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

NCT00652626 | Completed Phase 1 Results

• 1 other identifier: AZA PH US 2007 PK006
• Study Type: interventional
• Target: 31
• Locations: 1 country
• Sites: 11

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.

Conditions

MDS; AML; Solid Tumors; Multiple Myeloma; Non-Hodgkin's Lymphoma; Hodgkin's Disease

Keywords

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

Outcome Measures

Primary Outcomes (17)

• Area Under the Plasma Concentration-time Curve From Time 0 to 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.

  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

  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.

  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 Infinity

  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.

  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

• Maximum Plasma Concentration of Azacitidine (Cmax)

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

  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

• Time to Maximum Plasma Concentration of Azacitidine (Tmax)

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

  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

• Terminal Phase Half-life of Azacitidine (t½)

  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.

  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

• Apparent Total Clearance of Azacitidine (CL/F)

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

  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

• Apparent Volume of Distribution of Azacitidine (Vz/F)

  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)

  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 After Single and Multiple Doses of Azacitidine

  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.

  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

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

  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.

  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

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

  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.

  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

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

  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.

  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

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

  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.

  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

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

  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.

  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

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

  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.

  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

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

  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).

  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

• Number of Participants With Adverse Events (AEs)

  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).

  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).

Study Arms (5)

Azacitidine 25 mg/m^2

EXPERIMENTAL

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

Azacitidine 50 mg/m^2

EXPERIMENTAL

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

Azacitidine 75 mg/m^2

EXPERIMENTAL

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

Azacitidine 100 mg/m^2

EXPERIMENTAL

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

Severe RI: azacitidine 75 mg/m^2

EXPERIMENTAL

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

Interventions

azacitidine DRUG

Also known as: Vidaza

Azacitidine 100 mg/m^2; Azacitidine 25 mg/m^2; Azacitidine 50 mg/m^2; Azacitidine 75 mg/m^2; Severe RI: azacitidine 75 mg/m^2

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• 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,

You may not qualify if:

• 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

Sponsors & Collaborators

• Celgene: lead

Study Sites (11)

Sutter East Bay Hospitals

Berkeley, California, 94704, United States

Location

Palm Springs Research Institute

Hialeah, Florida, 33012, United States

Location

MCG Cancer Center

Augusta, Georgia, 30912, United States

Location

Joliet Oncology-Hematology Associates, Ltd.

Joliet, Illinois, 60435, United States

Location

University of Kentucky-Markey Cancer Center Clinical Research Organization

Lexington, Kentucky, 40536, United States

Location

Nevada Cancer Institute

Las Vegas, Nevada, 89135, United States

Location

Montefiore Medical Center

The Bronx, New York, 10461, United States

Location

Mid Dakota Clinical P.C. - Cancer Treatment and Research Center

Bismarck, North Dakota, 58501, United States

Location

Gabrail Cancer Center

Canton, Ohio, 44718, United States

Location

Pharma Resource

East Providence, Rhode Island, 02915, United States

Location

Cancer Therapy and Research Center

San Antonio, Texas, 78229, United States

Location

Related Publications (5)

• 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 BACKGROUND

• 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 BACKGROUND

• 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 BACKGROUND

• 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.

  BACKGROUND

• 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 BACKGROUND

MeSH Terms

Conditions

Multiple Myeloma; Lymphoma, Non-Hodgkin; Hodgkin Disease; Renal Insufficiency

Interventions

Azacitidine

Condition Hierarchy (Ancestors)

Neoplasms, Plasma Cell; Neoplasms by Histologic Type; Neoplasms; Hemostatic Disorders; Vascular Diseases; Cardiovascular Diseases; Paraproteinemias; Blood Protein Disorders; Hematologic Diseases; Hemic and Lymphatic Diseases; Hemorrhagic Disorders; Lymphoproliferative Disorders; Immunoproliferative Disorders; Immune System Diseases; Lymphoma; Lymphatic Diseases; Kidney Diseases; Urologic Diseases; Female Urogenital Diseases; Female Urogenital Diseases and Pregnancy Complications; Urogenital Diseases; Male Urogenital Diseases

Intervention Hierarchy (Ancestors)

Aza Compounds; Organic Chemicals; Cytidine; Pyrimidine Nucleosides; Pyrimidines; Heterocyclic Compounds, 1-Ring; Heterocyclic Compounds; Nucleosides; Nucleic Acids, Nucleotides, and Nucleosides; Ribonucleosides

Results Point of Contact

• Title: Associate Director, Clinical Trials Disclosure
• Organization: Celgene Corporation

clinicaltrialdisclosure@celgene.com

1-888-260-1599

Study Officials

• Jay Backstrom, MD

  Celgene Corporation

  STUDY DIRECTOR

Publication Agreements

• PI is Sponsor Employee: No
• Restriction Type: OTHER
• Restrictive Agreement: Yes

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: RANDOMIZED
• Masking: NONE
• Purpose: OTHER
• Intervention Model: PARALLEL
• Sponsor Type: INDUSTRY
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: April 1, 2008
• First Posted: April 4, 2008
• Study Start: November 1, 2008
• Primary Completion: July 1, 2012
• Study Completion: July 1, 2012
• Last Updated: November 19, 2019
• Results First Posted: October 17, 2013

Record last verified: 2019-11

Locations

US (11)