Effect of Sorafenib on ccRCC Uptake of Radiolabeled Bevacizumab or cG250

Clear Cell Renal Cell Carcinoma Clinical Trial

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)

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT00602862
• Other study ID #: Sorafenib-mAbs
• Status: Completed
• Phase: N/A
• First received: January 3, 2008
• Last updated: November 29, 2013
• Start date: July 2007
• Est. completion date: June 2012

Study information

• Verified date: February 2012
• Source: Radboud University
• Contact: n/a
• Is FDA regulated: No
• Health authority: Netherlands: The Central Committee on Research Involving Human Subjects (CCMO)
• Study type: Interventional

Clinical Trial 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.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 26
• Est. completion date: June 2012
• Est. primary completion date: April 2012
• Accepts healthy volunteers: No
• Gender: Both
• Age group: 18 Years and older

Eligibility

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 Design

Allocation: Non-Randomized, Endpoint Classification: Bio-availability Study, Intervention Model: Parallel Assignment, Masking: Open Label, Primary Purpose: Basic Science

Related Conditions & MeSH terms

• Carcinoma, Renal Cell
• Clear Cell Renal Cell Carcinoma

Intervention

Drug:
• Sorafenib
Sorafenib 200 mg 2dd2 po for 4 weeks before surgery
• 111Indium-bevacizumab
100 MBq / 1 mg 111Indium/bevacizumab iv
• 111Indium-cG250
100 MBq / 10 mg 111Indium-cG250 iv

Locations

Country	Name	City	State
Netherlands	Radboud University Nijmegen Medical Center	Nijmegen	Gelderland

Sponsors (2)

Lead Sponsor	Collaborator
Radboud University	Dutch Cancer Society

Country where clinical trial is conducted

Netherlands, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	To determine the effect of sorafenib treatment on 111In-cG250 uptake of the tumor		pre-surgery	No
Primary	To determine the effect of sorafenib treatment on 111In-bevacizumab uptake of the tumor		pre-surgery	No
Secondary	Immunohistochemical analysis of CA-IX expression, (p)VHL status, HIF1-a, VEGF and PDGF expression, apoptosis and necrosis of surgical specimen		within 6 months post-surgery	No