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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.
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| Label | Type | Description | Intervention Names |
|---|---|---|---|
| Imaging Phase + Continuation Phase | Experimental | In Part 1 of the study, participants will receive a dose of 89Zr-GSK2849330 (Dose 1), with an activity of no more than 37 MegaBequerel (MBq) and a variable total dose of GSK2849330. PET scans will be acquired within 7 days. Two weeks after Dose 1 participants will receive second dose of 89Zr-GSK2849330 (Dose 2) and a variable total dose of GSK2849330. Participants will continue to receive unlabelled GSK2849330 (in Part 2) either at established dose level or as decided by medical monitor. |
|
| Name | Type | Description | Arm Group Labels | Other Names |
|---|---|---|---|---|
| GSK2849330 | Drug | GSK2849330 solution (100 mg/mL) for infusion diluted in 0.9% sodium chloride to the appropriate concentration for the dose. |
|
| Measure | Description | Time Frame |
|---|---|---|
| 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. | Up to Day 21 |
| Volume of region of interest. | RoIs will be outlined to represent whole organs and include the volumes encircled | Up to Day 21 |
| Measure | Description | Time Frame |
|---|---|---|
| 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. | Up to Day 21 |
| Uptake of-GSK2849330 in tumors using pharmacometric model |
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Inclusion Criteria
Exclusion Criteria:
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| Name | Affiliation | Role |
|---|---|---|
| GSK Clinical Trials | GlaxoSmithKline | Study Director |
| GSK Clinical Trials | GlaxoSmithKline (for GlaxoSmithKline; Human Genome Sciences Inc., a GSK Company; Sirtris, a GSK Company; Stiefel, a GSK Company; ViiV Healthcare) | Study Director |
| Facility | Status | City | State | ZIP | Country | Contacts |
|---|---|---|---|---|---|---|
| GSK Investigational Site | Amsterdam | 1081 HV | Netherlands | |||
| GSK Investigational Site |
| PubMed Identifier | Type | Citation | Retractions |
|---|---|---|---|
| 30733323 | Background | Menke-van der Houven van Oordt CW, McGeoch A, Bergstrom M, McSherry I, Smith DA, Cleveland M, Al-Azzam W, Chen L, Verheul H, Hoekstra OS, Vugts DJ, Freedman I, Huisman M, Matheny C, van Dongen G, Zhang S. Immuno-PET Imaging to Assess Target Engagement: Experience from 89Zr-Anti-HER3 mAb (GSK2849330) in Patients with Solid Tumors. J Nucl Med. 2019 Jul;60(7):902-909. doi: 10.2967/jnumed.118.214726. Epub 2019 Feb 7. |
| Label | URL |
|---|---|
| Results for study 200980 can be found on the GSK Clinical Study Register. | View source |
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IPD for this study will be made available via the Clinical Study Data Request site.
IPD is available via the Clinical Study Data Request site (click on the link provided below)
Access is provided after a research proposal is submitted and has received approval from the Independent Review Panel and after a Data Sharing Agreement is in place. Access is provided for an initial period of 12 months but an extension can be granted, when justified, for up to another 12 months.
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| ID | Term |
|---|---|
| D009369 | Neoplasms |
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| ID | Term |
|---|---|
| C000622373 | GSK2849330 |
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| 89Zr-GSK2849330 | Drug | 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. |
|
Uptake of GSK2849330 in tumors will be estimated to establish dose-dependency of inhibition of target mediated uptake of 89Zr-GSK2849330 by unlabeled GSK2849330. |
| 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. | 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. | Up to Day 21 |
| Tumor features assessment | Features of tumor will include central necrosis, irregular shape, non-uniform uptake and lesion ID | 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) | Predose, and at 1, 3, 6, 12 and 24 hours post dose. |
| Organ dose measured in milliSievert (mSv) for each organ | Up to Day 21 |
| Effective dose value measured in mSv | 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 | 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 | 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 | Average of 6 months |
| Vital signs monitoring. | Vital sign measurements will include systolic and diastolic blood pressure (BP), temperature, and pulse rate | 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. | Average of 6 months |
| Amsterdam |
| 1081 H |
| Netherlands |