Decitabine + Other Drugs for Acute Myeloid Leukemia

Recruiting in Palo Alto (17 mi)

Overseen by Tapan Kadia, MD

Age: 18+

Sex: Any

Travel: May Be Covered

Time Reimbursement: Varies

Trial Phase: Phase 1

Recruiting

Sponsor: M.D. Anderson Cancer Center

Disqualifiers: APL, Active CNS disease, Uncontrolled illness, others

No Placebo Group

Breakthrough Therapy

Approved in 4 Jurisdictions

Trial Summary

What is the purpose of this trial?

This phase Ib trial is to find out the side effects and possible benefits of decitabine alone or given together with venetoclax, gilteritinib, enasidenib, or ivosidenib in treating patients with acute myeloid leukemia that is under control (remission). Chemotherapy drugs, such as decitabine, work in different ways to stop the growth of cancer cells, either by killing the cells, by stopping them from dividing, or by stopping them from spreading. Venetoclax may stop the growth of cancer cells by blocking a protein called Bcl-2 needed for cell growth. Gilteritinib, enasidenib, and ivosidenib may stop the growth of cancer cells by blocking some of the enzymes needed for cell growth. Giving decitabine alone or together with venetoclax, gilteritinib, enasidenib, or ivosidenib may help to control the disease.

Will I have to stop taking my current medications?

The trial protocol does not specify whether you need to stop taking your current medications. It's best to discuss your current medications with the trial team to get specific guidance.

What data supports the effectiveness of the drug Decitabine combined with other drugs for treating Acute Myeloid Leukemia?

Research shows that Decitabine, when used alone or in combination with other drugs, can improve survival and response rates in older patients with Acute Myeloid Leukemia (AML). It is generally well tolerated and offers a valuable treatment option, especially for those who cannot undergo standard chemotherapy. ^{1 2 3 4 5}

Is the combination of Decitabine and other drugs generally safe for treating acute myeloid leukemia?

Decitabine, when used alone or in combination with other drugs, has been shown to be generally safe for treating acute myeloid leukemia, especially in older patients and children. Common side effects include fever, low blood cell counts, and infections, but these are similar to other treatments. No treatment-related deaths were reported in the studies reviewed. ^{1 5 6 7 8}

How is the drug Decitabine + Other Drugs unique for treating acute myeloid leukemia?

Decitabine is unique because it is a DNA methyltransferase inhibitor that can be combined with cedazuridine to increase its oral bioavailability, making it easier to administer compared to traditional intravenous chemotherapy. This combination is particularly beneficial for older patients or those who cannot undergo standard intensive chemotherapy, offering a less toxic alternative with promising efficacy. ^{3 4 5 6 9}

Research Team

Tapan Kadia, MD

Principal Investigator

M.D. Anderson Cancer Center

Eligibility Criteria

Adults aged 18+ with Acute Myeloid Leukemia in remission after intensive or lower intensity therapy, not immediately proceeding to stem cell transplant. Participants must have completed at least one consolidation cycle (intensive) or two cycles (lower intensity), be within certain health parameters, and agree to contraception.

Inclusion Criteria

Platelet count > or = 50 x k/uL

Absolute neutrophil count (ANC) > 0.5 x k/uL

Ability to understand and sign informed consent

Exclusion Criteria

I do not have a history of AML outside the bone marrow, except for controlled CNS involvement.

I have been diagnosed with a specific type of leukemia (APL or AML - M3).

I am willing to leave my current trial to join and receive treatment in a new trial.

Trial Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants receive decitabine and cedazuridine alone or in combination with venetoclax, gilteritinib, enasidenib, or ivosidenib. Treatments repeat every 4 weeks for up to 24 cycles.

96 weeks

Follow-up

Participants are monitored for safety and effectiveness after treatment completion.

6-12 months

Treatment Details

Interventions

• Decitabine (Anti-metabolites)
• Enasidenib (Enzyme Inhibitor)
• Gilteritinib (Enzyme Inhibitor)
• Ivosidenib (Enzyme Inhibitor)
• Venetoclax (Bcl-2 Inhibitor)

Trial Overview This trial tests decitabine alone or combined with venetoclax, gilteritinib, enasidenib, or ivosidenib as maintenance therapy for AML in remission. It aims to see how these drugs affect cancer cell growth by killing them, stopping division/spread, and blocking proteins/enzymes needed for growth.

Participant Groups

Group I: Arm E (decitabine and cedazuridine, ivosidenib) Experimental Treatment 2 Interventions

Patients receive decitabine and cedazuridine PO QD on days 1-3 and ivosidenib PO QD on days 1-28. Treatments repeat every 4 weeks for up to 24 cycles in the absence of disease progression or unacceptable toxicity.

Group II: Arm D (decitabine and cedazuridine, enasidenib) Experimental Treatment 2 Interventions

Patients receive decitabine and cedazuridine PO QD on days 1-3 and enasidenib PO QD on days 1-28. Treatments repeat every 4 weeks for up to 24 cycles in the absence of disease progression or unacceptable toxicity.

Group III: Arm C (decitabine and cedazuridine, gilteritinib) Experimental Treatment 2 Interventions

Patients receive decitabine and cedazuridine PO QD on days 1-3 and gilteritinib PO QD on days 1-28. Treatments repeat every 4 weeks for up to 24 cycles in the absence of disease progression or unacceptable toxicity.

Group IV: Arm B (decitabine and cedazuridine, venetoclax) Experimental Treatment 2 Interventions

Patients receive decitabine and cedazuridine PO QD on days 1-3 and venetoclax PO QD on days 1-5. Treatments repeat every 4 weeks for up to 24 cycles in the absence of disease progression or unacceptable toxicity.

Group V: Arm A (decitabine and cedazuridine) Experimental Treatment 1 Intervention

Patients receive decitabine and cedazuridine PO QD on days 1-3. Treatments repeat every 28 days for up to 4 weeks in the absence of disease progression or unacceptable toxicity.

Decitabine is already approved in Canada, Japan for the following indications:

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+

Dr. Peter WT Pisters

M.D. Anderson Cancer Center

Chief Executive Officer since 2017

MD from University of Western Ontario

Dr. Jeffrey E. Lee

M.D. Anderson Cancer Center

Chief Medical Officer

MD from Stanford University School of Medicine

National Cancer Institute (NCI)

Collaborator

Trials

14,080

Recruited

41,180,000+

Dr. Douglas R. Lowy

National Cancer Institute (NCI)

Chief Executive Officer since 2023

MD from New York University School of Medicine

Dr. Monica Bertagnolli

National Cancer Institute (NCI)

Chief Medical Officer since 2022

MD from Harvard Medical School

Findings from Research

A new low-intensity treatment regimen combining cladribine and low-dose cytarabine alternating with decitabine showed promising results in elderly or unfit patients with acute myeloid leukaemia (AML), with a median disease-free survival of 10.8 months and a median overall survival of 13.8 months based on a study of 118 patients.

The regimen was well tolerated, with only 1% of patients experiencing early death within the first 4 weeks, indicating a favorable safety profile compared to traditional therapies, which often have higher toxicity.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Cladribine and low-dose cytarabine alternating with decitabine as front-line therapy for elderly patients with acute myeloid leukaemia: a phase 2 single-arm trial. Kadia, TM., Cortes, J., Ravandi, F., et al.[2019]

The D-CAG regimen, which combines decitabine with a modified chemotherapy approach, achieved a complete remission (CR) rate of 69.4% in 59 elderly patients (≥70 years) with newly diagnosed acute myeloid leukemia (AML), indicating its efficacy in this age group.

The treatment was found to be safe, with major adverse reactions including grade 3-4 myelosuppression and infections, but it significantly improved overall survival (OS) and event-free survival (EFS) for patients who achieved CR, with median OS of 19.8 months compared to 6.4 months for those who did not respond.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

[Efficacy and Safety of Decitabine Combined with Modified CAG Regimen in Patients Aged ≥ 70 Years with Newly Diagnosed Acute Myeloid Leukemia]. Cao, L., Jiang, ZQ., Liu, WJ., et al.[2023]

Decitabine is an effective hypomethylating agent for treating acute myeloid leukemia (AML), significantly improving overall survival and response rates compared to standard care, based on results from the phase 3 DACO-016 trial with adult patients who are not eligible for standard chemotherapy.

The treatment is generally well tolerated and remains effective even in patients with adverse-risk karyotypes or TP53 mutations, making it a valuable option for those unfit for more intensive therapies, with potential for future combination treatments.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

The Clinical Value of Decitabine Monotherapy in Patients with Acute Myeloid Leukemia. Santini, V., Lübbert, M., Wierzbowska, A., et al.[2022]

The combination of decitabine and idarubicin showed a synergistic effect in inducing cell death in various myeloid leukemia cell lines and primary AML cells, suggesting a more effective treatment strategy than decitabine alone.

This combination therapy not only inhibited tumor growth more effectively in mouse models but also triggered apoptosis and downregulated the Wnt/β-catenin pathway, which is linked to leukemia progression.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Sequential combination of decitabine and idarubicin synergistically enhances anti-leukemia effect followed by demethylating Wnt pathway inhibitor promoters and downregulating Wnt pathway nuclear target. Li, K., Hu, C., Mei, C., et al.[2021]

Decitabine, administered at a dose of 20 mg/m² for 5 consecutive days, has been approved for older patients (≥65 years) with acute myeloid leukaemia (AML) who cannot undergo standard treatment, showing clinically meaningful improvements in overall survival after extended follow-up.

In a pivotal phase III trial, decitabine demonstrated significantly higher complete remission rates compared to standard treatment options like cytarabine, with a safety profile similar to cytarabine, including common side effects like fever and low blood cell counts.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Decitabine: a review of its use in older patients with acute myeloid leukaemia. Curran, MP.[2021]

Decitabine is a DNA methyltransferase inhibitor with a long history of antileukemic efficacy, particularly effective in treating acute myeloid leukemia in older patients or those unable to undergo intensive therapy.

The current dosing regimen of decitabine (20 mg/m² for 5 days) has been refined to minimize nonhematologic toxicity, making it a promising option for patients who may not tolerate more aggressive treatments.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Decitabine for acute myeloid leukemia. Marks, PW.[2018]

In a study of 8 geriatric patients with acute myeloid leukemia, treatment with decitabine, with or without low-dose cytarabine, resulted in a 50% overall response rate, with 25% achieving complete remission and 25% achieving partial remission.

The treatment showed a median overall survival time of 9.5 months, with some patients surviving over a year, although it was associated with significant side effects, including severe myelosuppression in 87.5% of patients and pneumonia in 50%.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

[Clinical Efficacy of Decitabine Combined with or without Cytarabine-based Low Dose Regimen for Senile patients with Acute Myeloid Leukemia]. Zhou, HW., Zhou, MH., Wang, ZH., et al.[2019]

In a study of 19 children with high-risk, refractory, or relapsed acute myeloid leukemia (AML), treatment with decitabine combined with low dose chemotherapy resulted in a high response rate, with 15 achieving complete remission and only 1 not responding.

The treatment was found to be safe, with no treatment-related deaths, and led to a promising three-year overall survival rate of 79%, indicating it is an effective option for these challenging cases of pediatric AML.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

[Efficacy of decitabine combined with low dose chemotherapy on children with acute myeloid leukemia]. Fan, LY., Gao, L., Hu, DX., et al.[2023]

The fixed-dose oral combination of decitabine and cedazuridine (Inqovi®) has been approved for treating myelodysplastic syndromes (MDS) and chronic myelomonocytic leukaemia (CMML), enhancing the oral bioavailability of decitabine through the inhibition of cytidine deaminase by cedazuridine.

Decitabine is already an established treatment for MDS and CMML, and the combination therapy has shown promise in ongoing clinical studies for other cancers like acute myeloid leukaemia (AML), glioma, and solid tumors.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Decitabine/Cedazuridine: First Approval. Dhillon, S.[2021]

References

1. England pubmed.ncbi.nlm.nih.gov

Cladribine and low-dose cytarabine alternating with decitabine as front-line therapy for elderly patients with acute myeloid leukaemia: a phase 2 single-arm trial. [2019]

2. China pubmed.ncbi.nlm.nih.gov

[Efficacy and Safety of Decitabine Combined with Modified CAG Regimen in Patients Aged ≥ 70 Years with Newly Diagnosed Acute Myeloid Leukemia]. [2023]

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

The Clinical Value of Decitabine Monotherapy in Patients with Acute Myeloid Leukemia. [2022]

4. England pubmed.ncbi.nlm.nih.gov

Sequential combination of decitabine and idarubicin synergistically enhances anti-leukemia effect followed by demethylating Wnt pathway inhibitor promoters and downregulating Wnt pathway nuclear target. [2021]

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

Decitabine: a review of its use in older patients with acute myeloid leukaemia. [2021]

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

Decitabine for acute myeloid leukemia. [2018]

7. China pubmed.ncbi.nlm.nih.gov

[Clinical Efficacy of Decitabine Combined with or without Cytarabine-based Low Dose Regimen for Senile patients with Acute Myeloid Leukemia]. [2019]

8. China pubmed.ncbi.nlm.nih.gov

[Efficacy of decitabine combined with low dose chemotherapy on children with acute myeloid leukemia]. [2023]

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

Decitabine/Cedazuridine: First Approval. [2021]