Decitabine/Cedazuridine + Venetoclax + Ivosidenib/Enasidenib for Acute Myeloid Leukemia

Overseen By Courtney DiNardo, MD

Age: 18+

Sex: Any

Trial Phase: Phase 1 & 2

Sponsor: M.D. Anderson Cancer Center

Disqualifiers: Active infection, GVHD, QTc interval, others

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

Compensation: Varies

Number of Visits: Unknown

Duration: 12 cycles (28 days each)

84 Participants Needed

Trial Summary

What is the purpose of this trial?

This phase Ib/II trials studies the side effects of decitabine/cedazuridine (ASTX727) and venetoclax in combination with ivosidenib or enasidenib, and how well they work in treating patients with acute myeloid leukemia that has come back (relapsed) or does not respond to treatment (refractory). ASTX727 is the combination of a fixed dose of 2 drugs, cedazuridine and decitabine. Cedazuridine may slow down how fast decitabine is broken down by the body, and decitabine may block abnormal cells or cancer cells from growing. Venetoclax may stop the growth of cancer cells by blocking BCL-2, a protein needed for cancer cell survival. Enasidenib and ivosidenib may stop the growth of cancer cells by blocking some of the enzymes needed for cell growth. Giving decitabine/cedazuridine and venetoclax in combination with ivosidenib or enasidenib may help control acute myeloid leukemia.

Will I have to stop taking my current medications?

The trial protocol does not specify if you need to stop taking your current medications. However, there is a requirement for a 7-day interval from prior treatment to the start of the study, unless you have rapidly growing disease, in which case certain medications like hydroxyurea are allowed.

What data supports the effectiveness of the drug combination Decitabine/Cedazuridine + Venetoclax + Ivosidenib/Enasidenib for treating Acute Myeloid Leukemia?

Research shows that combining Venetoclax with Decitabine is effective for older patients with acute myeloid leukemia (AML), leading to longer survival and higher response rates compared to Decitabine alone. In one study, patients receiving this combination had a median overall survival of 13.4 months compared to 8.3 months for those on Decitabine alone. ^{1 2 3 4 5}

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

The combination of Venetoclax and Decitabine has been studied in elderly patients with acute myeloid leukemia and is generally well tolerated. Common side effects include nausea, diarrhea, constipation, fatigue, and low white blood cell count, but no severe tumor lysis syndrome (a serious condition caused by the rapid breakdown of cancer cells) was observed. ^{1 2 3 4 6}

What makes the drug combination of Decitabine/Cedazuridine, Venetoclax, and Ivosidenib/Enasidenib unique for treating acute myeloid leukemia?

This drug combination is unique because it combines multiple agents that target different pathways in acute myeloid leukemia (AML) cells, potentially improving treatment outcomes. Venetoclax targets BCL-2, a protein that helps cancer cells survive, while Decitabine/Cedazuridine and Ivosidenib/Enasidenib target specific genetic mutations in AML, offering a comprehensive approach for patients who may not respond well to standard chemotherapy. ^{1 2 3 4 7}

Research Team

Courtney DiNardo, MD

Principal Investigator

M.D. Anderson Cancer Center

Eligibility Criteria

This trial is for adults over 18 with relapsed or refractory acute myeloid leukemia, including those not eligible for intensive chemotherapy due to age (>60). Participants must have an IDH1 or IDH2 gene mutation, be able to perform daily activities (ECOG <=2), and have adequate kidney and liver function. Men must use contraception.

Inclusion Criteria

My kidney function is normal, with creatinine levels below 2.

I am over 60 with new AML and can't undergo intensive chemotherapy.

I haven't had cancer treatment in the last 7 days, except for specific cases approved by the study leader.

Exclusion Criteria

My white blood cell count is above 25,000 per microliter.

I do not have any severe illnesses or mental health conditions that could make the study unsafe for me.

I am not pregnant, nursing, or if capable of becoming pregnant, I agree to use effective contraception.

Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants receive decitabine/cedazuridine, venetoclax, and either ivosidenib or enasidenib. Treatment repeats every 28 days for 12 cycles.

12 cycles (28 days each)

Follow-up

Participants are monitored for safety and effectiveness after treatment completion.

Every 3 months

Treatment Details

Interventions

• Decitabine and Cedazuridine
• Enasidenib
• Ivosidenib
• Venetoclax

Trial Overview The trial tests a combination of decitabine/cedazuridine (ASTX727) and venetoclax with either ivosidenib or enasidenib. It aims to see how well these drugs work together in treating AML that's resistant or has returned after treatment.

Participant Groups

Group I: Arm B (decitabine/cedazuridine, venetoclax, enasidenib) Experimental Treatment 3 Interventions

Patients receive decitabine/cedazuridine PO daily on days 1-5, venetoclax PO daily on days 1-14, and enasidenib PO daily on days 1-28. Treatment repeats every 28 days for 12 cycles in the absence of disease progression or unacceptable toxicity.

Group II: Arm A (decitabine/cedazuridine, venetoclax, ivosidenib) Experimental Treatment 3 Interventions

Patients receive decitabine/cedazuridine PO daily on days 1-5, venetoclax PO daily on days 1-14, and ivosidenib PO daily on days 1-28. Treatment repeats every 28 days for 12 cycles in the absence of disease progression or unacceptable toxicity.

Decitabine and Cedazuridine is already approved in European Union, United States for the following indications:

Approved in European Union as Inaqovi for:

• Acute myeloid leukemia (AML) in adults who are ineligible for standard induction chemotherapy

Approved in United States as ASTX727 for:

• Adult patients with newly diagnosed acute myeloid leukemia (AML) who are 75 years or older, or who have comorbidities precluding intensive induction chemotherapy

Who Is Running the Clinical Trial?

M.D. Anderson Cancer Center

Lead Sponsor

Trials

3,107

Recruited

1,813,000+

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 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 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 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 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]

The FDA has approved several new treatments for acute myeloid leukemia, including venetoclax and glasdegib, aimed at older patients who may not tolerate intensive therapies, but concerns exist about the criteria used to define patient fitness for these treatments.

The efficacy of venetoclax and glasdegib is questioned due to modest remission rates and the lack of randomized comparisons with more intensive treatments, suggesting that better outcomes might be achievable with alternative therapies.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Recent drug approvals for newly diagnosed acute myeloid leukemia: gifts or a Trojan horse? Estey, E., Karp, JE., Emadi, A., et al.[2022]

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]

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

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

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. 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]

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

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

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

Recent drug approvals for newly diagnosed acute myeloid leukemia: gifts or a Trojan horse? [2022]

7. England pubmed.ncbi.nlm.nih.gov

Venetoclax in combination with azacitidine in Japanese patients with acute myeloid leukaemia: phase 1 trial findings. [2021]