Phase ib of sorafenib in combination with everolimus in patients with advanced solid tumors, selected on the basis of molecular targets.

BACKGROUND: Molecular alterations of the PI3K and Ras pathways often occur in human cancer. In this trial, the pharmacokinetics, toxicity, and activity of two drugs inhibiting these pathways-everolimus and sorafenib-were investigated. METHODS: Thirteen patients with progressing solid tumors were treated with everolimus and sorafenib, according to a 3+3 scheme. Patients were selected on the basis of immunohistochemical expression of tumor molecular targets, including phospho-AKT, -p70S6K, and -ERK1/2. RESULTS: The daily recommended dose identified was 2.5 mg of everolimus and 600 mg of sorafenib. Dose-limiting toxicities included grade 3 asthenia and hand-foot skin reaction. No grade 4 adverse events were observed. The most frequent grade 3 toxicities were hypophosphatemia (30.8%), alanine aminotransferase level increase, asthenia, and anorexia (14%). No pharmacokinetic interactions were identified between everolimus and sorafenib. Of 12 evaluable patients, we observed 2 partial responses, with greater than 10% shrinkage in an additional 5 patients. Objective responses were observed in one patient with a thymoma and in one patient with a lung adenocarcinoma. Tumor shrinkage that did not qualify as a partial response was seen in an abdominal leiomyosarcoma and in adenoid cystic carcinomas. CONCLUSION: The combination of everolimus and sorafenib is safe. The tumor activity observed in different tumor types could be the result of the combined action of these drugs as well as the molecular selection of the treated population. Further research is warranted to better investigate drugs simultaneously blocking the PI3K and the Ras pathways and to refine patient selection.

Hepatic intra-arterial cetuximab in combination with 5-fluorouracil and cisplatin as salvage treatment for sorafenib-refractory hepatocellular carcinoma.

BACKGROUND: Sorafenib is the only therapy approved for advanced hepatocellular carcinoma no longer eligible for transcatheter arterial chemoembolization. Hepatic intra-arterial chemotherapy has been shown to be an effective and safe therapy for advanced hepatocellular carcinoma. Cetuximab has been administered intravenously to patients with advanced hepatocellular carcinoma, showing encouraging results in terms of its safety and toxicity profile. AIM: Our purpose was to evaluate the safety and feasibility of hepatic arterial chemotherapy with cetuximab, cisplatin and 5-fluoruracil for patients with advanced hepatocellular carcinoma, not responsive or not eligible for sorafenib therapy. PATIENTS AND METHODS: From January 2010 to January 2011, 12 patients received a 2-day course of chemotherapy consisting of repeated daily hepatic arterial administration of 20 mg of cisplatin as 2-h infusion, 5-fluorouracil at 500 mg/m(2) as 5-h infusion and cetuximab 500 mg/m(2) as 12-h infusion. Cycles were repeated every 14 days. RESULTS: After a mean of four months of therapy, computed tomography revealed five partial responses, five cases of stable disease and two of progressive disease. The toxicity profile was favourable, with no G4 gastrointestinal, hematologic or skin side-effects, or severe deterioration of liver function. CONCLUSION: Hepatic intra-arterial chemotherapy with cetuximab is a safe and feasible treatment for advanced hepatocellular carcinoma, with promising results in patients with initial poor prognosis.

AVE8062: a new combretastatin derivative vascular disrupting agent.

Angiogenesis has an essential role in promoting and supporting tumor growth and it is an important therapeutic target. The tumor vascular network is the result of pro-angiogenic and inhibitory factors as well as of the interaction between endothelial cells and extracellular matrix. Different antiangiogenic therapeutics have been developed to improve tumor control through vascular-targeting agents (VTA). VTAs can be divided into two groups: antiangiogenic agents and vascular-disrupting agents (VDAs). VTAs inhibit specific factors required to induce and direct the angiogenic process, with major activity against small tumor masses and at the tumor periphery, encompassing monoclonal antibodies and small molecules inhibitors of the tyrosine kinase domain of the VEGF receptor. VDAs specifically target and destroy well-established tumor vessels with ischemia and destruction of large masses with central hemorrhagic necrosis and survival of a thin peripheral tumor layer. VDAs can be divided into biologics, such as ligand-based, and small-molecule agents; this second group includes small-molecule VDAs like flavonoids, such as 5,6-dimethylxanthenone-4-acetic acid (DMXAA), and microtubule-destabilizing agents. In this review we will discuss the mechanism of action, as well as the preclinical and clinical results, of one of the most promising antitubulin agents: the combretastatin A4-phosphate derivative, AVE8062A.