Enasidenib + Cedazuridine-Decitabine for Myelodysplastic Syndrome

Recruiting at 118 trial locations

Age: 18+

Sex: Any

Trial Phase: Phase 2

Sponsor: National Cancer Institute (NCI)

Must not be taking: Cytarabine therapy

Disqualifiers: AML therapy, DNA methyltransferase inhibitors, 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: 6

Duration: 6 cycles (24 weeks)

54 Participants Needed

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial aims to determine if adding enasidenib, a targeted therapy, to the usual treatment of cedazuridine-decitabine, a combination pill, is more effective for individuals with higher-risk, IDH2-mutated myelodysplastic syndrome (MDS). The study will compare the effectiveness of the combination treatment against the usual treatment in aiding the bone marrow to produce healthy blood cells. Individuals with MDS who have not yet received specific anti-cancer therapies and possess an IDH2 mutation might be suitable candidates for this trial. As a Phase 2 trial, the research focuses on evaluating the treatment's effectiveness in an initial, smaller group of participants.

Will I have to stop taking my current medications?

The trial does not specify if you need to stop taking your current medications. However, you cannot have received prior anti-cancer therapy for AML or MDS, and certain medications like cytarabine are restricted. It's best to discuss your current medications with the trial team.

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

A previous study found the combination of decitabine and cedazuridine to be safe. Participants generally tolerated these drugs well, with fewer cases of neutropenia, a condition involving low levels of a certain type of white blood cell. This suggests many people can handle these drugs effectively. Research shows enasidenib is usually safe for patients with IDH2-mutated conditions. Although some patients experienced serious side effects like pneumonia, these were uncommon. Overall, past studies have shown promising safety for both decitabine with cedazuridine and enasidenib. ^{1 2 3 4 5}

Why are researchers excited about this trial's treatments?

Researchers are excited about the treatments involving Enasidenib and Cedazuridine-Decitabine for myelodysplastic syndrome because they offer a novel approach compared to current options. Unlike the standard treatments that typically target DNA synthesis, Enasidenib specifically targets mutated IDH2 enzymes, potentially addressing a root cause of the disease. Additionally, Cedazuridine-Decitabine simplifies the administration process by combining two drugs into an oral form, which could improve patient convenience and adherence. This combination might enhance treatment effectiveness and offer a more personalized approach for patients with specific genetic profiles.

What evidence suggests that this trial's treatments could be effective for myelodysplastic syndrome?

Research shows that the combination of two drugs, decitabine and cedazuridine, known as ASTX727, effectively treats myelodysplastic syndrome (MDS). Studies have found that this oral treatment works as well as the intravenous version, aiding the bone marrow in producing normal blood cells. In this trial, participants in Regimen 1 will receive ASTX727 alone. Researchers are studying another drug, enasidenib, for its potential to halt the growth of abnormal cells in patients with higher-risk MDS that have a specific mutation called IDH2. Participants in Regimen 2 will receive ASTX727 with enasidenib, which might offer a more effective treatment by targeting the enzymes needed for cell growth. This combination is promising because it could enhance the usual treatment, offering hope for better outcomes in patients with this specific type of MDS. ^{3 5 6 7 8}

Who Is on the Research Team?

Anand A Patel

Principal Investigator

Alliance for Clinical Trials in Oncology

Are You a Good Fit for This Trial?

This trial is for patients with higher-risk myelodysplastic syndrome (MDS) who have an IDH2 mutation. They should not have had previous treatment with DNA methyltransferase inhibitors or anti-cancer therapy for AML/MDS, except certain allowed medications like hydroxyurea. Participants must be registered to the MSRP and assigned by MATCHBox.

Inclusion Criteria

I am registered with the MSRP and assigned to this protocol.

My cancer has a specific IDH2 mutation.

I am checking if I meet the initial requirements to join a study.

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants receive ASTX727 and/or enasidenib in cycles of 28 days, with bone marrow biopsy and aspiration throughout the study

6 cycles (24 weeks)

Monthly visits for each cycle

Follow-up

Participants are monitored for safety and effectiveness after treatment

Up to 5 years

Every 6 months

What Are the Treatments Tested in This Trial?

Interventions

• Decitabine and Cedazuridine
• Enasidenib

Trial Overview

The study compares usual MDS treatment (cedazuridine-decitabine, ASTX727) against a combination of ASTX727 and enasidenib. Enasidenib may block enzymes needed for cell growth, potentially improving treatment effectiveness in higher-risk IDH2-mutated MDS.

How Is the Trial Designed?

Group I: Regimen 2 (ASTX727, enasidenib) Experimental Treatment 5 Interventions

Patients receive ASTX727 PO QD on days 1-5 and enasidenib PO QD on days 1-28 of each cycle. Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity. Patients who experience CR, PR, or SD any time after 4 cycles of treatment may be reassessed in order to go to a higher myeloMATCH tier assignment or to TAP. Patients also undergo bone marrow biopsy and aspiration throughout the study. Patients may also undergo optional buccal swab on study, and/or optional additional bone marrow aspiration and blood sample collection on study and at disease progression.

Group II: Regimen 1 (ASTX727) Active Control 4 Interventions

Patients receive ASTX727 PO QD on days 1-5 of each cycle. Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity. Patients who do not achieve a CR, CRL, or CRh at the end of cycle 6 may cross-over to Regimen 2. Patients who experience CR, PR, or SD any time after 4 cycles of treatment may be reassessed in order to go to a higher myeloMATCH tier assignment or to TAP. Patients also undergo bone marrow biopsy and aspiration throughout the study. Patients may also undergo optional buccal swab on study, and/or optional additional bone marrow aspiration and blood sample collection on study and at disease progression.

Who Is Running the Clinical Trial?

National Cancer Institute (NCI)

Lead Sponsor

Trials

14,080

Recruited

41,180,000+

Published Research Related to This Trial

In a phase 1 study involving 44 patients with myelodysplastic syndromes or chronic myelomonocytic leukaemia, the combination of oral decitabine and the CDA inhibitor cedazuridine successfully increased the bioavailability of decitabine, achieving pharmacokinetics similar to intravenous administration without increasing toxicity.

The study demonstrated that oral decitabine combined with cedazuridine produced effective dose-dependent demethylation and clinical responses comparable to intravenous decitabine, suggesting it could be a viable alternative treatment for myeloid disorders.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

An oral fixed-dose combination of decitabine and cedazuridine in myelodysplastic syndromes: a multicentre, open-label, dose-escalation, phase 1 study. Savona, MR., Odenike, O., Amrein, PC., et al.[2019]

The fixed-dose oral combination of decitabine and cedazuridine (Inqovi®) has been approved for treating myelodysplastic syndromes (MDS) and chronic myelomonocytic leukaemia (CMML), enhancing the oral bioavailability of decitabine through the inhibition of cytidine deaminase by cedazuridine.

Decitabine is already an established treatment for MDS and CMML, and the combination therapy has shown promise in ongoing clinical studies for other cancers like acute myeloid leukaemia (AML), glioma, and solid tumors.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Decitabine/Cedazuridine: First Approval. Dhillon, S.[2021]

The combination of oral cedazuridine and decitabine (C-DEC) has been shown to have a similar pharmacokinetic and pharmacodynamic profile to parenteral decitabine, making it a promising alternative for treating higher-risk myelodysplastic syndromes (MDS) and chronic myelomonocytic leukemia (CMML).

Phase 2 and phase 3 clinical trials confirmed the bioequivalence of C-DEC to parenteral decitabine, leading to FDA approval for its use in intermediate/high-risk MDS and CMML, highlighting its efficacy and safety as an oral treatment option.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Cedazuridine/decitabine: from preclinical to clinical development in myeloid malignancies. Patel, AA., Cahill, K., Saygin, C., et al.[2023]

Luspatercept-aamt, approved by the FDA in April 2020, effectively promotes erythroid maturation and demonstrated significant efficacy in the MEDALIST trial, achieving transfusion independence in patients with refractory myelodysplastic syndromes.

Decitabine/cedazuridine, approved in July 2020, acts as a nucleoside metabolic inhibitor and showed comparable safety and efficacy to IV decitabine in the ASCERTAIN study, making it a viable treatment option for patients with intermediate or high-risk myelodysplastic syndromes.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Novel agents for myelodysplastic syndromes. Xu, K., Hansen, E.[2022]

Luspatercept has shown significant efficacy in treating low-risk myelodysplastic syndromes (MDS), with 63% of patients experiencing hematological improvement and 38% achieving transfusion independence in clinical trials.

Oral decitabine combined with oral cedazuridine has demonstrated pharmacological equivalence to intravenous decitabine, achieving overall response rates of 60% and 43% in phase 2 and 3 trials for high-risk MDS, respectively.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

[New treatment for myelodysplastic syndromes: luspatercept and oral hypomethylating agents]. Usuki, K.[2022]

A new oral drug combination, DEC-cedazuridine (C-DEC), has been developed to provide a more convenient treatment option for patients with myelodysplastic syndrome (MDS) and chronic myelomonocytic leukemia (CMML), which traditionally required lengthy parenteral therapies.

C-DEC has been approved by major health authorities, including the US FDA, for patients with newly diagnosed or previously treated intermediate or high-risk MDS and CMML, indicating its safety and potential efficacy in managing these complex disorders.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Role of cedazuridine/decitabine in the management of myelodysplastic syndrome and chronic myelomonocytic leukemia. Thota, S., Oganesian, A., Azab, M., et al.[2021]

In a phase III trial involving patients aged 60 and older with myelodysplastic syndromes (MDS), decitabine treatment resulted in a 15% complete or partial remission rate and significantly improved progression-free survival (PFS) and overall survival (OS) compared to best supportive care.

Specifically, patients with refractory anemia with excess blasts in transformation (RAEBt) treated with decitabine had a median PFS of 6.2 months versus 2.8 months in the supportive care group, indicating that decitabine is an effective treatment option for this patient population.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Decitabine versus best supportive care in older patients with refractory anemia with excess blasts in transformation (RAEBt) - results of a subgroup analysis of the randomized phase III study 06011 of the EORTC Leukemia Cooperative Group and German MDS Study Group (GMDSSG). Becker, H., Suciu, S., Rüter, BH., et al.[2018]

Citations

1.

pmc.ncbi.nlm.nih.gov

pmc.ncbi.nlm.nih.gov/articles/PMC7414597/

Oral cedazuridine/decitabine for MDS and CMML: a phase ...

This phase 2 study was designed to compare systemic decitabine exposure, demethylation activity, and safety in the first 2 cycles with cedazuridine 100 mg/ ...

2.

nature.com

nature.com/articles/s41408-025-01406-6

Oral decitabine cedazuridine with and without venetoclax ...

Prior studies have suggested that CMML may respond less favorably to venetoclax-based combinations [6, 7], potentially due to differential ...

3.

sciencedirect.com

sciencedirect.com/science/article/pii/S0006497121056044

Efficacy of Oral Decitabine/Cedazuridine (ASTX727) in the ...

In the overall study, oral decitabine/cedazuridine delivered equivalent PK exposure to 5 days of IV decitabine 20mg/m 2 with a resultant ...

4.

clinicaltrials.gov

clinicaltrials.gov/study/NCT03306264

NCT03306264 | Study of ASTX727 vs IV Decitabine in ...

Participants with MDS or CMML received ASTX727 tablet, containing the fixed-dose combination of 35 mg decitabine and 100 mg cedazuridine, orally, once daily, on ...

5.

astx.com

astx.com/2022-ash-astx727-03-phase-1-study-evaluating-oral-decitabine-cedazuridine-astx727-low-dose-ld-in-lower-risk-myelodysplastic-syndromes-lr-mds-patients/

ASTX727-03: Phase 1 Study Evaluating Oral Decitabine ...

The Phase 1 part of this study explores the optimal dosing schedule of LD oral decitabine/cedazuridine in patients with LR-MDS.

6.

pmc.ncbi.nlm.nih.gov

pmc.ncbi.nlm.nih.gov/articles/PMC10428680/

P719: RANDOMIZED PHASE 1-2 STUDY TO ASSESS ...

Summary/Conclusion: This Phase 1/2 study shows that a LD 5-day treatment regimen is tolerable and safe with less neutropenia, suggesting that it may be an ...

7.

sciencedirect.com

sciencedirect.com/science/article/abs/pii/S2152265023012065

MDS-641 Randomized Phase 1-2 Study to Assess Safety ...

MDS-641 Randomized Phase 1-2 Study to Assess Safety and Efficacy of Low-Dose (LD) Oral Decitabine/Cedazuridine (ASTX727) in Lower-Risk Myelodysplastic Syndromes ...

8.

thelancet.com

thelancet.com/journals/lanhae/article/PIIS2352-3026(23)00338-1/abstract

Oral decitabine–cedazuridine versus intravenous ...

Primary endpoint of total exposure of oral decitabine–cedazuridine versus intravenous decitabine was 98·93% (90% CI 92·66–105·60), indicating equivalent ...