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Bevacizumab

Antineoplastic Agents, Immunological

Angiogenesis Inhibitors

Growth Inhibitors

In this non-randomized, non-blinded, prospective, feasibility study, bevacizumab-IRDye800CW will be administered to a total of 30 patients with proven locally advanced rectal cancer.

Intravenous administration of a microdose (4.5mg, subtherapeutic) of Bevacizumab-IRDye800CW prior to the endoscopic procedure

Bevacizumab-IRDye800CW

48-72 hours administration of Bevacizumab-IRDye800CW a flexible NIR fluorescence endoscopy will be performed via the rectum

NIR fluorescence endoscopy

Wouter B Nagengast, MD, PhD

Geke AP Hospers, Prof. dr.

Boudewijn v. Etten, MD, PhD

To improve rectal cancer management, there is a need for better visualization of drug targets in rectal cancer to identify patients who might benefit from specific targeted treatments. Molecular imaging of rectal cancer associated targets is a promising technique to accommodate this need. Vascular Endothelial Growth Factor (VEGF), which is differentially expressed in normal versus malignant colon tissue, has proven to be a valid target for molecular imaging. Fluorescent labeling of bevacizumab (a VEGF targeting humanized monoclonal antibody currently used in anti-cancer therapy) using IRDye800CW (a fluorescent dye) has potential advantages in view of safety, infrastructure, costs, stability and imaging resolution. Therefore, the fluorescent tracer bevacizumab-IRDye800CW has been developed at the University Medical Center Groningen (UMCG) and was recently approved to be administered to patients in a tracer dose. To detect this tracer in vivo in patients with colorectal cancer, a newly developed flexible near-infrared (NIR) fluorescence endoscope and optoacoustic endoscope have been developed which can be used in clinical studies. Optical fluorescence imaging may support response evaluation following chemoradiotherapy and give insight which patient might benefit from anti-VEGF targeted therapy in future studies.

In this non-randomized, non-blinded, prospective, single center feasibility study, patients with locally advanced rectal cancer who are included in the RAPIDO study (NL36315.042.11) will undergo two times epi-illumination endoscopy (in other words flexible NIR fluorescence endoscopy).

The study consists of a total of five study procedure related visits:

* Visit 1: During a screening visit, eligibility will be evaluated and patient characteristics will be collected.
* Visit 2: During the second visit 4.5 mg of bevacizumab-IRDye800CW will be administered intravenously. The patient will then be observed for 1 hour post administration.
* Visit 3: First endoscopy will be performed at baseline (two days after tracer administration); before the start of chemoradiotherapy.
* Visit 4: After chemoradiotherapy patients will receive a second dose of 4.5 mg of bevacizumab-IRDye800CW (second tracer administration)
* Visit 5: A second flexible NIR fluorescence endoscopy procedure will be performed (two-three days after the second tracer injection), preferably right before surgery.

Optionally and when available, we will ask patients if they would like to undergo optoacoustic endoscopy. This is a form of endoscopic ultrasound which is able to detect bevacizumab-IRDye800CW up to 2 cm in depth. The procedure is comparable with NIR fluorescence endoscopy. If patients agree, after removal of the NIR fluorescence endoscope the optoacoustic endoscope will be introduced in the rectum of the patient for detection of bevacizumab-IRDye800CW in deeper areas of the tumor.

Visualization of Rectal Cancer During Endoscopy, Using a Fluorescent Tracer

Visualization of a VEGF-targeted Optical Fluorescent Imaging Tracer in Rectal Cancer During Flexible NIR Fluorescence Endoscopy

To determine the sensitivity of the marker bevacizumab-IRDye800CW measured by innovative molecular imaging flexible NIR fluorescence endoscopy, and optionally optoacoustic endoscopy, in identifying target expression and heterogeneity prior to the start, or during early treatment, of neoadjuvant radiochemotherapy, to identify patients who benefit from additional treatment targeting VEGF to increase pCR in future studies.

Research aim to assess primary objectives by evaluation of biopsy specimen:

* To assess accumulation of bevacizumab-IRDye800CW in rectal cancer tissue and surrounding tissue at baseline and following radiochemotherapy of patients included in the RAPIDO trial.
* Evaluation of tumor areas with high fluorescence and low fluorescence signal.
* To correlate the above to VEGF-levels determined by immuno-histochemistry.

To abtain information on safety aspectsof the tracer, side effects, adverse events (AE), serious adverse events (SAE) and suspected unexpected serious adverse reactions (SUSAR)

Spots Global Cancer Trial Database for nir fluorescence endoscopy