NCT00652626 - Pharmacokinetics and Safety Study of Azacitidine in Cancer Patients With and Without Impaired Renal Function | Crick

Eligibility

Sex: ALLMin age: 18 Years

Medical Language ↔ Plain English

Inclusion Criteria: * Diagnosis of one of the following: * MDS according to the French-American-British (FAB) classification system: refractory anemia (RA), refractory anemia with ringed sideroblasts (RARS), refractory anemia with excess blasts (RAEB), refractory anemia with excess blasts in transformation (RAEB-T), or chronic myelomonocytic leukemia (CMML); or * Acute myelogenous leukemia (AML) in remission, * Malignant solid tumor, * Multiple myeloma (MM), * Non-Hodgkin lymphoma (NHL), or * Hodgkin lymphoma (HD) * Patients with a history of treated brain metastases should be clinically stable for greater than 4 weeks prior to signing the informed consent form and off glucocorticoid therapy for central nervous system (CNS) edema for at least 4 weeks * Be capable of giving informed consent * Have an Eastern Cooperative Oncology Group (ECOG) performance status of 0-2 * Have a life expectancy ≥ 3 months * Have stable renal function for at least 2 months * Have average calculated creatinine clearance of: * \>80 mL/min/1.73m\^2 for Cohorts 1, 2, 3, and 4 * \<30 mL/min/1.73m\^2 for Cohort 5 - Severe renal impairment, * 50-80 mL/min/1.73m\^2 for Cohort 6 - Mild renal impairment, * 30 to \<50 mL/min/1.73m\^2 for Cohort 7 - Moderate renal impairment * Have organ and marrow function at the screening and pre-dose visits as defined below: * Hemoglobin ≥8 g/dL, * Absolute neutrophil count ≥0.75 x 10\^3/µL, * Platelets ≥30 x 10\^3/µL, * Total bilirubin ≤1.5 times the upper limit of normal (ULN), * Aspartate aminotransferase (AST) ≤2 times the ULN, and * Alanine transaminase (ALT) ≤2 times the ULN; * Have a 12-lead electrocardiogram (ECG) that is not clinically significant, as determined by the Investigator, at screening * Have serum bicarbonate: * 20 mEq/L for patients with normal renal function (cohorts 1, 2, 3 and 4), * 16 mEq/L for patients with impaired renal function (cohorts 5, 6 and 7) * Women of childbearing potential may participate, providing are not pregnant and agree to use at least 2 effective contraceptive methods throughout the study * Males with a female partner of childbearing potential must agree to use at least 2 effective contraceptive methods throughout the study and to avoid fathering a child for 6 months following the date of the last dose of study medication * Be a nonsmoker or must not have smoked for at least 30 days before the screening visit and agree to abstain from smoking during study participation Exclusion Criteria: * Women who are pregnant or nursing; * Had chemotherapy or radiotherapy within 4 weeks (6 weeks for nitrosoureas or mitomycin C) prior to signing informed consent * Have been treated with an investigational agent within 4 weeks prior to signing the informed consent form * Have ongoing clinically significant adverse event(s) due to chemotherapy, radiotherapy or investigational agents administered more than 4 weeks prior to signing the informed consent as determined by the Investigator * Have known or suspected hypersensitivity to azacitidine or mannitol * Have an uncontrolled intercurrent illness including, but not limited to, ongoing or active infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac arrhythmia * Have low blood pressure (supine blood pressure \<90/60 mmHg) * Have human immunodeficiency virus (HIV), or active hepatitis virus B or C * Have advanced malignant hepatic tumors * Have end stage renal disease requiring dialysis

Outcomes

Primary Outcomes

Area Under the Plasma Concentration-time Curve From Time 0 to 8 Hours Post-dose

Area under the plasma concentration-time curve from time 0 to 8 hours post-dose (AUC0-8) of azacitidine following a single dose of azacitidine on Day 1, calculated by the linear trapezoidal rule.

Time frame: Day 1 at predose, 5, 15, 30, 45 minutes and 1, 1.5, 2, 2.5, 3, 3.5, 4, 6, and 8 hours post-dose

Area Under the Plasma Concentration-time Curve From Time Zero to the Last Quantifiable Time Point

Area under the plasma concentration-time curve from time zero to the last quantifiable time point (AUC0-t) of azacitidine following a single dose of azacitidine on Day 1, calculated by the linear trapezoidal rule.

Time frame: Day 1 at predose, 5, 15, 30, 45 minutes and 1, 1.5, 2, 2.5, 3, 3.5, 4, 6, and 8 hours post-dose

Area Under the Plasma Concentration-time Curve From Time Zero to Infinity

The area under the plasma concentration-time curve from time zero to infinity (AUC0-inf) for azacitidine after a single dose, calculated by the linear trapezoidal rule and extrapolated to infinity according to the following equation: AUC0-inf = AUC0-t + (Ct/ke), where Ct is the last quantifiable concentration and ke = elimination rate constant.

Time frame: Day 1 at predose, 5, 15, 30, 45 minutes and 1, 1.5, 2, 2.5, 3, 3.5, 4, 6, and 8 hours post-dose

Maximum Plasma Concentration of Azacitidine (Cmax)

The maximum observed plasma concentration of azacitidine after a single dose on Day 1.

Time frame: Day 1 at predose, 5, 15, 30, 45 minutes and 1, 1.5, 2, 2.5, 3, 3.5, 4, 6, and 8 hours post-dose

Time to Maximum Plasma Concentration of Azacitidine (Tmax)

The time to first maximum observed plasma concentration of azacitidine after a single dose on Day 1.

Time frame: Day 1 at predose, 5, 15, 30, 45 minutes and 1, 1.5, 2, 2.5, 3, 3.5, 4, 6, and 8 hours post-dose

Terminal Phase Half-life of Azacitidine (t½)

The terminal phase half-life of azacitidine after a single dose on Day 1, calculated according to the following equation: t½ = 0.693/λz, where λz is the terminal phase rate constant.

Time frame: Day 1 at predose, 5, 15, 30, 45 minutes and 1, 1.5, 2, 2.5, 3, 3.5, 4, 6, and 8 hours post-dose

Apparent Total Clearance of Azacitidine (CL/F)

The apparent total clearance of azacitidine after a single dose on Day 1, calculated as Dose/AUC0-inf.

Time frame: Day 1 at predose, 5, 15, 30, 45 minutes and 1, 1.5, 2, 2.5, 3, 3.5, 4, 6, and 8 hours post-dose

Apparent Volume of Distribution of Azacitidine (Vz/F)

The apparent volume of distribution of azacitidine after a single dose on Day 1, calculated according to the equation: Vz/F = Apparent total clearance (CL/F) / terminal phase rate constant (λz)

Time frame: Day 1 at predose, 5, 15, 30, 45 minutes and 1, 1.5, 2, 2.5, 3, 3.5, 4, 6, and 8 hours post-dose

Area Under the Plasma Concentration-time Curve From Time 0 to 8 Hours Post-dose After Single and Multiple Doses of Azacitidine

The effect of renal impairment on azacitidine pharmacokinetics was analyzed by comparing PK parameters obtained on Days 1 and 5 from participants with severe renal impairment and those with normal renal function. Area under the plasma concentration-time curve from time 0 to 8 hours post-dose (AUC0-8) of azacitidine following a single dose (Day 1) and multiple doses (Day 5) was calculated by the linear trapezoidal rule.