Enasidenib + Azacitidine for Acute Myeloid Leukemia

Overseen By Courtney DiNardo

Age: 18+

Sex: Any

Trial Phase: Phase 2

Sponsor: M.D. Anderson Cancer Center

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

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

Prior Safety Data This treatment has passed at least one previous human trial

Compensation: Varies

Number of Visits: Unknown

Duration: 4-6 weeks per cycle

50 Participants Needed

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial explores the effectiveness of two medications, enasidenib (Idhifa) and azacitidine (Vidaza or 5-azacytidine), in treating acute myeloid leukemia (AML). It targets patients whose AML has returned or is unresponsive to treatment and who have the IDH2 gene mutation. The trial aims to determine if these medications can halt or slow cancer cell growth by blocking essential enzymes. Suitable candidates include those with AML who have not responded to other treatments and possess the IDH2 gene mutation. As a Phase 2 trial, this research measures the treatment's effectiveness in an initial, smaller group of participants.

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.

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

Research has shown that the combination of enasidenib and azacitidine is generally well-tolerated by patients. Studies have found this treatment effective for people with certain types of acute myeloid leukemia (AML) that have specific genetic changes, such as IDH2. In one study, many patients responded well to this therapy. Importantly, the combination proved safe, with manageable side effects.

Overall, these findings suggest that enasidenib and azacitidine together offer a promising option for treating AML, especially for those who have not responded to other treatments or whose cancer has returned. The treatment balances effectiveness with a safety profile that patients can handle. ^{1 2 3 4 5}

Why do researchers think this study treatment might be promising for acute myeloid leukemia?

Researchers are excited about the combination of enasidenib and azacitidine for treating Acute Myeloid Leukemia (AML) because it offers a novel approach compared to traditional treatments. Enasidenib targets a specific mutation in the IDH2 gene, which is present in some AML patients, offering a more personalized treatment strategy. This is different from the standard chemotherapy options, which don't specifically target genetic mutations. Additionally, combining enasidenib with azacitidine, a well-known chemotherapy drug, may enhance the overall effectiveness by attacking the cancer through multiple pathways. This dual-action strategy is what makes this treatment combination stand out and offers hope for better outcomes in AML patients.

What evidence suggests that enasidenib and azacitidine might be an effective treatment for acute myeloid leukemia?

Research has shown that combining enasidenib and azacitidine, which participants in this trial will receive, effectively treats acute myeloid leukemia (AML) with an IDH2 gene mutation. Studies have found that this combination works better than azacitidine alone, increasing the likelihood of successful treatment. Earlier research found that using both enasidenib and azacitidine led to an overall response rate of about 30% and a complete remission rate of around 20%. This suggests that patients with recurrent or difficult-to-treat AML might benefit from these medications working together. ^{1 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?

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

Total bilirubin < 2 x upper limit of normal (ULN) unless increase is due to Gilbert's disease or leukemic involvement

Women of childbearing potential must agree to use an adequate method of contraception during the study and until 3 months after the last treatment

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

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

Timeline for a Trial Participant

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

What Are the Treatments Tested in This Trial?

Interventions

• Azacitidine
• Enasidenib Mesylate

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.

How Is the Trial Designed?

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 European Union, United States, Canada, Japan for the following indications:

Approved in European Union as Vidaza for:

• Acute myeloid leukemia
• Chronic myelomonocytic leukemia
• Myelodysplastic syndromes

Approved in United States as Vidaza for:

• Myelodysplastic syndromes
• Chronic myelomonocytic leukemia

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+

National Cancer Institute (NCI)

Collaborator

Trials

14,080

Recruited

41,180,000+

Published Research Related to This Trial

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]

In a study of 38 acute myeloid leukemia (AML) patients treated with azacitidine, the median overall survival was approximately 10 months for both newly diagnosed and relapsed patients, indicating its efficacy as a treatment option for those unfit for intensive chemotherapy.

The treatment showed a 29% positive effect on reducing transfusion dependency, which was linked to better survival outcomes, highlighting the potential benefits of azacitidine in managing symptoms and improving quality of life for AML patients.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Efficacy of Azacitidine in De Novo and Relapsed Acute Myeloid Leukemia: A Retrospective Comparative Study. Gemuenden, C., Benz, R., Senn, O., et al.[2015]

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 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]

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, 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]

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]

Citations

1. pubmed.ncbi.nlm.nih.gov pubmed.ncbi.nlm.nih.gov/35078972/

Efficacy and safety of enasidenib and azacitidine ... ENA + AZA was a well-tolerated, and effective therapy for elderly pts with IDH2 mut ND AML as well as pts with R/R AML.

2. clinicaltrials.gov clinicaltrials.gov/study/NCT03683433

Study Details | NCT03683433 | Enasidenib and Azacitidine ... This phase II trial studies how well enasidenib and azacitidine work in treating patients with IDH2 gene mutation and acute myeloid leukemia that has come back ...

3. scientificarchives.com scientificarchives.com/article/molecular-features-associated-with-response-to-enasidenib-plus-azacitidine-in-newly-diagnosed-idh2-mutated-acute-myeloid-leukemia

Journal of Clinical Haematology In a phase 1b/2 trial (NCT02677922), combination therapy with azacitidine + enasidenib significantly improved overall response rate compared with azacitidine ...

4. theoncologynurse.com theoncologynurse.com/2020-year-in-review-aml/addition-of-enasidenib-to-azacitidine-improves-response-versus-azacitidine-alone-in-mutant-idh2-newly-diagnosed-acute-myeloid-leukemia

Addition of Enasidenib to Azacitidine Improves Response ... Enasidenib and azacitidine individually induce an overall response rate (ORR) of approximately 30% and a complete remission rate of approximately 20% in ...

5. cda-amc.ca cda-amc.ca/sites/default/files/pcodr/Reviews2019/10144EnasidenibAML_fnRec_ApprovedbyChair_Post_31Oct2019_final.pdf

Enasidenib (Idhifa) AML – pERC Final Recommendation The key efficacy outcomes (data cut-off September 01, 2017) deliberated by pERC included CR, EFS, duration of response (DOR), OS, and transfusion ...

6. nature.com nature.com/articles/s41408-021-00604-2

Efficacy and safety of enasidenib and azacitidine ... Interim results of the ongoing randomized study evaluating ENA + AZA in patients with ND IDH2mutAML reported a favorable ORR of 71%, with 53% CR ...

7. ashpublications.org ashpublications.org/blood/article/142/Supplement%201/159/502826/Final-Results-of-the-Phase-Ib-II-Study-Evaluating

Final Results of the Phase Ib/II Study Evaluating Enasidenib in ... Among 23 pts with R/R AML evaluable for response, the ORR was 70% (16/23), including 57% (13/23) CR ( Figure 1). In pts with R172 mut, the ORR ...

8. thelancet.com thelancet.com/journals/lanonc/article/PIIS1470-2045(21)00494-0/abstract

Enasidenib plus azacitidine versus ... Combination enasidenib plus azacitidine was well tolerated and significantly improved overall response rates compared with azacitidine ...