Oral Decitabine + Cedazuridine for Myelodysplastic Syndrome

Recruiting at 15 trial locations

Overseen By Taiho Oncology, Inc.

Age: 18+

Sex: Any

Trial Phase: Phase 1

Sponsor: Taiho Oncology, Inc.

Must not be taking: Azacitidine, Decitabine, Lenalidomide, others

Disqualifiers: Uncontrolled infections, HIV, Hepatitis, others

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

Compensation: Varies

Number of Visits: Unknown

Duration: 8 weeks

27 Participants Needed

Trial Summary

Do I need to stop my current medications for the trial?

The trial requires that you stop taking azacitidine or decitabine at least 4 weeks before screening and any investigational or certain other therapies at least 2 weeks before the first dose. Some medications, like those for MDS, must be stopped at least 1 week before the first dose, but short-term use of certain medications like G-CSF is allowed with a doctor's guidance.

What data supports the effectiveness of the drug oral decitabine and cedazuridine for myelodysplastic syndrome?

Research shows that the combination of oral decitabine and cedazuridine is as effective as the intravenous form of decitabine for treating myelodysplastic syndromes, with similar drug exposure and clinical responses. This oral drug has been approved in the USA and Canada for treating myelodysplastic syndromes and chronic myelomonocytic leukemia, offering a convenient alternative to injections. ^{1 2 3 4 5}

Is the combination of oral Decitabine and Cedazuridine safe for humans?

The combination of oral Decitabine and Cedazuridine has been studied for safety in humans, showing similar safety profiles to intravenous Decitabine. Common serious side effects include low white blood cell counts (neutropenia), low platelet counts (thrombocytopenia), and fever with low white blood cell counts (febrile neutropenia). ^{1 3 4 5 6}

What makes the drug oral decitabine and cedazuridine unique for treating myelodysplastic syndrome?

This drug is unique because it combines decitabine, a DNA methyltransferase inhibitor, with cedazuridine, a cytidine deaminase inhibitor, allowing it to be taken orally with similar effectiveness to the intravenous form. This oral administration is more convenient for patients compared to traditional intravenous treatments. ^{1 3 4 5 7}

What is the purpose of this trial?

This is a Phase 1b, multicenter, open-label, pharmacokinetic (PK), and safety study of multiple oral doses of oral decitabine and cedazuridine (formerly known as ASTX727) as a fixed-dose combination of decitabine 35 milligrams (mg) and cedazuridine 100 mg in cancer participants with moderate and severe hepatic impairment and cancer participants with normal hepatic function as control participants. Participants with severe hepatic impairment will be enrolled only after the safety evaluation of at least 6 participants with moderate hepatic impairment has been determined and supports the enrollment of participants with severe hepatic impairment. Adult participants with acute myeloid lymphoma (AML), myelodysplastic syndrome (MDS), or solid tumors who are candidates to receive oral decitabine and cedazuridine will be enrolled in this study. Study duration is per participant approximately up to 8 weeks.

Eligibility Criteria

This trial is for adults with certain types of blood cancer or solid tumors that are advanced and can't be removed by surgery. They should not have other treatment options available. Participants need to understand the study, follow its procedures, and give informed consent. They must have a specific level of platelets and white blood cells, an ECOG performance status from 0 to 2, and either normal liver function or moderate to severe hepatic impairment.

Inclusion Criteria

I understand the study, its risks, and can follow the treatment plan.

Platelet count ≥ 25,000/μL;

Absolute neutrophil count (ANC) ≥ 100 cells/μL.

Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants receive multiple oral doses of decitabine and cedazuridine for pharmacokinetic and safety evaluation

8 weeks

Multiple visits for dosing and monitoring

Follow-up

Participants are monitored for safety and effectiveness after treatment

4 weeks

Treatment Details

Interventions

• Oral Decitabine and Cedazuridine

Trial Overview The trial is testing ASTX727—a combination of oral decitabine (35 mg) and cedazuridine (100 mg)—in patients with varying levels of liver function. It's in Phase 1b, focusing on how the body processes the drug (pharmacokinetics) and safety over approximately up to an eight-week period per participant.

Participant Groups

Group I: Group C: Severe hepatic impairment Experimental Treatment 1 Intervention

Cancer participants with severe hepatic impairment (\>3X ULN; any AST level)

Group II: Group B: Moderate hepatic impairment Experimental Treatment 1 Intervention

Cancer participants with moderate hepatic impairment \[total bilirubin \>1.5X - 3X upper limit of normal (ULN); any aspartate aminotransferase (AST) level\]

Group III: Group A: Normal hepatic function Active Control 1 Intervention

Cancer participants with normal hepatic function (total bilirubin ≤ULN; AST ≤ULN)

Who Is Running the Clinical Trial?

Taiho Oncology, Inc.

Lead Sponsor

Trials

79

Recruited

12,700+

Tim Whitten

Taiho Oncology, Inc.

Chief Executive Officer since 2018

MBA and Pharmacy degree

Harold Keer

Taiho Oncology, Inc.

Chief Medical Officer

MD, PhD

Astex Pharmaceuticals, Inc.

Lead Sponsor

Trials

97

Recruited

7,400+

Dr. Harren Jhoti

Astex Pharmaceuticals, Inc.

Chief Executive Officer since 2007

PhD in Biochemistry from Birkbeck College, London

Dr. Harold N. Keer

Astex Pharmaceuticals, Inc.

Chief Medical Officer since 2020

MD

Findings from Research

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]

Decitabine/cedazuridine (DEC-C) is the first oral hypomethylating agent approved in Canada for treating myelodysplastic syndrome (MDS) and chronic myelomonocytic leukemia (CMML), showing a median overall survival of 21.6 months in a real-world study of 769 patients.

The treatment demonstrated a median progression-free survival of 10.7 months, indicating its potential as an effective and convenient alternative to traditional parenteral therapies, especially for older patients with limited treatment options.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Decitabine/Cedazuridine in the Management of Myelodysplastic Syndrome and Chronic Myelomonocytic Leukemia in Canada. Yun, JP., Ding, PQ., Dolley, A., et al.[2023]

The phase 2 study found that oral cedazuridine/decitabine (100 mg/35 mg) provided similar systemic exposure and DNA demethylation compared to standard IV decitabine (20 mg/m2) in patients with myelodysplastic syndromes or chronic myelomonocytic leukemia, indicating comparable efficacy.

Clinical responses were observed in 60% of patients, with 21% achieving a complete response, while the most common serious side effects included neutropenia (46%) and thrombocytopenia (38%), highlighting the treatment's safety profile.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Oral cedazuridine/decitabine for MDS and CMML: a phase 2 pharmacokinetic/pharmacodynamic randomized crossover study. Garcia-Manero, G., Griffiths, EA., Steensma, DP., et al.[2021]

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]

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]

Inqovi, a combination of decitabine and cedazuridine, was approved by the FDA for treating myelodysplastic syndromes (MDS) based on a phase III study involving 133 adults, showing similar effectiveness to intravenous decitabine.

The treatment demonstrated a complete remission rate of 21% in one study and 18% in another, with a median duration of remission lasting around 7.5 to 8.7 months, while adverse reactions were consistent with those seen in IV decitabine.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

FDA Approval Summary: Decitabine and Cedazuridine Tablets for Myelodysplastic Syndromes. Kim, N., Norsworthy, KJ., Subramaniam, S., et al.[2023]

References

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

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

2. Switzerland pubmed.ncbi.nlm.nih.gov

Decitabine/Cedazuridine in the Management of Myelodysplastic Syndrome and Chronic Myelomonocytic Leukemia in Canada. [2023]

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

Oral cedazuridine/decitabine for MDS and CMML: a phase 2 pharmacokinetic/pharmacodynamic randomized crossover study. [2021]

4. 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]

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

Decitabine/Cedazuridine: First Approval. [2021]

6. Japan pubmed.ncbi.nlm.nih.gov

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

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

FDA Approval Summary: Decitabine and Cedazuridine Tablets for Myelodysplastic Syndromes. [2023]