Immuno Positron Emission Tomography Study of GSK2849330 in Subjects With Human Epidermal Growth Factor Receptor 3-Positive Solid Tumors

Phase 1

Completed

• Conditions: Cancer; Neoplasms
• Interventions: Drug: GSK2849330; Drug: 89Zr-GSK2849330

• Registration Number: NCT02345174
• Lead Sponsor: GlaxoSmithKline

Brief Summary

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.

Detailed Description

Not available

Study Timeline

• Study First Submitted: 2015-01-19
• Study First Submitted QC: 2015-01-19
• Study First Posted: 2015-01-26
• Study Start: 2015-03-19
• Primary Completion: 2016-06-02
• Study Completion: 2016-06-02
• Status Verified: 2019-02
• Last Update Submitted: 2019-02-19
• Last Update Posted: 2019-02-21

Recruitment & Eligibility

• Status: COMPLETED
• Sex: All
• Target Recruitment: 6

Inclusion Criteria

Not provided

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Exclusion Criteria

• Subjects with leptomeningeal or brain metastases or spinal cord compression
• Prior HER3- directed treatment (HER2- or EGFR-directed treatment is acceptable).
• Unresolved toxicity greater than National Cancer Institute - Common Terminology Criteria for Adverse Events (NCI-CTCAE), version 4.0 Grade 1 from previous anti-cancer therapy
• Known or suspected hypersensitivity reaction to prior biologic therapy
• Evidence of another active malignancy (excludes non-melanoma skin cancer).
• Concurrent medical condition that would jeopardize compliance with the protocol.
• Receiving concurrent anti-tumor therapies, or chronic immunosuppressive therapies (includes daily steroid doses in excess of 20 milligram (mg)/day of prednisolone).

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Study & Design

• Study Type: INTERVENTIONAL
• Study Design: SINGLE_GROUP

Arm && Interventions

Group	Intervention	Description
Imaging Phase + Continuation Phase	GSK2849330	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.
Imaging Phase + Continuation Phase	89Zr-GSK2849330	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.

Primary Outcome Measures

Name	Time	Method
Standardized Uptake Value (SUV).	Up to Day 21	Regions of interest (RoI) will be outlined from PET-CT images to represent the tissue radioactivity concentration through the values of SUVmean and SUVpeak.
Volume of region of interest.	Up to Day 21	RoIs will be outlined to represent whole organs and include the volumes encircled

Secondary Outcome Measures

Name	Time	Method
Average radioactivity concentration in whole blood and plasma	Up to Day 21	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.
Tumor features assessment	Up to Day 21	Features of tumor will include central necrosis, irregular shape, non-uniform uptake and lesion ID
Composite of pharmacokinetic (PK) parameters of GSK2849330	Predose, and at 1, 3, 6, 12 and 24 hours post dose.	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)
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)	Average of 6 months	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
Change from baseline in laboratory parameters	Baseline and up to 6 months	Clinical laboratory tests will include clinical chemistry, routine urinalysis, haematology laboratory evaluations and additional parameters
Anatomical localization of radiolabel.	Up to Day 21	Anatomical localization of radiolabel will be evaluated to establish dose-dependency of inhibition of target mediated uptake of 89Zr-GSK2849330 by unlabeled GSK2849330.
Uptake of-GSK2849330 in tumors using pharmacometric model	Up to Day 21	Uptake of GSK2849330 in tumors will be estimated to establish dose-dependency of inhibition of target mediated uptake of 89Zr-GSK2849330 by unlabeled GSK2849330.
Change in uptake parameters in response to the dose difference between dose 1 and 2.	Up to Day 21	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.
Left ventricular ejection fraction (LVEF) assessment	Average of 6 months	LVEF will be assessed as a measure of safety and tolerability measured by echocardiography (ECHO) or multi gated acquisition (MUGA) scans
Vital signs monitoring.	Average of 6 months	Vital sign measurements will include systolic and diastolic blood pressure (BP), temperature, and pulse rate
Serum titer of the anti-GSK2849330 antibodies.	Average of 6 months	Samples will be analyzed for the presence of anti-GSK2849330 antibodies using a validated immunoelectrochemiluminescent (ECL) assay.

Trial Locations

Locations (1)

GSK Investigational Site; 🇳🇱 Amsterdam, Netherlands