What side effects are associated with this type of intervention?

Common treatments for AML, such as Enasidenib and Azacitidine, have several known side effects. Enasidenib, an IDH2 inhibitor, can cause differentiation syndrome, gastrointestinal issues, and elevated bilirubin levels. Azacitidine, a DNA methyltransferase inhibitor, is associated with hematologic toxicities like neutropenia, thrombocytopenia, and anemia, as well as non-hematologic side effects such as febrile neutropenia, pneumonia, and gastrointestinal symptoms (nausea, vomiting, diarrhea). These side effects are important considerations when choosing a treatment plan.

What prior FDA approvals exist?

Enasidenib, an IDH2 inhibitor, has been approved by the FDA for the treatment of relapsed or refractory AML with an IDH2 mutation. Azacitidine, a DNA methyltransferase inhibitor, is approved for the treatment of AML in patients who are not candidates for intensive chemotherapy. These approvals highlight the use of targeted therapies and hypomethylating agents in managing AML, particularly in patients with specific genetic mutations or those who are medically unfit for more aggressive treatments.

What other types of research exist?

Promising novel alternatives for AML treatment include: 1) Gilteritinib, particularly for relapsed or refractory FLT3-mutated AML, which has shown efficacy in clinical trials. 2) Venetoclax combined with Azacitidine, which has demonstrated effectiveness in patients with poor-risk cytogenetics. 3) IDH1 inhibitors like BAY1436032, which have shown synergistic activity with Azacitidine in IDH1-mutant AML. These alternatives represent significant advancements in targeted and combination therapies for AML.

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Nucleoside Analog

Enasidenib + Azacitidine for Acute Myeloid Leukemia

Q: What is the mechanism of action of this treatment?

Enasidenib, an IDH2 inhibitor, targets the mutated IDH2 enzyme to reduce the production of the oncometabolite 2-hydroxyglutarate (2-HG), thereby promoting normal cell differentiation and reducing leukemic cell proliferation. Azacitidine, a DNA methyltransferase inhibitor, incorporates into DNA and RNA, causing hypomethylation that reactivates tumor suppressor genes and induces cell differentiation and apoptosis in leukemic cells. These targeted therapies are significant for AML patients as they address specific molecular abnormalities, potentially offering more effective and less toxic treatment options compared to traditional chemotherapy.

Phase 2

Recruiting

Led By Courtney DiNardo

Research Sponsored by M.D. Anderson Cancer Center

Eligibility Criteria Checklist

Specific guidelines that determine who can or cannot participate in a clinical trial

Must have

AML patients with prior history of myelodysplastic syndrome (MDS) or chronic myelomonocytic leukemia (CMML) regardless of prior therapy received, are eligible at the time of diagnosis of AML

Subjects must have documented IDH2 gene mutation

Must not have

Active and uncontrolled comorbidities including active uncontrolled infection, uncontrolled hypertension despite adequate medical therapy, active and uncontrolled congestive heart failure New York Heart Association (NYHA) class III/IV, clinically significant and uncontrolled arrhythmia as judged by the treating physician

Patients with t(15;17) karyotypic abnormality or acute promyelocytic leukemia (French-American-British [FAB] class M3-AML)

Timeline

Screening 3 weeks

Treatment Varies

Follow Up up to 5 years

Awards & highlights

No Placebo-Only Group

Summary

This trial studies enasidenib and azacitidine in patients with acute myeloid leukemia (AML) that has come back or does not respond to treatment. These patients have a specific gene mutation called IDH2. The drugs work by blocking enzymes that cancer cells need to grow. Enasidenib is approved by the US FDA for adults with relapsed or refractory AML with an IDH2 mutation.

Who is the study for?

This trial is for adults with acute myeloid leukemia (AML) or related conditions, who have failed previous treatments or are not eligible for intensive chemotherapy. Participants must have an IDH2 gene mutation, be able to perform daily activities (ECOG <=3), and have acceptable liver and kidney function. Women of childbearing age must test negative for pregnancy and agree to use contraception.

What is being tested?

The trial is testing the effectiveness of enasidenib mesylate combined with azacitidine in patients with AML that has returned after treatment or hasn't responded at all. These drugs may inhibit enzymes that cancer cells need to grow.

What are the potential side effects?

Potential side effects include liver problems, digestive issues like nausea or constipation, fatigue, blood cell count changes leading to increased infection risk or bleeding tendencies, and possible allergic reactions.

Eligibility Criteria

Inclusion Criteria

You may be eligible if you check “Yes” for the criteria below

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I have AML and previously had MDS or CMML.

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My cancer has an IDH2 gene mutation.

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

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I am not able to have children, am postmenopausal, or have a negative pregnancy test.

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I am a male and will use birth control during and for 3 months after the study.

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I am capable of limited self-care and spend less than half of my day in bed.

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I have AML or a type of leukemia with a myeloid component and previous treatments didn't work.

Exclusion Criteria

You may be eligible for the trial if you check “No” for criteria below:

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I do not have any severe ongoing health issues like uncontrolled infections, high blood pressure, heart failure, or irregular heartbeats.

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My leukemia is of a specific type known as acute promyelocytic.

Timeline

Screening ~ 3 weeks3 visits

Treatment ~ Varies

Follow Up ~ up to 5 years

Screening ~ 3 weeks

Treatment ~ Varies

Follow Up ~up to 5 years

This trial's timeline: 3 weeks for screening, Varies for treatment, and up to 5 years for reporting.

Treatment Details

Study Objectives

Study objectives can provide a clearer picture of what you can expect from a treatment.

Primary study objectives

Overall response rate (ORR)

Secondary study objectives

Disease-free survival (DFS)

Duration of response

Event-free survival

+1 more

Other study objectives

Association of biomarkers to overall response

Change in markers over time

Minimal residual disease (MRD)

Awards & Highlights

No Placebo-Only Group

All patients enrolled in this study will receive some form of active treatment.

Trial Design

1Treatment groups

Experimental Treatment

Group I: Treatment (azacitidine, enasidenib mesylate)Experimental Treatment2 Interventions

Patients receive azacitidine SC or IV over 30 minutes on days 1-7 and enasidenib mesylate PO QD beginning on day 1. Cycles repeat every 4-6 weeks in the absence of disease progression or unacceptable toxicity.

Treatment

First Studied

Drug Approval Stage

How many patients have taken this drug

Azacitidine

2012

Completed Phase 3

~1440

0 / 9Eligibility criteria met

Research Highlights

Information in this section is not a recommendation. We encourage patients to speak with their healthcare team when evaluating any treatment decision.

Mechanism Of Action

Side Effect Profile

Prior Approvals

Other Research

Enasidenib, an IDH2 inhibitor, targets the mutated IDH2 enzyme to reduce the production of the oncometabolite 2-hydroxyglutarate (2-HG), thereby promoting normal cell differentiation and reducing leukemic cell proliferation. Azacitidine, a DNA methyltransferase inhibitor, incorporates into DNA and RNA, causing hypomethylation that reactivates tumor suppressor genes and induces cell differentiation and apoptosis in leukemic cells. These targeted therapies are significant for AML patients as they address specific molecular abnormalities, potentially offering more effective and less toxic treatment options compared to traditional chemotherapy.

The Molecular Mechanisms of Resistance to IDH Inhibitors in Acute Myeloid Leukemia.Epigenetic deregulation in myeloid malignancies.Role of epigenetic in leukemia: From mechanism to therapy.