Fluorescence Image Guided Surgery in Cholangiocarcinoma (COUGAR)

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

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.

Study Overview

• Status: Recruiting
• Conditions: Hilar Cholangiocarcinoma
• Intervention / Treatment: Drug: Bevacizumab-IRDye800CW; Device: near infrared (NIR) fluorescence imaging

Detailed Description

See brief summary

• Study Type: Interventional
• Enrollment (Anticipated): 12
• Phase: Phase 2; Phase 1

Contacts and Locations

• Study Contact: Name: A B de Vries, MD; Phone Number: +31503612586; Email: a.b.de.vries01@umcg.nl

Study Locations

• Netherlands
  • Groningen, Netherlands, 9713 GZ
    • Recruiting
    • University Medical Center Groningen
    • Contact: W. B. Nagengast, MD, PhD, PharmD; Phone Number: +31503612620; Email: w.b.nagengast@umcg.nl
    • Contact: A. B. de Vries, MD; Phone Number: +31503612586; Email: a.b.de.vries01@umcg.nl
    • Principal Investigator: W. B. Nagengast, MD, PhD, PharmD
    • Principal Investigator: G. M. van Dam, MD, PhD
    • Principal Investigator: M. T. de Boer, MD,PhD

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Diagnostic
• Allocation: N/A
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / Arm

Intervention / Treatment

Experimental: Intraoperative 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

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

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Optimal dose finding of Bevacizumab 800CW in hilar cholangiocarcinoma	- 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).	24 months

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Peroperative detection of hilar cholangiocarcinoma with real-time near-infrared fluorescence camera	- 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?	24 months
Detection of hilar cholangiocarcinoma in real-time near-infrared fluorescence ex-vivo endoscopy	- 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?	24 months
Establish tracer distribution in tumour tissue	- Visualisation of tracer distribution at microscopic level using ex vivo needle based confocal laser endomicroscopy.	24 months
Measurement of fluorescence in tumour tissue en surrounding normal tissue	- Correction for scattering and measurement of fluorescent signal using spectroscopy ex vivo.	24 months

Collaborators and Investigators

• Sponsor: University Medical Center Groningen
• Investigators: Principal Investigator: M. T. de Boer, MD, PhD, University Medical Center Groningen

Study record dates

Study Major Dates

• Study Start (Actual): April 1, 2019
• Primary Completion (Anticipated): December 1, 2021
• Study Completion (Anticipated): December 1, 2021

Study Registration Dates

• First Submitted: June 11, 2018
• First Submitted That Met QC Criteria: August 2, 2018
• First Posted (Actual): August 8, 2018

Study Record Updates

• Last Update Posted (Actual): April 28, 2021
• Last Update Submitted That Met QC Criteria: April 27, 2021
• Last Verified: April 1, 2021

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Neoplasms by Histologic Type; Neoplasms; Adenocarcinoma; Carcinoma; Neoplasms, Glandular and Epithelial; Cholangiocarcinoma; Klatskin Tumor; Physiological Effects of Drugs; Antineoplastic Agents; Antineoplastic Agents, Immunological; Angiogenesis Inhibitors; Angiogenesis Modulating Agents; Growth Substances; Growth Inhibitors; Bevacizumab
• Other Study ID Numbers: NL65378.042.18

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No