Enasidenib + Cedazuridine-Decitabine for Myelodysplastic Syndrome

Recruiting at 77 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

Trial Summary

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.

What data supports the effectiveness of the drug Enasidenib + Cedazuridine-Decitabine for Myelodysplastic Syndrome?

The combination of oral decitabine with cedazuridine has shown similar effectiveness to intravenous decitabine, with overall response rates of 60% and 43% for high-risk myelodysplastic syndromes in phase 2 and 3 trials, respectively. This combination has been approved for use in intermediate/high-risk myelodysplastic syndrome and chronic myelomonocytic leukemia. ^{1 2 3 4 5}

Is the combination of Enasidenib and Decitabine/Cedazuridine safe for humans?

The combination of Decitabine and Cedazuridine has been approved for treating myelodysplastic syndromes (MDS) and chronic myelomonocytic leukemia (CMML) in the USA and Canada, indicating it has been evaluated for safety. However, specific safety data for the combination with Enasidenib is not provided in the available research. ^{1 2 6 7 8}

How is the drug Enasidenib + Cedazuridine-Decitabine unique for treating myelodysplastic syndrome?

This drug combination is unique because it allows decitabine, which is usually given by injection, to be taken orally thanks to cedazuridine, which helps the body absorb it better. This makes treatment more convenient for patients compared to traditional intravenous options. ^{1 2 4 5 6}

What is the purpose of this trial?

This phase II MyeloMATCH treatment trial compares the usual treatment of cedazuridine-decitabine (ASTX727) to the combination treatment of ASTX727 and enasidenib in treating patients with higher-risk, IDH2-mutated myelodysplastic syndrome (MDS). ASTX727 is a combination of two drugs, decitabine and cedazuridine. Cedazuridine is in a class of medications called cytidine deaminase inhibitors. It prevents the breakdown of decitabine, making it more available in the body so that decitabine will have a greater effect. Decitabine is in a class of medications called hypomethylation agents. It works by helping the bone marrow produce normal blood cells and by killing abnormal cells in the bone marrow. Enasidenib is an enzyme inhibitor that may stop the growth of cells by blocking some of the enzymes needed for cell growth. Giving ASTX727 in combination with enasidenib may be effective in treating patients with higher-risk IDH2-mutated MDS.

Research Team

Anand A Patel

Principal Investigator

Alliance for Clinical Trials in Oncology

Eligibility Criteria

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

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

Treatment Details

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.

Participant Groups

Group I: Arm B (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: Arm A (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 Arm B. 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+

Findings from Research

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]

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]

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]

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]

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]

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]

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]

References

1. England 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. [2019]

2. Japan pubmed.ncbi.nlm.nih.gov

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

3. Germany 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). [2018]

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

Role of cedazuridine/decitabine in the management of myelodysplastic syndrome and chronic myelomonocytic leukemia. [2021]

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

Cedazuridine/decitabine: from preclinical to clinical development in myeloid malignancies. [2023]

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

Decitabine/Cedazuridine: First Approval. [2021]

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

Novel agents for myelodysplastic syndromes. [2022]

8. China pubmed.ncbi.nlm.nih.gov

[Efficacy and Safety of Different Dosages of Decitabine in the Treatment of High-Risk Patients with Myelodysplastic Syndrome]. [2021]