencedirect.com sciencedirect.com/science/article/abs/pii/S0145212620300230

Improved Post remission survival of non- favorable risk ... Our data shows that FLAG+/- Ida results in higher remission rates after one course of treatment, shorter time to count recovery, faster time to transplant and ...

4. researchgate.net researchgate.net/publication/336488197_FLAG-IDA_Regimen_Fludarabine_Cytarabine_Idarubicin_and_G-CSF_in_the_Treatment_of_Patients_with_High-Risk_Acute_Myeloid_Leukemia_and_Myelodysplastic_Syndromes

FLAG-IDA Regimen (Fludarabine, Cytarabine, Idarubicin ... Results: CR and partial remission (PR) was achieved in 84 patients (53%) and in 19 patients (12%), respectively. Twenty-three patients (15%) died during ...

5. pubmed.ncbi.nlm.nih.gov pubmed.ncbi.nlm.nih.gov/9432047/

Fludarabine, cytarabine, G-CSF and idarubicin (FLAG-IDA ... 18/19 (94.7%) patients responded to FLAG-idarubicin with 12 (63%) achieving complete remission (CR) (< 5% blasts and normal cytogenetics). 7/9 (78%) patients ...

6. clinicaltrials.gov clinicaltrials.gov/study/NCT03214562

Study Details | NCT03214562 | Venetoclax With ... This phase Ib/II trial studies the best dose and side effects of venetoclax and how well it works when given with combination chemotherapy in treating patients

7. aacrjournals.org aacrjournals.org/clincancerres/article/31/13/2608/763093/Venetoclax-plus-Modified-Intensity-Idarubicin-and

Venetoclax plus Modified-Intensity Idarubicin and Cytarabine ... Shorter duration of venetoclax administration to 14 days has same efficacy and better safety profile in treatment of acute myeloid leukemia . Ann Hematol.

8. pubmed.ncbi.nlm.nih.gov pubmed.ncbi.nlm.nih.gov/39594827/

Dose-Reduced FLA-IDA in Combination with Venetoclax Is ... Dose-reduced FLA-VIDA significantly improved response rates without increases in toxicity, showing promise for an improved R/R AML treatment.

9. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC9058453/

Advancing the standard: venetoclax combined with intensive ... Herein, we discuss ongoing trials investigating VEN in combination with IC in addition to outcomes within specific molecularly defined subgroups ...

10. mycancergenome.org mycancergenome.org/content/clinical_trials/NCT03214562/

Clinical Trial: NCT03214562 This phase Ib/II trial studies the best dose and side effects of venetoclax and how well it works when given with combination chemotherapy ...