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

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 Severe Renal Impairment and Cancer Patients With Normal Renal Function

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.

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 a histologically or cytologically confirmed malignancy as follows:

  1. A solid tumor that is metastatic or unresectable and for which standard life-prolonging measures are not available.

     or

  2. AML or MDS. or

  3. A hematologic malignancy other than AML or MDS 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 or
  2. 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 × upper limit of normal [ULN]); or
  3. Platelet count ≥25,000/per microliter (μL); or
  4. Absolute neutrophil count (ANC) ≥100 cells/μL.

• For participants with only hematologic malignancies other than AML or MDS, or solid tumors:

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

• ECOG performance status of 0 to 3.

• Adequate hepatic function defined as:

  1. Total or direct bilirubin ≤1.5X upper limit of normal (ULN); and
  2. Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) ≤2.5X ULN.

• Participants must have a body surface area (BSA)-adjusted CLcr using to the Cockcroft-Gault equation:

  1. Participants without renal impairment (Group B): ≥80 mL/min/1.73m^²;
  2. Participants with severe renal impairment (Group A): <30 mL/min/1.73m^², not requiring dialysis;
  3. CLcr must be stable with <30% deviation allowed from screening to Day -1 (Baseline). Participants shifting outside the prospected renal function category (normal renal function or severe renal function) on Day-1 Baseline need to be agreed by Taiho medical expert whether they are allowed to remain in the original category that was assessed at screening.

• 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 6 months 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 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 Taiho 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, e.g., inactivated or ribonucleic acid (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 participants at risk of not being able to complete 1 cycle of treatment.

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

  1. Corrected QT interval (QTc) using Fridericia's correction (QTcF) at Screening or Day -1 >470 milliseconds (ms) for males and >480 ms for females or
  2. History or disposition for torsades des pointes (TdP) (e.g., heart failure, hypokalemia, family history of long QT Syndrome) or
  3. Concomitant medications 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) or
  2. Uncontrolled treated/untreated hypertension (defined as a mean of 3 repeated measurements for systolic blood pressure ≥ 180 millimeters of mercury (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 participants 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 participants 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, that in the investigator opinion, could compromise the participant 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.

• Participants infected with human immunodeficiency virus (HIV).

• Participants with active hepatitis B or hepatitis C infection.

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

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

• 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.