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NCT00652626 · REGISTRY CONDITION SEARCH

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

Found through the registry condition index, not selected as a treatment recommendation. This discovery collection was restricted to studies with posted results.

Phase
PHASE1
Status at capture
COMPLETED
Registry last update
2019-11-19

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.

Open the original ClinicalTrials.gov record → · Download preserved record

What did the study report?

Outcomes, safety and baseline populations are separate source sections. Quality-of-life measures appear under their original outcome titles.

flow

Participant flow

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baseline

Baseline characteristics

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outcome · POSTED

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

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outcome · POSTED

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

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outcome · POSTED

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

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outcome · POSTED

Maximum Plasma Concentration of Azacitidine (Cmax)

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outcome · POSTED

Time to Maximum Plasma Concentration of Azacitidine (Tmax)

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outcome · POSTED

Terminal Phase Half-life of Azacitidine (t½)

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outcome · POSTED

Apparent Total Clearance of Azacitidine (CL/F)

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outcome · POSTED

Apparent Volume of Distribution of Azacitidine (Vz/F)

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outcome · POSTED

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

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outcome · POSTED

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

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outcome · POSTED

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

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outcome · POSTED

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

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outcome · POSTED

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

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outcome · POSTED

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

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outcome · POSTED

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

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outcome · POSTED

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

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outcome · POSTED

Number of Participants With Adverse Events (AEs)

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adverse events

Adverse events

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more info

Limitations, agreements, and source contact

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Who could take part
eligibility Criteria
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
healthy Volunteers
false
minimum Age
18 Years
sex
ALL
std Ages
  1. ADULT
  2. OLDER_ADULT
Treatment arms and interventions
arm Groups
  1. description
    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.
    intervention Names
    1. Drug: azacitidine
    label
    Azacitidine 25 mg/m^2
    type
    EXPERIMENTAL
  2. description
    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.
    intervention Names
    1. Drug: azacitidine
    label
    Azacitidine 50 mg/m^2
    type
    EXPERIMENTAL
  3. description
    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.
    intervention Names
    1. Drug: azacitidine
    label
    Azacitidine 75 mg/m^2
    type
    EXPERIMENTAL
  4. description
    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.
    intervention Names
    1. Drug: azacitidine
    label
    Azacitidine 100 mg/m^2
    type
    EXPERIMENTAL
  5. description
    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.
    intervention Names
    1. Drug: azacitidine
    label
    Severe RI: azacitidine 75 mg/m^2
    type
    EXPERIMENTAL
interventions
  1. arm Group Labels
    1. Azacitidine 100 mg/m^2
    2. Azacitidine 25 mg/m^2
    3. Azacitidine 50 mg/m^2
    4. Azacitidine 75 mg/m^2
    5. Severe RI: azacitidine 75 mg/m^2
    name
    azacitidine
    other Names
    1. Vidaza
    type
    DRUG
Study design
allocation
RANDOMIZED
intervention Model
PARALLEL
masking Info
masking
NONE
primary Purpose
OTHER
Enrollment
count
31
type
ACTUAL
Registered outcome plans (not posted results)
primary Outcomes
  1. description
    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.
    measure
    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
  2. description
    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.
    measure
    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
  3. description
    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.
    measure
    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
  4. description
    The maximum observed plasma concentration of azacitidine after a single dose on Day 1.
    measure
    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
  5. description
    The time to first maximum observed plasma concentration of azacitidine after a single dose on Day 1.
    measure
    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
  6. description
    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.
    measure
    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
  7. description
    The apparent total clearance of azacitidine after a single dose on Day 1, calculated as Dose/AUC0-inf.
    measure
    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
  8. description
    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)
    measure
    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
  9. description
    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.
    measure
    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
  10. description
    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.
    measure
    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
  11. description
    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.
    measure
    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
  12. description
    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.
    measure
    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
Full study description
brief Summary
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.
Source references
references
  1. citation
    Wehmeyer J, Zaiss M, Losem C, Schmitz S, Niemeier B, Harde J, Hannig CV, Harich HD, Muller J, Klausmann M, Tessen HW, Potthoff K. Impact of performance status and transfusion dependency on outcome of patients with myelodysplastic syndrome, acute myeloid leukemia and chronic myelomonocytic leukemia treated with azacitidine (PIAZA study). Eur J Haematol. 2018 Dec;101(6):766-773. doi: 10.1111/ejh.13160. Epub 2018 Oct 25.
    pmid
    30091166
    type
    BACKGROUND
  2. citation
    Platzbecker U, Middeke JM, Sockel K, Herbst R, Wolf D, Baldus CD, Oelschlagel U, Mutherig A, Fransecky L, Noppeney R, Bug G, Gotze KS, Kramer A, Bochtler T, Stelljes M, Groth C, Schubert A, Mende M, Stolzel F, Borkmann C, Kubasch AS, von Bonin M, Serve H, Hanel M, Duhrsen U, Schetelig J, Rollig C, Kramer M, Ehninger G, Bornhauser M, Thiede C. Measurable residual disease-guided treatment with azacitidine to prevent haematological relapse in patients with myelodysplastic syndrome and acute myeloid leukaemia (RELAZA2): an open-label, multicentre, phase 2 trial. Lancet Oncol. 2018 Dec;19(12):1668-1679. doi: 10.1016/S1470-2045(18)30580-1. Epub 2018 Nov 12.
    pmid
    30442503
    type
    BACKGROUND
  3. citation
    Stevens B, Winters A, Gutman JA, Fullerton A, Hemenway G, Schatz D, Miltgen N, Wei Q, Abbasi T, Vali S, Singh NK, Drusbosky L, Cogle CR, Hammes A, Abbott D, Jordan CT, Smith C, Pollyea DA. Sequential azacitidine and lenalidomide for patients with relapsed and refractory acute myeloid leukemia: Clinical results and predictive modeling using computational analysis. Leuk Res. 2019 Jun;81:43-49. doi: 10.1016/j.leukres.2019.04.005. Epub 2019 Apr 13.
    pmid
    31009835
    type
    BACKGROUND
  4. citation
    Laille E, et al. A 2-Part Phase I Study in Patients with Solid or Hematologic Malignancies: Dose Proportionality of Subcutaneous (SC) Azacitidine (AZA) and Pharmacokinetics of SC AZA in Patients with Severe Renal Impairment . Presented at American Society of Hematology 2011, December 10-13, 2011, San Diego, CA. Abstract No. 3480.
    type
    BACKGROUND
  5. citation
    Du X, Lai YY, Xiao Z, Liu T, Hu Y, Sun A, Li X, Shen ZX, Jin J, Yu L, Laille E, Dong Q, Songer S, Beach CL. Efficacy, safety and pharmacokinetics of subcutaneous azacitidine in Chinese patients with higher risk myelodysplastic syndromes: Results from a multicenter, single-arm, open-label phase 2 study. Asia Pac J Clin Oncol. 2018 Jun;14(3):270-278. doi: 10.1111/ajco.12835. Epub 2017 Dec 28.
    pmid
    29282890
    type
    BACKGROUND
Source notices and limitations
    Discovery and provenance
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    Preserved source evidence · Not medical advice