The purpose of this study is to determine the uptake, (semi-)quantification and localization of the VEGF targeting fluorescent tracer bevacizumab-IDRye800CW in breast cancer tissue, surrounding healthy tissue, tumor margins and lymph nodes. This is measured in surgical specimens after a single intravenous administration of 4,5 bevacizumab-IDRye800CW, using fluorescence microscopy and macroscopy techniques. Also the safety of bevacizumab-IDRye800CW is assessed. Another purpose is to assess the abilities of three different fluorescent signal detection systems to detect the fluorescent signal pre- and intra-operatively.
There is a need for better visualization of presence and extent of breast cancer to improve breast cancer management. Molecular imaging of breast cancer associated targets is a promising method to improve visualization. Vascular endothelial growth factor (VEGF) has proven to be a valid target for molecular imaging with radioactive labeled tracers. However in view of radiation safety, infrastructure, costs and stability, fluorescent labeling of bevacizumab (a VEGF targeting humanized monoclonal antibody) has potential advantages over radioactive labeling. Therefore recently the near-infrared fluorescent tracer bevacizumab-IRDye 800CW has been developed. In mice the fluorescent signal was clearly present in tumor tissue and could be visualized intra-operatively. The tracer was also approved for administration to patients in a microdose (tracer dose). In this prospective multicenter feasibility study the new tracer bevacizumab-IRDye 800CW will be administered to a maximum of 30 patients with proven breast cancer 3 days before surgery. Part of the surgical specimen will after surgery extensively be investigated by macroscopy and microscopy to determine the uptake of the tracer in tumor tissue, surrounding normal tissue and lymph nodes. To detect the tracer before surgery, two different pre-operative imaging methods are used: MSOT (in the UMCG en FDOT in the UMCU. During surgery the intra-operative MFRI camera is available at both centers to detect the fluorescent signal. The study consists of a total of five study procedure related patient visits. 1. During a screening visit, eligibility will be evaluated and patient characteristics will be collected. 2. During the administration visit, 3 days before surgery, 4.5 mg of bevacizumab-IRDye 800CW will be administered intravenously, followed by 4 hours observation. Also before and 4 hours after tracer injection pre-operative optical imaging will take place (in the UMC Groningen, the hand-held MSOT system will be used and in the UMC Utrecht, the FDOT system will be used) and blood samples are taken. 3. A third visit, approximately 36 hours after tracer administration, another pre-operative optical imaging procedure will take place. 4. At the day of surgery, first a blood sample will be taken and the last pre-operative optical imaging procedure will take place, followed by standard surgery. During surgery, the MFRI camera will be used to detect a fluorescent signal before and after incision an after removal of the tumor. Part of the surgical specimen will after surgery extensively be investigated by macroscopy and microscopy to determine the uptake of the tracer in tumor tissue, surrounding normal tissue and lymph nodes. 5. At an outpatient visit (approximately 10 days after surgery) (visit 5), the last blood sample will be taken.
In this two stage, non-randomized, non-blinded, prospective, multicenter feasibility study, bevacizumab-IRDye800CW will be administered to a total of 20 patients with proven breast cancer.
University Medical Center Groningen
Groningen, Netherlands
The uptake of bevacizumab-IRDye800CW in breast cancer tissue, surrounding tissue and lymph nodes in surgical specimens by fluorescence microscopy and macroscopy
Outcome measures: * The accumulation, tissue distribution, lokalization and (semi) quantification of bevacizumab-IRDye800CW in breast cancer tissue, surrounding tissue and lymph nodes. Measured by macroscopy using MSOT, Odessey and MFRI and by microscopy using fluorescence microscope and Odessey. * Correlation of the above to VEGF-levels and other biological parameters.
Time frame: After the last patient is included, which is expected to be within one year after the first inclusion
Occurrence of adverse events as a measure of safety and tolerability of bevacizumab-IRDye800CW
Obtaining information on safety aspects of bevacizumab-IRDye 800CW, side effects, AE, SAE, SUSAR by observing patients after tracer injection and follow up until 14 days after surgery
Time frame: Participants will be observed for the duration of hospital stay, an expected average of 4 hours after tracer injection. In case of adverse events, patients are observed and treated until recovery
Detection ability of preoperative optical fluorescence imaging techniques (FDOT; Fluorescence diffuse optical tomography and MSOT; multispectral opto-acoustic imaging) of the fluorescent signal from bevacizumab-IRDye800CW
* To assess and compare the presence of a fluorescent signal in breast cancer tissue and normal tissue * To explore pharmacokinetics and optical imaging time-points by peforming FDOT/MSOT at multiple time points after administration. * To correlate the fluorescence signal assessed by FDOT/MSOT with VEGF-levels, other biological parameters and the fluorescent signal assessed in the ex-vivo surgical specimen.
Time frame: detection of the tracer is performed at 4h, 36h and 72h after tracer injection.
Detection ability of the intra-operative mulitspectral fluorescence reflectance imaging (MFRI) of the fluorescent signal from bevacizumab-IRDye 800CW during surgery
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Study Type
INTERVENTIONAL
Allocation
NA
Purpose
TREATMENT
Masking
NONE
Enrollment
20
* To assess and compare the presence of a fluorescent signal in breast cancer tissue and normal tissue by assessing the images made by the MFRI during and after surgery. * the fluorescent signal assessed by MFRI will be correlated with VEGF levels in the ex-vivo surgical specimens.
Time frame: 72 hours after tracter injection, during surgery.
Detection ability of all optical imaging techniques (FDOT, MSOT, MFRI) of the fluorescent signal in surgical specimens ex vivo
Assessment of the ability of all optical imaging techniques (FDOT, MSOT, MFRI) to detect fluorescent signal in surgical specimens ex vivo by (semi) quantification of the images and to compare images between different techniques and different tissues (surrounding tissue, tumor tissue and lymph nodes)
Time frame: after the last patient is operated, which is approximately one year after study start.