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

  • STATUS
    Recruiting
  • End date
    Dec 27, 2024
  • participants needed
    27
  • sponsor
    Astex Pharmaceuticals, Inc.
Updated on 4 October 2022
cancer
hematologic malignancy
lymphoma
decitabine
leukemia
acute promyelocytic leukemia
aml/mds

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.

Details
Condition Acute Myeloid Leukemia, Myelodysplastic Syndromes
Treatment ASTX727
Clinical Study IdentifierNCT04953910
SponsorAstex Pharmaceuticals, Inc.
Last Modified on4 October 2022

Eligibility

Yes No Not Sure

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
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
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])
Platelet count ≥ 25,000/μL
Absolute neutrophil count (ANC) ≥ 100 cells/μL
For participants with solid tumors only
Platelet count ≥ 100,000/μL
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
Normal hepatic function: total bilirubin ≤1x ULN aspartate aminotransferase (AST): ≤1x ULN
Moderate hepatic impairment: total bilirubin >1.5x to 3x ULN AST: any value
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)
Corrected QT interval (QTc) using Bazett's correction (QTcB) or QTc using Fridericia correction (QTcF) at Screening or Day -1 > 450 ms
History or disposition for torsades des pointes (TdP) (eg, heart failure, hypokalemia, family history of long QT Syndrome)
Concomitant medication that prolong the QT/QTc interval
Cardiac abnormalities or unstable cardiovascular conditions
Unstable ischemic heart disease or severe heart failure (New York Heart Association Class III or IV)
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
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