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

Trial Summary

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.

What data supports the effectiveness of the drug Azacitidine for treating myelodysplastic syndrome?

Research shows that Azacitidine significantly prolongs survival in patients with higher-risk myelodysplastic syndromes, with studies indicating improved overall survival and delayed progression to acute myeloid leukemia compared to conventional care. ^{1 2 3 4 5}

Is the combination of Azacitidine and Enasidenib safe for humans?

Azacitidine has been studied for safety in patients with myelodysplastic syndromes, acute myeloid leukemia, and chronic myelomonocytic leukemia. Common side effects include low blood cell counts and gastrointestinal issues, but these can often be managed with supportive care. The combination with other drugs like panobinostat showed more severe side effects, suggesting careful monitoring is needed. ^{1 3 5 6 7}

How is the drug Azacitidine + Enasidenib unique for treating myelodysplastic syndrome?

The combination of Azacitidine and Enasidenib is unique because Azacitidine is a hypomethylating agent that can prolong survival in higher-risk myelodysplastic syndrome (MDS) patients, while Enasidenib targets specific genetic mutations (IDH2 mutations) that may be present in some MDS cases, potentially offering a more tailored treatment approach. ^{1 5 8 9 10}

What is the purpose of this trial?

This phase II trial studies the side effects and how well azacitidine and enasidenib work in treating patients with IDH2-mutant myelodysplastic syndrome. Azacitidine and enasidenib may stop the growth of cancer cells by blocking some of the enzymes needed for cell growth.

Research Team

Courtney DiNardo, MD

Principal Investigator

M.D. Anderson Cancer Center

Eligibility Criteria

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

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

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

I have previously been treated with a drug targeting IDH2.

Timeline

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

Treatment Details

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.

Participant Groups

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

>- **Revlimid (lenalidomide)**: Multiple myeloma, myelodysplastic syndromes, and mantle cell lymphoma treatment. - **Pomalyst (pomalidomide)**: Relapsed/refractory multiple myeloma treatment. - **Otezla (apremilast)**: Psoriatic arthritis treatment. - **Thalomid (thalidomide)**: Erythema nodosum leprosum and multiple myeloma treatment.

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

Findings from Research

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]

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]

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]

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 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]

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 (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]

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]

References

1. England 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). [2019]

2. England pubmed.ncbi.nlm.nih.gov

Review of azacitidine trials in Intermediate-2-and High-risk myelodysplastic syndromes. [2022]

3. 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]

4. England 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. [2013]

5. England pubmed.ncbi.nlm.nih.gov

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

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

Management and supportive care measures for adverse events in patients with myelodysplastic syndromes treated with azacitidine*. [2021]

7. England 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. [2018]

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

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

9. United States 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. [2021]

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

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