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

This study has been completed.
Sponsor:
Information provided by (Responsible Party):
Celgene Corporation
ClinicalTrials.gov Identifier:
NCT00652626
First received: April 1, 2008
Last updated: August 2, 2013
Last verified: August 2013
  Purpose

The primary study objectives were:

  • to assess the dose proportionality of azacitidine pharmacokinetics (PK) after single subcutaneous (SC) doses of the drug ranging from 25 to 100 mg/m^2 (Part 1)
  • to determine the effect of renal impairment on azacitidine PK after single and multiple (5 days) SC doses of 75mg/m^2 azacitidine (Part 2)
  • to assess the safety and tolerability of azacitidine given SC in cancer patients with normal renal function (Part 1) and in patients with varying degrees of renal impairment (Part 2).

Condition Intervention Phase
MDS
AML
Solid Tumors
Multiple Myeloma
Non-Hodgkin's Lymphoma
Hodgkin's Disease
Drug: azacitidine
Phase 1

Study Type: Interventional
Study Design: Allocation: Randomized
Endpoint Classification: Pharmacokinetics Study
Intervention Model: Parallel Assignment
Masking: Open Label
Official 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

Resource links provided by NLM:


Further study details as provided by Celgene Corporation:

Primary Outcome Measures:
  • 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 ] [ Designated as safety issue: No ]
    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 [ 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 ] [ Designated as safety issue: No ]
    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.

  • 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 ] [ Designated as safety issue: No ]

    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.


  • 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 ] [ Designated as safety issue: No ]
    The maximum observed plasma concentration of azacitidine after a single dose on Day 1.

  • 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 ] [ Designated as safety issue: No ]
    The time to first maximum observed plasma concentration of azacitidine after a single dose on Day 1.

  • 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 ] [ Designated as safety issue: No ]
    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.

  • 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 ] [ Designated as safety issue: No ]
    The apparent total clearance of azacitidine after a single dose on Day 1, calculated as Dose/AUC0-inf.

  • 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 ] [ Designated as safety issue: No ]
    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)

  • 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 ] [ Designated as safety issue: No ]

    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.


  • 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 ] [ Designated as safety issue: No ]
    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.

  • 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 ] [ Designated as safety issue: No ]

    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.


  • 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 ] [ Designated as safety issue: No ]
    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.

  • 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 ] [ Designated as safety issue: No ]
    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.

  • 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 ] [ Designated as safety issue: No ]
    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.

  • 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 ] [ Designated as safety issue: No ]
    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.

  • 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 ] [ Designated as safety issue: No ]
    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).

  • 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). ] [ Designated as safety issue: Yes ]

    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).



Enrollment: 31
Study Start Date: November 2008
Study Completion Date: July 2012
Primary Completion Date: July 2012 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Experimental: Azacitidine 25 mg/m^2
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. 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
Other Name: Vidaza
Experimental: Azacitidine 50 mg/m^2
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
Other Name: Vidaza
Experimental: Azacitidine 75 mg/m^2
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
Other Name: Vidaza
Experimental: Azacitidine 100 mg/m^2
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
Other Name: Vidaza
Experimental: Severe RI: azacitidine 75 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. 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
Other Name: Vidaza

  Eligibility

Ages Eligible for Study:   18 Years and older
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  • Diagnosis of one of the following:

    • Myelodysplastic syndromes (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)
  • Solid tumor patients with metastatic (except hepatic) or inoperable solid tumors for which no standard treatment existed, or had progressed or recurred following prior therapy. The lack of eligibility for therapy of higher curative potential (where an alternative therapy has been shown to prolong survival in an analogous population).
  • 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 milliequivalents (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.
  • 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 Day 1.
  • Have been treated with an investigational agent within 4 weeks prior to Day 1.
  • Have ongoing clinically significant adverse event(s) due to chemotherapy, radiotherapy or investigational agents administered more than 4 weeks prior to Day 1 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.
  • Have psychiatric illness or alcohol/chemical abuse, which could have prevented granting of informed consent.
  • Have advanced malignant hepatic tumors.
  Contacts and Locations
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT00652626

Locations
United States, California
Sutter East Bay Hospitals
Berkley, California, United States, 94704
United States, Florida
Palm Springs Research Institute
Hialeah, Florida, United States, 33012
United States, Georgia
MCG Cancer Center
Augusta, Georgia, United States, 30912
United States, Illinois
Joliet Oncology-Hematology Associates, Ltd.
Joliet, Illinois, United States, 60435
United States, Kentucky
University of Kentucky-Markey Cancer Center Clinical Research Organization
Lexington, Kentucky, United States, 40536
United States, Nevada
Nevada Cancer Institute
Las Vegas, Nevada, United States, 89135
United States, New York
Montefiore Medical Center
Bronx, New York, United States, 10461
United States, North Dakota
Mid Dakota Clinical P.C. - Cancer Treatment and Research Center
Bismarck, North Dakota, United States, 58501
United States, Ohio
Gabrail Cancer Center
Canton, Ohio, United States, 44718
United States, Rhode Island
Pharma Resource
East Providence, Rhode Island, United States, 02915
United States, Texas
Cancer Therapy and Research Center
San Antonio, Texas, United States, 78229
Sponsors and Collaborators
Celgene Corporation
Investigators
Study Director: CL Beach, PharmD Celgene Corporation
  More Information

No publications provided

Responsible Party: Celgene Corporation
ClinicalTrials.gov Identifier: NCT00652626     History of Changes
Other Study ID Numbers: AZA PH US 2007 PK006
Study First Received: April 1, 2008
Results First Received: August 2, 2013
Last Updated: August 2, 2013
Health Authority: United States: Food and Drug Administration

Keywords provided by Celgene Corporation:
MDS
AML
Solid Tumors
Azacitidine
PK
Pharmacokinetics
Renal Impairment
Multiple Myeloma
Non-Hodgkin's Lymphoma
Hodgkin's Disease

Additional relevant MeSH terms:
Multiple Myeloma
Neoplasms, Plasma Cell
Lymphoma, Non-Hodgkin
Lymphoma
Hodgkin Disease
Renal Insufficiency
Neoplasms by Histologic Type
Neoplasms
Hemostatic Disorders
Vascular Diseases
Cardiovascular Diseases
Paraproteinemias
Blood Protein Disorders
Hematologic Diseases
Hemorrhagic Disorders
Lymphoproliferative Disorders
Immunoproliferative Disorders
Immune System Diseases
Lymphatic Diseases
Kidney Diseases
Urologic Diseases
Azacitidine
Antimetabolites, Antineoplastic
Antimetabolites
Molecular Mechanisms of Pharmacological Action
Pharmacologic Actions
Antineoplastic Agents
Therapeutic Uses
Enzyme Inhibitors

ClinicalTrials.gov processed this record on October 01, 2014