Detection of PitNET Tissue During TSS Using Bevacizumab-800CW

Study Overview
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Brief Summary
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There is a need for improved visualization of presence and extent of pituitary neuroendocrine tumor (PitNET) tissue during transsphenoidal surgery (TSS), especially in tumors invading the cavernous sinus (CS). Optical molecular imaging of PitNET associated biomarkers is a promising technique to accommodate this need. Vascular Endothelial Growth Factor (VEGF-A) is overexpressed in PitNET tissue compared to normal pituitary tissue and has proven to be a valid target for molecular imaging. Bevacizumab is an antibody that binds VEGF-A. By conjugating a fluorescent dye to this antibody, the fluorescent tracer molecule bevacizumab-800CW is created, which binds to VEGF-A. The investigators hypothesize that bevacizumab-800CW accumulates in PitNET tissue, enabling visualization using a molecular fluorescence endoscopy system. In this pilot intervention study the investigators will determine the feasibility of using microdoses (4.5, 10 and 25 mg) of bevacizumab-800CW to detect PitNET tissue intraoperatively.

Official Title
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Detection of Pituitary Neuroendocrine Tumor (PitNET) Tissue During Endoscopic Transsphenoidal Surgery Using Bevacizumab-800CW

Conditions
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Pituitary Tumor, Pituitary Adenoma, Pituitary Macroadenoma

Intervention / Treatment
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* Drug: Bevacizumab-IRDye800CW
* Device: Molecular Fluorescence Endoscopy platform


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Patients with an established diagnosis of PitNET with a Knosp grade of 3 or 4 who are scheduled to undergo TSS. WHO performance status 0-2 Signed written informed consent Exclusion Criteria: Medical or psychiatric conditions that compromise the patient's ability to give informed consent Pregnant or lactating women. Documentation of a negative pregnancy test must be available for woman of childbearing potential. Woman of childbearing potential are pre- menopausal women with intact reproductive organs and women less than two years after menopause History of infusion reactions to bevacizumab or other monoclonal antibody therapies. Inadequately controlled hypertension with or without current antihypertensive medication Within 6 months prior to inclusion: myocardial infarction, TIA, CVA, pulmonary embolism, uncontrolled chronic hepatic failure, unstable angina pectoris

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: Diagnostic
Allocation: Non-Randomized
Intervention Model: Sequential Assignment
Interventional Model Description: The study is a non-randomized, non-blinded, prospective, single center, pilot dose-finding study.
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: NIR endoscopic TSS with 4.5 mg bevacizumab-800CW<br>IV-administration of 4.5 mg of the fluorescent tracer bevacizumab-800CW to 3 patients with a pituitary neuroendocrine tumor (PitNET) with a Knosp grade of 3 or 4. The optimal dose will be expanded to include 6 patients. | Drug: Bevacizumab-IRDye800CW<br>* Intravenous administration of 4.5, 10 or 25 mg of Bevacizumab-IRDye800CW prior to endoscopic transsphenoidal surgery<br>* Other names: Tracer administration;Device: Molecular Fluorescence Endoscopy platform<br>* A flexible fluorescence fiber-bundle is attached to a fluorescence camera platform to enable the detection of fluorescence signals. The fluorescence fiber-probe is inserted through the standard working channel of the Surgvision explorer endoscope. During surgery, three imaging moments are defined in which the fluorescence molecular endoscopy system will detect the fluorescent signal<br>* Other names: Fluorescence endoscopy;|
| Experimental: NIR endoscopic TSS with 10 mg bevacizumab-800CW<br>IV-administration of 10 mg of the fluorescent tracer bevacizumab-800CW to 3 patients with a pituitary neuroendocrine tumor (PitNET) with a Knosp grade of 3 or 4. The optimal dose will be expanded to include 6 patients. | Drug: Bevacizumab-IRDye800CW<br>* Intravenous administration of 4.5, 10 or 25 mg of Bevacizumab-IRDye800CW prior to endoscopic transsphenoidal surgery<br>* Other names: Tracer administration;Device: Molecular Fluorescence Endoscopy platform<br>* A flexible fluorescence fiber-bundle is attached to a fluorescence camera platform to enable the detection of fluorescence signals. The fluorescence fiber-probe is inserted through the standard working channel of the Surgvision explorer endoscope. During surgery, three imaging moments are defined in which the fluorescence molecular endoscopy system will detect the fluorescent signal<br>* Other names: Fluorescence endoscopy;|
| Experimental: NIR endoscopic TSS with 25 mg bevacizumab-800CW<br>IV-administration of 25 mg of the fluorescent tracer bevacizumab-800CW to 3 patients with a pituitary neuroendocrine tumor (PitNET) with a Knosp grade of 3 or 4. The optimal dose will be expanded to include 6 patients. | Drug: Bevacizumab-IRDye800CW<br>* Intravenous administration of 4.5, 10 or 25 mg of Bevacizumab-IRDye800CW prior to endoscopic transsphenoidal surgery<br>* Other names: Tracer administration;Device: Molecular Fluorescence Endoscopy platform<br>* A flexible fluorescence fiber-bundle is attached to a fluorescence camera platform to enable the detection of fluorescence signals. The fluorescence fiber-probe is inserted through the standard working channel of the Surgvision explorer endoscope. During surgery, three imaging moments are defined in which the fluorescence molecular endoscopy system will detect the fluorescent signal<br>* Other names: Fluorescence endoscopy;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Discrimination of tumorous and non-tumorous tissue based on in vivo and ex vivo fluorescence measurements from bevacizumab-800CW gained during fluorescence endoscopic transsphenoidal surgery of pituitary neuroendocrine tumors (PitNETs) | To determine the sensitivity of the marker bevacizumab-800CW in discriminating between tumorous and non-tumorous tissue during endoscopic transsphenoidal surgery of pituitary neuroendocrine tumors (PitNETs) defined as the tumor to background ratio and intrinsic fluorescence | Three days after tracer injection | 
| Number of participants with adverse events (AE), serious adverse events (SAE) and suspected unexpected serious adverse reactions (SUSAR) | Data collection as a measure of safety and tolerability regarding administration of bevacizumab-800CW | Up to 7 days after tracer injection | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| The correlation of in vivo and ex vivo fluorescent signals to histopathological analysis results | Correlate the H/E images to the fluorescent images made with multiple ex vivo imaging modalities | Up to 1,5 year | 
| Quantification of the fluorescent signal by MDSFR/SFF spectroscopy | Multi-diameter single-fiber reflectance with single-fiber fluorescence (MDSFR/SFF) spectroscopy can measure the fluorescence signal quantitatively, both in vivo and ex vivo | Up to 1,5 year | 
| Assessment of the (sub)-cellular distribution of bevacizumab-800CW by ex vivo fluorescence microscopy | Imaging of the distribution of bevacizumab-800CW with a fluorescence microscope | Up to 1,5 year |