Angiogenic Factor Expression During Fractionated Irradiation

Pilot Study to Determine the Effect of Fractionated Radiotherapy on Expression of Pro-angiogenic Factors in Oesophagus Carcinoma

The main question of this study is if and when VEGF (vascular endothelial growth factor) expression in the tumor is upregulated during chemoradiation and if bevacizumab inhibits subsequent vessel growth in the tumor.

• Therefore the first aim of this study is to identify the time point of induction of VEGF in the tumor tissue of esophagus carcinoma during chemoradiation (after 1,2,3 or 4 weeks of chemoradiation).
• If we identify increased expression of VEGF at a certain time point, our second aim is to determine if we can inhibit the subsequent tumor vessel growth by administration of bevacizumab.

Study Overview

• Status: Unknown
• Conditions: Primary Esophageal Carcinoma
• Intervention / Treatment: Drug: Bevacizumab

• Study Type: Interventional
• Enrollment (Anticipated): 40
• Phase: Early Phase 1

Contacts and Locations

Study Locations

• Netherlands
  • Alkmaar, Netherlands
    • Recruiting
    • Noordwest Ziekenhuisgroep
    • Contact: A. M. Van Berkel
  • Amsterdam, Netherlands
    • Recruiting
    • Academisch Medisch Centrum
    • Contact: H. W.M. van Laarhoven
  • Noord-Holland
    • Amsterdam, Noord-Holland, Netherlands, 1081 HV
      • Recruiting
      • VU University Medical Center
      • Principal Investigator: Henk Verheul, 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 that will receive chemoradiation following CROSS-schedule before surgery for esophageal carcinoma
• ability to give informed consent
• age 18 years or older

Exclusion Criteria:

• pregnancy
• evidence of bleeding diathesis, coagulopathy
• inflammation of the GI-tract
• brain metastases
• diastolic/ systolic hypertension, not responding to treatment
• arterial thromboembolism in medical history
• surgery within the month prior to start of bevacizumab treatment

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Non-Randomized
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
No Intervention: on-treatment tumor biopsie; patients will undergo an pre-treatment and on-treatment tumor biopsy, to measure VEGF expression, and identify the time point of induction of VEGF expression.
Experimental: bevacizumab; These patients will receive bevacizumab once a week during their chemoradiation, starting at the identified time point of enhanced VEGF expression. These patients will also undergo and pre-treatment tumor biopsy and 1 tumor biopsy 1 week after the start of bevacizumab treatment.	Drug: Bevacizumab; patients will receive bevacizumab (3mg/kg/wk) starting from the identified induction time point of VEGF expression; Other Names: Bevacizumab (Avastin).

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Change of VEGF mRNA expression in tumor biopsies	To compare the VEGF mRNA expression in the pre-treatment and on-treatment tumor biopsies, to measure the change in VEGF expression from baseline.	5 weeks
Change of VEGFR2 phosphorylation with IHC	To determine the level of pVEGFR2 expression in tumor biopsies of patients that received bevacizumab, and to compare that to their pre-treatment expression levels, to identify the changes in expression from baseline.	8 weeks

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Changes of mRNA expression of other pro-angiogenic factors	To identify the expression of other pro-angiogenic factors in the tumor, and to measure the changes from baseline expression (pre-treatment vs on-treatment biopsies).	5 weeks
Changes in protein expression of pro-angiogenic factors	To identify the protein expression of other pro-angiogenic factors in the tumor, and to measure the changes from baseline expression (pre-treatment vs on-treatment biopsies).	5 weeks
Changes in vascular parameters in the tumor tissue to asses ongoing angiogenesis	To identify the expression of CD31+ and pericyte markers with IHC staining in the tumor, and to measure the changes from baseline expression (pre-treatment vs on-treatment biopsies).	5 weeks

Collaborators and Investigators

• Sponsor: Amsterdam UMC, location VUmc
• Collaborators: Academisch Medisch Centrum - Universiteit van Amsterdam (AMC-UvA); Noordwest Ziekenhuisgroep

Study record dates

Study Major Dates

• Study Start: February 1, 2014
• Primary Completion (Anticipated): March 1, 2021
• Study Completion (Anticipated): May 1, 2021

Study Registration Dates

• First Submitted: February 19, 2014
• First Submitted That Met QC Criteria: February 24, 2014
• First Posted (Estimate): February 26, 2014

Study Record Updates

• Last Update Posted (Actual): October 2, 2019
• Last Update Submitted That Met QC Criteria: October 1, 2019
• Last Verified: October 1, 2019

More Information

Terms related to this study

• Keywords: bevacizumab; VEGF; Radiotherapy; esophagus carcinoma
• Additional Relevant MeSH Terms: Digestive System Diseases; Neoplasms by Histologic Type; Neoplasms; Neoplasms by Site; Neoplasms, Glandular and Epithelial; Gastrointestinal Neoplasms; Digestive System Neoplasms; Gastrointestinal Diseases; Head and Neck Neoplasms; Esophageal Diseases; Carcinoma; Esophageal Neoplasms; Physiological Effects of Drugs; Antineoplastic Agents; Antineoplastic Agents, Immunological; Angiogenesis Inhibitors; Angiogenesis Modulating Agents; Growth Substances; Growth Inhibitors; Bevacizumab
• Other Study ID Numbers: 2013/340