Safety and Tolerability Study Of PF-06835375 In Subjects With Seropositive Systemic Lupus Erythematosus Or Rheumatoid Arthritis

Study Overview
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Brief Summary
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This is a Phase 1 single and multiple dose escalation study to evaluate the safety, tolerability, pharmacokinetics, and pharmacodynamics of PF-06835375 in subjects with seropositive SLE or RA. The design is double-blind, sponsor open and placebo controlled. This study will include two parts: Part A and Part B. Part A will consist of single ascending dose cohorts, Part B of multiple ascending dose cohorts. This study will enroll up to a total of approximately 112 subjects at approximately 10 sites.

Official Title
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A PHASE 1, RANDOMIZED, MULTI-CENTER, DOUBLE-BLIND, SPONSOR OPEN, PLACEBO-CONTROLLED, SINGLE AND MULTIPLE DOSE-ESCALATION STUDY TO EVALUATE THE SAFETY, TOLERABILITY, PHARMACOKINETICS AND PHARMACODYNAMICS OF PF-06835375 IN SUBJECTS WITH SEROPOSITIVE SYSTEMIC LUPUS ERYTHEMATOSUS OR RHEUMATOID ARTHRITIS

Conditions
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Systemic Lupus Erythematosus, Rheumatoid Arthritis

Intervention / Treatment
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* Drug: PF-06835375
* Drug: Placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Patients with Rheumatoid Arthritis: confirmed diagnosis according to 2010 ACR/EULAR criteria with symptom duration at least 6 months and positive with Rheumatoid Factor and/or anti citrullinated peptide antibody Patients with Systemic Lupus Erythematosus: Confirmed diagnosis according to the SLICC Classification Criteria with symptom duration at least 6 months and at least one of the following: positive antinuclear antibody titer, positive anti-dsDNA, anti-Smith antibodies Exclusion Criteria: Active central nervous system manifestations, systemic vasculitis or pleuro/pericarditis Active lupus nephritis Treatment with B cell depleting agents within 52 weeks prior to screening

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 70 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

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: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Part A, Cohort 1<br>Subjects will receive a single dose of PF-06835375 or placebo on Day 1 via intravenous administration | Drug: PF-06835375<br>* Intravenous (IV) or subcutaneous (SC) administration. Subjects will receive one or two doses. Doses will be ascending and determined by emerging data.<br>Drug: Placebo<br>* Matching placebo for PF-06835375 IV or SC. Subjects will receive one or two doses.<br>|
| Experimental: Part A, Cohort 2<br>Subjects will receive a single dose of PF-06835375 or placebo on Day 1 via intravenous administration. | Drug: PF-06835375<br>* Intravenous (IV) or subcutaneous (SC) administration. Subjects will receive one or two doses. Doses will be ascending and determined by emerging data.<br>Drug: Placebo<br>* Matching placebo for PF-06835375 IV or SC. Subjects will receive one or two doses.<br>|
| Experimental: Part A, Cohort 3<br>Subjects will receive a single dose of PF-06835375 or placebo on Day 1 via intravenous administration. | Drug: PF-06835375<br>* Intravenous (IV) or subcutaneous (SC) administration. Subjects will receive one or two doses. Doses will be ascending and determined by emerging data.<br>Drug: Placebo<br>* Matching placebo for PF-06835375 IV or SC. Subjects will receive one or two doses.<br>|
| Experimental: Part A, Cohort 4<br>Subjects will receive a single dose of PF-06835375 or placebo on Day 1 via intravenous administration. | Drug: PF-06835375<br>* Intravenous (IV) or subcutaneous (SC) administration. Subjects will receive one or two doses. Doses will be ascending and determined by emerging data.<br>Drug: Placebo<br>* Matching placebo for PF-06835375 IV or SC. Subjects will receive one or two doses.<br>|
| Experimental: Part A, Cohort 5<br>Subjects will receive a single dose of PF-06835375 or placebo on Day 1 via intravenous administration. | Drug: PF-06835375<br>* Intravenous (IV) or subcutaneous (SC) administration. Subjects will receive one or two doses. Doses will be ascending and determined by emerging data.<br>Drug: Placebo<br>* Matching placebo for PF-06835375 IV or SC. Subjects will receive one or two doses.<br>|
| Experimental: Part A, Cohort 6<br>Subjects will receive a single dose of PF-06835375 or placebo on Day 1 via intravenous administration. | Drug: PF-06835375<br>* Intravenous (IV) or subcutaneous (SC) administration. Subjects will receive one or two doses. Doses will be ascending and determined by emerging data.<br>Drug: Placebo<br>* Matching placebo for PF-06835375 IV or SC. Subjects will receive one or two doses.<br>|
| Experimental: Part A, Cohort 7<br>Subjects will receive a single dose of PF-06835375 or placebo on Day 1 via intravenous administration. | Drug: PF-06835375<br>* Intravenous (IV) or subcutaneous (SC) administration. Subjects will receive one or two doses. Doses will be ascending and determined by emerging data.<br>Drug: Placebo<br>* Matching placebo for PF-06835375 IV or SC. Subjects will receive one or two doses.<br>|
| Experimental: Part A, Cohort 8<br>Subjects will receive a single dose of PF-06835375 or placebo on Day 1 via intravenous administration. | Drug: PF-06835375<br>* Intravenous (IV) or subcutaneous (SC) administration. Subjects will receive one or two doses. Doses will be ascending and determined by emerging data.<br>Drug: Placebo<br>* Matching placebo for PF-06835375 IV or SC. Subjects will receive one or two doses.<br>|
| Experimental: Part B, Cohort 1<br>Subjects will receive two doses of PF-06835375 or placebo on Day 1 and Day 29 via subcutaneous administration. | Drug: PF-06835375<br>* Intravenous (IV) or subcutaneous (SC) administration. Subjects will receive one or two doses. Doses will be ascending and determined by emerging data.<br>Drug: Placebo<br>* Matching placebo for PF-06835375 IV or SC. Subjects will receive one or two doses.<br>|
| Experimental: Part B, Cohort 2<br>Subjects will receive two doses of PF-06835375 or placebo on Day 1 and Day 29 via subcutaneous or intravenous administration. | Drug: PF-06835375<br>* Intravenous (IV) or subcutaneous (SC) administration. Subjects will receive one or two doses. Doses will be ascending and determined by emerging data.<br>Drug: Placebo<br>* Matching placebo for PF-06835375 IV or SC. Subjects will receive one or two doses.<br>|
| Experimental: Part B, Cohort 3<br>Subjects will receive two doses of PF-06835375 or placebo on Day 1 and Day 29 via subcutaneous or intravenous administration. | Drug: PF-06835375<br>* Intravenous (IV) or subcutaneous (SC) administration. Subjects will receive one or two doses. Doses will be ascending and determined by emerging data.<br>Drug: Placebo<br>* Matching placebo for PF-06835375 IV or SC. Subjects will receive one or two doses.<br>|
| Experimental: Part B, Cohort 4<br>Subjects will receive two doses of PF-06835375 or placebo on Day 1 and Day 29 via subcutaneous or intravenous administration. | Drug: PF-06835375<br>* Intravenous (IV) or subcutaneous (SC) administration. Subjects will receive one or two doses. Doses will be ascending and determined by emerging data.<br>Drug: Placebo<br>* Matching placebo for PF-06835375 IV or SC. Subjects will receive one or two doses.<br>|
| Experimental: Part B, Cohort 5<br>Subjects will receive two doses of PF-06835375 or placebo on Day 1 and Day 29 via subcutaneous or intravenous administration. | Drug: PF-06835375<br>* Intravenous (IV) or subcutaneous (SC) administration. Subjects will receive one or two doses. Doses will be ascending and determined by emerging data.<br>Drug: Placebo<br>* Matching placebo for PF-06835375 IV or SC. Subjects will receive one or two doses.<br>|
| Experimental: Part B, cohort 6<br>Subjects will receive two doses of PF-06835375 or placebo on Day 1 and Day 29 via subcutaneous or intravenous administration. | Drug: PF-06835375<br>* Intravenous (IV) or subcutaneous (SC) administration. Subjects will receive one or two doses. Doses will be ascending and determined by emerging data.<br>Drug: Placebo<br>* Matching placebo for PF-06835375 IV or SC. Subjects will receive one or two doses.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Participants With Dose-Limiting Toxicity (DLT) | DLT was defined as any of the following events meeting the criteria: (1) >=2 participants within a dose cohort developed Common Terminology Criteria for Adverse Events (CTCAE) v4.0 Grade 3 adverse event considered to be serious in the same organ system or 1 participant developed a CTCAE v4.0 Grade 4 or higher SAE considered related to study drug; (2) 50% or more participants within a dose cohort experienced a CTCAE v4.0 Grade 3 or higher infusion reaction; (3) a confirmed or probable case of Progressive Multifocal Leukoencephalopathy was observed; (4) the mean exposure for the treatment group reached or exceeded the exposure stopping limit of Cav of 261 mg/mL, or, based on the observed data, the group mean Cav of the next planned dose was projected to exceed the exposure stopping limit. Cav = average serum concentration. | From the first dose of study treatment up to 7-14 days after end of study criteria met (maximum duration for end of study criteria met: Day 225 for Part A, Day 281 for Part B) | 
| Number of Participants With Treatment-Emergent Adverse Events (TEAEs) by Severity | An AE was any untoward medical occurrence in a participant who received study drug without regard to possibility of causal relationship. Treatment-related AE was any untoward medical occurrence attributed to study drug in a participant who received study drug. Relatedness to study drug was assessed by the investigator. Treatment-emergent were events between first dose of study drug and up to approximately Week 40 that were absent before treatment or that worsened relative to pretreatment state. AEs are classified according to the severity in 3 categories a) mild - AEs does not interfere with participant's usual function b) moderate - AEs interferes to some extent with participant's usual function c) severe - AEs interferes significantly with participant's usual function. | From the first dose of study treatment up to 7-14 days after end of study criteria met (maximum duration for end of study criteria met: Day 225 for Part A, Day 281 for Part B) | 
| Number of Participants With All-Causality and Treatment-Related TEAEs | An AE was any untoward medical occurrence in a participant who received study drug without regard to possibility of causal relationship. Treatment-related AE was any untoward medical occurrence attributed to study drug in a participant who received study drug. Relatedness to study drug was assessed by the investigator. A serious adverse event (SAE) was an AE resulting in any of the following outcomes or deemed significant for any other reason: death; initial or prolonged inpatient hospitalization; life-threatening experience (immediate risk of dying); persistent or significant disability/incapacity; congenital anomaly. Treatment-emergent were events between first dose of study drug and up to approximately Week 40 that were absent before treatment or that worsened relative to pretreatment state. | From the first dose of study treatment up to 7-14 days after end of study criteria met (maximum duration for end of study criteria met: Day 225 for Part A, Day 281 for Part B) | 
| Number of Participants With Permanent Discontinuation Due to TEAEs | An AE was any untoward medical occurrence in a participant who received study drug without regard to possibility of causal relationship. Treatment-emergent were events between first dose of study drug and up to approximately Week 40 that were absent before treatment or that worsened relative to pretreatment state. | From the first dose of study treatment up to 7-14 days after end of study criteria met (maximum duration for end of study criteria met: Day 225 for Part A, Day 281 for Part B) | 
| Number of Participants With Clinically Significant Laboratory Abnormalities in Hematology, Chemistry, and Urinalysis | Hematology included hemoglobin, hematocrit, red blood cell, mean corpuscular volume, mean corpuscular hemoglobin, mean corpuscular hemoglobin concentration, platelet and white blood cell count, total neutrophils, eosinophils, monocytes, basophils and lymphocytes. Chemistry included blood urea nitrogen, creatinine, glucose, calcium, sodium, potassium, chloride, bicarbonate, aspartate aminotransferase, alanine aminotransferase, total bilirubin, alkaline phosphatase, uric acid, albumin, total protein and creatine kinase. Urinalysis included pH, glucose, protein, blood, ketones, nitrites, leukocyte esterase, urobilinogen, urine bilirubin, microscopy and creatinine. Clinical significance was judged by the investigator and those met the criteria of AE are listed here. Clinically significant laboratory abnormalities reported for at least 1 participant in the whole study are presented here. Baseline was the last pre-dose measurement (first treatment for MAD cohorts). | From baseline up to end of study criteria met (maximum duration for end of study criteria met: Day 225 for Part A, Day 281 for Part B) | 
| Number of Participants With Post-Baseline Vital Signs Data Meeting Categorical Summarization Criteria | Criteria for abnormality in vital signs: supine pulse rate <40 beats per minute (bpm) or >120 bpm; standing pulse rate <40 bpm or >120 bpm; sitting systolic blood pressure (BP) <90 mmHg, maximum increase or decrease from baseline of >=30 mmHg; sitting diastolic BP <50 mmHg, maximum increase or decrease from baseline of >=20 mmHg. Baseline was defined as the last pre-dose measurement in Day 1. Only those categories in which at least 1 participant had data were reported. | From baseline up to end of study criteria met (maximum duration for end of study criteria met: Day 225 for Part A, Day 281 for Part B) | 
| Number of Participants With Post-Baseline Electrocardiogram (ECG) Data Meeting Categorical Summarization Criteria | ECG abnormalities criteria included: 1) maximum QTc interval (ms): 450<= QTc <480, 480<= QTc <500, and QTc >=500; QTc maximum increase from baseline (ms): 30<= change <60, and change >=60; 2) maximum PR interval (ms): >=300; PR increase from baseline (ms): baseline >200 with 25% increase at maximum, baseline <=200 with 50% increase at maximum; 3) maximum QRS (ms): >=140; QRS increase from baseline (ms) >=50%. QTcF indicates QT interval corrected using the Fridericia's formula. QTcB indicates QT interval corrected using the Bazett's formula. Baseline was defined as the average of the triplicate pre-dose recordings at Day 1. Only those categories in which at least 1 participant had data were reported. | From baseline up to end of study criteria met (maximum duration for end of study criteria met: Day 225 for Part A, Day 281 for Part B) | 
| Number of Participants With All-Causality and Treatment-Related Infections and Infestations | An AE was any untoward medical occurrence in a participant who received study drug without regard to possibility of causal relationship. Treatment-related AE was any untoward medical occurrence attributed to study drug in a participant who received study drug. Relatedness to study drug was assessed by the investigator. The incidence of AEs by system organ class infections and infestations was reported here. | From the first dose of study treatment up to 7-14 days after end of study criteria met (maximum duration for end of study criteria met: Day 225 for Part A, Day 281 for Part B) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| B Cell Maximum Decrease (%) From Baseline Over Time Following Single and Multiple Doses of PF-06835375 | Blood samples for the assessment of B cell were collected and analyzed by flow cytometry. Baseline was defined as the average of screening and pre-dose measures. | Screening, Day 1, 2, 4, 8, 15, 29, 36 (Part B only), 43, 57, 85, 113, and every 4 weeks until criteria for end of study met (maximum duration for end of study criteria met: Day 225 for Part A, Day 281 for Part B) | 
| cTfh Cell Depletion Maximum Decrease (%) From Baseline Over Time Following Single and Multiple Doses of PF-06835375 | Blood samples for the assessment of circulating follicular T helper like (cTfh) cell were collected and analyzed by flow cytometry. Baseline was defined as the average of screening and pre-dose measures. | Screening, Day 1, 2, 4, 8, 15, 29, 36 (Part B only), 43, 57, 85, 113, and every 4 weeks until criteria for end of study met (maximum duration for end of study criteria met: Day 225 for Part A, Day 281 for Part B) | 
| Maximum Observed Serum Concentration (Cmax) of PF-06835375 in Part A (SAD) | Cmax is maximum observed serum concentration. Cmax for PF-06835375 was observed directly from data. | Day 1 (pre-dose, 2, 4, 6, 8, 12 hours post dose), 2, 4, 8, 15, 29, 43, 57, 85, 113 and 141 for Day 1 PK estimates | 
| Time to Reach Cmax (Tmax) of PF-06835375 in Part A (SAD) | Tmax is the time for Cmax. Tmax for PF-06835375 was observed directly from data as time of first occurrence. | Day 1 (pre-dose, 2, 4, 6, 8, 12 hours post dose), 2, 4, 8, 15, 29, 43, 57, 85, 113 and 141 for Day 1 PK estimates | 
| Area Under the Curve From Time Zero to Extrapolated Infinite Time (AUCinf) of PF-06835375 in Part A (SAD) | AUCinf is the area under the serum concentration-time profile from time zero extrapolated to infinite time. | Day 1 (pre-dose, 2, 4, 6, 8, 12 hours post dose), 2, 4, 8, 15, 29, 43, 57, 85, 113 and 141 for Day 1 PK estimates | 
| Area Under the Curve From Time Zero to Last Quantifiable Concentration (AUClast) of PF-06835375 in Part A (SAD) | AUClast is the area under the curve from time zero to last quantifiable concentration. AUClast for PF-06835375 was determined using linear/log trapezoidal method. | Day 1 (pre-dose, 2, 4, 6, 8, 12 hours post dose), 2, 4, 8, 15, 29, 43, 57, 85, 113 and 141 for Day 1 PK estimates | 
| Cmax of PF-06835375 Following First Dose and Multiple Doses in Part B (MAD) | Cmax is maximum observed serum concentration. Cmax for PF-06835375 was observed directly from data. There were less than 3 quantifiable concentrations for participants in PF-06835375 0.3 mg SC MAD cohort, therefore the serum PK parameters were not calculated. | Day 1 (pre-dose, 2, 4, 6, 8, 12 hours post dose), 2, 4, 8 and 15 for Day 1 PK estimates; Day 29 (pre-dose, 2, 4, 6, 8, hours post dose), 36, 43, 57, 85 and 113 for Day 29 PK estimates | 
| Tmax of PF-06835375 Following First Dose and Multiple Doses in Part B (MAD) | Tmax is the time for Cmax. Tmax for PF-06835375 was observed directly from data as time of first occurrence. There were less than 3 quantifiable concentrations for participants in PF-06835375 0.3 mg SC MAD cohort, therefore the serum PK parameters were not calculated. | Day 1 (pre-dose, 2, 4, 6, 8, 12 hours post dose), 2, 4, 8 and 15 for Day 1 PK estimates; Day 29 (pre-dose, 2, 4, 6, 8, hours post dose), 36, 43, 57, 85 and 113 for Day 29 PK estimates | 
| Area Under the Curve From Time Zero to End of Dosing Interval (AUCtau) of PF-06835375 Following First Dose and Multiple Doses in Part B (MAD) | AUCtau is area under the serum concentration-time profile from time 0 to time tau, the dosing interval, where tau= 28 days. AUCtau for PF-06835375 was determined using linear/log trapezoidal method. There were less than 3 quantifiable concentrations for participants in PF-06835375 0.3 mg SC MAD cohort, therefore the serum PK parameters were not calculated. | Day 1 (pre-dose, 2, 4, 6, 8, 12 hours post dose), 2, 4, 8 and 15 for Day 1 PK estimates; Day 29 (pre-dose, 2, 4, 6, 8, hours post dose), 36, 43, 57, 85 and 113 for Day 29 PK estimates | 
| AUClast of PF-06835375 Following Multiple Doses in Part B (MAD) | AUClast is the area under the curve from time zero to last quantifiable concentration. AUClast for PF-06835375 was determined using linear/log trapezoidal method. There were less than 3 quantifiable concentrations for participants in PF-06835375 0.3 mg SC MAD cohort, therefore the serum PK parameters were not calculated. | Day 29 (pre-dose, 2, 4, 6, 8, hours post dose), 36, 43, 57, 85 and 113 for Day 29 PK estimates | 
| Minimum Observed Serum Trough Concentration (Cmin) of PF-06835375 Following Multiple Doses in Part B (MAD) | Cmin is minimum observed serum trough concentration. Cmin was observed directly from data. There were less than 3 quantifiable concentrations for participants in PF-06835375 0.3 mg SC MAD cohort, therefore the serum PK parameters were not calculated. | Day 29 (pre-dose, 2, 4, 6, 8, hours post dose), 36, 43, 57, 85 and 113 for Day 29 PK estimates | 
| Observed Accumulation Ratio (Rac) of PF-06835375 Following Multiple Doses in Part B (MAD) | Rac is observed accumulation ratio. Rac = Day 29 AUCtau / Day 1 AUCtau. There were less than 3 quantifiable concentrations for participants in PF-06835375 0.3 mg SC MAD cohort, therefore the serum PK parameters were not calculated. | Day 1 (pre-dose, 2, 4, 6, 8, 12 hours post dose), 2, 4, 8 and 15 for Day 1 PK estimates; Day 29 (pre-dose, 2, 4, 6, 8, hours post dose), 36, 43, 57, 85 and 113 for Day 29 PK estimates | 
| Peak-to-trough Fluctuation (PTF) of PF-06835375 Following Multiple Doses in Part B (MAD) | PTF is peak-to-trough fluctuation at steady state. PTF = (Cmax-Cmin)/Cav. Cav is average serum concentration. There were less than 3 quantifiable concentrations for participants in PF-06835375 0.3 mg SC MAD cohort, therefore the serum PK parameters were not calculated. | Day 29 (pre-dose, 2, 4, 6, 8, hours post dose), 36, 43, 57, 85 and 113 for Day 29 PK estimates | 
| Number of Participants With Anti-Drug Antibodies (ADA) and Neutralizing Antibody (NAb) Against PF-06835375 | To evaluate the immunogenicity as measured by presence of ADA and NAb in participants treated with PF-06835375. | Day 1, 15, 29, 43, 57, 85, 113, and every 4 weeks until criteria for end of study met (maximum duration for end of study criteria met: Day 225 for Part A, Day 281 for Part B) |