Clinical trial NCT00652626: Pharmacokinetics and Safety Study of Azacitidine in Cancer Patients With and Without Impaired Renal Function
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
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE1
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
Lead sponsor: Celgene
Sponsor class: INDUSTRY
First posted: 2008-04-04
Enrollment: 31
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: OTHER

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.


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

Primary outcomes:
measure: Area Under the Plasma Concentration-time Curve From Time 0 to 8 Hours Post-dose
timeFrame: 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
measure: Area Under the Plasma Concentration-time Curve From Time Zero to the Last Quantifiable Time Point
timeFrame: 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
measure: Area Under the Plasma Concentration-time Curve From Time Zero to Infinity
timeFrame: 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
measure: Maximum Plasma Concentration of Azacitidine (Cmax)
timeFrame: 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
measure: Time to Maximum Plasma Concentration of Azacitidine (Tmax)
timeFrame: 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
measure: Terminal Phase Half-life of Azacitidine (t½)
timeFrame: 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
measure: Apparent Total Clearance of Azacitidine (CL/F)
timeFrame: 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
measure: Apparent Volume of Distribution of Azacitidine (Vz/F)
timeFrame: 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
measure: Area Under the Plasma Concentration-time Curve From Time 0 to 8 Hours Post-dose After Single and Multiple Doses of Azacitidine
timeFrame: 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
measure: Area Under the Plasma Concentration-time Curve From Time 0 to the Last Quantifiable Time Point After Single and Multiple Doses of Azacitidine
timeFrame: 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
measure: Area Under the Plasma Concentration-time Curve From Time 0 to Infinity After Single and Multiple Doses of Azacitidine
timeFrame: 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
measure: Maximum Plasma Concentration of Azacitidine (Cmax) After Single and Multiple Doses of Azacitidine
timeFrame: 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
measure: Time to Maximum Plasma Concentration of Azacitidine (Tmax) After Single and Multiple Doses of Azacitidine
timeFrame: 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
measure: Terminal Phase Half-life of Azacitidine (t½) After Single and Multiple Doses of Azacitidine
timeFrame: 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
measure: Apparent Total Clearance of Azacitidine (CL/F) After Single and Multiple Doses of Azacitidine
timeFrame: 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
measure: Apparent Volume of Distribution of Azacitidine (Vz/F) After Single and Multiple Doses of Azacitidine
timeFrame: 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
measure: Number of Participants With Adverse Events (AEs)
timeFrame: 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).
Secondary outcomes:
Other outcomes:
Locations:
city: Berkeley
country: United States
facility: Sutter East Bay Hospitals
state: California
city: Hialeah
country: United States
facility: Palm Springs Research Institute
state: Florida
city: Augusta
country: United States
facility: MCG Cancer Center
state: Georgia
city: Joliet
country: United States
facility: Joliet Oncology-Hematology Associates, Ltd.
state: Illinois
city: Lexington
country: United States
facility: University of Kentucky-Markey Cancer Center Clinical Research Organization
state: Kentucky
city: Las Vegas
country: United States
facility: Nevada Cancer Institute
state: Nevada
city: Bronx
country: United States
facility: Montefiore Medical Center
state: New York
city: Bismarck
country: United States
facility: Mid Dakota Clinical P.C. - Cancer Treatment and Research Center
state: North Dakota
city: Canton
country: United States
facility: Gabrail Cancer Center
state: Ohio
city: East Providence
country: United States
facility: Pharma Resource
state: Rhode Island
city: San Antonio
country: United States
facility: Cancer Therapy and Research Center
state: Texas
Study officials:
affiliation: Celgene Corporation
name: Jay Backstrom, MD
role: STUDY_DIRECTOR
References:
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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.
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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.
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.