Visualization of Rectal Cancer During Endoscopy, Using a Fluorescent Tracer

NCT01972373 | Completed Phase 1 DMC

• 2 other identifiers: NL43407.042.132013-000333-12
• Study Type: interventional
• Target: 30
• Locations: 1 country
• Sites: 1

Brief Summary

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.

Conditions

Rectal Cancer

Keywords

VEGF; Fluorescence; Endoscopy; Rectal cancer

Outcome Measures

Primary Outcomes (1)

• Sensitivity of the marker bevacizumab-IRDye800CW

  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.

  First endoscopic procedure before start radio-chemotherapy and second endoscopic procedure 3 weeks after start of radiochemotherapy

Secondary Outcomes (5)

• Correlation between bevacizumab-IRDye800CW uptake and pathological response (pCR)

  Endoscopic procedures before and after chemoradiation therapy, assesing of pathological respons after churgical intervention

• In vivo quantification of the NIR fluorescent signal of bevacizumab-IRDye800CW using the NIR fluorescence endoscope vs. ex vivo VEGF levels in biopsies

  Before start and after chemoradiation therapy

• To Perform correlate pathways analyses using RNA/DNA/protein analyses to NIR fluorescence data

  After surgery

• The ability of optoacoustic endoscopy to detect bevacizumab-IRDye800CW in deeper areas of the tumor

  Before start and after chemoradiation therapy

• Collection of safety regarding administration of Bevacizumab-IRDye800CW

  Participants will be followed the duration of the chemoradiation therapy till surgery

Study Arms (1)

NIR endoscopy with Bevacizumab-IRDye800CW

EXPERIMENTAL

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.

Drug: Bevacizumab-IRDye800CW; Device: NIR fluorescence endoscopy

Interventions

Bevacizumab-IRDye800CW DRUG

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

Also known as: Fluorescence tracer imaging, Beva-800CW, Bevacizumab-800CW

NIR endoscopy with Bevacizumab-IRDye800CW

NIR fluorescence endoscopy DEVICE

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

Also known as: Sigmoid endoscopy using near infrared fluorescence

NIR endoscopy with Bevacizumab-IRDye800CW

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• Biopsy-proven, newly diagnosed primary rectal adenocarcinoma, i.e. with the lowest part of the tumor less than 16 cm from the anal verge using a rigid rectoscope or flexible endoscope.
• Locally advanced tumor fulfilling at least one of the following criteria on pelvic MRI indicating high risk of failing locally and/or systemically:
• Clinical stage (c)T4a
• cT4b
• Extramural vascular invasion (EMVI+)
• N2 i.e. four or more lymph nodes in the mesorectum showing morphological signs on MRI indicating metastatic disease
• positive mesorectal fascia (MRF), i.e. tumor or lymph node one mm or less from the mesorectal fascia
• metastatic lateral nodes, \> 1 cm (lat Lymph Node+)
• Staging done within 5 weeks before randomization.
• No contraindications to chemotherapy, including adequate blood counts:
• White blood count ≥4.0 x 109/L;
• Platelet count ≥100 x 109/L;
• Clinically acceptable haemoglobin levels;
• Creatinine levels indicating renal clearance of ≥50 ml/min;
• Bilirubin \<35 μmol/l

You may not qualify if:

• Extensive growth into cranial part of the sacrum (above S3) or the lumbosacral nerve roots indicating that surgery will never be possible even if substantial tumour down-sizing is seen.
• Presence of metastatic disease or recurrent rectal tumour. Familial Adenomatosis Polyposis coli (FAP), Hereditary Non-Polyposis Colorectal Cancer (HNPCC), active Crohn's disease or active ulcerative Colitis.
• Concomitant malignancies, except for adequately treated basocellular carcinoma of the skin or in situ carcinoma of the cervix uteri. Subjects with prior malignancies must be disease-free for at least 5 years.
• Known dihydropyrimidine dehydrogenase (DPD) deficiency.
• Any contraindications to MRI (e.g. patients with pacemakers).
• Medical or psychiatric conditions that compromise the patient's ability to give informed consent.
• Concurrent uncontrolled medical conditions.
• Any investigational treatment for rectal cancer within the past month.
• Pregnancy or breast feeding.
• Patients with known malabsorption syndromes or a lack of physical integrity of the upper gastrointestinal tract.
• Clinically significant (i.e. active) cardiac disease (e.g. congestive heart failure, symptomatic coronary artery disease and cardiac dysrhythmia, e.g. atrial fibrillation, even if controlled with medication) or myocardial infarction within the past 12 months.
• Patients with symptoms or history of peripheral neuropathy.

Sponsors & Collaborators

• University Medical Center Groningen: lead
• Dutch Cancer Society: collaborator

Study Sites (1)

University Medical Centre Groningen

Groningen, 9713 GZ, Netherlands

Location

Related Publications (2)

• de Jongh SJ, Tjalma JJJ, Koller M, Linssen MD, Vonk J, Dobosz M, Jorritsma-Smit A, Kleibeuker JH, Hospers GAP, Havenga K, Hemmer PHJ, Karrenbeld A, van Dam GM, van Etten B, Nagengast WB. Back-Table Fluorescence-Guided Imaging for Circumferential Resection Margin Evaluation Using Bevacizumab-800CW in Patients with Locally Advanced Rectal Cancer. J Nucl Med. 2020 May;61(5):655-661. doi: 10.2967/jnumed.119.232355. Epub 2019 Oct 18.

  PMID: 31628218 DERIVED

• Tjalma JJJ, Koller M, Linssen MD, Hartmans E, de Jongh SJ, Jorritsma-Smit A, Karrenbeld A, de Vries EG, Kleibeuker JH, Pennings JP, Havenga K, Hemmer PH, Hospers GA, van Etten B, Ntziachristos V, van Dam GM, Robinson DJ, Nagengast WB. Quantitative fluorescence endoscopy: an innovative endoscopy approach to evaluate neoadjuvant treatment response in locally advanced rectal cancer. Gut. 2020 Mar;69(3):406-410. doi: 10.1136/gutjnl-2019-319755. Epub 2019 Sep 18. No abstract available.

  PMID: 31533965 DERIVED

MeSH Terms

Conditions

Rectal Neoplasms

Condition Hierarchy (Ancestors)

Colorectal Neoplasms; Intestinal Neoplasms; Gastrointestinal Neoplasms; Digestive System Neoplasms; Neoplasms by Site; Neoplasms; Digestive System Diseases; Gastrointestinal Diseases; Intestinal Diseases; Rectal Diseases

Study Officials

• Wouter B Nagengast, MD, PhD

  University Medical Center Groningen

  PRINCIPAL INVESTIGATOR

• Geke AP Hospers, Prof. dr.

  University Medical Center Groningen

  PRINCIPAL INVESTIGATOR

• Boudewijn v. Etten, MD, PhD

  University Medical Center Groningen

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: NA
• Masking: NONE
• Purpose: DIAGNOSTIC
• Intervention Model: SINGLE GROUP
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: October 21, 2013
• First Posted: October 30, 2013
• Study Start: October 1, 2013
• Primary Completion: December 1, 2016
• Study Completion: January 1, 2017
• Last Updated: April 16, 2024

Record last verified: 2024-04

Locations

NL (1)