Fluorescence Image Guided Surgery in Cholangiocarcinoma

NCT03620292 — Phase 1 / Phase 2, Unknown, 12 participants, University Medical Center Groningen

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Cholangiocarcinoma Detection Using an Intraoperative Fluorescence Image Guided Approach With Bevacizumab-IRDye 800CW

Registry	NCT03620292, acronym COUGAR
Status	Unknown
Phase	Phase 1 / Phase 2
Study type	Interventional; na, single group, masking: none, diagnostic
Enrollment	12 (Estimated)
Sponsor	University Medical Center Groningen (Other)
Conditions	Hilar Cholangiocarcinoma
Interventions	Bevacizumab-IRDye800CW, near infrared (NIR) fluorescence imaging (Drug, device)
Dates	start 2019-04-01, primary completion 2021-12-01 (estimated), completion 2021-12-01 (estimated), first posted 2018-08-08, last updated 2021-04-28
Locations	1 site in Netherlands

-Summary

Cholangiocarcinoma is an epithelial cell malignancy arising from varying locations within the biliary tree and is difficult to diagnose due to the often-silent clinical nature. The best chance of long-term survival and potential cure is surgical resection with negative surgical margins, but many patients are unresectable due to locally advanced or metastatic disease at diagnosis. Because cholangiocarcinoma is difficult to diagnose at an early stage and extends diffusely, most patients have unresectable disease at clinical presentation, and prognosis is very poor (5-year survival is 0-40% even in resected cases)

There is a need for better visualization of tumor tissue, lymph nodes and resection margins during surgery for perihilar cholangiocarcinoma (PHCC). Optical molecular imaging of PHCC associated biomarkers is a promising technique to accommodate this need. The biomarkers Vascular Endothelial Growth Factor (VEGF-A), Epidermal Growth Factor Receptor (EGFR) and c-MET are all overexpressed in PHCC versus normal tissue and are proven to be valid targets for molecular imaging. Currently, tracers that target these biomarkers are available for use in clinical studies. In previous studies with other tumor types, the investigators tested the tracer bevacizumab-IRDye800CW for the biomarker VEGF-A with very promising results. Since all markers show roughly similar expression in ex vivo studies, the initial study will be performed with bevacizumab-IRDye800CW as the investigators have the most experience with this tracer. The investigators hypothesize that the tracer bevacizumab-IRDye 800CW accumulates in PHCC tissue, enabling visualization using a NIR intraoperative camera system and ex vivo NIR endoscopy. In this pilot study, the investigators will determine if it is possible to detect PHCC intraoperatively and by ex vivo NIR endoscopy using bevacizumab 800CW, and which tracer dose gives the best target-to-background ratio. The most optimal tracer dose will be selected for a future phase II trial.

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+Detailed description

See brief summary

+Arms and interventions

Arm	Type	Interventions	Description
Intraoperative NIR fluorescence imaging	Experimental	Drug: Bevacizumab-IRDye800CW; Device: near infrared (NIR) fluorescence imaging	A non-randomized, non-blinded, prospective, single center pilot dose escalation study with bevacizumab-800CW for NIR fluorescence image guided surgery in hilar cholangiocarcinoma * IV-administration of 10, 25 or 50 mg of the fluorescent tracer bevacizumab-800CW to a total of 15 patients with resectable hilar cholangiocarcinoma 3 days prior to surgery. * Peroperative open air NIR fluorescence imaging * Ex vivo endoscopic and histopathological NIR fluorescence imaging

Bevacizumab-IRDye800CW (Drug), also known as Tracer administration: Intravenous administration of Bevacizumab-IRDye800CW prior to surgery for hilar cholangiocarcinoma
near infrared (NIR) fluorescence imaging (Device), also known as optical imaging: Intraoperative NIR fluorescence imaging of hilar cholangiocarcinoma, lymph nodes, resection margins, resection specimens

+Outcome measures

Primary outcomes

Optimal dose finding of Bevacizumab 800CW in hilar cholangiocarcinoma [24 months]: \- Comparison of three doses of Bevacizumab 800CW by calculating target to background ratios in fluorescence images obtained during and directly after the surgical procedure and fluorescence images obtained during ex vivo analyses in bread loaf slices and in histological slices (odyssey scanner, fluorescence microscopy).

Secondary outcomes

Peroperative detection of hilar cholangiocarcinoma with real-time near-infrared fluorescence camera [24 months]: \- Comparison between perioperative fluorescent imaging and ex vivo analysis (histology, breadloaf slices) to see if detection of tumor tissue is feasible. I.e. is high fluorescent signal corresponding with localization of tumor tissue in ex-vivo analysis?
Detection of hilar cholangiocarcinoma in real-time near-infrared fluorescence ex-vivo endoscopy [24 months]: \- Comparison of endoscopic fluorescent imaging and ex vivo analysis(histology, breadloaf slices) to see if endoscopic detection is feasible. I.e. is high fluorescent signal seen during ex-vivo endoscopy corresponding with localization of tumor tissue in ex-vivo analysis?
Establish tracer distribution in tumour tissue [24 months]: \- Visualisation of tracer distribution at microscopic level using ex vivo needle based confocal laser endomicroscopy.
Measurement of fluorescence in tumour tissue en surrounding normal tissue [24 months]: \- Correction for scattering and measurement of fluorescent signal using spectroscopy ex vivo.

+Eligibility

Sex: All, ages: 18 Years to any

Inclusion Criteria:

* Patients with clinical suspicion of PHCC who are scheduled to undergo surgical intervention with curative intent
* WHO performance score 0-2.

Exclusion Criteria:

* Medical or psychiatric conditions that compromise the patient's ability to give informed consent.
* Other invasive malignancy
* Pregnant or lactating women.
* History of infusion reactions to bevacizumab or other monoclonal antibody therapies.
* Inadequately controlled hypertension with or without current antihypertensive medications
* Within 6 months prior to inclusion: myocardial infarction, TIA, CVA pulmonary embolism, uncontrolled chronic hepatic failure, unstable angina pectoris.

+Locations (1)

Facility	City	Country	Status
University Medical Center Groningen	Groningen	Netherlands	Recruiting

+Investigators

G. M. van Dam, MD, PhD, Principal investigator, University Medical Center Groningen
M. T. de Boer, MD, PhD, Principal investigator, University Medical Center Groningen
W. B. Nagengast, MD, PhD, PharmD, Principal investigator, University Medical Center Groningen