Decitabine + Venetoclax + Olutasidenib for AML

Overseen By Courtney DiNardo, MD

Age: 18+

Sex: Any

Trial Phase: Phase 1 & 2

Sponsor: M.D. Anderson Cancer Center

Disqualifiers: Acute promyelocytic leukemia, Uncontrolled CNS leukemia, Active GVHD, Severe infection, others

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

Compensation: Varies

Number of Visits: Unknown

78 Participants Needed

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial tests a combination of three drugs—decitabine, venetoclax, and olutasidenib—to determine the optimal dose for treating acute myeloid leukemia (AML). Researchers aim to evaluate how well this combination works for individuals whose AML has returned, isn't responding to other treatments, or who are newly diagnosed and unable to undergo aggressive chemotherapy. Suitable candidates have AML with an IDH1 gene mutation and meet specific health criteria affecting daily life, such as certain heart or lung conditions. As a Phase 1 and Phase 2 trial, this research seeks to understand how the treatment works in people and measure its effectiveness in an initial, smaller group.

Will I have to stop taking my current medications?

The trial protocol does not specify if you must stop taking your current medications. However, there is a requirement for a 14-day interval from prior treatment to the start of the study, unless you have rapidly proliferative disease, in which case some medications like hydroxyurea and cytarabine may be allowed.

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

Research has shown that the combination of decitabine, venetoclax, and olutasidenib is generally safe and manageable for patients with certain types of acute myeloid leukemia (AML). Studies have found that these drugs work well together in treating both new and recurring cases of AML.

Olutasidenib has been especially well-tolerated by older patients with a specific mutation in AML, leading to lasting improvements. Its safety profile has remained consistent, behaving as expected based on past experiences.

Researchers continue to study the combination of decitabine, venetoclax, and olutasidenib, but early results are promising for safety. These treatments have been used for other conditions before, suggesting they might be safe for this purpose too, but ongoing studies will confirm this. ^{1 2 3 4 5}

Why are researchers excited about this trial's treatments?

Researchers are excited about the combination of Decitabine, Venetoclax, and Olutasidenib for treating Acute Myeloid Leukemia (AML) because it brings together unique mechanisms of action that target cancer cells more effectively. Unlike traditional chemotherapy, which attacks all rapidly dividing cells, Venetoclax specifically targets and inhibits BCL-2, a protein that helps cancer cells survive. Olutasidenib is another novel component that inhibits mutant IDH1 enzymes, which are often present in AML, and helps stop the growth of cancerous cells. By combining these targeted therapies with Decitabine, which enhances the response of cancer cells to treatment, this approach may offer a more precise and potentially effective option for patients with AML.

What evidence suggests that this trial's treatments could be effective for AML?

Research has shown that using decitabine with venetoclax effectively treats patients with acute myeloid leukemia (AML), particularly older adults. Some studies found that this combination can lead to remission, where the cancer's signs and symptoms reduce or disappear. Olutasidenib has also achieved lasting remissions in patients with a specific genetic mutation in AML. In this trial, participants will receive a combination of these treatments. Part 1 focuses on determining the optimal dose of venetoclax and decitabine, while all participants will receive the same dose of olutasidenib. Although researchers are still studying this combination, evidence suggests it could effectively treat AML. ^{2 3 6 7 8}

Who Is on the Research Team?

Courtney DiNardo, MD

Principal Investigator

M.D. Anderson Cancer Center

Are You a Good Fit for This Trial?

Adults with relapsed or refractory AML, high-risk MDS, or not eligible for intensive chemotherapy due to age/comorbidities. Must have IDH1 mutation, be at least 14 days post-prior treatment, and have good kidney/liver function. ECOG Performance Status must be </=2. Excludes those with active CNS leukemia, severe GI/metabolic conditions, active GVHD after stem cell transplant, certain blood disorders (like FAB class M3-AML), uncontrolled medical conditions, and known hepatitis B/C or HIV.

Inclusion Criteria

It has been at least 14 days since my last cancer treatment.

My cancer has an IDH1 gene mutation.

Willing and able to provide informed consent

Exclusion Criteria

I have leukemia that is affecting my brain and it's not under control.

I have a severe stomach or metabolic condition.

I am currently experiencing active graft-versus-host disease after a stem cell transplant.

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Phase 1b Treatment

Participants receive decitabine and venetoclax in combination with olutasidenib to determine safety, tolerability, and recommended phase 2 dose

12 weeks

Phase 2 Treatment

Participants receive the recommended dose of decitabine and venetoclax in combination with olutasidenib to determine remission rates

24 weeks

Follow-up

Participants are monitored for safety and effectiveness after treatment, including duration of response and survival outcomes

4 weeks

What Are the Treatments Tested in This Trial?

Interventions

• Decitabine
• Olutasidenib
• Venetoclax

Trial Overview The trial is testing a combination of three drugs: Olutasidenib (targeting mutant IDH1), Venetoclax and Decitabine in adults with AML to find the safest dose that can work together effectively. The study will determine the best dosage of Decitabine and Venetoclax alongside Olutasidenib.

How Is the Trial Designed?

Group I: Part 2 Experimental Treatment 4 Interventions

Participants enrolled in Part 2, you will receive venetoclax/decitabine at the recommended dose that was found in Part 1. \- All participants will receive the same dose level of olutasidenib.

Group II: Part 1 Experimental Treatment 4 Interventions

Participants enrolled in Part 1, the dose of venetoclax/decitabine you receive will depend on when you join this study. Up to 3 dose levels will be tested. Up to 6 participants will be enrolled at each dose level. \- All participants will receive the same dose level of olutasidenib.

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

Approved in European Union as Dacogen for:

• Acute myeloid leukemia
• Myelodysplastic syndromes

Approved in United States as Dacogen for:

• Myelodysplastic syndromes
• Acute myeloid leukemia

Approved in Canada as Dacogen for:

• Myelodysplastic syndromes
• Acute myeloid leukemia

Approved in Japan as Dacogen for:

• Myelodysplastic syndromes
• Acute myeloid leukemia

Who Is Running the Clinical Trial?

M.D. Anderson Cancer Center

Lead Sponsor

Trials

3,107

Recruited

1,813,000+

Rigel Pharmaceuticals,Inc.

Collaborator

Trials

1

Recruited

80+

Published Research Related to This Trial

The combination of venetoclax with hypomethylating agents (HMA) has significantly improved survival rates in patients with acute myeloid leukemia (AML), as demonstrated in a phase 3 study.

Venetoclax is also safe when added to standard intensive regimens, leading to high remission rates and measurable residual disease negativity in both newly diagnosed and relapsed/refractory AML patients.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Venetoclax in combination with nucleoside analogs in acute myelogenous leukemia. Ball, BJ., Koller, PB., Pullarkat, V.[2023]

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]

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]

A once-weekly low-dose decitabine (LDDec) combined with venetoclax (VEN) showed high efficacy in treating elderly patients with acute myeloid leukemia (AML) and myelodysplastic syndrome (MDS), achieving an overall response rate of 88% for AML and 64% for MDS in a retrospective study of 39 patients.

Patients receiving the LDDec/VEN regimen experienced longer treatment durations and a trend towards higher transfusion independence compared to those on standard dosing, suggesting that this approach may reduce severe myelosuppression while maintaining effectiveness.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

A Metabolically Optimized, Noncytotoxic Low-Dose Weekly Decitabine/Venetoclax in MDS and AML. Levitz, D., Saunthararajah, Y., Fedorov, K., et al.[2023]

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]

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 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]

Citations

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NCT06445959 | Phase 1b/2 Study of Decitabine and ... To find a recommended combination dose of decitabine and venetoclax that can be given in combination with olutasidenib to participants with AML. Detailed ...

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Phase 1b/2 Study of Decitabine and Venetoclax in ... Background and Significance: Outcomes for most patients with AML remain poor. Efforts to improve both the remission rate and the durability ...

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The efficacy and safety of venetoclax combined with ... The efficacy and safety of venetoclax combined with decitabine in elderly patients with acute myeloid leukemia: a systematic review and meta- ...

4. ascopubs.org ascopubs.org/doi/10.1200/JCO.2024.42.16_suppl.6527

Safety and efficacy of olutasidenib treatment in elderly ... Olutasidenib was generally well tolerated in elderly patients with R/R mIDH1AML and induced durable remissions.

5. nature.com nature.com/articles/s41420-025-02678-4

Comprehensive view on chemotherapy-free management ... Moreover, duration of response was similar in patients receiving VEN for 14 days (8.7 months, 95% CI 1–37) vs 28 days (8.3 months, 95% CI 1–5, P ...

6. cancer.gov cancer.gov/research/participate/clinical-trials-search/v?id=NCI-2024-04807

Decitabine and Venetoclax in Combination with ... Giving decitabine and venetoclax in combination with olutasidenib may be safe, tolerable and effective in treating patients with newly diagnosed, recurrent or ...

7. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC12350645/

Comprehensive view on chemotherapy-free management ... Phase II trial of 10-day ASTX727 (decitabine/cedazuridine) with venetoclax for relapsed or refractory acute myeloid leukemia. Blood. 2023 ...

8. tandfonline.com tandfonline.com/doi/full/10.1080/10428194.2024.2333451

Full article: Olutasidenib in post-venetoclax patients with ... Safety was consistent with the overall profile of olutasidenib. Olutasidenib offers a valuable treatment option for patients with mIDH1 AML ...