Clinical trial NCT00602862: 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
Overall status: COMPLETED
Phase: NA
Conditions: Clear Cell Renal Cell Carcinoma
Keywords: Angiogenesis inhibitors
Lead sponsor: Radboud University Medical Center
Sponsor class: OTHER
Collaborators: name: Dutch Cancer Society
First posted: 2008-01-28
Enrollment: 26
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NON_RANDOMIZED
Intervention model: PARALLEL
Primary purpose: BASIC_SCIENCE

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.


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

Primary outcomes:
measure: To determine the effect of sorafenib treatment on 111In-cG250 uptake of the tumor
timeFrame: pre-surgery
measure: To determine the effect of sorafenib treatment on 111In-bevacizumab uptake of the tumor
timeFrame: pre-surgery
Secondary outcomes:
measure: Immunohistochemical analysis of CA-IX expression, (p)VHL status, HIF1-a, VEGF and PDGF expression, apoptosis and necrosis of surgical specimen
timeFrame: within 6 months post-surgery
Other outcomes:
Locations:
city: Nijmegen
country: Netherlands
facility: Radboud University Nijmegen Medical Center
state: Gelderland
Study officials:
affiliation: Department of Nuclear Medicine, Radboud University Nijmegen Medical Center, Nijmegen, The Netherlands
name: WJG Oyen, MD, PhD
role: PRINCIPAL_INVESTIGATOR
affiliation: Department of Urology, Radboud University Nijmegen Medical Center, Nijmegen, The Netherlands
name: PFA Mulders, MD, PhD
role: PRINCIPAL_INVESTIGATOR
References:
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.