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

Study Overview
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Brief Summary
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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.

Official Title
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An Open Label Positron Emission Tomography (PET) Imaging Study Using 89Zirconium to Investigate the Biodistribution of Anti-HER3 Monoclonal Antibody (mAb) GSK2849330 and Characterize Its Dose-receptor Occupancy Relationship in Subjects With Advanced HER3-Positive Solid Tumors

Conditions
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Cancer, Neoplasms

Intervention / Treatment
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* Drug: GSK2849330
* Drug: 89Zr-GSK2849330


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria Males and females >=18 years of age (at the time consent is obtained). Written informed consent provided. Performance Status score of 0 or 1 according to the Eastern Cooperative Oncology Group (ECOG) scale. Sufficient archival tumor specimen is available for HER3 immunohistochemistry (IHC) analysis, or subject is willing to undergo a tumor biopsy for HER3 IHC analysis. Subjects must have tumours with documented HER3 expression on the cell surface (1+, 2+ or 3+) of the invasive component of tumour (either on archival tissue or a fresh biopsy) using an analytically validated IHC assay by central laboratory. Histologically or cytologically confirmed diagnosis of solid tumour malignancy for which no standard therapeutic alternatives exist. Adequate baseline organ functions Left ventricular ejection fraction (LVEF) >=50% by Echocardiogram (ECHO) or Multi gated acquisition scan (MUGA). Subjects must have at least two measurable lesions on Computed tomography (CT) or Magnetic resonance imaging (MRI) scan with a shortest axis of at least 20 millimeter (mm). 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).

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Other
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Imaging Phase + Continuation Phase<br>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. | Drug: GSK2849330<br>* GSK2849330 solution (100 mg/mL) for infusion diluted in 0.9% sodium chloride to the appropriate concentration for the dose.<br>Drug: 89Zr-GSK2849330<br>* 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.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | 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 | 

Secondary Outcome Measures

| Outcome Measure | 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 | 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 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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zirconium, oncology, mAb, receptor occupancy, dose, PET, HER3, 89-Zr, biodistribution, tumours