Effect of Sorafenib on ccRCC Uptake of Radiolabeled Bevacizumab or cG250

November 29, 2013 updated by: Radboud University Medical Center

The Effect of Sorafenib (Nexavar®) on 111-Indium Labeled Chimeric Monoclonal Antibody G250 or 111-Indium Labeled Bevacizumab (Avastin®) Uptake in Patients With Clear Cell RCC (ccRCC)

Sorafenib is a tyrosine kinase inhibitor that is registered for the treatment of metastasized clear cell Renal Cell Carcinoma (ccRCC). It inhibits signal transduction of the Vascular Endothelial Growth Factor Receptor (VEGFR) and the Platelet Derived Growth Factor Receptor (PDGFR). In the tumorigenesis of ccRCC, VEGF and PDGF are upregulated due to the defective Von-Hippel-Lindau (VHL) gene. CcRCC has a high Interstitial Fluid Pressure (IFP) and Tumor Microvascular Density (TMD), hampering the delivery of chemotherapeutics and monoclonal antibodies (mAbs). It was hypothesized that antiangiogenic compounds decrease tumor IFP and TMD, thus normalizing tumor vasculature, before diminishing tumor vasculature. Bevacizumab is an anti-VEGF mAb which depletes soluble VEGF from plasma, depriving VEGFR of its ligand. Chimeric monoclonal antibody cG250 recognizes carbonic anhydrase IX (CAIX), an antigen that is abundantly expressed in Renal Cell Carcinoma (RCC) and has limited expression in normal tissue. The aim of this study was to investigate the effect of Sorafenib on ccRCC physiology, by determining tumor uptake of 111In labeled cG250 or 111In labeled Bevacizumab.

Study Overview

Status

Completed

Conditions

Intervention / Treatment

Study Type

Interventional

Enrollment (Actual)

26

Phase

  • Not Applicable

Contacts and Locations

This section provides the contact details for those conducting the study, and information on where this study is being conducted.

Study Locations

  • Netherlands
    • Gelderland
      • Nijmegen, Gelderland, Netherlands, 6500 HB
        • Radboud University Nijmegen Medical Center

Participation Criteria

Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.

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:

  • Renal cell carcinoma patients planned for surgery (nephrectomy/metastasectomy)
  • Karnofsky > 70 %

  • Laboratory values within 14 days prior to start:

    • White blood cells (WBC) > 3.5 x 109/L
    • Platelets > 100 x 109/L
    • Hemoglobin > 6 mmol/L
    • Total bilirubin < 1.5 upper limit of normal (ULN)
    • ASAT, ALAT < 2.5 x ULN (<5 x in case of liver metastases)
    • Lactate dehydrogenase (LDH) > 1.5. ULN
    • Serum creatinine < 2 x ULN
    • Amylase and Lipase < 1.5 ULN
  • Negative pregnancy test in premenopausal women
  • Age over 18 years
  • Signed informed consent
  • Life expectancy > 24 weeks
  • PT/APTT/ INR < 1.5 ULN
  • No current use of coumarin derivatives

Exclusion Criteria:

  • Known subtype other than clear cell RCC
  • Pre-exposure to murine/chimeric antibody therapy
  • Known brain metastases
  • Untreated hypercalcemia
  • Uncontrolled hypertension
  • Concurrent therapeutic anticoagulation
  • Chemotherapy, immunotherapy or radiation therapy within 4 weeks prior to start of study. Palliative limited field external radiation for fracture prevention is allowed
  • Cardiac arrhythmias requiring antiarrhythmics (beta-blockers, digoxin), symptomatic coronary artery disease and congestive heart failure New York Heart Association III or IV.
  • Previous malignancy < 2 years prior to the study (except for cervical carcinoma in situ, basal cell carcinoma, or superficial bladder tumours (Ta, Tis, T1)
  • Any medical condition present that in the opinion of the investigator will affect patients' clinical status. No other concurrent malignancy except nonmetastatic nonmelanoma skin cancer or carcinoma in situ of the cervix.
  • Active clinically serious bacterial or fungal infections (< grade 2 NCI-CTC version 3)
  • Known history of Human Immunodeficiency virus (HIV) infection or chronic hepatitis B/C.
  • Prior use of Raf-kinase inhibitors, MEK and Farnesyl transferase inhibitors
  • Prior use of Bevacizumab and all other drugs that target VEGF/ VEGF-receptors
  • Use of antiepileptic drugs
  • Pregnancy and lactation

Study Plan

This section provides details of the study plan, including how the study is designed and what the study is measuring.

How is the study designed?

Design Details

  • Primary Purpose: BASIC_SCIENCE
  • Allocation: NON_RANDOMIZED
  • Interventional Model: PARALLEL
  • Masking: NONE

Arms and Interventions

Participant Group / Arm
Intervention / Treatment
EXPERIMENTAL: 1
10 Patients planned to undergo (partial) nephrectomy or metastasectomy receive an iv injection of 100 MBq/1mg 111In-Bevacizumab. Patients are then treated with Sorafenib 200 mg 2dd2 po for 4 weeks. In the last week of treatment, the same injection is given to determine tumor accumulation of the radiolabeled mAb after Sorafenib treatment. Whole-body scintigraphic images are recorded 1 week after both injections to calculate tumor uptake. After Sorafenib treatment, patients will undergo surgery.
Drug: Sorafenib
Sorafenib 200 mg 2dd2 po for 4 weeks before surgery
Other Names:
  • Avastin
  • Bevacizumab
  • Nexavar
  • cG250
  • Rencarex
Drug: 111Indium-bevacizumab
100 MBq / 1 mg 111Indium/bevacizumab iv
Other Names:
  • avastin
  • indium
EXPERIMENTAL: 2
10 Patients planned to undergo (partial) nephrectomy or metastasectomy receive an iv injection of 100 MBq/10mg 111In-cG250. Patients are then treated with Sorafenib 200 mg 2dd2 po for 4 weeks. In the last week of treatment, the same injection is given to determine tumor accumulation of the radiolabeled mAb after Sorafenib treatment. Whole-body scintigraphic images are recorded 1 week after both injections to calculate tumor uptake. After Sorafenib treatment, patients will undergo surgery.
Drug: Sorafenib
Sorafenib 200 mg 2dd2 po for 4 weeks before surgery
Other Names:
  • Avastin
  • Bevacizumab
  • Nexavar
  • cG250
  • Rencarex
Drug: 111Indium-cG250
100 MBq / 10 mg 111Indium-cG250 iv
Other Names:
  • indium
  • rencarex
ACTIVE_COMPARATOR: 3
5 Patients planned to undergo (partial) nephrectomy or metastasectomy receive an iv injection of 100 MBq/1mg 111In-Bevacizumab. Whole-body scintigraphic images are recorded 1 week after the injection to calculate tumor uptake. Hereafter, patients will undergo surgery.
Drug: 111Indium-bevacizumab
100 MBq / 1 mg 111Indium/bevacizumab iv
Other Names:
  • avastin
  • indium

What is the study measuring?

Primary Outcome Measures

Outcome Measure
Time Frame
To determine the effect of sorafenib treatment on 111In-cG250 uptake of the tumor
Time Frame: pre-surgery
pre-surgery
To determine the effect of sorafenib treatment on 111In-bevacizumab uptake of the tumor
Time Frame: pre-surgery
pre-surgery

Secondary Outcome Measures

Outcome Measure
Time Frame
Immunohistochemical analysis of CA-IX expression, (p)VHL status, HIF1-a, VEGF and PDGF expression, apoptosis and necrosis of surgical specimen
Time Frame: within 6 months post-surgery
within 6 months post-surgery

Collaborators and Investigators

This is where you will find people and organizations involved with this study.

Sponsor

Radboud University Medical Center

Collaborators

Dutch Cancer Society

Investigators

  • Principal Investigator: WJG Oyen, MD, PhD, Department of Nuclear Medicine, Radboud University Nijmegen Medical Center, Nijmegen, The Netherlands
  • Principal Investigator: PFA Mulders, MD, PhD, Department of Urology, Radboud University Nijmegen Medical Center, Nijmegen, The Netherlands

Publications and helpful links

The person responsible for entering information about the study voluntarily provides these publications. These may be about anything related to the study.

General Publications

Study record dates

These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.

Study Major Dates

Study Start

July 1, 2007

Primary Completion (ACTUAL)

April 1, 2012

Study Completion (ACTUAL)

June 1, 2012

Study Registration Dates

First Submitted

January 3, 2008

First Submitted That Met QC Criteria

January 15, 2008

First Posted (ESTIMATE)

January 28, 2008

Study Record Updates

Last Update Posted (ESTIMATE)

December 2, 2013

Last Update Submitted That Met QC Criteria

November 29, 2013

Last Verified

February 1, 2012

More Information

Terms related to this study

Keywords

Additional Relevant MeSH Terms

Other Study ID Numbers

  • Sorafenib-mAbs

This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.

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