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

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial studies the effects and side effects of combining three drugs—decitabine/cedazuridine (a chemotherapy drug combination), venetoclax, and either ivosidenib or enasidenib—to treat acute myeloid leukemia (AML) that has returned or isn't responding to treatment. The focus is on how well these drugs work together to control the cancer. This trial may suit those with relapsed or stubborn AML or those with a new AML diagnosis who can't undergo intensive chemotherapy and have specific gene mutations (IDH1 or IDH2). As a Phase 1 trial, the research aims to understand how the treatment works in people, offering participants a chance to be among the first to receive this combination therapy.

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.

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

Previous studies have found decitabine/cedazuridine and venetoclax to be generally well-tolerated by patients with acute myeloid leukemia (AML). Research shows that decitabine/cedazuridine helps control cancer cell growth by slowing the body's processing of the drug. Venetoclax blocks a protein that cancer cells need to survive.

Ivosidenib and enasidenib are also part of the treatment plan, working by blocking enzymes necessary for cancer cell growth. These drugs have been used in other treatments and have shown reasonable safety.

Since this trial is in the early stages (phases 1 and 2), it primarily aims to identify any side effects and determine the safety of these drug combinations. Prospective participants should discuss with their doctor how these treatments might affect them personally. ^{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 combine novel mechanisms of action with existing therapies to potentially enhance effectiveness. Unlike standard treatments, which often involve chemotherapy and bone marrow transplants, this approach uses a combination of drugs like Decitabine/Cedazuridine to inhibit DNA methylation, and Venetoclax to target BCL-2 proteins, which helps in killing cancer cells. Additionally, Ivosidenib and Enasidenib target specific mutations in the IDH1 and IDH2 genes, respectively, offering a more personalized treatment option for patients with these genetic markers. These combinations aim to provide a more targeted and potentially effective treatment with fewer side effects compared to traditional therapies.

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

Research has shown that combining decitabine/cedazuridine with venetoclax can effectively treat acute myeloid leukemia (AML), particularly for patients unable to undergo strong chemotherapy. In this trial, participants will receive either ivosidenib or enasidenib alongside decitabine/cedazuridine and venetoclax. Studies indicate that this combination can help manage the disease by slowing cancer cell growth. Adding ivosidenib or enasidenib may block certain enzymes that cancer cells need to grow, potentially enhancing treatment effectiveness. Early results suggest this approach can improve survival rates and control the disease in AML patients. Overall, this treatment strategy appears promising for managing AML that has returned or is resistant to other treatments. ^{1 2 3 4 6}

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 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 for a Trial Participant

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

What Are the Treatments Tested in This Trial?

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.

How Is the Trial Designed?

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+

Published Research Related to This Trial

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 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 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]

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 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]

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. 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 ...

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

Decitabine/Cedazuridine (ASTX727) Combined with a ... Methods: Patients ≥ 18 years with AML in first complete remission (CR) or CR with incomplete blood count recovery (CRi) not currently eligible ...

4. 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.

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

Personalized Oral Maintenance Therapy with Decitabine ... Oral azacitidine (QUAZAR AML-001) and 3-day IV decitabine (ECOG ACRIN E2906) have demonstrated efficacy as maintenance. In this phase 1b multi- ...

6. sciencedirect.com sciencedirect.com/science/article/pii/S0006497123095113

Decitabine/Cedazuridine (ASTX727) Combined with a ... A fully oral, targeted maintenance regimen is feasible in AML. Early results show encouraging RFS and OS. Further enrollment and follow-up are required.