ASTX727 for Myelodysplastic Syndrome

Recruiting at 14 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

Trial Summary

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.

What data supports the effectiveness of the drug ASTX727 (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 combination has been approved by the FDA for use in intermediate/high-risk myelodysplastic syndrome and chronic myelomonocytic leukemia. ^{1 2 3 4 5}

Is ASTX727 (Oral Decitabine and Cedazuridine) safe for humans?

In clinical trials, the most common serious side effects of ASTX727 were low white blood cell counts (neutropenia), low platelet counts (thrombocytopenia), and fever with low white blood cell counts (febrile neutropenia). These side effects were similar to those seen with the intravenous form of decitabine. ^{1 2 3 4 6}

How is the drug ASTX727 unique for treating myelodysplastic syndrome?

ASTX727 is unique because it combines decitabine with cedazuridine, allowing it to be taken orally rather than intravenously. Cedazuridine inhibits an enzyme that would otherwise break down decitabine in the body, improving its availability and making the treatment more convenient for patients. ^{1 2 3 4 5}

What is the purpose of this trial?

This is a Phase 1b, multicenter, open-label, 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 severe renal impairment and cancer participants with normal renal function as matched control participants. 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 per participant is approximately up to 8 weeks.

Eligibility Criteria

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

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

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 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.

Participant Groups

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

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]

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]

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]

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]

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

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

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

Decitabine/Cedazuridine: First Approval. [2021]

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

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

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

The role of decitabine in the treatment of myelodysplastic syndromes. [2019]

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

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