First-in-Human Study to Evaluate Safety and Tolerability of Single and Multiple Ascending Doses of Janus Kinase-1 Inhibitor PF-04965842 in Healthy Western and Japanese Subjects

Study Overview
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Brief Summary
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This single- and multiple-ascending dose study is the first evaluation of PF-04965842, a Janus kinase1 (JAK1) inhibitor, in humans. The goal is to assess the safety, tolerability, pharmacokinetics and pharmacodynamics in healthy Western and Japanese subjects.

Official Title
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A Phase 1, Within Cohort, Randomized, Double Blind, Third-Party Open, Placebo-Controlled, Single- And Multiple Dose Escalation, Parallel Group Study To Evaluate The Safety, Tolerability, Pharmacokinetics And Pharmacodynamics Of Pf-04965842 In Healthy Western and Japanese Subjects

Conditions
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Healthy

Intervention / Treatment
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* Drug: PF-04965842
* Drug: Placebo
* Drug: PF-04965842
* Drug: Placebo
* Drug: PF-04965842
* Drug: Placebo
* Drug: PF-04965842
* Drug: Placebo
* Drug: PF-04965842
* Drug: Placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Healthy male and/or female subjects between the ages of 18 and 55 years, inclusive. Females must be of non-child bearing potential and either at least 1 year post menopausal (FSH ≥40 IU/L), or have documented hysterectomy (with or without bilateral oophrectomy) at least 6 months prior to study day Subjects willing to defer receiving prophylactic immunizations (e.g. influenza or pneumococcal vaccines) during the study. Absolute lymphocyte count must be greater than or equal to the lower limit of the laboratory reference range. Subjects enrolled in Cohort 8 must have four Japanese grandparents born in Japan. Exclusion Criteria: Evidence or history of clinically significant hematological, renal, , pulmonary, gastrointestinal, cardiovascular, hepatic, psychiatric, neurologic, or allergic disease (including drug allergies, but excluding untreated, asymptomatic, seasonal allergies at time of dosing). History of hepatitis or positive testing for human immunodeficiency virus (HIV), hepatitis B surface antigen (HBsAg), hepatitis B core antibody (HBc Ab) or hepatitis C antibodies (HCV). Clinically significant abnormality on chest X-ray performed at screening or within 3 months of screening date; or history of tuberculosis or active or latent or inadequately treated infection.

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: Parallel Assignment
Masking: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: SAD Cohorts 1-8 Experimental Arm<br> | Drug: PF-04965842<br>* Subjects will receive single doses of 3, 10, 30, 100, 200, 400, or 800 mg of PF-04695842 (solution or suspension) in a dose escalation format.<br>|
| Placebo Comparator: SAD Cohorts 1-8 Placebo Arm<br> | Drug: Placebo<br>* Subjects will receive single doses of PF-04695842 matching placebo (solution or suspension) in a dose escalation format.<br>|
| Experimental: MAD Cohorts 3 through 5 Experimental Arm<br> | Drug: PF-04965842<br>* Subjects will receive doses of 30, 100 or 200 mg (solution or suspension) once daily for 10 days.<br>|
| Placebo Comparator: MAD Cohorts 3 through 5 Placebo Arm<br> | Drug: Placebo<br>* Subjects will receive PF-04965842 matching placebo (solution or suspension) once daily for 10 days.<br>|
| Experimental: MAD Cohorts 6 and 7 Experimental Arm<br> | Drug: PF-04965842<br>* Subjects will receive doses of 100 or 200 mg (suspension or solution) twice daily for 10 days.<br>|
| Placebo Comparator: MAD Cohorts 6 and 7 Placebo Arm<br> | Drug: Placebo<br>* Subjects will receive PF-04965842 matching placebo doses (suspension or solution) twice daily for 10 days.<br>|
| Experimental: MAD Cohort 8 Experimental Arm<br> | Drug: PF-04965842<br>* Subjects will receive 200 mg dose (suspension or solution) twice daily for 10 days.<br>|
| Placebo Comparator: MAD Cohort 8 Placebo Arm<br> | Drug: Placebo<br>* Subjects will receive PF-04965842 matching placebo dose (suspension or solution) twice daily for 10 days.<br>|
| Experimental: MAD Cohort 9 Experimental Arm<br> | Drug: PF-04965842<br>* Subjects will receive 400 mg dose (suspension or solution) once daily for 10 days.<br>|
| Placebo Comparator: MAD Cohort 9 Placebo Arm<br> | Drug: Placebo<br>* Subjects will receive PF-04965842 matching placebo dose (suspension or solution) once daily for 10 days.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Changes from baseline vital signs (blood pressure, pulse rate, oral temperature and respiration rate) and physical examinations |  | 6 weeks | 
| Changes from baseline in 12 lead ECG parameters | Quantitative changes in ECG intervals | 6 weeks | 
| Incidence and severity of treatment emergent adverse events and withdrawals due to treatment emergent adverse events |  | 6 weeks | 
| Incidence and magnitude of treatment emergent clinical laboratory abnormalities including hematology (with white blood cell count differentials, platelets, PT and aPTT), chemistry, fasting glucose, urinalysis |  | 6 weeks | 
| Change from baseline in immunoglobulin levels | Quantitative IgG, IgA, IgM, and IgE levels | 6 weeks | 
| 24-hour urine creatinine clearance (Single Ascending Dose Period) |  | Baseline, Day 1 | 
| 24-hour urine creatinine clearance (Multiple Ascending Dose Period) |  | Baseline, Day 1 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Complement Level: C3 |  | 6 weeks | 
| Complement Level: C4 |  | 6 weeks | 
| Complement Level: C3A | Cohorts 1-7 and Cohort 9 | 6 weeks | 
| Complement Level: Bb | Cohorts 1-7 and Cohort 9 | 6 weeks | 
| Single Ascending Dose: Dose-normalized Area Under the Curve From Time Zero to Infinity (AUCinf(dn)) |  | 8 days | 
| Multiple Ascending Dose: Accumulation Ratio based on Cmax (Rac(Cmax)) |  | 6 weeks | 
| Urinary Pharmacokinetics; for twice-a-day dosing, amount of PF-0496842 excreted unchanged in 12 hours (AE12) |  | 6 weeks | 
| Urinary Pharmacokinetics; for twice-a-day dosing, percent of PF-0496842 excreted unchanged in 12 hours (AE12%) |  | 6 weeks | 
| Multiple Ascending Dose: Apparent Volume of Distribution at Steady State (Vz/F) | Vz/F is the distribution of a drug between plasma and the rest of the body following oral adminstration. | 6 weeks | 
| Multiple Ascending Dose: Apparent Total Body Clearance (CL/F) |  | 6 weeks | 
| Urinary Pharmacokinetics; for once-a-day dosing, amount of PF-0496842 excreted unchanged in 24 hours (AE24) |  | 6 weeks | 
| Urinary Pharmacokinetics; for once-a-day dosing, percent of PF-0496842 excreted unchanged in 24 hours (AE24%) |  | 6 weeks | 
| Renal Clearance (CLr) |  | 6 weeks | 
| High-Sensitivity C-Reactive Protein (hsCRP) |  | 6 weeks | 
| Neutrophil counts |  | 6 weeks | 
| Reticulocyte counts |  | 6 weeks | 
| Complement Level: CH50 |  | 6 weeks | 
| Single Ascending Dose: Apparent Total Body Clearance (CL/F) |  | 8 days | 
| Multiple Ascending Dose: Maximum Observed Plasma Concentration (Cmax) |  | 6 weeks | 
| Multiple Ascending Dose: Time to Reach Maximum Observed Plasma Concentration (Tmax) |  | 6 weeks | 
| Multiple Ascending Dose: Dose-normalized Maximum Observed Plasma Concentration (Cmax(dn)) |  | 6 weeks | 
| Multiple Ascending Dose: Area Under the Curve to the end of the dosing period (AUCtau(dn)) |  | 6 weeks | 
| Multiple Ascending Dose: Accumulation Ratio based on AUC predicted (Rss) |  | 6 weeks | 
| Multiple Ascending Dose: Accumulation Ration based on AUC observed (Rac) |  | 6 weeks | 
| Multiple 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 | 
| Multiple Ascending Dose: Peak to Trough Fluctuation (PTF) |  | 6 weeks | 
| Single Ascending Dose: Dose-normalized Area Under the Curve to the end of the dosing period (AUCtau(dn)) |  | 8 days | 
| Single Ascending Dose: Area Under the Curve From Time Zero to Infinity (AUCinf) |  | 8 days | 
| Single Ascending Dose: Area Under the Curve From Time Zero to Last Quantifiable Concentration (AUClast) |  | 8 days | 
| Single Ascending Dose: Dose-normalized Maximum Observed Plasma Concentration (Cmax(dn)) |  | 8 days | 
| Single Ascending Dose: Area Under the Curve to the end of the dosing period (AUCtau) |  | 8 days | 
| Single Ascending Dose: Dose-normalized Area Under the Curve From Time Zero to Last Quantifiable Concentration (AUClast(dn)) | Dose-normalized area under the plasma concentration time-curve from zero to the last measured concentration (AUClast(dn)) | 8 days | 
| 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. | 8 days | 
| Multiple Ascending Dose: Area Under the Curve to the end of the dosing period (AUCtau) |  | 6 weeks | 
| Single Ascending Dose: Apparent Volume of Distribution (Vz/F) |  | 8 days | 
| Single Ascending Dose: Maximum Observed Plasma Concentration (Cmax) |  | 8 days | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Phase 1, Randomized, Double Blind, Placebo-Controlled, Single- & Multiple Dose Escalation, Safety, Tolerability, PK, PD, Pf-04965842