Neoplasms

Heart and Blood Diseases

Blood and Lymph Conditions

Immune System Diseases

All Conditions

Urinary Tract, Sexual Organs, and Pregnancy Conditions

Rare Diseases

Multiple Myeloma

Neoplasms, Plasma Cell

Lymphoma

Renal Insufficiency

Hodgkin Disease

Lymphoma, Non-Hodgkin

Neoplasms by Histologic Type

Lymphoproliferative Disorders

Lymphatic Diseases

Immunoproliferative Disorders

Hemostatic Disorders

Blood Coagulation Disorders

Vascular Diseases

Paraproteinemias

Blood Protein Disorders

Hematologic Diseases

Hemorrhagic Disorders

Kidney Diseases

Urologic Diseases

Urogenital Diseases

Female Urogenital Diseases

Pregnancy Complications

Female Urogenital Diseases and Pregnancy Complications

Male Urogenital Diseases

Lymphosarcoma

Hodgkin Lymphoma

Antineoplastic Agents

All Drugs and Chemicals

Azacitidine

Antimetabolites

Enzyme Inhibitors

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.

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.

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.

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.

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.

azacitidine

Jay Backstrom, MD

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.

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

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

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.

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.

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.

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

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

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.

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

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)

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.

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.

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.

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.

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.

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.

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.

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).

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).

Celgene

Participants with normal renal function (defined as creatinine clearance \> 80 mL/min/1.73m\^2) received a single subcutaneous dose of azacitidine 25 mg/m\^2 on Day 1.

Azacitidine 25 mg/m^2

Participants with normal renal function received a single subcutaneous dose of azacitidine 50 mg/m\^2 on Day 1.

Azacitidine 50 mg/m^2

Participants with normal renal function received subcutaneous doses of azacitidine 75 mg/m\^2 on Days 1 to 5.

Azacitidine 75 mg/m^2

Participants with normal renal function received a single subcutaneous dose of azacitidine 100 mg/m\^2 on Day 1.

Azacitidine 100 mg/m^2

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.

Severe RI: Azacitidine 75 mg/m^2

Participants with normal renal function (RF) received up to 6 cycles of treatment with 75 mg/m\^2 azacitidine daily on Days 1-7 of each 28-day cycle.

Extension Phase: Normal RF

Participants with severe renal impairment (RI) received up to 6 cycles of treatment with 75 mg/m\^2 azacitidine daily on Days 1-7 of each 28-day cycle.

Extension Phase: Severe RI

Total

Initial Treatment Period

Extension Treatment Period

Age, Continuous

Female

Male

Data provided for initial treatment phase groups only.

Sex/Gender, Customized

Black

White

Race/Ethnicity, Customized

United States

Region of Enrollment

Gender of Extension Period Participants

Race: Extension Phase

Scale used by doctors and researchers to assess how a patient's disease is progressing, assess how the disease affects the daily living abilities of the patient, and determine appropriate treatment and prognosis. 0 = fully active, no restrictions; 1 = restricted but ambulatory and capable of light work; 2 = ambulatory and capable of self-care but unable to work. 3 = Capable of only limited self care, confined to bed or chair more than 50% of waking hours. 4 = Completely disabled. Cannot carry on any self care. Totally confined to bed or chair. 5 = Dead.

Eastern Cooperative Oncology Group (ECOG) Performance Status: Initial Treatment Phase

Eastern Cooperative Oncology Group (ECOG) Performance Status: Extension Phase

Extension Period

Body Surface Area (BSA)

Myelodysplastic syndrome-RA

Myelodysplastic syndrome-RARS

Myelodysplastic syndrome-RAEB-T

Chronic myelomonocytic leukemia

Solid tumor

Multiple myeloma

MDS = myelodysplastic syndrome; MM = multiple myeloma; RA = refractory anemia; RAEB-T = refractory anemia with excess blasts in transformation; RARS = refractory anemia with ringed sideroblasts; CMML = chronic myelomonocytic leukemia.

Cancer Diagnosis: Initial Treatment Phase

Cancer Diagnosis: Extension Phase

Safety population. The total number of participants in the study was 27; 18 continued treatment in the extension phase.

Associate Director, Clinical Trials Disclosure

Pharmacokinetic (PK) Population, consisting of all participants with evaluable plasma or urine concentration data for azacitidine. This analysis was performed for participants with normal renal function only.

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

Geometric means, ratio and 90% confidence interval (CI) of ratio of geometric means are from one way analysis of variance models on the nature log-transformed dose-normalized AUC0-t, obtained on Day 1. Azacitidine 25 mg/m\^2 is the reference group for comparisons

Geometric means, ratio and 90% CI of ratio of geometric means are from one way analysis of variance models on the nature log-transformed dose-normalized AUC0-t, obtained on Day 1. Azacitidine 25 mg/m\^2 is the reference group for comparisons

Pharmacokinetic Population, consisting of all participants with evaluable plasma or urine concentration data for azacitidine. This analysis was performed for participants with normal renal function only.

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

Geometric means, ratio and 90% CI of ratio of geometric means are from one way analysis of variance models on the nature log-transformed dose-normalized AUC0-inf, obtained on Day 1. Azacitidine 25 mg/m\^2 is the reference group for comparisons.

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

Geometric means, ratio and 90% CI of ratio of geometric means are from one way analysis of variance models on the nature log-transformed dose-normalized Cmax, obtained on Day 1. Azacitidine 25 mg/m\^2 is the reference group for comparisons

Maximum Plasma Concentration of Azacitidine (Cmax)

Time to Maximum Plasma Concentration of Azacitidine (Tmax)

Terminal Phase Half-life of Azacitidine (t½)

Geometric means, ratio and 90% CI of ratio of geometric means are from one way analysis of variance model on the nature log-transformed CL/F obtained on Day 1. Azacitidine 25 mg/m\^2 is the reference group for comparisons.

Apparent Total Clearance of Azacitidine (CL/F)

Apparent Volume of Distribution of Azacitidine (Vz/F)

Day 1

Day 5

Participants with normal renal function (RF) received subcutaneous doses of azacitidine 75 mg/m\^2 on Days 1 to 5.

Normal RF: Azacitidine 75 mg/m^2

Participants with severe renal impairment (RI) received subcutaneous doses of azacitidine 75 mg/m\^2 on Days 1 to 5.

Pharmacokinetic Population, consisting of all participants with evaluable plasma or urine concentration data for azacitidine. This analysis was performed for participants in the 2 treatment groups who received azacitidine treatment for 5 days.

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

Comparison of AUC0-t after a single dose (Day 1) in participants with normal renal function and participants with severe renal impairment.

Geometric means, ratio and 90% CI of ratio of geometric means are from an analysis of variance model with renal function group (normal and severe), visit (Day 1 and Day 5), renal function group by visit interaction as fixed effect, and patient nested within renal function group as a random effect on the nature log-transformed pharmacokinetic parameters

Comparison of AUC0-t after multiple doses (Day 5) in participants with normal renal function and participants with severe renal impairment.

Geometric means, ratio and 90% CI of ratio of geometric means are from an analysis of variance model with renal function group (normal and severe), visit (Day 1 and Day 5), renal function group by visit interaction as fixed effect, and patient nested within renal function group as a random effect on the nature log-transformed pharmacokinetic parameters.

Area Under the Plasma Concentration-time Curve From Time 0 to the Last Quantifiable Time Point After Single and Multiple Doses of Azacitidine

Comparison of AUC0-inf after a single dose (Day 1) in participants with normal renal function and participants with severe renal impairment.

Geometric means, ratio and 90% CI of ratio of geometric means are from an analysis of variance model with renal function group (normal and severe), visit (Day 1 and Day 5), renal function group by visit interaction as fixed effect, and patient nested within renal function group as a random effect on the nature log-transformed pharmacokinetic parameters.

Comparison of AUC0-inf after multiple doses (Day 5) in participants with normal renal function and participants with severe renal impairment.

Geometric means, ratio and 90% CI of ratio of geometric means are from an analysis of variance model with renal function group (normal and severe), visit (Day 1 and Day 5), renal function group by visit interaction as fixed effect, and patient nested within renal function group as a random effect on the nature log-transformed pharmacokinetic parameters.

Area Under the Plasma Concentration-time Curve From Time 0 to Infinity After Single and Multiple Doses of Azacitidine

Comparison of Cmax after a single dose (Day 1) in participants with normal renal function and participants with severe renal impairment.

Geometric means, ratio and 90% CI of ratio of geometric means are from an analysis of variance model with renal function group (normal and severe), visit (Day 1 and Day 5), renal function group by visit interaction as fixed effect, and patient nested within renal function group as a random effect on the nature log-transformed pharmacokinetic parameters.

Comparison of Cmax after multiple doses (Day 5) in participants with normal renal function and participants with severe renal impairment.

Geometric means, ratio and 90% CI of ratio of geometric means are from an analysis of variance model with renal function group (normal and severe), visit (Day 1 and Day 5), renal function group by visit interaction as fixed effect, and patient nested within renal function group as a random effect on the nature log-transformed pharmacokinetic parameters.

Maximum Plasma Concentration of Azacitidine (Cmax) After Single and Multiple Doses of Azacitidine

Comparison of Tmax after a single dose (Day 1) in participants with normal renal function and participants with severe renal impairment.

Comparison of Tmax after multiple doses (Day 5) in participants with normal renal function and participants with severe renal impairment.

Time to Maximum Plasma Concentration of Azacitidine (Tmax) After Single and Multiple Doses of Azacitidine

Terminal Phase Half-life of Azacitidine (t½) After Single and Multiple Doses of Azacitidine

Apparent Total Clearance of Azacitidine (CL/F) After Single and Multiple Doses of Azacitidine

Apparent Volume of Distribution of Azacitidine (Vz/F) After Single and Multiple Doses of Azacitidine

Any adverse event

Adverse event related to study drug

Serious adverse event

Serious adverse event related to study drug

Grade 3 or 4 adverse event

AE leading to study drug discontinuation

AE leading to study drug interruption

AE leading to a dose reduction

AE leading to other action taken

Death

Safety population, all enrolled patients who received at least one dose of azacitidine and who had at least one post-treatment safety assessment.

Spots Global Cancer Trial Database for Pharmacokinetics and Safety Study of Azacitidine in Cancer Patients With and Without Impaired Renal Function

Trial Identification

Conditions

Interventions

Study Description

Keywords

Eligibility

Locations

Contact Details

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