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

  • STATUS
    Recruiting
  • End date
    Jan 25, 2023
  • participants needed
    18
  • sponsor
    Astex Pharmaceuticals, Inc.
Updated on 25 July 2022
cancer
hematologic malignancy
lymphoma
decitabine
direct bilirubin
leukemia
acute promyelocytic leukemia
aml/mds

Summary

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 mg and cedazuridine 100 mg in cancer participants with severe renal impairment and cancer participants with normal renal function as matched control subjects. 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 IdentifierNCT04953897
SponsorAstex Pharmaceuticals, Inc.
Last Modified on25 July 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
Adequate hepatic function defined as
Total or direct bilirubin ≤1.5 × upper limit of normal (ULN)
AST and alanine aminotransferase (ALT) ≤2.5 × ULN
Participants must have a body surface area (BSA)-adjusted CLcr using to the
Cockcroft-Gault equation
Patients without renal impairment (Group B): ≥80 mL/min/1.73m²
Patients 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). Patients shifting outside the prospected renal function category (normal renal function or severe renal function) at Baseline need to be agreed by Astex 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 patients 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 during the individual screening period
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 patient 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 patient 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 patient 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's opinion, could compromise the patient'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)
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 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 tablets
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