Study to Characterize the Effect of Heparin on Palifermin Activity

Study Overview
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Brief Summary
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The purpose of this study is to evaluate the effect of a continuous intravenous infusion of unfractionated heparin on the multiple-dose pharmacodynamics of palifermin in healthy adult subjects.

Detailed Description
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The planned study is designed to characterize the impact of heparin on the biologic activity of palifermin and assess the impact of the combination of palifermin and heparin on tolerability. Approximately forty-three (43) eligible healthy adult men and oophorectomized or postmenopausal women between 18-45 years of age will be assigned to one of three treatment groups where treatment group A will receive a daily dose of palifermin 40 µg/kg for three consecutive days as intravenous (IV) bolus injections and continuous heparin IV infusion, treatment B will receive a daily dose of palifermin 40 µg/kg for three consecutive days as IV bolus injections and treatment C will be a control group without any treatment administered. The subjects will be randomized in a 20:15:8 ratio (Treatment A:B:C). The study consists of a up to 21-days screening period, a 5-days treatment period and a up to 45-days follow-up period.

Official Title
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An Open-label, Randomized, Parallel-Design Study to Characterize the Effect of Heparin on Palifermin Activity in Healthy Adult Subjects

Conditions
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Oral Mucositis

Intervention / Treatment
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* Drug: Palifermin
* Drug: Heparin


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Healthy men or postmenopausal or oophorectomized women. Subjects should have a Body Mass Index between 19 and 30 inclusive. A negative screen for drug abuse, tobacco use and alcohol breath test. Subjects should be willing to be resident in the research facility for up to 6 nights and return to the research facility for scheduled study and follow-up procedures. Men must agree for the duration of the study to use an appropriate method of birth control Exclusion Criteria: History or evidence of clinically significant disorder, condition or disease that would pose a risk to subject safety or interfere with the study evaluation, procedures, or completion. History or evidence of any oral mucosal disease that may affect mucosal keratinocyte proliferation. Evidence or history of thrombocytopenia, heparin-induced thrombocytopenia or other contraindications to heparin (e.g. recent surgeries). Known hypersensitivity to heparin or topical or injectable local anesthetic. Known allergies to Escherichia coli-derived products or allergies to palifermin or its excipients. Use of medications (except vitamins, hormonal replacement therapy and topical medications) within 10 days of admission to research facility. Blood donation within 8 weeks prior to dosing of investigational drug. History of hypertension, clinically significant bleeding, gastrointestinal ulcers, arteriovenous malformation (AVM), aneurysm, or other vascular malformation. History of coagulopathy, bleeding disorders or abnormal platelet counts. History of malignancy of any type, other than surgically excised non-melanoma skin cancers or in situ cervical cancer. For males, past history of epididymitis. Known alcohol abuse or use of illicit drugs within 12 months prior to admission to the research facility. History of smoking or using smokeless tobacco within the past year before admission to the research facility. Any other condition that might reduce the chance of obtaining data (eg, known poor compliance) required by the protocol or that might compromise the ability to give informed consent. Previous participation in a palifermin study.

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 45 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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Accepts Healthy Volunteers

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Palifermin 40 µg/kg and heparin IV infusion<br>Treatment A: palifermin 40 µg/kg/day for three consecutive days as IV bolus injections and continuous heparin IV infusion | Drug: Palifermin<br>* 40 µg/kg IV bolus injections for three consecutive days<br>Drug: Heparin<br>* Heparin continuous IV infusion<br>|
| Experimental: Palifermin 40 µg/kg<br>Treatment B: palifermin 40 µg/kg/day for three consecutive days as IV bolus injections | Drug: Palifermin<br>* 40 µg/kg IV bolus injections for three consecutive days<br>|
| No Intervention: Control group without any treatment<br>Treatment C: control group without any treatment administered. | |

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Ratio to Baseline of Epithelial Cell Proliferation as Assessed by Ki67 Staining of Buccal Mucosal Tissue. | This outcome is a measure of the palifermin effect on the buccal mucosal cells. Ki67 is a measure of proliferation of cells in the buccal mucosa. This measure assess the number of cells per millimeter (mm) before and after palifermin treatment. | Day 4 | 
| Incidence of Grade 2 or Higher Specific Skin-related Adverse Events. | Incidence of grade 2 or higher specific skin-related treatment emergent adverse events following palifermin administration was calculated for subjects in treatment groups A and B. Incidence was calculated by treatment as number of subjects with grade 2 or higher specific skin-related AEs divided by the total number of subjects. The Common Terminology Criteria for Adverse Events (CTCAE v3.0) for Dermatology/Skin was used to determine the toxicity grade for a skin-related adverse event. (http://ctep.cancer.gov/protocolDevelopment/electronic_applications/docs/ctcaev3.pdf) | Day 45 | 
| Ratio to Baseline of Amylase | Ratio to baseline amylase at Day 5 was calculated as Day 5 amylase divided by baseline amylase. | Day 5 | 
| Ratio to Baseline of Lipase. | Ratio to baseline lipase at Day 5 was calculated as Day 5 lipase divided by baseline lipase. | Day 5 | 
| Ratio to Baseline of Protein/Creatinine | Protein/creatinine ratio is the urinary protein (mg) divided by the urinary creatinine (g) result. Ratio to baseline protein/creatinine ratio was calculated as protein/creatinine ratio at specified day divided by baseline protein/creatinine ratio. | Day 4 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Palifermin Pharmacokinetic (PK) Parameters: Clearance (CL) | Blood samples for palifermin PK was collected pre-dose on Days 1 and 3 of the treatment period; 2, 5, 15 and 30 minutes; and 1, 2, 4, 6, 12, 18 and 24 hours after the Day 1 and Day 3 dose of palifermin. Descriptive PK parameters for palifermin CL for subjects assigned to Treatment A and Treatment B was determined by linear/log trapezoidal method. Parameters was calculated from individual subject serum concentration-time data using actual subject blood collection times. Serum concentrations reported below the lower limit of quantification (LLOQ) was treated as zero. | Day 1 | 
| Palifermin PK Parameters: CL | Blood samples for palifermin PK was collected pre-dose on Days 1 and 3 of the treatment period; 2, 5, 15 and 30 minutes; and 1, 2, 4, 6, 12, 18 and 24 hours after the Day 1 and Day 3 dose of palifermin. Descriptive PK parameters for palifermin CL for subjects assigned to Treatment A and Treatment B was determined by linear/log trapezoidal method. Parameters was calculated from individual subject serum concentration-time data using actual subject blood collection times. Serum concentrations reported below the lower limit of quantification (LLOQ) was treated as zero. | Day 3 | 
| Palifermin PK Parameters: Area Under the Serum Curve (AUC) (0-24) | Blood samples for palifermin PK was collected pre-dose on Days 1 and 3 of the treatment period; 2, 5, 15 and 30 minutes; and 1, 2, 4, 6, 12, 18 and 24 hours after the Day 1 and Day 3 dose of palifermin. Descriptive pharmacokinetic parameters for palifermin AUC(0-24) was determined by linear/log trapezoidal method. Parameters was calculated from individual subject serum concentration-time data using actual subject blood collection times. Serum concentrations reported below the lower limit of quantification (LLOQ) was deleted from calculation. | Day 1 | 
| Palifermin PK Parameters: AUC (0-24) | Blood samples for palifermin PK was collected pre-dose on Days 1 and 3 of the treatment period; 2, 5, 15 and 30 minutes; and 1, 2, 4, 6, 12, 18 and 24 hours after the Day 1 and Day 3 dose of palifermin. Descriptive pharmacokinetic parameters for palifermin AUC(0-24) was determined by linear/log trapezoidal method. Parameters was calculated from individual subject serum concentration-time data using actual subject blood collection times. Serum concentrations reported below the lower limit of quantification (LLOQ) was deleted from calculation. | Day 3 | 
| Palifermin PK Parameters: Estimated Concentration at Time 0 (C0) | Blood samples for palifermin PK was collected pre-dose on Days 1 and 3 of the treatment period; 2, 5, 15 and 30 minutes; and 1, 2, 4, 6, 12, 18 and 24 hours after the Day 1 and Day 3 dose of palifermin. Descriptive pharmacokinetic parameters for palifermin C0 was determined by linear/log trapezoidal method. Parameters was calculated from individual subject serum concentration-time data using actual subject blood collection times. Serum concentrations reported below the lower limit of quantification (LLOQ) was treated as zero. | Day 1 | 
| Palifermin PK Parameters: C0 | Blood samples for palifermin PK was collected pre-dose on Days 1 and 3 of the treatment period; 2, 5, 15 and 30 minutes; and 1, 2, 4, 6, 12, 18 and 24 hours after the Day 1 and Day 3 dose of palifermin. Descriptive pharmacokinetic parameters for palifermin C0 was determined by linear/log trapezoidal method. Parameters was calculated from individual subject serum concentration-time data using actual subject blood collection times. Serum concentrations reported below the lower limit of quantification (LLOQ) was treated as zero. | Day 3 | 
| Palifermin PK Parameters: Apparent Volume of Distribution at Steady State (Vss) | Blood samples for palifermin PK was collected pre-dose on Days 1 and 3 of the treatment period; 2, 5, 15 and 30 minutes; and 1, 2, 4, 6, 12, 18 and 24 hours after the Day 1 and Day 3 dose of palifermin (Treatment A and Treatment B only). Descriptive pharmacokinetic parameters for palifermin Vss was determined by linear/log trapezoidal method. Parameters was calculated from individual subject serum concentration-time data using actual subject blood collection times. Serum concentrations reported below the lower limit of quantification (LLOQ) was treated as zero. | Day 1 | 
| Palifermin PK Parameters: Vss | Blood samples for palifermin PK was collected pre-dose on Days 1 and 3 of the treatment period; 2, 5, 15 and 30 minutes; and 1, 2, 4, 6, 12, 18 and 24 hours after the Day 1 and Day 3 dose of palifermin (Treatment A and Treatment B only). Descriptive pharmacokinetic parameters for palifermin Vss was determined by linear/log trapezoidal method. Parameters was calculated from individual subject serum concentration-time data using actual subject blood collection times. Serum concentrations reported below the lower limit of quantification (LLOQ) was treated as zero. | Day 3 | 
| Subject Incidence of Treatment-emergent Adverse Event | Adverse events (AE) was considered treatment emergent if the AE started after the time of heparin titration (Treatment A), palifermin dosing on Day 1 (Treatment B), or set zero point (Treatment C). | Day 45 | 
| Subject Incidence of Proteinuria | Protein/creatinine ratio is the urinary protein (mg) divided by the urinary creatinine (g) result at the specified time point. Incidence of proteinuria defined as urinary protein/creatinine ratio exceeding 200 mg/g was calculated at Day 4 and overall at any time point. Incidence was calculated by treatment as number of subjects with proteinuria divided by the total number of subjects. | Day 4 | 
| Ratio to Baseline of Protein/Creatinine | Protein/creatinine ratio is the urinary protein (mg) divided by the urinary creatinine (g) result. Ratio to baseline protein/creatinine ratio was calculated as protein/creatinine ratio at specified day divided by baseline protein/creatinine ratio. | Day 1 | 
| Ratio to Baseline of Protein/Creatinine | Protein/creatinine ratio is the urinary protein (mg) divided by the urinary creatinine (g) result. Ratio to baseline protein/creatinine ratio was calculated as protein/creatinine ratio at specified day divided by baseline protein/creatinine ratio. | Day 2 | 
| Ratio to Baseline of Protein/Creatinine | Protein/creatinine ratio is the urinary protein (mg) divided by the urinary creatinine (g) result. Ratio to baseline protein/creatinine ratio was calculated as protein/creatinine ratio at specified day divided by baseline protein/creatinine ratio. | Day 3 | 
| Ratio to Baseline of Albumin/Creatinine | The albumin/creatinine ratio is the urinary albumin (mg) divided by the urinary creatinine (g) result at the specified time point. Ratio to baseline was calculated as albumin/creatinine ratio at specified day divided by baseline albumin/creatinine ratio. | Day 1 | 
| Ratio to Baseline of Albumin/Creatinine | The albumin/creatinine ratio is the urinary albumin (mg) divided by the urinary creatinine (g) result at the specified time point. Ratio to baseline was calculated as albumin/creatinine ratio at specified day divided by baseline albumin/creatinine ratio. | Day 2 | 
| Ratio to Baseline of Albumin/Creatinine | The albumin/creatinine ratio is the urinary albumin (mg) divided by the urinary creatinine (g) result at the specified time point. Ratio to baseline was calculated as albumin/creatinine ratio at specified day divided by baseline albumin/creatinine ratio. | Day 3 | 
| Ratio to Baseline of Albumin/Creatinine | The albumin/creatinine ratio is the urinary albumin (mg) divided by the urinary creatinine (g) result at the specified time point. Ratio to baseline was calculated as albumin/creatinine ratio at specified day divided by baseline albumin/creatinine ratio. | Day 4 |