Effect of Sorafenib on ccRCC Uptake of Radiolabeled Bevacizumab or cG250

NCT00602862 | Completed DMC

• 1 other identifier: Sorafenib-mAbs
• Study Type: interventional
• Target: 26
• Locations: 1 country
• Sites: 1

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.

Conditions

Clear Cell Renal Cell Carcinoma

Keywords

Angiogenesis inhibitors

Outcome Measures

Primary Outcomes (2)

• 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 Outcomes (1)

• 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

Study Arms (3)

1

EXPERIMENTAL

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; Drug: 111Indium-bevacizumab

2

EXPERIMENTAL

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; Drug: 111Indium-cG250

3

ACTIVE COMPARATOR

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

Interventions

Sorafenib DRUG

Sorafenib 200 mg 2dd2 po for 4 weeks before surgery

Also known as: Bevacizumab, Avastin, Nexavar, cG250, Rencarex

1; 2

111Indium-bevacizumab DRUG

100 MBq / 1 mg 111Indium/bevacizumab iv

Also known as: avastin, indium

1; 3

111Indium-cG250 DRUG

100 MBq / 10 mg 111Indium-cG250 iv

Also known as: rencarex, indium

2

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• 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

You may not qualify if:

• 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

Sponsors & Collaborators

• Radboud University Medical Center: lead
• Dutch Cancer Society: collaborator

Study Sites (1)

Radboud University Nijmegen Medical Center

Nijmegen, Gelderland, 6500 HB, Netherlands

Location

Related Publications (1)

• 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.

  PMID: 20956472 DERIVED

MeSH Terms

Conditions

Carcinoma, Renal Cell

Interventions

Sorafenib; Bevacizumab; G250 monoclonal antibody; Indium

Condition Hierarchy (Ancestors)

Adenocarcinoma; Carcinoma; Neoplasms, Glandular and Epithelial; Neoplasms by Histologic Type; Neoplasms; Kidney Neoplasms; Urologic Neoplasms; Urogenital Neoplasms; Neoplasms by Site; Female Urogenital Diseases; Female Urogenital Diseases and Pregnancy Complications; Urogenital Diseases; Kidney Diseases; Urologic Diseases; Male Urogenital Diseases

Intervention Hierarchy (Ancestors)

Phenylurea Compounds; Urea; Amides; Organic Chemicals; Benzene Derivatives; Hydrocarbons, Aromatic; Hydrocarbons, Cyclic; Hydrocarbons; Niacinamide; Nicotinic Acids; Acids, Heterocyclic; Heterocyclic Compounds; Pyridines; Heterocyclic Compounds, 1-Ring; Antibodies, Monoclonal, Humanized; Antibodies, Monoclonal; Antibodies; Immunoglobulins; Immunoproteins; Blood Proteins; Proteins; Amino Acids, Peptides, and Proteins; Serum Globulins; Globulins; Metals, Heavy; Elements; Inorganic Chemicals; Metals

Study Officials

• 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

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: interventional
• Phase: not applicable
• Allocation: NON RANDOMIZED
• Masking: NONE
• Purpose: BASIC SCIENCE
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: January 3, 2008
• First Posted: January 28, 2008
• Study Start: July 1, 2007
• Primary Completion: April 1, 2012
• Study Completion: June 1, 2012
• Last Updated: December 2, 2013

Record last verified: 2012-02

Locations

NL (1)