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Effect of Sorafenib on ccRCC Uptake of Radiolabeled Bevacizumab or cG250

Primary Purpose

Clear Cell Renal Cell Carcinoma

Status

Completed

Phase

Not Applicable

Locations

Netherlands

Study Type

Interventional

Intervention

Sorafenib

111Indium-bevacizumab

111Indium-cG250

About this trial

This is an interventional basic science trial for Clear Cell Renal Cell Carcinoma focused on measuring Angiogenesis inhibitors

Eligibility Criteria

18 Years - undefined (Adult, Older Adult)All SexesDoes not accept healthy volunteers

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

Sites / Locations

Radboud University Nijmegen Medical Center

Arms of the Study

Arm 1

Arm 2

Arm 3

Arm Type

Experimental

Active Comparator

Arm Label

Arm Description

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.

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.

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.

Outcomes

Primary Outcome Measures

To determine the effect of sorafenib treatment on 111In-cG250 uptake of the tumor

To determine the effect of sorafenib treatment on 111In-bevacizumab uptake of the tumor

Secondary Outcome Measures

Immunohistochemical analysis of CA-IX expression, (p)VHL status, HIF1-a, VEGF and PDGF expression, apoptosis and necrosis of surgical specimen

Full Information

NCT ID

NCT00602862

First Posted

January 3, 2008

Last Updated

November 29, 2013

Sponsor

Radboud University Medical Center

Collaborators

Dutch Cancer Society

1. Study Identification

Unique Protocol Identification Number

NCT00602862

Brief Title

Effect of Sorafenib on ccRCC Uptake of Radiolabeled Bevacizumab or cG250

Official Title

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)

Study Type

Interventional

2. Study Status

Record Verification Date

February 2012

Overall Recruitment Status

Completed

Study Start Date

July 2007 (undefined)

Primary Completion Date

April 2012 (Actual)

Study Completion Date

June 2012 (Actual)

3. Sponsor/Collaborators

Responsible Party, by Official Title

Sponsor

Name of the Sponsor

Radboud University Medical Center

Collaborators

Dutch Cancer Society

4. Oversight

Data Monitoring Committee

Yes

5. Study Description

Brief Summary

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.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study

Clear Cell Renal Cell Carcinoma

Keywords

Angiogenesis inhibitors

7. Study Design

Primary Purpose

Basic Science

Study Phase

Not Applicable

Interventional Study Model

Parallel Assignment

Masking

None (Open Label)

Allocation

Non-Randomized

Enrollment

26 (Actual)

8. Arms, Groups, and Interventions

Arm Title

Arm Type

Experimental

Arm Description

Arm Title

Arm Type

Experimental

Arm Description

Arm Title

Arm Type

Active Comparator

Arm Description

Intervention Type

Drug

Intervention Name(s)

Sorafenib

Other Intervention Name(s)

Bevacizumab, Avastin, Nexavar, cG250, Rencarex

Intervention Description

Sorafenib 200 mg 2dd2 po for 4 weeks before surgery

Intervention Type

Drug

Intervention Name(s)

111Indium-bevacizumab

Other Intervention Name(s)

avastin, indium

Intervention Description

100 MBq / 1 mg 111Indium/bevacizumab iv

Intervention Type

Drug

Intervention Name(s)

111Indium-cG250

Other Intervention Name(s)

rencarex, indium

Intervention Description

100 MBq / 10 mg 111Indium-cG250 iv

Primary Outcome Measure Information:

Title

To determine the effect of sorafenib treatment on 111In-cG250 uptake of the tumor

Time Frame

pre-surgery

Title

To determine the effect of sorafenib treatment on 111In-bevacizumab uptake of the tumor

Time Frame

pre-surgery

Secondary Outcome Measure Information:

Title

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

10. Eligibility

Sex

All

Minimum Age & Unit of Time

18 Years

Accepts Healthy Volunteers

Eligibility Criteria

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

Overall Study Officials:

First Name & Middle Initial & Last Name & Degree

WJG Oyen, MD, PhD

Organizational Affiliation

Department of Nuclear Medicine, Radboud University Nijmegen Medical Center, Nijmegen, The Netherlands

Official's Role

Principal Investigator

First Name & Middle Initial & Last Name & Degree

PFA Mulders, MD, PhD

Organizational Affiliation

Department of Urology, Radboud University Nijmegen Medical Center, Nijmegen, The Netherlands

Official's Role

Principal Investigator

Facility Information:

Facility Name

Radboud University Nijmegen Medical Center

City

Nijmegen

State/Province

Gelderland

ZIP/Postal Code

6500 HB

Country

Netherlands

12. IPD Sharing Statement

Citations:

PubMed Identifier

20956472

Citation

Desar IM, Stillebroer AB, Oosterwijk E, Leenders WP, van Herpen CM, van der Graaf WT, Boerman OC, Mulders PF, Oyen WJ. 111In-bevacizumab imaging of renal cell cancer and evaluation of neoadjuvant treatment with the vascular endothelial growth factor receptor inhibitor sorafenib. J Nucl Med. 2010 Nov;51(11):1707-15. doi: 10.2967/jnumed.110.078030. Epub 2010 Oct 18.

Results Reference

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Effect of Sorafenib on ccRCC Uptake of Radiolabeled Bevacizumab or cG250

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