ASTX727 for Myelodysplastic Syndrome

Recruiting at 17 trial locations

Overseen By Taiho Oncology, Inc.

Age: 18+

Sex: Any

Trial Phase: Phase 1

Sponsor: Taiho Oncology, Inc.

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

Disqualifiers: Uncontrolled infections, Heart disease, HIV, others

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

Compensation: Varies

Number of Visits: Unknown

Duration: 8 weeks

18 Participants Needed

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial tests an oral medication combination called Oral Decitabine and Cedazuridine for individuals with certain cancers, such as acute myeloid lymphoma (AML), myelodysplastic syndrome (MDS), or solid tumors. The trial aims to assess the treatment's effects on people with varying kidney functions. Participants will be divided into two groups: those with severe kidney issues and those with normal kidney function. Individuals with these cancers and either severe kidney problems or normal kidney health might be suitable for this study. As a Phase 1 trial, the research focuses on understanding how the treatment works in people, offering participants the opportunity to be among the first to receive this new treatment.

Will I have to stop taking my current medications?

The trial requires that you stop taking certain medications, such as azacitidine or decitabine, at least 4 weeks before starting the study. Other investigational or targeted therapies should be stopped 2 weeks or 5 half-lives before the first dose. Some medications, like those that prolong the QT interval, may also need to be stopped.

Is there any evidence suggesting that this treatment is likely to be safe for humans?

Research has shown that the treatment under study, combining oral decitabine and cedazuridine, has been used to treat myelodysplastic syndromes (MDS). In earlier studies, some patients experienced common side effects like low blood cell counts, which could lead to infections or bleeding. Severe anemia, a condition with insufficient healthy red blood cells, was also reported, and some patients required blood transfusions.

The FDA has approved the treatment for MDS, indicating some confidence in its safety for that condition. However, safety and effectiveness can vary based on the specific health issues being treated. This study aims to assess how patients with different kidney functions respond to the treatment, so researchers are closely monitoring safety. ^{1 2 3 4 5}

Why do researchers think this study treatment might be promising?

Researchers are excited about ASTX727, which combines oral decitabine and cedazuridine, because it offers a novel approach to treating myelodysplastic syndrome (MDS). Unlike traditional treatments that require intravenous administration, ASTX727 can be taken orally, which makes it much more convenient for patients. Additionally, cedazuridine is included to enhance the effectiveness of decitabine by inhibiting the enzyme that breaks it down, potentially leading to better outcomes. This new delivery method and combination could make managing MDS easier and more effective for patients.

What evidence suggests that oral decitabine and cedazuridine might be an effective treatment for myelodysplastic syndrome?

Research has shown that taking decitabine and cedazuridine orally is effective for treating myelodysplastic syndrome (MDS). Studies have found that this oral treatment provides the same level of medication in the body as the intravenous (IV) form, benefiting patients who prefer pills. In one study, 53% of patients with specific genetic changes in their cancer cells responded positively to the treatment. On average, this positive response lasted about 23 months, which is encouraging for long-term management of the condition. Additionally, the oral form simplifies adherence to the treatment plan and can improve quality of life compared to the more demanding IV treatment. Overall, evidence supports the effectiveness of oral decitabine and cedazuridine for MDS.

In this trial, researchers will divide participants into two groups based on renal function to further evaluate the treatment's effectiveness and safety. Group A will include participants with severe renal impairment, while Group B will consist of those with normal renal function. ^{1 5 6 7 8}

Are You a Good Fit for This Trial?

This study is for adults with certain types of blood cancer or solid tumors that can't be removed or have spread, and who can't undergo standard treatments. They must understand the study and agree to its procedures, especially the PK assessment schedule. Participants should not be suitable for induction therapy if they are over 75 years old, have a performance status ≥2, severe lung issues, or high bilirubin levels.

Inclusion Criteria

I haven't had major surgery in the last 30 days.

For participants with AML/MDS only: Cytologically or histologically confirmed diagnosis of AML (except M3 acute promyelocytic leukemia) or MDS according to the 2008 World Health Organization (WHO) classification, Participants with frontline MDS or treatment naïve AML not suitable for induction therapy (e.g., age >75 years, Eastern Cooperative Oncology Group [ECOG] performance ≥2, severe pulmonary disorder, total bilirubin 1.5 X upper limit of normal [ULN]), Platelet count ≥25,000/per microliter (μL), Absolute neutrophil count (ANC) ≥100 cells/μL.

Participants must have a body surface area (BSA)-adjusted CLcr using to the Cockcroft-Gault equation: Participants without renal impairment (Group B): ≥80 mL/min/1.73m², Participants with severe renal impairment (Group A): <30 mL/min/1.73m², not requiring dialysis, CLcr must be stable with <30% deviation allowed from Screening to Baseline (Day -1). Participants shifting outside the prospected renal function category (normal renal function or severe renal function) at Baseline need to be agreed by Taiho medical expert whether they are allowed to remain in the original category that was assessed at Screening.

Exclusion Criteria

History of alcohol abuse or drug addiction (including soft drugs like cannabis products).

Known significant mental illness or other condition, such as active alcohol or other substance abuse or addiction, that in the opinion of the investigator predisposes the participants to high risk of noncompliance with the protocol.

I am not allergic to decitabine, cedazuridine, or their ingredients.

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2 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

What Are the Treatments Tested in This Trial?

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 severe renal impairment compared to those with normal kidney function. It's an open-label Phase 1b study focusing on how the body processes the drug and its safety over approximately eight weeks.

How Is the Trial Designed?

Group I: Group A: Severe Renal Impairment Experimental Treatment 1 Intervention

Cancer participants with severe renal impairment not requiring dialysis (creatinine clearance \[CLcr\] \<30 mL/min/1.73m\^2)

Group II: Group B: Normal Renal Function Active Control 1 Intervention

Cancer participants with normal renal function (CLcr ≥80 mL/min/1.73m\^2)

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

Published Research Related to This Trial

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]

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, a hypomethylating agent, has been shown to improve outcomes in patients with myelodysplastic syndromes (MDS), achieving a 17% overall response rate and 9% complete remissions in a Phase III trial compared to best supportive care.

In high-risk MDS patients, decitabine significantly prolonged the time to transformation to acute myelogenous leukemia or death, indicating its potential to alter the disease's natural history.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

The role of decitabine in the treatment of myelodysplastic syndromes. Atallah, E., Kantarjian, H., Garcia-Manero, G.[2019]

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 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]

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. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC10428441/

S172: PHASE 1/2 STUDY OF ORAL DECITABINE ... In patients with cytogenetic abnormalities at diagnosis, 53% achieved cytogenetic response. The median duration of response was 23 months. After a median follow ...

3. ashpublications.org ashpublications.org/blood/article/144/Supplement%201/6709/528741/Oral-Decitabine-Cedazuridine-Adverse-Effects-and

Oral Decitabine-Cedazuridine: Adverse Effects and ... During treatment with decitabine-cedazuridine, patients experienced an average hemoglobin (Hb) nadir of 6.9 g/dL from a baseline of 9.1 g/dL.

4. 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 ...

5. tandfonline.com tandfonline.com/doi/full/10.1080/14737140.2025.2544859

Oral decitabine and cedazuridine for the treatment of ... Oral DEC-C reduces the burden of treatment compared with IV/SC HMAs, resulting in greater treatment persistence, improved HRQOL, and better clinical outcomes in ...

6. mayoclinic.org mayoclinic.org/drugs-supplements/decitabine-and-cedazuridine-oral-route/description/drg-20490770

Decitabine and cedazuridine (oral route) - Side effects & ... Decitabine and cedazuridine combination is used to treat myelodysplastic syndromes (MDS) ... Safety and efficacy have not been established.

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. fda.gov fda.gov/drugs/resources-information-approved-drugs/fda-approves-oral-combination-decitabine-and-cedazuridine-myelodysplastic-syndromes

FDA approves oral combination of decitabine and ... The most common grade 3 or 4 laboratory abnormalities (≥ 50%) were leukocytes decreased, platelet count decreased, neutrophil count decreased, ...