Enasidenib + Venetoclax for Acute Myeloid Leukemia

Not currently recruiting at 86 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

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial aims to determine if adding enasidenib to the standard treatment of ASTX727 (a combination of decitabine and cedazuridine) and venetoclax can more effectively treat acute myeloid leukemia (AML) with an IDH2 gene mutation. AML affects blood and bone marrow, and the IDH2 mutation can promote its growth and spread. The trial compares two groups: one receiving the standard treatment and another receiving the standard treatment plus enasidenib. Individuals with newly diagnosed, untreated AML who have an IDH2 mutation and are not eligible for standard intensive treatment may be suitable for this study. As a Phase 2 trial, the research focuses on measuring the treatment's effectiveness in an initial, smaller group of participants.

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.

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

Studies have shown that the combination of ASTX727 (a mix of decitabine and cedazuridine) and venetoclax is generally well-tolerated by patients. Previous research on these drugs found manageable side effects, including common issues like low blood cell counts, which are expected with cancer treatments.

Adding enasidenib specifically targets a mutation in the IDH2 gene found in some acute myeloid leukemia (AML) patients. This combination aims to improve treatment results. Enasidenib has been used in other situations and generally has a safety profile that patients handle well, though it can cause side effects like nausea and fatigue.

Overall, earlier studies have tested these medications, and while they do have some side effects, they are usually manageable with medical supervision. Ongoing trials will further clarify how these drugs work together and their safety in treating AML with the IDH2 mutation. ^{1 2 3 4 5}

Why are researchers excited about this trial's treatments?

Researchers are excited about these treatments for Acute Myeloid Leukemia (AML) because they offer a new approach by combining enasidenib, venetoclax, and ASTX727. Unlike the standard treatments, which typically involve chemotherapy, enasidenib targets a specific mutation in the IDH2 gene, potentially making it effective for patients with that mutation. Venetoclax works by inhibiting BCL-2, a protein that helps cancer cells survive, thereby promoting cancer cell death. The combination of these drugs with ASTX727, which includes decitabine and cedazuridine, could enhance the effectiveness of the treatment by allowing the cancer-fighting agents to work more efficiently. This multi-faceted approach aims to improve outcomes for patients with AML compared to existing therapies.

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

Research has shown that combining decitabine/cedazuridine (ASTX727) with venetoclax can effectively treat acute myeloid leukemia (AML), particularly for those unable to undergo intensive chemotherapy. This combination manages the disease by enhancing the bone marrow's ability to produce normal blood cells and eliminating abnormal cells. In this trial, one group of participants will receive ASTX727 and venetoclax, while another group will receive ASTX727, venetoclax, and enasidenib. Adding enasidenib may further aid by specifically targeting and inhibiting the growth of cancer cells with the IDH2 mutation, which often causes AML to spread. Early findings suggest that this "triplet" treatment—ASTX727, venetoclax, and enasidenib—could offer a more personalized and effective option for patients with this specific mutation. ^{1 2 3 6 7}

Who Is on the Research Team?

Eric J Huselton

Principal Investigator

SWOG Cancer Research Network

Are You a Good Fit for This Trial?

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 for a Trial Participant

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

What Are the Treatments Tested in This Trial?

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.

How Is the Trial Designed?

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+

Published Research Related to This Trial

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 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 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 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 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 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]

Citations

1. clinicaltrials.gov clinicaltrials.gov/study/NCT04774393

NCT04774393 | Decitabine/Cedazuridine and Venetoclax ... Giving decitabine/cedazuridine and venetoclax in combination with ivosidenib or enasidenib may help control acute myeloid leukemia. Detailed Description.

2. ashpublications.org ashpublications.org/blood/article/142/Supplement%201/2909/501755/Decitabine-Cedazuridine-ASTX727-Combined-with-a

Decitabine/Cedazuridine (ASTX727) Combined with a ... Decitabine/Cedazuridine (ASTX727) Combined with a Molecularly-Targeted Agent (Venetoclax, Gilteritinib, Ivosidenib, or Enasidenib) As Personalized Maintenance ...

3. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC12268998/

Oral decitabine/cedazuridine plus venetoclax for older or ... Hypomethylating agents combined with venetoclax are effective regimens in patients with acute myeloid leukaemia who are ineligible for intensive chemotherapy.

4. sciencedirect.com sciencedirect.com/science/article/abs/pii/S2152265025016295

A Phase 1b/2 Trial of an All-Oral “Triplet” Regimen for IDH- ... In this phase 1b/2 clinical trial, we report on outcomes of the first alloral “triplet” regimen of decitabine/cedazuridine (DEC-C) + venetoclax (VEN) + IVO/ENA ...

5. ash.confex.com ash.confex.com/ash/2024/webprogram/Paper198928.html

Personalized Oral Maintenance Therapy with Decitabine ... In this phase 1b multi-arm study (NCT05010772), we evaluated the combination of ASTX727 (decitabine/cedazuridine), an oral formulation of ...

6. thelancet.com thelancet.com/journals/lanhae/article/PIIS2352-3026(24)00033-4/abstract

Oral decitabine and cedazuridine plus venetoclax for older ... We performed a single centre phase 2 study to evaluate the efficacy and safety of ASTX727 plus venetoclax. Methods. This study enrolled patients ...

7. sciencedirect.com sciencedirect.com/science/article/abs/pii/S0006497124070356

Personalized Oral Maintenance Therapy with Decitabine ... ASTX727 is not currently approved by the FDA for AML. Background: Most patients with acute myeloid leukemia (AML) experience relapse after initial remission, ...