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Fluorescence Image Guided Surgery in Cholangiocarcinoma (COUGAR)

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Know the risks and potential benefits of clinical studies and talk to your health care provider before participating. Read our disclaimer for details. Identifier: NCT03620292
Recruitment Status : Recruiting
First Posted : August 8, 2018
Last Update Posted : April 28, 2021
Information provided by (Responsible Party):
dr. W.B. Nagengast, MD, University Medical Center Groningen

Brief 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.

Condition or disease Intervention/treatment Phase
Hilar Cholangiocarcinoma Drug: Bevacizumab-IRDye800CW Device: near infrared (NIR) fluorescence imaging Phase 1 Phase 2

Detailed Description:
See brief summary

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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 12 participants
Allocation: N/A
Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Diagnostic
Official Title: Cholangiocarcinoma Detection Using an Intraoperative Fluorescence Image Guided Approach With Bevacizumab-IRDye 800CW
Actual Study Start Date : April 1, 2019
Estimated Primary Completion Date : December 1, 2021
Estimated Study Completion Date : December 1, 2021

Resource links provided by the National Library of Medicine

Drug Information available for: Bevacizumab

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 Name: Tracer administration

Device: near infrared (NIR) fluorescence imaging
Intraoperative NIR fluorescence imaging of hilar cholangiocarcinoma, lymph nodes, resection margins, resection specimens
Other Name: optical imaging

Primary Outcome Measures :
  1. Optimal dose finding of Bevacizumab 800CW in hilar cholangiocarcinoma [ Time Frame: 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 Outcome Measures :
  1. Peroperative detection of hilar cholangiocarcinoma with real-time near-infrared fluorescence camera [ Time Frame: 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?

  2. Detection of hilar cholangiocarcinoma in real-time near-infrared fluorescence ex-vivo endoscopy [ Time Frame: 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?

  3. Establish tracer distribution in tumour tissue [ Time Frame: 24 months ]
    - Visualisation of tracer distribution at microscopic level using ex vivo needle based confocal laser endomicroscopy.

  4. Measurement of fluorescence in tumour tissue en surrounding normal tissue [ Time Frame: 24 months ]
    - Correction for scattering and measurement of fluorescent signal using spectroscopy ex vivo.

Information from the National Library of Medicine

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Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No

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.

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its identifier (NCT number): NCT03620292

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Contact: W B Nagengast, MD, PhD, PharmD +31503612620
Contact: A B de Vries, MD +31503612586

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University Medical Center Groningen Recruiting
Groningen, Netherlands, 9713 GZ
Contact: W. B. Nagengast, MD, PhD, PharmD    +31503612620   
Contact: A. B. de Vries, MD    +31503612586   
Principal Investigator: W. B. Nagengast, MD, PhD, PharmD         
Principal Investigator: G. M. van Dam, MD, PhD         
Principal Investigator: M. T. de Boer, MD,PhD         
Sponsors and Collaborators
University Medical Center Groningen
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Principal Investigator: G. M. van Dam, MD, PhD University Medical Center Groningen
Principal Investigator: M. T. de Boer, MD, PhD University Medical Center Groningen
Principal Investigator: W. B. Nagengast, MD, PhD, PharmD University Medical Center Groningen
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Responsible Party: dr. W.B. Nagengast, MD, Dr. W.B. Nagengast, Gastroenterologist, Principal Investigator, University Medical Center Groningen Identifier: NCT03620292    
Other Study ID Numbers: NL65378.042.18
First Posted: August 8, 2018    Key Record Dates
Last Update Posted: April 28, 2021
Last Verified: April 2021
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: No

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Studies a U.S. FDA-regulated Drug Product: No
Studies a U.S. FDA-regulated Device Product: No
Additional relevant MeSH terms:
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Klatskin Tumor
Neoplasms, Glandular and Epithelial
Neoplasms by Histologic Type
Antineoplastic Agents, Immunological
Antineoplastic Agents
Angiogenesis Inhibitors
Angiogenesis Modulating Agents
Growth Substances
Physiological Effects of Drugs
Growth Inhibitors