Azacitidine + Enasidenib for Myelodysplastic Syndrome

Recruiting at 2 trial locations

Overseen By Courtney DiNardo, MD

Age: Any Age

Sex: Any

Trial Phase: Phase 2

Sponsor: M.D. Anderson Cancer Center

Must not be taking: IDH2 inhibitors

Disqualifiers: Uncontrolled infection, CNS disease, cardiac disease, 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: 3

Duration: 28 days per cycle, repeated

63 Participants Needed

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial tests the effectiveness of azacitidine and enasidenib for individuals with myelodysplastic syndrome (MDS) who have a specific IDH2 gene mutation. The researchers aim to determine if these drugs can inhibit cancer cell growth by blocking certain enzymes. Participants are divided into two groups: one receives both drugs, while the other receives only enasidenib. This trial targets those diagnosed with MDS, possessing an IDH2 mutation, and having specific prior treatment experiences. As a Phase 2 trial, the research focuses on evaluating the treatment's effectiveness in an initial, smaller group.

Will I have to stop taking my current medications?

The trial protocol does not specify whether you need to stop taking your current medications. However, if you have previously taken a targeted IDH2 inhibitor, you cannot participate in this trial.

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

Research has shown that the combination of azacitidine and enasidenib has been studied for safety and tolerability. A study on this combination in patients identified common side effects, such as low levels of white blood cells (neutropenia), platelets (thrombocytopenia), and red blood cells (anemia). Medical care can usually manage these side effects.

When used alone, enasidenib is generally well-tolerated, as studies have found. Some patients experienced similar blood-related side effects, but these were less common than with the combination treatment.

Regarding safety, it is important to note that this trial is in phase 2. Researchers have already collected some safety information from earlier studies, but they continue to monitor side effects and patient tolerability. ^{1 2 3 4 5}

Why are researchers excited about this trial's treatments?

Researchers are excited about these treatments because they combine azacitidine and enasidenib, offering a fresh approach for myelodysplastic syndromes (MDS). Unlike standard treatments that primarily use hypomethylating agents like azacitidine alone, this combination leverages enasidenib, which specifically targets mutant IDH2 proteins, a novel mechanism. This dual-action strategy not only aims to address the cancer cells more directly but also potentially enhances the overall effectiveness of the treatment, offering hope for better outcomes in patients who are new to treatment and those who have relapsed or are resistant to standard therapies.

What evidence suggests that azacitidine and enasidenib might be effective treatments for myelodysplastic syndrome?

Research has shown that using azacitidine with enasidenib may help treat IDH2-mutant myelodysplastic syndrome (MDS). In this trial, one group of participants will receive both azacitidine and enasidenib. One study found that patients with high-risk MDS lived an average of 32.2 months when treated with both drugs, compared to 21.3 months with just enasidenib. Another group in this trial will receive enasidenib alone, which has proven effective in 43.1% of patients with this condition, with an average survival of 16.9 months in other studies. These findings suggest that both treatments can be effective, but the combination might lead to better outcomes for patients. ^{1 2 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 patients with IDH2-mutant myelodysplastic syndrome who have specific gene mutations, normal liver and kidney function, can consent to the study's requirements, and are not pregnant or nursing. Men must use contraception if with a partner of childbearing potential. It includes those new to treatment (Arm A) or who didn't respond well to previous therapies (Arm B).

Inclusion Criteria

My cancer has an IDH2 gene mutation.

I have been diagnosed with MDS, RAEB-T, or CMML.

Serum bilirubin =< 2 x the upper limit of normal (ULN) (except for patients with Gilbert's disease)

Exclusion Criteria

Subjects with a corrected QT (QTc) > 480 ms (QTc > 510 msec for subjects with a bundle branch block at baseline

I do not have major stomach issues that could affect medication absorption.

I have previously been treated with a drug targeting IDH2.

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Patients receive enasidenib and azacitidine or enasidenib alone in 28-day cycles

28 days per cycle, repeated

Monthly visits for treatment administration

Follow-up

Participants are monitored for safety and effectiveness after treatment

Up to 3 years

Every 3 months

What Are the Treatments Tested in This Trial?

Interventions

• Azacitidine
• Enasidenib

Trial Overview The trial is testing how effective azacitidine combined with enasidenib is in treating myelodysplastic syndrome linked to IDH2 mutations. The goal is to see if these drugs can halt cancer cell growth by inhibiting certain enzymes.

How Is the Trial Designed?

Group I: Arm II (enasidenib) Experimental Treatment 2 Interventions

Patients relapsed and/or refractory to HMA therapy receive enasidenib PO QD on days 1-28. Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity.

Group II: Arm I (enasidenib, azacitidine) Experimental Treatment 3 Interventions

Patients who are HMA-naive receive enasidenib PO QD on days 1-28 and azacitidine IV over 30-60 minutes or SC on days 1-7. Cycles repeat every 28 days 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+

Celgene

Industry Sponsor

Trials

649

Recruited

130,000+

Top Products

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Jay Backstrom

Celgene

Chief Medical Officer since 2016

MD

Mark Alles

Celgene

Chief Executive Officer since 2016

Bachelor's degree from Lock Haven University of Pennsylvania

Published Research Related to This Trial

In a study of 149 patients with higher-risk myelodysplastic syndromes (MDS), chronic myelomonocytic leukemia (CMML), and acute myeloid leukemia (AML), azacitidine treatment resulted in a median progression-free survival (PFS) of 10.9 months and an overall survival (OS) of 14.1 months, demonstrating its effectiveness in a real-world clinical setting.

The safety profile of azacitidine was consistent with previous clinical trials, and factors such as Eastern Cooperative Oncology Group (ECOG) performance status and red blood cell transfusion prior to treatment were identified as predictive factors for better PFS.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Impact of performance status and transfusion dependency on outcome of patients with myelodysplastic syndrome, acute myeloid leukemia and chronic myelomonocytic leukemia treated with azacitidine (PIAZA study). Wehmeyer, J., Zaiss, M., Losem, C., et al.[2019]

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 90 patients with high-risk myelodysplastic syndromes (MDS), chronic myelomonocytic leukaemia (CMML), and acute myeloid leukaemia (AML), azacitidine showed an overall response rate of 57% in low-risk MDS and 39% in AML, indicating its efficacy across different risk groups.

The median overall survival for patients treated with azacitidine was 13 months, with factors like circulating blasts and poor risk cytogenetics identified as predictors for survival, while a doubling of platelets after the first treatment cycle was a positive indicator for better outcomes.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Platelet doubling after the first azacitidine cycle is a promising predictor for response in myelodysplastic syndromes (MDS), chronic myelomonocytic leukaemia (CMML) and acute myeloid leukaemia (AML) patients in the Dutch azacitidine compassionate named patient programme. van der Helm, LH., Alhan, C., Wijermans, PW., et al.[2013]

Azacitidine is an effective and well-tolerated treatment for patients with higher-risk myelodysplastic syndromes (MDS) and acute myeloid leukaemia (AML), including older patients who are ineligible for stem cell transplants, as demonstrated in pivotal phase 3 trials.

It is the only approved hypomethylating agent that has been shown to prolong overall survival compared to conventional care, making it the recommended first-line treatment for most patients with higher-risk MDS.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Azacitidine: A Review in Myelodysplastic Syndromes and Acute Myeloid Leukaemia. Scott, LJ.[2022]

In two large phase III trials involving 325 patients with myelodysplastic syndrome (MDS), azacitidine was associated with common adverse events (AEs) such as cytopenias and gastrointestinal issues, but most were transient and manageable, allowing patients to continue treatment.

The frequency of hematologic AEs decreased over time, and effective management strategies, including dosing delays and supportive medications, helped patients tolerate azacitidine better, maximizing the potential benefits of the therapy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Management and supportive care measures for adverse events in patients with myelodysplastic syndromes treated with azacitidine*. Santini, V., Fenaux, P., Mufti, GJ., et al.[2021]

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]

In a phase 1b/2b trial involving 113 patients with higher-risk myelodysplastic syndromes (MDS), the combination of panobinostat (PAN) and azacitidine (AZA) resulted in a higher rate of composite complete responses compared to AZA alone (27.5% vs 14.3%).

However, the combination treatment did not significantly improve overall survival or time to progression compared to AZA monotherapy, and it was associated with a higher incidence of severe adverse events and on-treatment deaths, indicating a need for further optimization of the treatment regimen.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

A phase 1b/2b multicenter study of oral panobinostat plus azacitidine in adults with MDS, CMML or AML with ⩽30% blasts. Garcia-Manero, G., Sekeres, MA., Egyed, M., et al.[2018]

Azacitidine has been shown to significantly prolong the time to progression to acute myeloid leukemia or death in myelodysplastic syndromes (MDS) patients, with a median time of 21 months compared to 13 months for supportive care in a study of 191 patients.

In a larger trial with 358 patients, azacitidine also significantly improved overall survival, extending it to 24.5 months compared to 15.0 months with conventional care, establishing it as a key first-line treatment for higher-risk MDS patients.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Review of azacitidine trials in Intermediate-2-and High-risk myelodysplastic syndromes. Fenaux, P., Ades, L.[2022]

Azacitidine (Vidaza) is the only drug approved in the EU that significantly prolongs survival in adults with high-risk myelodysplastic syndromes (MDS) and acute myeloid leukaemia (AML), making it a crucial treatment option for patients not eligible for stem cell transplantation.

The treatment is associated with a lower risk of AML progression and higher rates of remission and blood transfusion independence, while maintaining an acceptable safety profile, with peripheral cytopenias being the most common side effect.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Azacitidine: a review of its use in higher-risk myelodysplastic syndromes/acute myeloid leukaemia. Keating, GM.[2021]

In a study of 149 patients with high-risk myelodysplastic syndrome and acute myeloid leukemia, azacitidine (AZA) alone achieved a hematologic normalization (HN) rate of 32%, while the combination of AZA and entinostat resulted in a lower HN rate of 27%.

The addition of entinostat did not enhance the clinical response and was associated with less demethylation, indicating a potential antagonistic effect, while AZA alone showed promise with a median overall survival of 18 months.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Prolonged administration of azacitidine with or without entinostat for myelodysplastic syndrome and acute myeloid leukemia with myelodysplasia-related changes: results of the US Leukemia Intergroup trial E1905. Prebet, T., Sun, Z., Figueroa, ME., et al.[2021]

Citations

1. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC10220255/

Targeted therapy with the mutant IDH2 inhibitor enasidenib ... Enasidenib is an effective treatment option for mIDH2 MDS, both in combination with azacitidine for treatment-naïve high-risk MDS, and as a single agent ...

2. onclive.com onclive.com/view/enasidenib-elicits-clinical-efficacy-in-high-risk-idh2-mutated-mds

Enasidenib Elicits Clinical Efficacy in High-Risk, IDH2 ... Findings from the phase 1 AG221-C-001 study (NCT01915498) demonstrated a 53% response rate and a median overall survival (OS) of 16.9 months ...

3. 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 ...

4. 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 ... Almost all pts had AML, except one with MDS who progressed on treatment with azacitidine. The data cutoff date was June 30, 2023. The median ...

5. hematologyadvisor.com hematologyadvisor.com/news/myelodysplastic-syndrome-enasidenib-azacitidine-improve-survival/

Enasidenib With Azacitidine May Improve Survival in ... The median OS in the enasidenib and azacitidine group was 32.2 months vs 21.3 months in the enasidenib only group. Grade 3-4 adverse events were ...

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. mds-hub.com mds-hub.com/medical-information/safety-and-efficacy-of-enasidenib-in-idh2-mutated-myelodysplastic-syndrome

Safety and efficacy of enasidenib in IDH2-mutated ... Among responders, two patients (n = 1 in cohorts B and C) lost their response after 80 days of treatment. In cohort B, three patients did not ...

8. haematologica.org haematologica.org/article/view/11858

Treatment of high-risk myelodysplastic syndromes The overall response rate after azacitidine was 60% versus 5% in the best supportive care group (P<0.0001) and time to leukemic transformation ...