Human epidermal growth factor receptor 3 (HER3) expression is seen across a wide variety of solid malignancies and is associated with poor prognosis. Up-regulation of HER3 expression and activity is also associated with resistance to multiple pathway inhibitors. GSK2849330, a monoclonal antibody (mAb) targeting HER3, is a new agent for subjects whose tumors express HER3. This study aims to characterise the biodistribution and dose-receptor occupancy relationship of GSK2849330 in patients with advanced HER3 expressing solid tumours via the use of PET imaging. This study will be conducted in two parts. Part 1 will be the imaging phase where each subject will receive two doses of GSK2849330 containing both Zirconium-89 (89Zr) labelled GSK2849330 and unlabeled GSK2849330. The amount of unlabeled GSK2849330 present in each dose will be varied to explore the effect on target mediated uptake of 89Zr into HER3 expressing tissues and tumors. Subjects will then proceed to the continuation phase (Part 2) for continued treatment with unlabelled GSK2849330. The study is planned to enroll approximately 12-15 subjects.
Study Type
INTERVENTIONAL
Allocation
NA
Purpose
OTHER
Masking
NONE
Enrollment
6
GSK2849330 solution (100 mg/mL) for infusion diluted in 0.9% sodium chloride to the appropriate concentration for the dose.
89Zr-GSK2849330 solution for intravenous administration diluted with GSK2849330 Solution for Infusion (unlabelled GSK2849330) with a target radioactivity of 37MBq and a total antibody concentration of 0.4 mg/mL or 1.2 mg/mL.
GSK Investigational Site
Amsterdam, Netherlands
GSK Investigational Site
Amsterdam, Netherlands
Standardized Uptake Value (SUV).
Regions of interest (RoI) will be outlined from PET-CT images to represent the tissue radioactivity concentration through the values of SUVmean and SUVpeak.
Time frame: Up to Day 21
Volume of region of interest.
RoIs will be outlined to represent whole organs and include the volumes encircled
Time frame: Up to Day 21
Anatomical localization of radiolabel.
Anatomical localization of radiolabel will be evaluated to establish dose-dependency of inhibition of target mediated uptake of 89Zr-GSK2849330 by unlabeled GSK2849330.
Time frame: Up to Day 21
Uptake of-GSK2849330 in tumors using pharmacometric model
Uptake of GSK2849330 in tumors will be estimated to establish dose-dependency of inhibition of target mediated uptake of 89Zr-GSK2849330 by unlabeled GSK2849330.
Time frame: Up to Day 21
Change in uptake parameters in response to the dose difference between dose 1 and 2.
Change in uptake parameters following dose 1 and 2 will estimated to establish dose-dependency of inhibition of target mediated uptake of 89Zr-GSK2849330 by unlabeled GSK2849330.
Time frame: Up to Day 21
Average radioactivity concentration in whole blood and plasma
Average radioactivity concentration will be determined and expressed as SUV and is equal to tissue radioactivity concentration normalized by administered amount of radioactivity per body weight.
Time frame: Up to Day 21
Tumor features assessment
Features of tumor will include central necrosis, irregular shape, non-uniform uptake and lesion ID
Time frame: Up to Day 21
Composite of pharmacokinetic (PK) parameters of GSK2849330
Measurements will include: maximum observed plasma concentration (Cmax), time to Cmax (tmax), area under the plasma concentration-time curve (AUC(0-t), AUC(0-Tau) (repeat dosing) and/or AUC(0-Infinity) (single dose), apparent terminal phase elimination rate constant (lambda z) and apparent terminal phase half-life (t½)
Time frame: Predose, and at 1, 3, 6, 12 and 24 hours post dose.
Organ dose measured in milliSievert (mSv) for each organ
Time frame: Up to Day 21
Effective dose value measured in mSv
Time frame: Up to Day 21
Overall incidence of Adverse events (AEs) and Serious Adverse events (SAEs)
AEs and SAEs will be collected from the time the first dose of study treatment is administered until 45 days following discontinuation of study treatment
Time frame: Average of 6 months
Change from baseline in laboratory parameters
Clinical laboratory tests will include clinical chemistry, routine urinalysis, haematology laboratory evaluations and additional parameters
Time frame: Baseline and up to 6 months
Left ventricular ejection fraction (LVEF) assessment
LVEF will be assessed as a measure of safety and tolerability measured by echocardiography (ECHO) or multi gated acquisition (MUGA) scans
Time frame: Average of 6 months
Vital signs monitoring.
Vital sign measurements will include systolic and diastolic blood pressure (BP), temperature, and pulse rate
Time frame: Average of 6 months
Serum titer of the anti-GSK2849330 antibodies.
Samples will be analyzed for the presence of anti-GSK2849330 antibodies using a validated immunoelectrochemiluminescent (ECL) assay.
Time frame: Average of 6 months
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