Phase II Study of Sorafenib (Bay 43-9006) and Infusional 5-Fluorouracil in Advanced Hepatocellular Carcinoma.
Numerous chemotherapeutic regimens have been tested for use against hepatocellular carcinoma
(HCC). HCC is, however, highly resistant to chemotherapy; doxorubicin and 5- fluorouracil
containing regimens, alone or in combinations, results in less than a 20% response, with a
median survival of less than 4 months. Furthermore even the objective responses are
short-lasting. In a metaanalysis of the published randomized studies on HCC, neither
doxorubicin nor any chemotherapeutic agent has been shown to have any survival benefit for
HCC patients.
Sorafenib (Bay 43-9006) is a novel signal transduction inhibitor that prevent tumor cell
proliferation and angiogenesis through blockade of the Raf/Mek/Erk pathway at the level of
Raf Kinase and the receptor tyrosine kinases VEGFR-2 and PDGFR-beta.
Recent preclinical studies have shown the activation of Mek-1/2 and its downstream target
MAPK in HCC tumors. In a phase II study 137 patients advanced primary liver cancer with
have been treated with Sorafenib administered as a single agent. Investigators reported
seven patients with partial responses, five minor responses and 59 with stable disease for
at least 4 months. Median overall survival was 9.2 months and median time to progression 4.2
months. This study showed that Sorafenib was well tolerated and side-effects were manageable
and reversible.
Rationale
5-Fluorouracil (5-FU) is a widely used agent for patients with unresectable advanced HCC,
with objective responses rates around 10%. Compared to bolus administration, infusional 5-FU
in metastatic colorectal cancers has demonstrated increased activity with less toxicity.
Sorafenib as single agent in HCC has demonstrated activity in terms of objective responses
and promising duration of stable disease.
The combination of Sorafenib and 5-FU was evaluated in a phase I study where the drug is
associated with different 5FU based schedules with good toxicity profile and objectives
responses in particular in colorectal carcinoma.
Based on these data our purpose is to study infusional 5-FU with Sorafenib to evaluate the
activity, efficacy, safety, pharmacokinetics and pharmacodynamics of this combination.
Study design and duration of treatment
5-FU 3000 mg/sqm 48 hours continuous infusion every 14 days Sorafenib 400 mg bid orally
continuously 5-FU will be administered for a maximum of 12 cycles. Sorafenib will be
administered from the start of treatment in combination with 5-FU until progression of
disease.
Interventional
Endpoint Classification: Pharmacokinetics/Dynamics Study, Intervention Model: Single Group Assignment, Masking: Open Label, Primary Purpose: Treatment
N° of non progressive disease (complete and partial responses, stable disease)
1 year
Yes
Italy: Ethics Committee
PISADUE
NCT00619541
January 2007
January 2009
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