Single Ascending Doses Study of Anti- Interleukin-7 Receptor α Monoclonal Antibody (GSK2618960) in Healthy Volunteers

Study Overview
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Brief Summary
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GSK2618960 is a humanized Immunoglobulin G 1 ( IgG1) monoclonal antibody (mAb) that binds to the alpha component (CD127) of the heterodimeric Interleukin-7 receptor (IL-7R). It is being developed for the treatment of autoimmune indications. This study is intended to further explore the safety, tolerability, pharmacokinetics (PK), pharmacodynamics (PD) and immunogenicity of single ascending doses GSK2618960 in healthy volunteers beyond those already evaluated in I7R116702 (First Time In Human study). The study is anticipated to enrol 18 subjects in total, with 9 subjects in each of the two cohorts.

Official Title
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A Randomised, Double-Blind (Sponsor Unblind), Placebo-Controlled Study to Evaluate the Safety, Tolerability, Pharmacokinetics, Pharmacodynamics and Immunogenicity of Single Ascending Doses of a Fully Humanized Anti-IL-7 Receptor α Monoclonal Antibody (GSK2618960) in Healthy Volunteers

Conditions
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Autoimmune Diseases

Intervention / Treatment
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* Drug: GSK2618960
* Drug: Placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Males aged between 18 and 65 years of age inclusive, at the time of signing the informed consent OR females of non-child bearing potential aged between 18 and 65 years of age at the time of signing the informed consent. Non-childbearing potential defined as:- pre-menopausal females with a documented tubal ligation or hysterectomy, or post-menopausal defined as 24 months of spontaneous amenorrhea [in questionable cases a blood sample with simultaneous follicle stimulating hormone (FSH) >40 milli-international units (MIU) per millilitre (mL) and oestradiol <40 picograms (pg) /mL (< 140 picomole/liter) is confirmatory. [Females on hormone replacement therapy (HRT) and whose menopausal status is in doubt must discontinue HRT to allow confirmation of postmenopausal status prior to study enrolment. For most forms of HRT, at least 2-4 weeks will elapse between the cessation of therapy and the blood draw; this interval depends on the type and dosage of HRT. Following confirmation of their postmenopausal status, they can resume use of HRT during the study.] Male subjects with female partners of child-bearing potential must agree to use one of the contraception methods listed in Protocol. This criterion must be followed from the time of the first dose of study medication until 5 half-lives after the infusion (Week 16 visit). Healthy as determined by a responsible and experienced physician, based on a medical evaluation including medical history, physical examination, laboratory tests and cardiac monitoring. A subject with a clinically significant abnormality or laboratory parameter(s) which is/are not specifically listed in the inclusion or exclusion criteria, outside the local reference range being used for healthy volunteers may be included only if the Investigator in consultation with the GSK Medical Monitor agree and document that the finding is unlikely to introduce additional risk factors and will not interfere with the study procedures. White blood cell count >=Lower Limit of Normal (LLN), including both lymphocyte and neutrophil counts >=LLN. Body weight >=50 kilogram (kg) and body mass index (BMI) within the range 19.0 - 32.0 kilogram / square meter (kg/m^2) (inclusive). Capable of giving written informed consent, which includes compliance with the requirements and restrictions listed in the consent form. Subjects with a confirmed positive vaccination status for tetanus, diphtheria, pertussis, measles, mumps, rubella, pneumococcus and meningococcus (or consent to vaccination) Exclusion Criteria: Criteria Based Upon Medical Histories Current evidence of ongoing or acute infection within 3 months prior to the first dose of study drug, such as: serious local infection (e.g. cellulitis, abscess); systemic infection [e.g. pneumonia, septicaemia, Tuberculosis (TB)]. Current or chronic history of liver disease, or known hepatic or biliary abnormalities (with the exception of Gilbert's syndrome or asymptomatic gallstones). A QT duration corrected for heart rate by Fridericia's formula (QTcF) >450 millisecond (msec) based on either single or averaged QTcF values of triplicate ECGs obtained over a brief recording period. History of regular alcohol consumption within 6 months of the study defined as an average weekly intake of >21 units for males or >14 units for females. One unit is equivalent to 8 grams (g) of alcohol: a half-pint  240 mL of beer, 1 glass (125 mL) of wine or 1 (25 mL) measure of spirits. History of sensitivity to any of the study medications, or components thereof or a history of drug or other allergy that, in the opinion of the investigator or GSK Medical Monitor, contraindicates their participation. Previous history of anaphylaxis and severe allergic reaction. Receipt of live vaccination within 1 month of screening or plan to receive live vaccination at any time during the study i.e. 6 months following dosing (which covers the period when the predicted target duration of receptor occupancy is >= 95%). Subjects from a high risk area of the world for tuberculosis or have history of tuberculosis or have close family members with confirmed TB infection or positive at screening by Quantiferon testing (an indeterminate test result at screen may be repeated once). Criteria Based Upon Diagnostic Assessments A positive pre-study Hepatitis B surface and/or core antibody or positive Hepatitis C antibody result within 3 months of screening A positive pre-study drug screen. A positive test for Human Immunodeficiency Virus (HIV) antibody. Other Criteria Smokers who would not be able to refrain from smoking whilst in the phase I unit. Unable to refrain from the use of prescription or non-prescription drugs (unless permitted as per protocol Where participation in the study would result in donation of blood or blood products in excess of 500 mL within a 56 day rolling period. The subject has participated in a clinical trial and has received an investigational product within the following time period prior to the first dosing day in the current study: 30 days, 5 half-lives or twice the duration of the biological effect of the investigational product (whichever is longer). Exposure to more than four new chemical entities within 12 months prior to the first dosing day.

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 65 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: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Cohort A GSK2618960<br>Subjects will receive GSK2618960 0.6 milligram per kilogram (mg/kg) | Drug: GSK2618960<br>* GSK2618960 will be provided as 100 mg/mL solution for injection to be administered as single dose IV infusion that has to be diluted at the study site with placebo<br>|
| Placebo Comparator: Cohort A Placebo<br>Subjects will receive Sodium Chloride Intravenous as placebo | Drug: Placebo<br>* It is Sodium Chloride Intravenous Infusion<br>|
| Experimental: Cohort B GSK2618960<br>Subjects will receive GSK2618960,planned dose being 2mg/kg. However, actual dose level for Cohort B may be adjusted based on the emerging data on safety, tolerability, PK and RO from Cohort A. The maximum dose will not exceed 2.4 mg/kg (i.e. a 4-fold dose escalation from 0.6 mg/kg) | Drug: GSK2618960<br>* GSK2618960 will be provided as 100 mg/mL solution for injection to be administered as single dose IV infusion that has to be diluted at the study site with placebo<br>|
| Placebo Comparator: Cohort B Placebo<br>Subjects will receive Sodium Chloride Intravenous as placebo | Drug: Placebo<br>* It is Sodium Chloride Intravenous Infusion<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Participants with Adverse events (AE) | An AE is any untoward medical occurrence in a patient or clinical investigation subject, temporally associated with the use of a medicinal product, whether or not considered related to the medicinal product | Up to Day 169 | 
| Absolute values of vital signs | Vital signs includes systolic and diastolic blood pressure, pulse rate and body temperature. | Up to Day 169 | 
| Change from baseline in vital signs | Vital signs includes systolic and diastolic blood pressure, pulse rate and body temperature. | Baseline (Day1) and up to Day 169 | 
| Absolute values of Electrocardiogram (ECG) parameters | Single 12-lead ECGs will be obtained. | Up to Day 169 | 
| Change from baseline in ECG parameters | Single 12-lead ECGs will be obtained. | Baseline (Day1) and up to Day 169 | 
| Absolute values of haematology | Haematology parameters includes Platelet Count, Red blood cells (RBC) Count, White blood cells Count (absolute) (WBC), Haemoglobin and Haematocrit | Up to Day 169 | 
| Change from baseline in haematology | Haematology parameters includes Platelet Count, RBC, WBC, Haemoglobin and Haematocrit | Baseline (Day -1) and up to Day 169 | 
| Absolute values of clinical chemistry | Clinical chemistry includes Blood urea nitrogen, Potassium, Aspartate aminotransferase (SGOT), Total and direct bilirubin, Creatinine, Chloride, Alanine aminotransferase (SGPT), Albumin, Glucose, Total Carbon dioxide, Gamma glutamyltransferase, Total Protein, Sodium, Calcium and Alkaline phosphatase | Up to Day 169 | 
| Change from baseline in clinical chemistry | Clinical chemistry includes Blood urea nitrogen, Potassium, SGOT, Total and direct bilirubin, Creatinine, Chloride, SGPT, Albumin, Glucose, Total Carbon dioxide, Gamma glutamyltransferase, Total Protein, Sodium, Calcium and Alkaline phosphatase | Baseline (Day -1) and up to Day 169 | 
| Absolute values of urinalysis | Urinalysis includes Specific gravity, pH, glucose, protein, blood and ketones by dipstick, Microscopic examination (if blood or protein is abnormal) | Up to Day 169 | 
| Change from baseline in urinalysis | Urinalysis includes Specific gravity, pH, glucose, protein, blood and ketones by dipstick, Microscopic examination (if blood or protein is abnormal) | Baseline (Day -1) and up to Day 169 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Composite of PK parameters | PK parameters includes Area Under the Concentration-time curve (AUC) from zero (pre-dose) extrapolated to infinite time (AUC[0-infinite]); AUC from time zero (pre-dose) to last quantifiable concentration within a subject across all treatments (AUC[0-t]); Percentage of AUC(0- infinite) obtained by extrapolation (%AUC-[ex]); Clearance (CL); Volume of distribution (Vss); Maximum observed concentration (Cmax); Time of occurrence of Cmax (Tmax); Terminal half life (t1/2). | Up to Day 29 | 
| Duration of full receptor occupancy (RO) for Cohort A | The extent and duration of receptor occupancy and the inhibition of IL-7 signalling in Stat5 phosphorylation (pSTAT5) will be determined | Up to Day 43 | 
| Duration of full RO for Cohort B | The extent and duration of receptor occupancy and the inhibition of IL-7 signalling in pSTAT5 will be determined | Up to Day 57 | 
| Relationship between dose/exposure and duration of full RO for Cohort A | The PD/RO relationship of GSK2618960 following single and repeat Intravenous (IV) doses will be determined. | Up to Day 43 | 
| Relationship between dose/exposure and duration of full RO for Cohort B | The PD/RO relationship of GSK2618960 following single and repeat IV doses will be determined. | Up to Day 57 | 
| Degree of blocking of IL-7R alpha signalling for Cohort A | It will be assessed by residual IL-7- and Thymic Stromal Lymphopoietin (TSLP)-mediated pSTAT5 and Thymus and Activation-Regulated Chemokine (TARC) secretion | Up to Day 43 | 
| Degree of blocking of IL-7R alpha signalling for Cohort B | It will be assessed by residual IL-7- and TSLP-mediated pSTAT5 and TARC secretion | Up to Day 57 | 
| Incidence of anti-drug antibodies (ADAs) | Blood samples will be collected for the assessment of ADAs in serum using validated electrochemiluminescent (ECL)assays | Up to Day 85 | 
| Titre of ADAs | Blood samples will be collected for the assessment of ADAs in serum using validated ECL assays | Up to Day 85 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Interleukin-7 Receptor α, monoclonal antibody