Study of Sorafenib and Infusional 5-Fluorouracil in Advanced Hepatocellular Carcinoma (HCC) (P2)
The purpose of this study is to use Sorafenib + 5-FU to evaluate activity, efficacy, safety, pharmacodynamics (PD) and pharmacokinetics (PK) in patients with advanced hepatocellular carcinoma (HCC).
Drug: Infusional 5-Fluorouracil
Drug: Sorafenib (Bay 43-9006)
|Study Design:||Endpoint Classification: Pharmacokinetics/Dynamics Study
Intervention Model: Single Group Assignment
Masking: Open Label
Primary Purpose: Treatment
|Official Title:||Phase II Study of Sorafenib (Bay 43-9006) and Infusional 5-Fluorouracil in Advanced Hepatocellular Carcinoma.|
- N° of non progressive disease (complete and partial responses, stable disease) [ Time Frame: 1 year ] [ Designated as safety issue: Yes ]
- Toxicity of the combination,ORR,Duration of responses, TTP and OS.PK, PD,Baseline pERK concentration, phospho VEGF-R2 concentration, plasma proteomics and gene expression profiling on blood cells and tumor biopsy [ Time Frame: 1 year ] [ Designated as safety issue: Yes ]
|Study Start Date:||January 2007|
|Study Completion Date:||January 2009|
|Primary Completion Date:||November 2007 (Final data collection date for primary outcome measure)|
Drug: Infusional 5-Fluorouracil
5-FU 3000 mg/sqm 48 hours continuous infusion every 14 days. 5-FU will be administered for a maximum of 12 cycles.Drug: Sorafenib (Bay 43-9006)
Sorafenib 400 mg bid orally continuously. Sorafenib will be administered from the start of treatment in combination with 5-FU until progression of disease.
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.
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.
|Dipartimento di Oncologia, dei Trapianti e delle Nuove Tecnologie in Medicina ... Indirizzo: via Roma, 55 - 56100 Pisa Tel. 050-2218690 - Fax. 050-2218685|
|Pisa, Italy, 56100|