Effect of Sorafenib on ccRCC Uptake of Radiolabeled Bevacizumab or cG250

Study Overview
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Brief Summary
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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.

Official Title
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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)

Conditions
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Clear Cell Renal Cell Carcinoma

Intervention / Treatment
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* Drug: Sorafenib
* Drug: 111Indium-bevacizumab
* Drug: 111Indium-cG250


Participation Criteria
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Eligibility Criteria
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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

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Basic Science
Allocation: Non-Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: 1<br>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<br>* Sorafenib 200 mg 2dd2 po for 4 weeks before surgery<br>* Other names: Rencarex;Drug: 111Indium-bevacizumab<br>* 100 MBq / 1 mg 111Indium/bevacizumab iv<br>* Other names: indium;|
| Experimental: 2<br>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<br>* Sorafenib 200 mg 2dd2 po for 4 weeks before surgery<br>* Other names: Rencarex;Drug: 111Indium-cG250<br>* 100 MBq / 10 mg 111Indium-cG250 iv<br>* Other names: indium;|
| Active Comparator: 3<br>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<br>* 100 MBq / 1 mg 111Indium/bevacizumab iv<br>* Other names: indium;|

What is the study measuring?
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Primary Outcome Measures

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

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Angiogenesis inhibitors