Enasidenib + Venetoclax for Acute Myeloid Leukemia

Recruiting at 32 trial locations

Age: 18+

Sex: Any

Trial Phase: Phase 2

Sponsor: National Cancer Institute (NCI)

Must not be taking: Cytarabine therapy

Disqualifiers: Pregnancy, Prior malignancy, 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: 2

Duration: 28 days per cycle, repeated

93 Participants Needed

Trial Summary

What is the purpose of this trial?

This phase II MyeloMATCH treatment trial studies how well ASTX727 and venetoclax plus enasidenib works compared to ASTX727 and venetoclax alone for the treatment of older patients with newly diagnosed acute myeloid leukemia (AML) or younger patients who are considered unfit for standard treatment, and who have an abnormal change (mutation) in the IDH2 gene. This gene mutation can cause AML to grow and spread. This trial is being done to see if adding enasidenib to the usual treatment can help more patients with the IDH2 gene get rid of AML. Cedazuridine is in a class of medications called cytidine deaminase inhibitors. It prevents the breakdown of decitabine, making it more available in the body so that decitabine will have a greater effect. Decitabine is in a class of medications called hypomethylation agents. It works by helping the bone marrow produce normal blood cells and by killing abnormal cells in the bone marrow. Venetoclax is in a class of medications called B-cell lymphoma-2 (BCL-2) inhibitors. It may stop the growth of cancer cells by blocking Bcl-2, a protein needed for cancer cell survival. Enasidenib works by stopping the growth and spread of tumor cells that have the IDH2 mutation. Giving ASTX727 and venetoclax plus enasidenib may work better in treating AML patients with the IDH2 mutation.

Will I have to stop taking my current medications?

The trial does not specify if you need to stop taking your current medications, but you cannot receive other investigational agents while on the trial. Some medications like hydroxyurea must be stopped before starting the trial treatment.

What data supports the effectiveness of the drug combination Enasidenib + Venetoclax for Acute Myeloid Leukemia?

Research shows that combining venetoclax with decitabine or azacitidine is effective for treating older patients with acute myeloid leukemia (AML), leading to higher response rates and longer survival compared to using decitabine alone. This suggests that venetoclax, when combined with other drugs, can be effective in treating AML. ^{1 2 3 4 5}

What safety information is available for the combination of Enasidenib, Venetoclax, and Decitabine in treating acute myeloid leukemia?

The combination of Venetoclax with Decitabine has been studied in patients with acute myeloid leukemia, showing common side effects like nausea, diarrhea, constipation, and fatigue. Serious side effects included febrile neutropenia (fever with low white blood cell count) and thrombocytopenia (low platelet count). No tumor lysis syndrome (a serious condition caused by the rapid breakdown of cancer cells) was observed. ^{1 3 5 6 7}

What makes the Enasidenib + Venetoclax treatment for acute myeloid leukemia unique?

This treatment combines Enasidenib, Venetoclax, and Decitabine with Cedazuridine, which is unique because it targets specific genetic mutations in acute myeloid leukemia (AML) and may offer a new option for patients who have relapsed or are resistant to other treatments. The combination of these drugs aims to improve outcomes by using different mechanisms to attack the cancer cells. ^{1 2 8 9 10}

Research Team

Eric J Huselton

Principal Investigator

SWOG Cancer Research Network

Eligibility Criteria

This trial is for older adults with newly diagnosed acute myeloid leukemia (AML) or younger patients unfit for standard treatment, who have an IDH2 gene mutation. Participants must not have received prior AML therapy except certain allowed treatments like hydroxyurea and must agree to discontinue them before the study starts. They should be over 60 years old or at least 18 if ineligible for cytarabine-based induction therapy, with a performance status allowing daily activity.

Inclusion Criteria

* Note: Pre-enrollment/diagnosis labs must have already been performed under MYELOMATCH

I have been diagnosed with a type of leukemia that is not being treated yet.

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

Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants receive ASTX727 and venetoclax, with or without enasidenib, in 28-day cycles

28 days per cycle, repeated

Monthly visits for treatment and monitoring

Follow-up

Participants are monitored for safety and effectiveness after treatment

5 years

Monthly visits for the first year, then every 2-6 months

Treatment Details

Interventions

• Decitabine and Cedazuridine
• Enasidenib
• Venetoclax

Trial Overview The trial tests ASTX727 (cedazuridine plus decitabine) and venetoclax with or without enasidenib in treating AML patients with the IDH2 mutation. It aims to see if adding enasidenib improves outcomes by stopping tumor growth. Cedazuridine enhances decitabine's effect on bone marrow cells, while venetoclax targets proteins essential for cancer cell survival.

Participant Groups

Group I: Arm 2 (ASTX727 + venetoclax + enasidenib) Experimental Treatment 6 Interventions

Patients receive ASTX727 PO QD on days 1-5, venetoclax PO QD on days 1-28, and enasidenib PO QD on days 1-28 of each cycle. Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity. Patients undergo blood sample collection, bone marrow aspiration, and bone marrow biopsy throughout the trial.

Group II: Arm 1 (ASTX727 + venetoclax) Active Control 5 Interventions

Patients receive ASTX727 PO QD on days 1-5 and venetoclax PO QD on days 1-28 of each cycle. Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity. Patients undergo blood sample collection, bone marrow aspiration, and bone marrow biopsy throughout the trial.

Who Is Running the Clinical Trial?

National Cancer Institute (NCI)

Lead Sponsor

Trials

14,080

Recruited

41,180,000+

Findings from Research

In a study of 22 heavily pre-treated patients with relapsed or refractory acute myeloid leukaemia (RR-AML), the combination of venetoclax and decitabine resulted in a 45.5% overall response rate, with 40.9% achieving complete remission, demonstrating its efficacy in a real-world setting.

While the treatment was effective, it was associated with significant side effects, including grade IV neutropenia and thrombocytopenia in all patients, but no deaths were attributed to the treatment side effects, indicating that the adverse effects were manageable.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Efficacy of Venetoclax Combined with Decitabine-Based Treatment for Heavily Pre-Treated Relapsed or Refractory AML Patients in a Real-World Setting. Tong, J., Zhao, N., Hu, X., et al.[2022]

In a study of 86 patients with relapsed or refractory acute myeloid leukemia (RR-AML) treated with venetoclax combinations, the complete remission rate was 24%, and the overall response rate was 31%, indicating that venetoclax is an effective treatment option for this patient group.

Azacitidine combined with venetoclax showed significantly better outcomes than low-dose cytarabine with venetoclax, with median overall survival of 25 months compared to 3.9 months, highlighting the importance of treatment choice in improving survival in RR-AML.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Clinical and molecular predictors of response and survival following venetoclax therapy in relapsed/refractory AML. Stahl, M., Menghrajani, K., Derkach, A., et al.[2021]

In a study involving 145 older patients (median age 74) with acute myeloid leukemia (AML) who were ineligible for intensive chemotherapy, the combination of venetoclax with decitabine or azacitidine resulted in a high complete remission (CR) rate of 67%, demonstrating its efficacy in this challenging population.

The treatment was well tolerated, with no cases of tumor lysis syndrome reported, and the median overall survival was 17.5 months, indicating that venetoclax combined with hypomethylating agents is a promising option for elderly patients with AML.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Venetoclax combined with decitabine or azacitidine in treatment-naive, elderly patients with acute myeloid leukemia. DiNardo, CD., Pratz, K., Pullarkat, V., et al.[2021]

In a study comparing older adults with newly diagnosed acute myeloid leukemia (AML), those treated with the combination of decitabine (DEC) and venetoclax (VEN) had a significantly longer median overall survival of 13.4 months compared to 8.3 months for those receiving DEC alone.

The combination therapy also resulted in a higher response rate of 70.3% versus 24.3% for DEC monotherapy, indicating that DEC+VEN is more effective in treating AML without increasing short-term mortality rates.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Venetoclax with decitabine versus decitabine monotherapy in elderly acute myeloid leukemia: a propensity score-matched analysis. Kwag, D., Cho, BS., Bang, SY., et al.[2022]

In a phase 2 trial involving 168 patients with acute myeloid leukaemia (AML), the combination of venetoclax and a 10-day regimen of decitabine resulted in a high overall response rate of 74%, with particularly impressive results in newly diagnosed AML patients (89%).

The treatment demonstrated a manageable safety profile, with common adverse events including neutropenia and infections, and a 30-day mortality rate of only 3.6%, indicating that this combination therapy is both effective and relatively safe for older patients or those unfit for intensive chemotherapy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

10-day decitabine with venetoclax for newly diagnosed intensive chemotherapy ineligible, and relapsed or refractory acute myeloid leukaemia: a single-centre, phase 2 trial. DiNardo, CD., Maiti, A., Rausch, CR., et al.[2021]

In a study of 81 patients with acute myeloid leukemia (AML) receiving venetoclax with decitabine or azacitidine, 72.8% experienced infections, with the most common pathogens being Candida albicans and Klebsiella pneumonia.

The study found that the incidence of infectious complications was lower with this treatment compared to conventional chemotherapy, and high leukemia burden and fever were identified as significant risk factors for developing infections.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

A real-world study of infectious complications of venetoclax combined with decitabine or azacitidine in adult acute myeloid leukemia. Zhu, LX., Chen, RR., Wang, LL., 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]

References

1. New Zealand pubmed.ncbi.nlm.nih.gov

Efficacy of Venetoclax Combined with Decitabine-Based Treatment for Heavily Pre-Treated Relapsed or Refractory AML Patients in a Real-World Setting. [2022]

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

Clinical and molecular predictors of response and survival following venetoclax therapy in relapsed/refractory AML. [2021]

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

Venetoclax combined with decitabine or azacitidine in treatment-naive, elderly patients with acute myeloid leukemia. [2021]

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

Venetoclax with decitabine versus decitabine monotherapy in elderly acute myeloid leukemia: a propensity score-matched analysis. [2022]

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

Venetoclax with decitabine or azacitidine in the first-line treatment of acute myeloid leukemia. [2023]

6. England pubmed.ncbi.nlm.nih.gov

10-day decitabine with venetoclax for newly diagnosed intensive chemotherapy ineligible, and relapsed or refractory acute myeloid leukaemia: a single-centre, phase 2 trial. [2021]

7. Germany pubmed.ncbi.nlm.nih.gov

A real-world study of infectious complications of venetoclax combined with decitabine or azacitidine in adult acute myeloid leukemia. [2022]

8. 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]

9. Switzerland pubmed.ncbi.nlm.nih.gov

Venetoclax-Based Regimens for Relapsed/Refractory Acute Myeloid Leukemia in a Real-Life Setting: A Retrospective Single-Center Experience. [2021]

10. England pubmed.ncbi.nlm.nih.gov

AML with BCR-ABL1 Fusion treated with Imatinib, a Hypomethylating Agent and Venetoclax. [2022]