Pharmacokinetics and Safety Study of Azacitidine in Cancer Patients With and Without Impaired Renal Function

Study Overview
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Brief Summary
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The purpose of this study is to evaluate three things. The first being whether azacitidine is absorbed in the body at the same rate or proportion for different concentrations. The second is to determine the effect renal impairment has or does not have on the absorption of azacitidine. The third is to determine if azacitidine is safe and well tolerated in patients with renal function impairment.

Official Title
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A Phase 1, Open-Label, Multi-Center, Parallel Group Study to the Pharmacokinetics and Safety of Subcutaneous Azacitidine in Adult Cancer Patients With and Without Impaired Renal Function

Conditions
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MDS, AML, Solid Tumors, Multiple Myeloma, Non-Hodgkin's Lymphoma, Hodgkin's Disease

Intervention / Treatment
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* Drug: azacitidine


Participation Criteria
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Eligibility Criteria
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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

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Other
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Azacitidine 25 mg/m^2<br>Participants with normal renal function received a single subcutaneous dose of azacitidine 25 mg/m^2 on Day 1. Participants could continue treatment in the extension phase, which allowed up to 6 cycles of treatment with 75 mg/m^2 daily on Days 1-7 of each 28-day cycle. | Drug: azacitidine<br> <br> * Other names: Vidaza;|
| Experimental: Azacitidine 50 mg/m^2<br>Participants with normal renal function received a single subcutaneous dose of azacitidine 50 mg/m^2 on Day 1. Participants could continue treatment in the extension phase, which allowed up to 6 cycles of treatment with 75 mg/m^2 daily on Days 1-7 of each 28-day cycle. | Drug: azacitidine<br> <br> * Other names: Vidaza;|
| Experimental: Azacitidine 75 mg/m^2<br>Participants with normal renal function received subcutaneous doses of azacitidine 75 mg/m^2 on Days 1 to 5. Participants could continue treatment in the extension phase, which allowed up to 6 cycles of treatment with 75 mg/m^2 daily on Days 1-7 of each 28-day cycle. | Drug: azacitidine<br> <br> * Other names: Vidaza;|
| Experimental: Azacitidine 100 mg/m^2<br>Participants with normal renal function received a single subcutaneous dose of azacitidine 100 mg/m^2 on Day 1. Participants could continue treatment in the extension phase, which allowed up to 6 cycles of treatment with 75 mg/m^2 daily on Days 1-7 of each 28-day cycle. | Drug: azacitidine<br> <br> * Other names: Vidaza;|
| Experimental: Severe RI: azacitidine 75 mg/m^2<br>Participants with severe renal impairment (RI; defined as creatinine clearance < 30 mL/min/1.73 m^2) received subcutaneous doses of azacitidine 75 mg/m^2 on Days 1 to 5. Participants could continue treatment in the extension phase, which allowed up to 6 cycles of treatment with 75 mg/m^2 daily on Days 1-7 of each 28-day cycle. | Drug: azacitidine<br> <br> * Other names: Vidaza;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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. | 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. | 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. | 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. | 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. | 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. | 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. | 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) | 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. | Day 1 and Day 5: 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 the Last Quantifiable Time Point After Single and Multiple Doses of Azacitidine | The area under the plasma concentration-time curve from time zero to the last quantifiable time point (AUC0-t) of azacitidine following a single dose (Day 1) and multiple doses (Day 5) was calculated by the linear trapezoidal rule for participants with normal renal function and for participants with severe renal impairment. | Day 1 and Day 5: 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 Infinity After Single and Multiple Doses of Azacitidine | The area under the plasma concentration-time curve from time zero to infinity (AUC0-inf) for azacitidine, after a single dose (Day 1) and multiple doses (Day 5), 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. | Day 1 and Day 5: 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) After Single and Multiple Doses of Azacitidine | The maximum observed plasma concentration of azacitidine after a single dose (Day 1) or multiple doses (Day 5) for participants with normal renal function and for participants with severe renal impairment. | Day 1 and Day 5: 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) After Single and Multiple Doses of Azacitidine | The time to first maximum observed plasma concentration of azacitidine after a single dose (Day 1) or multiple doses (Day 5) for participants with normal renal function and severe renal impairment. | Day 1 and Day 5: 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) After Single and Multiple Doses of Azacitidine | The terminal phase half-life of azacitidine after a single dose (Day 1) or multiple doses (Day 5) for participants with normal renal function and severe renal impairment, calculated according to the following equation: t½ = 0.693/λz, where λz is the terminal phase rate constant. | Day 1 and Day 5: 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) After Single and Multiple Doses of Azacitidine | The apparent total clearance of azacitidine after a single dose (Day 1) and multiple doses (Day 5) for participants with normal renal function and severe renal impairment, calculated as Dose/AUC0-inf. | Day 1 and Day 5: 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) After Single and Multiple Doses of Azacitidine | The apparent volume of distribution of azacitidine after a single dose (Day 1) and multiple doses (Day 5) for participants with normal renal function and severe renal impairment, calculated according to the equation: Vz/F = Apparent total clearance (CL/F) / terminal phase rate constant (λz). | Day 1 and Day 5: predose, 5, 15, 30, 45 minutes and 1, 1.5, 2, 2.5, 3, 3.5, 4, 6, and 8 hours post-dose | 
| Number of Participants With Adverse Events (AEs) | A serious adverse event is one that at any dose of the study drug or at any time during the period of observation: Results in death; Is life threatening; Requires inpatient hospitalization or prolongation of existing hospitalization; Results in persistent or significant disability/incapacity; Is a congenital anomaly/birth defect; Is medically important. The Investigator assessed each AE for potential causal relationship between the event and study drug. The intensity of adverse changes in physical signs or symptoms was graded from 1 to 5 according to the National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE) Version 3, and according to the following: Mild (Grade 1), Moderate (Grade 2), Severe (Grade 3), Life threatening (Grade 4), or Death (Grade 5). | Initial treatment phase: Days 1-11 for participants who received a single dose; Days 1-29 for participants who received multiple doses. Extension treatment period: From the date of first dose until 28 days after the date of last dose (up to 7 months). | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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MDS, AML, Solid Tumors, Azacitidine, PK, Pharmacokinetics, Renal Impairment, Multiple Myeloma, Non-Hodgkin's Lymphoma, Hodgkin's Disease