Clinical trial NCT02345174: Immuno Positron Emission Tomography Study of GSK2849330 in Subjects With Human Epidermal Growth Factor Receptor 3-Positive Solid Tumors
Official title: 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
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE1
Conditions: Cancer
Neoplasms
Keywords: zirconium
oncology
mAb
receptor occupancy
dose
PET
HER3
89-Zr
biodistribution
tumours
Lead sponsor: GlaxoSmithKline
Sponsor class: INDUSTRY
First posted: 2015-01-26
Enrollment: 6
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NA
Intervention model: SINGLE_GROUP
Primary purpose: OTHER

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.


Eligibility criteria: 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).

Primary outcomes:
measure: Standardized Uptake Value (SUV).
timeFrame: Up to Day 21
measure: Volume of region of interest.
timeFrame: Up to Day 21
Secondary outcomes:
measure: Anatomical localization of radiolabel.
timeFrame: Up to Day 21
measure: Uptake of-GSK2849330 in tumors using pharmacometric model
timeFrame: Up to Day 21
measure: Change in uptake parameters in response to the dose difference between dose 1 and 2.
timeFrame: Up to Day 21
measure: Average radioactivity concentration in whole blood and plasma
timeFrame: Up to Day 21
measure: Tumor features assessment
timeFrame: Up to Day 21
measure: Composite of pharmacokinetic (PK) parameters of GSK2849330
timeFrame: Predose, and at 1, 3, 6, 12 and 24 hours post dose.
measure: Organ dose measured in milliSievert (mSv) for each organ
timeFrame: Up to Day 21
measure: Effective dose value measured in mSv
timeFrame: Up to Day 21
measure: Overall incidence of Adverse events (AEs) and Serious Adverse events (SAEs)
timeFrame: Average of 6 months
measure: Change from baseline in laboratory parameters
timeFrame: Baseline and up to 6 months
measure: Left ventricular ejection fraction (LVEF) assessment
timeFrame: Average of 6 months
measure: Vital signs monitoring.
timeFrame: Average of 6 months
measure: Serum titer of the anti-GSK2849330 antibodies.
timeFrame: Average of 6 months
Other outcomes:
Locations:
city: Amsterdam
country: Netherlands
facility: GSK Investigational Site
city: Amsterdam
country: Netherlands
facility: GSK Investigational Site
Study officials:
affiliation: GlaxoSmithKline
name: GSK Clinical Trials
role: STUDY_DIRECTOR
affiliation: GlaxoSmithKline (for GlaxoSmithKline; Human Genome Sciences Inc., a GSK Company; Sirtris, a GSK Company; Stiefel, a GSK Company; ViiV Healthcare)
name: GSK Clinical Trials
role: STUDY_DIRECTOR
References:
citation: 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.