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Completed

NCT Number: NCT00652626

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

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.

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Key information

Conditions

MDS AML Blood Protein Disorders Cardiovascular Diseases Female Urogenital Diseases Female Urogenital Diseases and Pregnancy Complications Hematologic Diseases Hemic and Lymphatic Diseases Hemorrhagic Disorders Hemostatic Disorders Hodgkin Disease Hodgkin's Disease Immune System Diseases Immunoproliferative Disorders Kidney Diseases Lymphatic Diseases Lymphoma Lymphoma, Non-Hodgkin Lymphoproliferative Disorders Male Urogenital Diseases Multiple Myeloma Neoplasms Neoplasms by Histologic Type Neoplasms, Plasma Cell Non-Hodgkin's Lymphoma Paraproteinemias Renal Insufficiency Solid Tumors Urogenital Diseases Urologic Diseases Vascular Diseases

Age range

18 year and older

Sex eligibility

All sexes

Study type

Interventional

Phase

Phase 1

Primary location

Sutter East Bay Hospitals, Berkeley, California, United States

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Who can participate

Healthy volunteers accepted: No

Only the study team can determine whether someone qualifies for participation.

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

Treatment and study plan

Azacitidine

Drug

Other names: Vidaza

Primary outcomes

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

    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 (AUC0-8) of azacitidine following a single dose of azacitidine on Day 1, calculated by the linear trapezoidal rule.

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

    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 (AUC0-t) of azacitidine following a single dose of azacitidine on Day 1, calculated by the linear trapezoidal rule.

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

    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

    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.

  4. Maximum Plasma Concentration of Azacitidine (Cmax)

    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

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

  5. Time to Maximum Plasma Concentration of Azacitidine (Tmax)

    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

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

  6. Terminal Phase Half-life of Azacitidine (t½)

    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

    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.

  7. Apparent Total Clearance of Azacitidine (CL/F)

    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

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

  8. Apparent Volume of Distribution of Azacitidine (Vz/F)

    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

    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)

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

    Time frame: 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

    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.

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

    Time frame: 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

    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.

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

    Time frame: 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

    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.

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

    Time frame: 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

    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.

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

    Time frame: 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

    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.

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

    Time frame: 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

    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.

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

    Time frame: 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

    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.

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

    Time frame: 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

    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).

  17. Number of Participants With Adverse Events (AEs)

    Time frame: 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).

    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).

Sponsors and collaborators

Lead sponsor

Celgene

Industry

Registry information

Official study title

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

Acronym: RENAL

Important dates

Study start
2008
Primary completion
2012
Study completion
2012
First posted
Apr 4, 2008
Registry last updated
Nov 19, 2019

OpenTrials presents study information sourced from ClinicalTrials.gov. The official registry record should be consulted for the latest information.

View the official ClinicalTrials.gov record (opens in a new tab)

This listing is for discovery and informational purposes only. It is not medical advice, does not guarantee that a study is recruiting, and does not determine eligibility. Contact the study team and a qualified healthcare professional when considering participation.

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