A Phase 1b, Open-label, Parallel Group, Multiple-dose Study to Evaluate the Pharmacokinetics, Safety, and Tolerability of Oral Decitabine and Cedazuridine (ASTX727) in Cancer Patients With Moderate and Severe Hepatic Impairment
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.
• 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 malignancy as follows:
‣ A solid tumor that is metastatic or unresectable and for which standard life-prolonging measures are not available.
⁃ AML or MDS.
⁃ A hematologic malignancy other than AML or MDS for which standard life-prolonging measures are not available.
• 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., \>75 years, Eastern Cooperative Oncology Group \[ECOG\] performance status ≥2, severe pulmonary disorder, total bilirubin \>1.5X ULN;
⁃ Platelet count ≥25,000/per microliter (μL);
⁃ Absolute neutrophil count (ANC) ≥100 cells/μL.
• For participants only with hematologic malignancies other than AML or MDS, or with solid tumors:
‣ Platelet count ≥100,000/μL;
⁃ ANC ≥1000 cells/μL.
• 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:
‣ Normal hepatic function (Group A): total bilirubin ≤1X ULN; aspartate aminotransferase (AST): ≤1X ULN;
⁃ Moderate hepatic impairment (Group B): total bilirubin \>1.5X to 3X ULN; AST: any value;
⁃ Severe hepatic impairment (Group C): total bilirubin \>3 times ULN; AST: any value.
• Adequate renal function defined as creatinine clearance (CLcr, according to the Cockcroft-Gault equation) \>50 mL/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.