A single arm Pharmacokinetic/Pharmacodynamic Study of Sunitinib and Pazopanib in Patients with Metastasized Renal Cell Carcinoma

Kidney cancer is one of the most common cancer types in Europe with 88,400 new
cases and 39 400 deaths in 2008. Nearly 90% of those cases are renal cell
carcinomas. While mortality constantly decreases concerning better diagnosis
and treatment, the prognosis with diagnosed renal cell carcinoma is still poor.
A therapy of renal cell carcinoma with established anticancer agents is not
successful as the pathology of this kind of cancer cells includes a high
expression of P-glycoprotein conferring a multi drug resistance. Before the
introduction of antiangiogenic treatment the only available systemic therapy
for metastasized renal cell carcinoma (mRCC) patients was a cytokine-therapy
with high dose interleukin-2 or interferon-alpha treatment in combination with
surgical ablation of metastases, if possible. With the understanding of the
basic mechanism of RCC genesis, a big step ahead was made on the way to
targeted therapy. Tumours need an autonomous blood supply to continue growing.
Therefore, they release several growth factors to stimulate the genesis of new
blood vessels.
The genes involved in these processes vary between different histological types
of RCC. Most common is the so called clear cell carcinoma which accounts for
75% of all RCC. Here, the cause of the increased angiogenesis is the
inactivation of the von Hippel-Lindau gene which causes an accumulation of
hypoxia-inducible factor (HIF) and leads to an over expression of angiogenic
factors such as vascular endothelial growth factor (VEGF) and platelet-derived
growth factor (PDGF). These proteins bind to receptors on the surface of
endothelial cells where they stimulate angiogenesis. This led to the
development of drugs which specifically target the process of angiogenesis.
In 2005 the first antiangiogenic agent was introduced onto the market,
bevacizumab (Avastin®), a monoclonal anti body against VEGF. The combination of
interferon-alpha and bevacizumab showed a significant improvement in terms of
progression-free survival (PFS) over the previously used mono therapy with
interferon only. Since the introduction of the multiple-tyrosine-kinase
inhibitors sunitinib (Sutent®) and sorafenib (Nexavar®) in 2006 a potent oral
antiangiogenic therapy of mRCC is available. The decision which antiangiogenic
agent is chosen depends on the Motzer-criteria to predict survival of patients
with advanced RCC. While sunitinib is indicated as first-line therapy for low
or medium-risk mRCC patients, sorafenib is only second line for patients who
already received a cytokine-treatment.

Sunitinib
Sunitinib is an inhibitor of several receptor-tyrosine kinases which are
associated with angiogenesis and the growth of metastases. Sunitinib inhibits
platelet-derived growth factor (PDGF) receptor α and β, vascular endothelial
growth factor (VEGF) receptor 1-3, the KIT (stem cell factor)-receptor,
Fms-like tyrosine kinase 3 (FLT) receptor, the colony stimulating factor 1 (CSF
1) receptor as well as the *rearranged during transfection* (RET) receptor.
Sunitinib is primarily metabolized by Cytochrome P450 A4 which leads to the
active metabolite N-desethyl-sunitinib (SU12662). The metabolite shows similar
pharmacodynamic and pharmacokinetic effects and is responsible for 23 to 27 %
of total drug exposure. The volume of distribution is about 2230 L, the
elimination half-life approximately 40 to 60 h and 80 to 110 h for the active
metabolite.

Pazopanib
Pazopanib is an oral multi-tyrosine kinase inhibitor which targets VEGF
receptor -1, -2 and- 3, PDGFR-alfa and -beta as well as *stem cell factor* -
receptor (c-KIT). Pazopanib is primarily metabolized by CYP3A4 and partly by
CYP1A2 and CYP2C8. There are four metabolites which only contribute for 6% of
the overall exposure. In-vivo binding to human plasma proteins is higher than
99% which results in a large volume of distribution. Excretion is primarily via
feces with renal elimination accounting for only < 4%. The elimination
half-life is about 30.9 h.

The primary goal of this research is to develop a
pharmacokinetic/pharmacodynamic (PK/PD) model for sunitinib and pazopanib in
patients with metastatic renal cell carcinoma, so that the possible use of
biomarkers can be tested as predictors for the treatment outcome for individual
patients. These biomarkers could be: blood pressure, sVEGFR2 and sVEGFFR3.
Furthermore, there will be investigations on the extent to which patient
specific data, so called covariates, such as age, weight, disease status,
several genotypes, organ function or compliance could influence pharmacokinetic
and pharmacodynamic parameters and thereby the result of therapy outcome.

Single-arm, phase IV study in patients with metastatic renal cell carcinoma and
a planned first-line treatment with either sunitinib (Sutent®) or pazopanib
(Votrient®). This research is performed as a substudy of EuroTARGET as a
non-interventional EuroTARGET study.

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