Study to Evaluate the Pharmacokinetics and Safety of Oral Decitabine and Cedazuridine in Cancer Patients With Hepatic Impairment

Phase 1

Recruiting

• Conditions: Acute Myeloid Leukemia; Myelodysplastic Syndromes
• Interventions: Drug: ASTX727

• Registration Number: NCT04953910
• Lead Sponsor: Taiho Oncology, Inc.

Brief Summary

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 mg and cedazuridine 100 mg in cancer participants with moderate and severe hepatic impairment and cancer participants with normal hepatic function as control subjects. 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 approximately up to 8 weeks.

Detailed Description

Not available

Study Timeline

• Study First Submitted: 2021-06-30
• Study First Submitted QC: 2021-06-30
• Study First Posted: 2021-07-08
• Study Start: 2022-12-23
• Status Verified: 2025-03
• Last Update Submitted: 2025-03-31
• Last Update Posted: 2025-04-02
• Primary Completion: 2026-12
• Study Completion: 2026-12

Recruitment & Eligibility

• Status: RECRUITING
• Sex: All
• Target Recruitment: 27

Inclusion Criteria

• Able to understand and comply with the study procedures, understand the risks involved in the study, and provide legally effective informed consent before the first study-specific procedure; specifically able to comply with the PK assessment schedule during the first treatment cycle.

• Participants must have histologically or cytologically confirmed solid tumor or hematologic malignancy that is metastatic or unresectable and for which standard life-prolonging measures are not available.

• For participants with AML/MDS only:

  1. Cytologically or histologically confirmed diagnosis of AML (except M3 acute promyelocytic leukemia) or MDS according to the 2008 World Health Organization (WHO) classification with the disease being refractory, relapsed, or unresponsive to standard treatment;
  2. Participants with frontline MDS or treatment naïve AML not suitable for induction therapy (eg, age of >75 years, Eastern Cooperative Oncology Group [ECOG] performance status ≥ 2, severe pulmonary disorder, total bilirubin > 1.5x upper limit of normal [ULN]);
  3. Platelet count ≥ 25,000/μL;
  4. Absolute neutrophil count (ANC) ≥ 100 cells/μL.

• For participants with solid tumors only:

  1. Platelet count ≥ 100,000/μL;
  2. ANC ≥ 1000 cells/μL.

• Eastern Cooperative Oncology Group (ECOG) performance status of 0 to 2.

• Hepatic function defined per the National Cancer Institute Cancer Therapy Evaluation Program (NCI CTEP) Organ Dysfunction Working Group (ODWG) as:

  1. Normal hepatic function: total bilirubin ≤1x ULN aspartate aminotransferase (AST): ≤1x ULN;
  2. Moderate hepatic impairment: total bilirubin >1.5x to 3x ULN AST: any value;
  3. Severe hepatic impairment: total bilirubin >3x ULN AST: any value.

• Adequate renal function defined as creatinine clearance (CLcr, according to the Cockcroft-Gault equation) >50mL/min.

• No major surgery within 30 days of first administration of oral decitabine and cedazuridine.

• Life expectancy of at least 3 months.

• Women of childbearing potential (according to recommendations of the Clinical Trial Facilitation Group) must not be pregnant or breastfeeding and must have a negative pregnancy test at Screening.

• Women of childbearing potential must agree to practice 1 highly effective contraceptive measure of birth control with low user dependency and must agree not to become pregnant for 6months after completing treatment

• Male participants with female partners of childbearing potential must agree to use a male condom and advise his partner to practice 1 highly effective contraceptive measure of birth control (user dependent or with low user dependency) and must agree not to father a child while receiving treatment with oral decitabine and cedazuridine and for at least 3 months after completing treatment.

Exclusion Criteria

• Treatment with azacitidine or decitabine within 4 weeks before Screening. Prior cytotoxic chemotherapy for AML except for hydroxyurea to control high white blood cell (WBC) counts.

• Hospitalization for more than 2 days for documented febrile neutropenia, pneumonia, sepsis, or systemic infection 30 days prior to first dose.

• Treatment with any investigational medicinal product (IMP), investigational therapy, chemotherapy, immunotherapy, or targeted therapy within 2 weeks or 5 half-lives, whichever is longer, before the first dose of study treatment, or ongoing clinically significant adverse events from previous treatment.

• Concurrent MDS therapies, including lenalidomide, cyclosporine/tacrolimus, granulocyte-colony-stimulating factor (G-CSF), granulocyte-macrophage colony-stimulating factor, etc. Prior treatment with these agents is permitted, provided that completion is at least 1 week before the first dose of study treatment. Short-term use of G-CSF for febrile neutropenia is permitted at the discretion of the treating physician and should be guided by accepted practice or institutional guidelines. Hematopoietic growth factors will not be routinely used unless cleared by Astex medical expert.

• Administration of live (attenuated) vaccines within 4 weeks before the first administration of oral decitabine and cedazuridine until after the follow-up visit. Other vaccines, eg, inactivated or RNA-based, may be administered but should not occur from 7 days before first administration of oral decitabine and cedazuridine until after the follow-up visit.

• High medical risk because of other conditions such as uncontrolled systemic diseases, active uncontrolled infections, or comorbidities that may put the participant at risk of not being able to complete at least 2 cycles of treatment.

• Conditions which likely promote delayed ventricular repolarization (QT prolongation):

  1. Corrected QT interval (QTc) using Bazett's correction (QTcB) or QTc using Fridericia correction (QTcF) at Screening or Day -1 > 450 ms;
  2. History or disposition for torsades des pointes (TdP) (eg, heart failure, hypokalemia, family history of long QT Syndrome);
  3. Concomitant medication that prolong the QT/QTc interval.

• Cardiac abnormalities or unstable cardiovascular conditions:

  1. Unstable ischemic heart disease or severe heart failure (New York Heart Association Class III or IV);
  2. Uncontrolled treated/untreated hypertension (defined as a mean of 3 repeated measurements for systolic blood pressure ≥ 180 mmHg and/or diastolic blood pressure ≥ 110 mmHg; current or documented history of repeated clinically significant hypotension or severe episodes of orthostatic hypotension (systolic blood pressure < 90 mmHg and/or diastolic blood pressure < 50 mmHg).

• 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 participant to high risk of noncompliance with the protocol.

• In participants with AML/MDS, rapidly progressive or highly proliferative disease or other criteria that render the participant at high risk of requiring intensive cytotoxic chemotherapy within the next 3 months.

• Life-threatening illness or severe organ system dysfunction, such as uncontrolled congestive heart failure or chronic obstructive pulmonary disease, or other reasons including laboratory abnormalities, which, in the investigator's opinion, could compromise the participant's safety, interfere with the absorption or metabolism of oral decitabine and cedazuridine, or compromise completion of the study or integrity of the study outcomes.

• Untreated central nervous system (CNS) metastases. Participants with treated CNS metastases are eligible provided they have been clinically stable for at least 4 weeks before screening.

• Positive nasopharyngeal test for SARS-CoV-2 at Screening or Day -1. Participants may be rescreened if they become SARS-CoV-2 negative.

• Participants infected with human immunodeficiency virus (HIV).

• Positive blood screen for hepatitis C antibody (HCV+) and positive RNA polymerase chain reaction (PCR). Participant can be included if HCV+ but negative for RNA PCR.

• Positive blood screen for hepatitis B surface antigen (HBsAg+). Participants with positive blood screen for hepatitis B surface antibody (HBsAb+) and negative hepatitis B core antibody (HBcAb-) can be included if negative for hepatitis B surface antigen (HBsAg-).

• Average intake of more than 24 units of alcohol per week for male subjects and 17 units per week for female subjects (1 unit of alcohol equals 10 mL of pure alcohol, ie, approximately 250 mL of beer, 75 mL of wine, or 25 mL of spirits).

• Positive drugs of abuse or alcohol test at Screening and Day -1, except for the use of prescribed and medically indicated drugs (eg, benzodiazepines, opiates, or cannabinoids).

• Donation or loss of more than 500 mL of blood within 60 days prior to the first study drug administration.

• Hypersensitivity to decitabine, cedazuridine, or any of the excipients in oral decitabine and cedazuridine.

Study & Design

• Study Type: INTERVENTIONAL
• Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
Group A: Normal hepatic function	ASTX727	Cancer participants with normal hepatic function (total bilirubin ≤ULN; AST ≤ULN)
Group B: Moderate hepatic impairment	ASTX727	Cancer participants with moderate hepatic impairment \[total bilirubin \>1.5X - 3X upper limit of normal (ULN); any aspartate aminotransferase (AST) level\]
Group C: Severe hepatic impairment	ASTX727	Cancer participants with severe hepatic impairment (\>3X ULN; any AST level)

Primary Outcome Measures

Name	Time	Method
Pharmacokinetic Parameter: 5-day Cumulative Area Under the Concentration-time Curve Within 1 Dosing Interval (AUCtau)	Predose and at multiple timepoints post-dose from Day 1 to Day 5	AUCtau from Day 1 to Day 5 for decitabine

Secondary Outcome Measures

Name	Time	Method
Pharmacokinetic Parameter: Apparent Clearance (CL/F)	Predose from Day 1 to Day 5 and at multiple timepoints post-dose from Day 1 to Day 8	CL/F of decitabine, cedazuridine, and cedazuridine-epimer.
Pharmacokinetic Parameter: Renal Clearance (CLR)	Predose from Day 1 to Day 5 and at multiple timepoints post-dose from Day 1 to Day 8	CLR of decitabine, cedazuridine, and cedazuridine-epimer.
Pharmacokinetic Parameter: Apparent Nonrenal Clearance (CLNR/F)	Predose from Day 1 to Day 5 and at multiple timepoints post-dose from Day 1 to Day 8	CLNR/F of decitabine, cedazuridine, and cedazuridine-epimer.
Pharmacokinetic Parameter: Time to Maximum Observed Plasma Concentration (Tmax)	Predose from Day 1 to Day 5 and at multiple timepoints post-dose from Day 1 to Day 8	Tmax of decitabine, cedazuridine, and cedazuridine-epimer.
Pharmacokinetic Parameter: Maximum Observed Plasma Concentration (Cmax)	Predose from Day 1 to Day 5 and at multiple timepoints post-dose from Day 1 to Day 8	Cmax of decitabine, cedazuridine, and cedazuridine-epimer.
Pharmacokinetic Parameter: Area Under the Concentration-time Curve from Time 0 (Time of Dosing) to Time t (AUCt)	Predose from Day 1 to Day 5 and at multiple timepoints post-dose from Day 1 to Day 8	AUCt of decitabine, cedazuridine, and cedazuridine-epimer, where t is the last time point with concentrations above the lower limit of quantitation.
Pharmacokinetic Parameter: Area Under the Concentration-time Curve from Time 0 to 24 Hours (AUC0-24)	Predose and at multiple timepoints post-dose up to 24 hours	AUC0-24 of decitabine, cedazuridine, and cedazuridine-epimer.
Pharmacokinetic Parameter: Area Under the Concentration-time Curve AUC From Time 0 to Infinity (AUC0-inf)	Predose from Day 1 to Day 5 and at multiple timepoints post-dose from Day 1 to Day 8	AUC0-inf of decitabine, cedazuridine, and cedazuridine-epimer.
Pharmacokinetic Parameter: Terminal Elimination Half-life (t1/2)	Predose from Day 1 to Day 5 and at multiple timepoints post-dose from Day 1 to Day 8	t1/2 of decitabine, cedazuridine, and cedazuridine-epimer.
Pharmacokinetic Parameter: Apparent Volume of Distribution During Terminal Phase (Vz/F)	Predose from Day 1 to Day 5 and at multiple timepoints post-dose from Day 1 to Day 8	Vz/F of decitabine, cedazuridine, and cedazuridine-epimer.
Pharmacokinetic Parameter: Fraction of Administered Drug Excreted into Urine (Fe/F))	Predose and at multiple timepoints post-dose up to 24 hours	Fe/F of decitabine, cedazuridine, and cedazuridine-epimer.
Pharmacokinetic Parameter: Cumulative Amount Excreted from Time 0 to the Time of the Last Quantifiable Sample (Aelast)	Predose and at multiple timepoints post-dose up to 24 hours	Aelast of decitabine, cedazuridine, and cedazuridine-epimer.
Safety Parameter: Number of Participants with Adverse Events (AEs)	Up to 8 weeks	Adverse events included any untoward medical occurrence in a participant administered a drug; it does not necessarily have to have a causal relationship with this treatment also including clinically meaningful findings in laboratory safety tests, vital signs, physical examinations, and electrocardiogram (ECG) findings.

Trial Locations

Locations (18)

MD Anderson; 🇺🇸 Houston, Texas, United States

Erebuni Medical Center; 🇦🇲 Yerevan, Armenia

Hematology Center After Prof. R. Yeolyan (Adult Blood Disorders); 🇦🇲 Yerevan, Armenia

Summit Clinical Research s.r.o; 🇸🇰 Bratislava, Slovakia

Hospital Universitari Dexeus - Grupo Quirónsalud; 🇪🇸 Barcelona, Spain

Hospital Universitari Arnau de Vilanova; 🇪🇸 Lleida, Spain

Hematology Center After Prof. R. Yeolyan (Clinic of Adults Oncology); 🇦🇲 Yerevan, Armenia

National Center of Oncology Named After V.A. Fanarjyan; 🇦🇲 Yerevan, Armenia

Complex Oncology Center - Plovdiv - Base II; 🇧🇬 Plovdiv, Bulgaria

BIO1; 🇱🇹 Vilnius, Lithuania

Centrum Badań Klinicznych Piotr Napora Lekarze Sp. p.; 🇵🇱 Wrocław, Poland

Institutul Oncologic Bucuresti - Prof. Dr. Alexandru Trestioreanu; 🇷🇴 Bucharest, Romania

Institutul Oncologic Prof. Dr. Ion Chiricuta; 🇷🇴 Cluj-Napoca, Romania

Hospital Universitario La Paz; 🇪🇸 Madrid, Spain

Hospital Universitario 12 de Octubre; 🇪🇸 Madrid, Spain

Hospital Clínico Universitario Virgen de la Arrixaca (Hematology Dept); 🇪🇸 Murcia, Spain

Hospital Clínico Universitario Virgen de la Arrixaca (Solid Tumor Dept); 🇪🇸 Murcia, Spain

Hospital Universitari i Politècnic La Fe; 🇪🇸 Valencia, Spain