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

• ClinicalTrials.gov Identifier: NCT00652626
• Recruitment Status: Completed
• First Posted: April 4, 2008
• Results First Posted: October 17, 2013
• Last Update Posted: November 19, 2019
• Sponsor: Celgene
• Information provided by (Responsible Party): Celgene

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.

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

Study Design

• Study Type: Interventional (Clinical Trial)
• Actual Enrollment: 31 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: None (Open Label)
• Primary Purpose: Other
• 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
• Actual Study Start Date: November 1, 2008
• Actual Primary Completion Date: July 1, 2012
• Actual Study Completion Date: July 1, 2012

Arms and Interventions

Arm	Intervention/treatment
Experimental: Azacitidine 25 mg/m^2; 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; 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

Outcome Measures

Primary Outcome Measures :

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).

Eligibility Criteria

• Ages Eligible for Study: 18 Years and older (Adult, Older Adult)
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

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

Contacts and Locations

Locations

United States, California

Sutter East Bay Hospitals

Berkeley, 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

Investigators

• Study Director: Jay Backstrom, MD; Celgene Corporation

More Information

Publications:

Wehmeyer J, Zaiss M, Losem C, Schmitz S, Niemeier B, Harde J, Hannig CV, Harich HD, Müller 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.

Platzbecker U, Middeke JM, Sockel K, Herbst R, Wolf D, Baldus CD, Oelschlägel U, Mütherig A, Fransecky L, Noppeney R, Bug G, Götze KS, Krämer A, Bochtler T, Stelljes M, Groth C, Schubert A, Mende M, Stölzel F, Borkmann C, Kubasch AS, von Bonin M, Serve H, Hänel M, Dührsen U, Schetelig J, Röllig C, Kramer M, Ehninger G, Bornhäuser 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.

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.

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.

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.

• Responsible Party: Celgene
• ClinicalTrials.gov Identifier: NCT00652626
• Other Study ID Numbers: AZA PH US 2007 PK006
• First Posted: April 4, 2008
• Results First Posted: October 17, 2013
• Last Update Posted: November 19, 2019
• Last Verified: November 2019

Keywords provided by Celgene:

MDS; AML; Solid Tumors; Azacitidine; PK; Pharmacokinetics; Renal Impairment; Multiple Myeloma; Non-Hodgkin's Lymphoma; Hodgkin's Disease

Additional relevant MeSH terms:

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