Study to Evaluate the Safety, Tolerability, Pharmacokinetics and Pharmacodynamics of Single Intravenous and Multiple Subcutaneous and Intravenous Doses of PF-06480605 in Healthy Subjects.

Study Overview
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Brief Summary
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This single and multiple ascending dose study is a first in human assessment of PF-06480605. The goal is to study the safety, tolerability, pharmacokinetics and pharmacodynamics.

Official Title
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A Phase 1, Randomzied, Double-blind, Third-party Open Placebo-controlled, Dose Escalating Study To Evaluate The Safety, Tolerability, Pharmacokinetics And Pharmacodynamics Of Single Intravenous And Multiple Subcutaneous And Intravenous Doses Of Pf-06480605 In Healthy Subjects

Conditions
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Healthy

Intervention / Treatment
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* Drug: PF-06480605
* Drug: Placebo
* Drug: PF-06480605
* Drug: Placebo
* Drug: PF-06480605
* Drug: Placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Healthy male and/or female subjects of non childbearing potential between the ages of 18 and 55 years, inclusive (Healthy is defined as no clinically relevant abnormalities identified by a detailed medical history, full physical examination, including blood pressure and pulse rate measurement, 12 lead ECG and clinical laboratory tests). Female subjects of non childbearing potential must meet at least one of the following criteria: Achieved postmenopausal status, defined as: cessation of regular menses for at least 12 consecutive months with no alternative pathological or physiological cause; and have a serum follicle stimulating hormone (FSH) level within the laboratory's reference range for postmenopausal females; Have undergone a documented hysterectomy and/or bilateral oophorectomy; Have medically confirmed ovarian failure. All other female subjects (including females with tubal ligations and females that do NOT have a documented hysterectomy, bilateral oophorectomy and/or ovarian failure) will be considered to be of childbearing potential. Body Mass Index (BMI) of 17.5 to 30.5 kg/m2; and a total body weight >50 kg (110 lbs). Evidence of a personally signed and dated informed consent document indicating that the subject (or a legal representative) has been informed of all pertinent aspects of the study. X-ray with no evidence of current, active TB or previous inactive TB, general infections, heart failure, malignancy, or other clinically significant abnormalities taken at Screening or within 3 months prior to Day 1 and read by a qualified radiologist. Exclusion Criteria: Evidence or history of clinically significant hematological, renal, endocrine, pulmonary, gastrointestinal, cardiovascular, hepatic, psychiatric, neurologic, or allergic disease (including drug allergies, but excluding untreated, asymptomatic, seasonal allergies at time of dosing). Subjects with a history of or current positive results for any of the following serological tests: Hepatitis B surface antigen (HBsAg), Hepatitis B core antibody (HBcAb), anti Hepatitis C antibody (HCV Ab) or human immunodeficiency virus (HIV). Subjects with a history of autoimmune disorders. Subjects with a history of allergic or anaphylactic reaction to a therapeutic drug. History of tuberculosis or active, latent or inadequately treated tuberculosis infection. Treatment with an investigational drug within 30 days (or as determined by the local requirement, whichever is longer) or 5 half lives or 180 days for biologics preceding the first dose of study medication. Pregnant females; breastfeeding females; and females of childbearing potential.

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 55 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: Basic Science
Allocation: Randomized
Intervention Model: Sequential Assignment
Masking: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: SAD Cohorts 1-8 Experimental Arm<br> | Drug: PF-06480605<br>* Subjects will receive single intravenous doses of 1, 3, 10, 30, 100, 300, 600 or 800 mg of PF-06480605 solution in a dose escalation format.<br>|
| Placebo Comparator: SAD Cohorts 1-8 Placebo Arm<br> | Drug: Placebo<br>* Subjects will receive single intravenous doses of PF-06480605 matching placebo solution in a dose escalation format.<br>|
| Experimental: MAD Cohorts 9-11 Experimental Arm<br> | Drug: PF-06480605<br>* Subjects will receive three subcutaneous doses of 30, 100, or 300 mg of PF-06480605 solution in a dose escalation format of one dose every 2 weeks (q2wk).<br>|
| Placebo Comparator: MAD Cohorts 9-11 Placebo Arm<br> | Drug: Placebo<br>* Subjects will receive three subcutaneous doses of PF-06480605 matching placebo solution in a dose escalation format of one dose every 2 weeks (q2wk).<br>|
| Experimental: MAD Cohort 12 Experimental Arm<br> | Drug: PF-06480605<br>* Subjects will receive three intravenous doses of 500 mg of PF-06480605 solution in a dose escalation format of one dose every 2 weeks (q2wk).<br>|
| Placebo Comparator: MAD Cohort 12 Placebo Arm<br> | Drug: Placebo<br>* Subjects will receive three intravenous doses of PF-06480605 matching placebo solution in a dose escalation format of one dose every 2 weeks (q2wk).<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Incidence of dose limiting or intolerability treatment related adverse events (AEs). |  | 6 weeks | 
| Incidence, severity and causal relationship of treatment emergent AEs (TEAEs) and withdrawals due to treatment emergent adverse events. |  | 6 weeks | 
| Incidence and magnitude of abnormal laboratory findings. |  | 6 weeks | 
| Abnormal and clinically relevant changes in vital signs, blood pressure (BP) and electrocardiogram (ECG) parameters. |  | 6 weeks | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Single Ascending Dose: Maximum Observed Plasma Concentration (Cmax) |  | 6 weeks | 
| Single Ascending Dose: Time to Reach Maximum Observed Plasma Concentration (Tmax) |  | 6 weeks | 
| Single Ascending Dose: Area under the plasma concentration-time profile from time zero to 14 days (AUC14 days) |  | 6 weeks | 
| Single Ascending Dose: Area under the plasma concentration-time profile from time zero extrapolated to infinite time (AUCinf) |  | 6 weeks | 
| Single Ascending Dose: Area under the plasma concentration-time profile from time zero to the time of last quantifiable concentration (AUClast) |  | 6 weeks | 
| Single Ascending Dose: Dose normalized maximum plasma concentration (Cmax[dn]) |  | 6 weeks | 
| Single Ascending Dose: Dose normalized area under the plasma concentration-time profile from time zero extrapolated to infinite time (AUCinf[dn]) |  | 6 weeks | 
| Single Ascending Dose: Dose normalized area under the plasma concentration-time profile from time zero to the time of last quantifiable concentration (AUClast[dn]) |  | 6 weeks | 
| Single Ascending Dose: Plasma Decay Half-Life (t1/2) | Plasma decay half-life is the time measured for the plasma concentration to decrease by one half. | 6 weeks | 
| Single Ascending Dose: Mean residence time(MRT) |  | 6 weeks | 
| Single Ascending Dose: Volume of Distribution at Steady State (Vss) | Volume of distribution is defined as the theoretical volume in which the total amount of drug would need to be uniformly distributed to produce the desired blood concentration of a drug. Steady state volume of distribution (Vss) is the apparent volume of distribution at steady-state. | 6 weeks | 
| Single Ascending Dose: Systemic Clearance (CL) | CL is a quantitative measure of the rate at which a drug substance is removed from the body. | 6 weeks | 
| Multiple Ascending Dose First Dose: Maximum Observed Plasma Concentration (Cmax) |  | 6 weeks | 
| Multiple Ascending Dose First Dose: Time to Reach Maximum Observed Plasma Concentration (Tmax) |  | 6 weeks | 
| Multiple Ascending Dose First Dose: Area under the plasma concentration-time profile from time zero to time τ, the dosing interval where τ=2 weeks (AUCτ) |  | 6 weeks | 
| Multiple Ascending Dose First Dose: Dose normalized maximum plasma concentration (Cmax[dn]) |  | 6 weeks | 
| Multiple Ascending Dose First Dose: Dose normalized Area under the plasma concentration-time profile from time zero to time τ, the dosing interval where τ=2 weeks (AUCτ [dn]) |  | 6 weeks | 
| Plasma Decay Half-Life (t1/2) | Plasma decay half-life is the time measured for the plasma concentration to decrease by one half. | 6 weeks | 
| Multiple Ascending Dose First Dose: Mean residence time (MRT) |  | 6 weeks | 
| Apparent Volume of Distribution (Vz/F) | Volume of distribution is defined as the theoretical volume in which the total amount of drug would need to be uniformly distributed to produce the desired plasma concentration of a drug. Apparent volume of distribution after oral dose (Vz/F) is influenced by the fraction absorbed. | 6 weeks | 
| Multiple Ascending Dose First Dose: Volume of Distribution at Steady State (Vss) | Volume of distribution is defined as the theoretical volume in which the total amount of drug would need to be uniformly distributed to produce the desired blood concentration of a drug. Steady state volume of distribution (Vss) is the apparent volume of distribution at steady-state. | 6 weeks | 
| Multiple Ascending Dose First Dose: Apparent Oral Clearance (CL/F) | Clearance of a drug is a measure of the rate at which a drug is metabolized or eliminated by normal biological processes. Clearance obtained after oral dose (apparent oral clearance) is influenced by the fraction of the dose absorbed. Clearance was estimated from population pharmacokinetic (PK) modeling. Drug clearance is a quantitative measure of the rate at which a drug substance is removed from the blood. | 6 weeks | 
| Multiple Ascending Dose First Dose: Systemic Clearance (CL) | CL is a quantitative measure of the rate at which a drug substance is removed from the body. | 6 weeks | 
| Multiple Ascending Dose Multiple Dose: Maximum Observed Plasma Concentration (Cmax) |  | 6 weeks | 
| Multiple Ascending Dose Multiple Dose: Time to Reach Maximum Observed Plasma Concentration (Tmax) |  | 6 weeks | 
| Multiple Ascending Dose Multiple Dose: Area under the plasma concentration-time profile from time zero to time τ, the dosing interval where τ=2 weeks (AUCτ) |  | 6 weeks | 
| Multiple Ascending Dose Multiple Dose: Dose normalized maximum plasma concentration (Cmax[dn]) |  | 6 weeks | 
| Multiple Ascending Dose Multiple Dose: Dose normalized Area under the plasma concentration-time profile from time zero to time τ, the dosing interval where τ=2 weeks (AUCτ [dn]) |  | 6 weeks | 
| Multiple Ascending Dose Multiple Dose: Plasma Decay Half-Life (t1/2) | Plasma decay half-life is the time measured for the plasma concentration to decrease by one half. | 6 weeks | 
| Multiple Ascending Dose Multiple Dose: Apparent Volume of Distribution (Vz/F) | Volume of distribution is defined as the theoretical volume in which the total amount of drug would need to be uniformly distributed to produce the desired plasma concentration of a drug. Apparent volume of distribution after oral dose (Vz/F) is influenced by the fraction absorbed. | 6 weeks | 
| Multiple Ascending Dose Multiple Dose: Volume of Distribution at Steady State (Vss) | Volume of distribution is defined as the theoretical volume in which the total amount of drug would need to be uniformly distributed to produce the desired blood concentration of a drug. Steady state volume of distribution (Vss) is the apparent volume of distribution at steady-state. | 6 weeks | 
| Multiple Ascending Dose Multiple Dose: Apparent Oral Clearance (CL/F) | Clearance of a drug is a measure of the rate at which a drug is metabolized or eliminated by normal biological processes. Clearance obtained after oral dose (apparent oral clearance) is influenced by the fraction of the dose absorbed. Clearance was estimated from population pharmacokinetic (PK) modeling. Drug clearance is a quantitative measure of the rate at which a drug substance is removed from the blood. | 6 weeks | 
| Multiple Ascending Dose Multiple Dose: Systemic Clearance (CL) | CL is a quantitative measure of the rate at which a drug substance is removed from the body. | 6 weeks | 
| Multiple Ascending Dose Multiple Dose: Minimum Observed Plasma Trough Concentration (Cmin) |  | 6 weeks | 
| Multiple Ascending Dose Multiple Dose: Average concentration at steady state (Cav) |  | 6 weeks | 
| Multiple Ascending Dose Multiple Dose: Observed accumulation ratio (Rac) |  | 6 weeks | 
| Multiple Ascending Dose Multiple Dose: Peak to trough fluctuation (PTF) |  | 6 weeks | 
| Multiple Ascending Dose Additional Parameter: estimate of bioavailability (F) for subcutaneous administration at the corresponding intravenous dose |  | 6 weeks | 
| Immunogenicity for both Single Ascending Dose and Multiple Ascending Dose: Development of anti-drug antibodies (ADA) |  | 6 weeks | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Safety, Phase 1, Randomized, Double-blind, Placebo-controlled, Dose escalating, Single and Multiple doses, Tolerability, PK/PD, PF-06480605