Phase I and Pharmacokinetic Study of BAY 43-9006 (Sorafenib) in Patients With Kaposi's Sarcoma
BACKGROUND: This study is designed to test the toxicity and pharmacokinetics of different
doses of BAY 43-9006 (Sorafenib) in patients with Kaposi's sarcoma (KS). It will also
assess, in a preliminary manner, the activity of BAY 43-9006 in this disease and its effect
on biological markers. BAY 43-9006 is a potent inhibitor of wild-type and mutant c-Raf
kinase isoforms. In addition, this agent also inhibits p38, c-kit, vascular endothelial
growth factor receptor 2(VEGF-R2), VEGF-R3, and platelet derived growth factor receptor beta
(PDGFR-beta). There is evidence that several of these receptors, and especially VEGF-R2,
VEGF-R3, and PDGF-Rbeta, are important in KS pathogenesis. The principle tumor cells of KS
lesions are spindle cells, which are derived from endothelial cells. Spindle cells
proliferate in response to VEGF, VEGF-C (a ligand for VEGF-R3), and PDGF, and the
stimulation of spindle cells by these factors appears to be an important component in the
pathogenesis of KS. There is also evidence that c-kit is important in KS. Because BAY
43-9006 can inhibit the function of these receptors and c-kit, it may have specific activity
against this tumor. BAY 43-9006 is metabolized at least in part by CYP 3A4, and ritonavir,
an HIV protease inhibitor commonly used in AIDS patients, is an inhibitor of CYP 3A4. Also,
AIDS patients are often quite sensitive to drug toxicities. Thus, patients with AIDS-KS on
ritonavir may be particularly sensitive to BAY 43-9006.
OBJECTIVES: To assess the toxicity profile and pharmacokinetics of BAY 43-9006 at oral dose
regimens of 200 mg once daily, 200mg twice daily, or 400 mg twice daily, up to the toxic
dose, in patients with HIV-associated Kaposi's sarcoma (KS) who are receiving ritonavir.
Also, to assess in a preliminary manner the pharmacokinetics and toxicity profile of BAY
43-9006 in patients who are not receiving ritonavir.
ELIGIBILITY: Key eligibility criteria are as follows: patients 18 years of age or older,
with or without HIV infection, and with KS and at least 5 cutaneous lesions untreated by
local therapy; patients with HIV infection must have KS that is progressing or stable on
highly active antiretroviral therapy (HAART); patients with extensive active, visceral, or
symptomatic KS are excluded.
DESIGN: Patients with AIDS-KS who are receiving ritonavir will be administered BAY 43-9006.
An initial group of patients will be administered 200 mg BAY 43-9006 once daily, and
subsequent groups will receive 200 mg twice daily and 400 mg twice daily respectively. Also
two groups of patients with KS and not on ritonavir will be administered 200 mg and 400 mg
BAY 43-9006 twice daily respectively. Patients will be studied for toxicity,
pharmacokinetics, KS response, the effect on biological markers such as target receptor
kinase phosphorylation and signaling molecules in KS tissue. Other parameters that will be
assessed will include VEGF levels, the viral load of KSHV, and KS lesion blood flow by
non-invasive techniques. If patients tolerate BAY 43-9006, they will receive it for up to 24
weeks. If they have evidence of stable KS or a tumor response, they may receive the drug for
up to 54 weeks total.
Primary Purpose: Treatment
Robert Yarchoan, M.D.
National Cancer Institute (NCI)
United States: Federal Government
|National Institutes of Health Clinical Center, 9000 Rockville Pike||Bethesda, Maryland 20892|