Safety, Pharmacokinetics (PK), And Hematological Activity Of AMD3100 (Plerixafor) In Subjects With Renal Impairment

Study Overview
=================
Brief Summary
-----------------
Eligible male and female subjects with renal impairment (aged 18-78 years) and healthy control subjects (aged 35 to 78 years) will be enrolled in the study. Subjects with renal impairment will be enrolled and entered into three groups based on their renal function: Mild Impairment, Moderate Impairment, and Severe Impairment(not requiring dialysis). Control subjects will have normal renal function. The screening visits will occur within 14 days prior to plerixafor administration on study day one. Subjects will be monitored for 10 hours following administration of the study drug. In addition, subjects will return to the clinic at 24 and 48 hours after plerixafor administration for blood samples and safety assessments.

Detailed Description
-----------------
This is a phase I, open label, multi-center study in which up to eighteen subjects with renal impairment and six healthy control subjects with normal renal function will receive a single dose of plerixafor (240 µg/kg) administered by subcutaneous (SC) injection. Eligible male and female subjects with renal impairment (aged 18-78 years) and healthy control subjects (aged in the upper age range of the renal impairment subjects) will be enrolled in the study. Subjects with renal impairment will be enrolled and stratified into three cohorts using their Screening 24 hour urine collection to measured creatinine clearance (CLcr) values (an estimate of Glomerular Filtration Rate): Mild Impairment (CLcr = 51-80 ml/min), Moderate Impairment (CLcr = 31-50 ml/min), and Severe Impairment (CLcr <31 ml/min, not requiring dialysis). Control subjects will have normal renal function (CLcr >90 ml/min), as determined by a Screening 24 hour urine collection. The screening visits will occur within 14 days prior to plerixafor administration on study day one. Subjects will be monitored for 10 hours following administration of the study drug. In addition, subjects will return to the clinic at 24 and 48 hours after plerixafor administration for blood samples and safety assessments. This study was previously posted by AnorMED, Inc. In November 2006, AnorMED, Inc. was acquired by Genzyme Corporation. Genzyme Corporation is the sponsor of the trial.

Official Title
-----------------
A Phase I Study Of The Safety, Pharmacokinetics, And Hematological Activity Of AMD3100 (240 µg/kg) In Subjects With Renal Impairment

Conditions
-----------------
Renal Impairment

Intervention / Treatment
-----------------
* Drug: plerixafor


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: Signed patient informed consent form prior to any study procedures at Screening. Subject has not consumed alcohol in the 48 hours prior to the administration of study drug. Subject agrees to refrain from consumption of alcohol for the duration of the trial. Subject agrees to practice an approved method of contraception for the duration of the study. White blood cell count ≧3.5*10^9/L. Absolute polymorphonuclear leukocyte count >2.5*10^9/L. Platelet count >125*10^9/L. Serum glutamic oxaloacetic transaminase (SGOT), serum glutamic pyruvic transaminase (SGPT) and total bilirubin <2 times upper limit of normal (ULN). Negative for Human Immunodeficiency Virus (HIV). Age: Renal impairment subjects, 18-78 years. Control subjects, 35-78 years. Creatinine clearance measured from 24-hour urine collection (CLcr u): Renal impairment cohorts, Mild Impairment (CLcr u = 51-80 ml/min), Moderate Impairment (CLcr u = 31-50 ml/min), and Severe Impairment (CLcr u <31 ml/min, not requiring dialysis). Control subjects, CLcr u >90 ml/min. Exclusion Criteria: Known sensitivity to plerixafor or any of its components. Pregnant or breast-feeding. Actual body weight exceeds 175% of ideal body mass index. Subjects judged by the investigator to be at significant risk of failing to comply with the requirements of the protocol. Any subject who has started new medication within 14 days prior to study drug administration. Treatment with an investigational product within 30 days prior to trial entry. Any significant untreated or newly diagnosed medical condition other than renal impairment that in the opinion of the investigator may interfere with the conduct of the study. Abnormal electrocardiogram with clinically significant rhythm disturbance,(ventricular arrhythmias), or other conduction abnormality that in the opinion of the investigator warrants exclusion of the subject from the trial. History of clinically significant thrombocytopenia. Received blood transfusions within 30 days prior to trial entry. Any subject who requires therapeutic intervention within the 30 days prior to administration of study medication in order to meet the inclusion/exclusion criteria. Active malignant/neoplastic disease requiring treatment of any kind. Active infection requiring antibiotics Renal impairment requiring any method of dialysis History of kidney transplant Subjects having clinical status or laboratory parameter deterioration between the time of enrollment and dosing with plerixafor (such that they no longer meet entry criteria) may be removed from the study at the discretion of the treating physician, principal investigator, or sponsor.

Ages Eligible for Study
-----------------
Minimum Age: 18 Years
Maximum Age: 78 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Treatment
Allocation: Non-Randomized
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: Normal renal function<br>Participants with normal renal function (creatinine clearance (CLcr) > 90 ml/min) who serve as the study control. Participants treated with one dose of plerixafor (240 µg/kg) administered by subcutaneous (SC) injection. | Drug: plerixafor<br>* Single dose of plerixafor (240 µg/kg) administered by subcutaneous (SC) injection<br>* Other names: AMD3100;|
| Experimental: Mild renal impairment<br>Participants have mild renal impairment (creatinine clearance (CLcr) = 51 to 80 mL/min). Participants treated with one dose of plerixafor (240 µg/kg) administered by subcutaneous (SC) injection. | Drug: plerixafor<br>* Single dose of plerixafor (240 µg/kg) administered by subcutaneous (SC) injection<br>* Other names: AMD3100;|
| Experimental: Moderate renal impairment<br>Participants have moderate renal impairment (creatinine clearance (CLcr) = 31 to 50 mL/min). Participants treated with one dose of plerixafor (240 µg/kg) administered by subcutaneous (SC) injection. | Drug: plerixafor<br>* Single dose of plerixafor (240 µg/kg) administered by subcutaneous (SC) injection<br>* Other names: AMD3100;|
| Experimental: Severe renal impairment<br>Participants have severe renal impairment (creatinine clearance (CLcr) < 31 mL/min, not requiring dialysis). Participants treated with one dose of plerixafor (240 µg/kg) administered by subcutaneous (SC) injection. | Drug: plerixafor<br>* Single dose of plerixafor (240 µg/kg) administered by subcutaneous (SC) injection<br>* Other names: AMD3100;|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Dose-Normalized Maximum Concentration of Plerixafor (Cmax) | Evaluation of Cmax following a single dose of 240 µg/kg plerixafor administered on Day 1. Cmax was normalized by dose. | Pre-dose of plerixafor to 24 hours post-plerixafor | 
| Dose-Normalized Area Under the Plerixafor Concentration Time Curve From Time 0 to 24 Hours Post-dose (AUC0-24h) | Evaluation of AUC0-24 hour following a single dose of 240 µg/kg plerixafor administered on Day 1. AUC0-24 was normalized by dose. | Pre-dose of plerixafor to 24 hours post-plerixafor | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change From Baseline in Absolute CD34+ Cell Counts at Day 2 | Change in circulating CD34+ cells from baseline to Day 2 (24 hours post-plerixafor) following a single dose of plerixafor. Change from baseline = CD34+ cell count at 24 hours post dose - CD34+ cell count at Baseline. | Baseline, Day 2 | 
| Change From Baseline in Absolute White Blood Cell (WBC) Counts at Day 2 | Change in absolute white blood cells from baseline to Day 2 (24 hours post-plerixafor) following a single dose of plerixafor. Change from baseline = absolute white blood cells at 24 hours post dose - absolute white blood cells at Baseline. | Baseline and Day 2 | 
| Number of Participants in Overall Safety Summary of Adverse Events (TEAE) | Number of participants with adverse events (AEs) collected from Day 1 (post plerixafor administration) to Day 3. AEs were graded by the investigator using the World Health Organization (WHO) Adverse Event Grading Scale and were assessed for severity (mild, moderate, severe, life-threatening) and relatedness to study treatment (5 point scale from 'not related' to 'definitely related'). | up to Day 3 | 

 Terms related to the study
=================
Keywords Provided by Centre Hospitalier Valida
-----------------
AMD3100