Clinical trial NCT02293161: Single Ascending Doses Study of Anti- Interleukin-7 Receptor α Monoclonal Antibody (GSK2618960) in Healthy Volunteers
Official title: 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
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE1
Conditions: Autoimmune Diseases
Keywords: Interleukin-7 Receptor α
monoclonal antibody
Lead sponsor: GlaxoSmithKline
Sponsor class: INDUSTRY
First posted: 2014-11-18
Enrollment: 18
Sex: ALL
Minimum age (years): 18
Maximum age (years): 65
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: yes
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: 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.


Eligibility criteria: 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.

Primary outcomes:
measure: Number of Participants with Adverse events (AE)
timeFrame: Up to Day 169
measure: Absolute values of vital signs
timeFrame: Up to Day 169
measure: Change from baseline in vital signs
timeFrame: Baseline (Day1) and up to Day 169
measure: Absolute values of Electrocardiogram (ECG) parameters
timeFrame: Up to Day 169
measure: Change from baseline in ECG parameters
timeFrame: Baseline (Day1) and up to Day 169
measure: Absolute values of haematology
timeFrame: Up to Day 169
measure: Change from baseline in haematology
timeFrame: Baseline (Day -1) and up to Day 169
measure: Absolute values of clinical chemistry
timeFrame: Up to Day 169
measure: Change from baseline in clinical chemistry
timeFrame: Baseline (Day -1) and up to Day 169
measure: Absolute values of urinalysis
timeFrame: Up to Day 169
measure: Change from baseline in urinalysis
timeFrame: Baseline (Day -1) and up to Day 169
Secondary outcomes:
measure: Composite of PK parameters
timeFrame: Up to Day 29
measure: Duration of full receptor occupancy (RO) for Cohort A
timeFrame: Up to Day 43
measure: Duration of full RO for Cohort B
timeFrame: Up to Day 57
measure: Relationship between dose/exposure and duration of full RO for Cohort A
timeFrame: Up to Day 43
measure: Relationship between dose/exposure and duration of full RO for Cohort B
timeFrame: Up to Day 57
measure: Degree of blocking of IL-7R alpha signalling for Cohort A
timeFrame: Up to Day 43
measure: Degree of blocking of IL-7R alpha signalling for Cohort B
timeFrame: Up to Day 57
measure: Incidence of anti-drug antibodies (ADAs)
timeFrame: Up to Day 85
measure: Titre of ADAs
timeFrame: Up to Day 85
Other outcomes:
Locations:
city: Cambridge
country: United Kingdom
facility: GSK Investigational Site
Study officials:
affiliation: GlaxoSmithKline
name: GSK Clinical Trials
role: STUDY_DIRECTOR
References:
citation: Ellis J, van Maurik A, Fortunato L, Gisbert S, Chen K, Schwartz A, McHugh S, Want A, Santos Franco S, Oliveira JJ, Price J, Coles A, Brown K, Su D, Craigen JL, Yang J, Brett S, Davis B, Cheriyan J, Kousin-Ezewu O, Gray F, Thompson PW, Fernando D. Anti-IL-7 receptor alpha monoclonal antibody (GSK2618960) in healthy subjects - a randomized, double-blind, placebo-controlled study. Br J Clin Pharmacol. 2019 Feb;85(2):304-315. doi: 10.1111/bcp.13748. Epub 2018 Dec 3.