Enasidenib + Azacitidine for Acute Myeloid Leukemia

Overseen by Courtney DiNardo, MD

Age: 18+

Sex: Any

Travel: May Be Covered

Time Reimbursement: Varies

Trial Phase: Phase 2

Recruiting

Sponsor: M.D. Anderson Cancer Center

Disqualifiers: Acute promyelocytic leukemia, Uncontrolled infection, Uncontrolled hypertension, Congestive heart failure, others

No Placebo Group

Prior Safety Data

Trial Summary

What is the purpose of this trial?

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.

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, oral hydroxyurea and/or cytarabine are allowed before the start of the study, and concurrent therapy for certain conditions is permitted. It's best to discuss your current medications with the study team.

What data supports the effectiveness of the drug Enasidenib + Azacitidine for Acute Myeloid Leukemia?

Research shows that Azacitidine can be effective for certain patients with acute myeloid leukemia (AML), especially those who are not fit for intensive chemotherapy. Enasidenib has shown promise in patients with specific genetic mutations (IDH2) in AML, with a notable response rate and improved survival in some cases. ^{1 2 3 4 5}

Is the combination of Enasidenib and Azacitidine safe for treating acute myeloid leukemia?

Enasidenib and Azacitidine have been studied separately for safety in treating acute myeloid leukemia. Enasidenib is generally well tolerated, but it can cause serious side effects like differentiation syndrome, which doctors need to monitor. Azacitidine has been used safely in real-life settings for similar blood disorders. ^{4 5 6 7 8}

What makes the drug combination of Enasidenib and Azacitidine unique for treating acute myeloid leukemia?

This drug combination is unique because Enasidenib specifically targets and inhibits mutant IDH2 proteins, which are involved in blocking cell differentiation in acute myeloid leukemia, while Azacitidine is a chemotherapy drug that helps to kill cancer cells. Together, they offer a novel approach for patients with mutant-IDH2 acute myeloid leukemia who are not eligible for intensive chemotherapy. ^{4 5 7 8 9}

Research Team

Courtney DiNardo, MD

Principal Investigator

M.D. Anderson Cancer Center

Eligibility Criteria

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.

Inclusion Criteria

I am over 60 and have AML but can't undergo intensive chemotherapy.

I have AML and previously had MDS or CMML.

My cancer has an IDH2 gene mutation.

Exclusion Criteria

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

Any other medical, psychological, or social condition that may interfere with study participation or compliance, or compromise patient safety in the opinion of the investigator

Pregnant or breastfeeding

Trial Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Patients receive azacitidine subcutaneously or intravenously on days 1-7 and enasidenib mesylate orally once daily. Cycles repeat every 4-6 weeks in the absence of disease progression or unacceptable toxicity.

4-6 weeks per cycle

Follow-up

Participants are monitored for safety and effectiveness after treatment completion, with follow-ups at 30 days and then every 3-6 months for up to 5 years.

Up to 5 years

Treatment Details

Interventions

• Azacitidine (Nucleoside Analog)
• Enasidenib Mesylate (IDH2 Inhibitor)

Trial Overview 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.

Participant Groups

Group I: Treatment (azacitidine, enasidenib mesylate) Experimental Treatment 2 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.

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

Approved in Canada as Vidaza for:

• Myelodysplastic syndromes
• Acute myeloid leukemia

Approved in Japan as Vidaza 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

In a study of 100 patients with acute myeloid leukemia (AML) treated with hypomethylating agents (HMA) like azacitidine and decitabine, 24% achieved a response, and the median overall survival (OS) was 6.5 months, indicating some efficacy as salvage therapy.

Patients with secondary AML (sAML) had a significantly better median OS of 12.3 months compared to 6.1 months for those with de novo AML, suggesting that HMA may be particularly beneficial for sAML patients who typically have poorer outcomes.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Hypomethylating Agents (HMAs) as Salvage Therapy in Relapsed or Refractory AML: An Italian Multicentric Retrospective Study. Lessi, F., Laurino, M., Papayannidis, C., et al.[2021]

In the AZA-001 trial, azacitidine significantly improved survival in patients with high-risk myelodysplastic syndrome and acute myeloid leukemia, with 91 out of 179 patients responding to treatment after a median of 14 cycles.

Continued treatment with azacitidine beyond the first response led to an improved response category in 48% of patients, suggesting that ongoing therapy can enhance clinical benefits for those who initially respond.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Continued azacitidine therapy beyond time of first response improves quality of response in patients with higher-risk myelodysplastic syndromes. Silverman, LR., Fenaux, P., Mufti, GJ., et al.[2022]

Enasidenib is an effective oral treatment for acute myeloid leukemia (AML) that specifically targets IDH2 mutations, showing clinical improvement in 19.6% of patients and laboratory improvement in 38.8% of cases based on clinical trials.

While enasidenib is generally well-tolerated, it can cause differentiation syndrome, a serious side effect that requires careful monitoring by healthcare providers.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

An evaluation of enasidenib for the treatment of acute myeloid leukemia. Del Principe, MI., Paterno, G., Palmieri, R., et al.[2019]

Enasidenib, an oral selective inhibitor of mutant-IDH2 enzymes, was well tolerated in patients with relapsed or refractory acute myeloid leukemia (AML), showing an overall response rate of 40.3% and a median response duration of 5.8 months.

The drug works by inducing differentiation of myeloblasts rather than causing cytotoxicity, leading to a median overall survival of 9.3 months for patients, and 19.7 months for those who achieved complete remission.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Enasidenib in mutant IDH2 relapsed or refractory acute myeloid leukemia. Stein, EM., DiNardo, CD., Pollyea, DA., et al.[2023]

In a real-life study of 49 patients with myelodysplastic syndrome (MDS), acute myeloid leukaemia (AML), and chronic myelomonocytic leukaemia (CMML), azacitidine demonstrated a clinically acceptable safety profile, with 67.3% of patients experiencing treatment-related adverse events.

Efficacy results showed that 41.4% of MDS and CMML patients achieved a complete or partial response, and 43.8% of transfusion-dependent patients became transfusion-independent, with a median overall survival of 490 days.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Safety and efficacy of azacitidine in Belgian patients with high-risk myelodysplastic syndromes, acute myeloid leukaemia, or chronic myelomonocytic leukaemia: results of a real-life, non-interventional post-marketing survey. Beguin, Y., Selleslag, D., Meers, S., et al.[2015]

The Vidaza Access Program in Belgium successfully facilitated access to azacitidine treatment for 175 patients with myelodysplastic syndromes (MDS), acute myeloid leukemia (AML), and chronic myelomonocytic leukemia (CMML) by streamlining the approval process for patient dossiers.

Out of the 175 patient dossiers submitted, 163 were approved by Celgene, demonstrating the program's effectiveness in ensuring timely treatment initiation without financial risk to hospitals, which is crucial for patient outcomes.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Azacitidine access program for Belgian patients with myelodysplastic syndromes, acute myeloid leukemia or chronic myelomonocytic leukemia. Meers, S., Selleslag, D., Potier, H., et al.[2018]

Enasidenib is a targeted treatment for relapsed or refractory acute myeloid leukemia that effectively inhibits mutant IDH2 proteins, as shown in a Phase I/II study assessing its safety and efficacy in patients with IDH2 mutations.

The study revealed that enasidenib significantly induces CYP3A enzyme activity, which is important to consider when prescribing other medications that are metabolized by this pathway, due to the potential for drug interactions.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Modeling and simulation of the endogenous CYP3A induction marker 4β-hydroxycholesterol during enasidenib treatment. Li, Y., Connarn, JN., Chen, J., et al.[2022]

In a clinical trial involving 107 patients with newly diagnosed mutant-IDH2 acute myeloid leukaemia, the combination of enasidenib and azacitidine significantly improved overall response rates, with 74% of patients responding compared to 36% in the azacitidine-only group.

The combination treatment was well tolerated, with no treatment-related deaths reported, although some patients experienced common grade 3 or 4 adverse events like thrombocytopenia and neutropenia.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Enasidenib plus azacitidine versus azacitidine alone in patients with newly diagnosed, mutant-IDH2 acute myeloid leukaemia (AG221-AML-005): a single-arm, phase 1b and randomised, phase 2 trial. DiNardo, CD., Schuh, AC., Stein, EM., et al.[2022]

References

1. Switzerland pubmed.ncbi.nlm.nih.gov

Hypomethylating Agents (HMAs) as Salvage Therapy in Relapsed or Refractory AML: An Italian Multicentric Retrospective Study. [2021]

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

Efficacy of Azacitidine in De Novo and Relapsed Acute Myeloid Leukemia: A Retrospective Comparative Study. [2015]

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

Continued azacitidine therapy beyond time of first response improves quality of response in patients with higher-risk myelodysplastic syndromes. [2022]

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

An evaluation of enasidenib for the treatment of acute myeloid leukemia. [2019]

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

Enasidenib in mutant IDH2 relapsed or refractory acute myeloid leukemia. [2023]

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

Safety and efficacy of azacitidine in Belgian patients with high-risk myelodysplastic syndromes, acute myeloid leukaemia, or chronic myelomonocytic leukaemia: results of a real-life, non-interventional post-marketing survey. [2015]

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

Azacitidine access program for Belgian patients with myelodysplastic syndromes, acute myeloid leukemia or chronic myelomonocytic leukemia. [2018]

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

Modeling and simulation of the endogenous CYP3A induction marker 4β-hydroxycholesterol during enasidenib treatment. [2022]

9. England pubmed.ncbi.nlm.nih.gov

Enasidenib plus azacitidine versus azacitidine alone in patients with newly diagnosed, mutant-IDH2 acute myeloid leukaemia (AG221-AML-005): a single-arm, phase 1b and randomised, phase 2 trial. [2022]