Tumor cells rely on the existence of a specialized vasculature for the oxygen and nutrients that they require in order to grow and survive. Targeting the tumor vasculature as a technique for inhibiting tumor growth was first attempted with angiogenesis inhibitors, a class of drugs that compromise the formation of new blood vessels. More recently a new class of drugs called vascular disrupting agents (VDAs) has been reported. Rather than preventing the formation of new blood vessels, VDAs target endothelial cells and pericytes in the already-established vascular network supporting the tumor. VDAs are designed to induce massive downstream tumor cell death in a tumor-specific manner, i.e. by shutting down the supporting vasculature. Two subtypes of VDAs have been described: ligand-directed VDAs, which incorporate a targeting moiety linked to an effector moiety, and small molecules. Small molecules have several potential advantages over ligand-directed VDAs, including lower cost, greater specificity and reduced toxicity (Gridelli, C. et al., The Oncologist 2009, 14(6): 612; Hinnen, P. and Eskens, F.A., Br J Cancer 2007, 96(8): 1159).

Codevelopment partners Antisoma and Novartis are currently conducting two phase III trials of the small-molecule tumor vascular disrupting agent vadimezan (ASA-404) in non-small cell lung cancer (NSCLC). Vadimezan exerts its antitumor effects partly through inhibition of tumor blood flow, but unlike other small-molecule vascular-targeting agents under clinical investigation, it does not act through modulation of the tubulin cytoskeleton of vascular endothelial cells. While the molecular target of vadimezan is unknown, a hallmark of its preclinical activity is its induction of cytokine production within the tumor tissue. These cytokines confer a multiplicity of indirect effects, including vascular collapse and enhanced immune response, making this one of the most promising agents of its class under clinical development (Ching, L.M. et al., Drugs Fut 2008, 33(7): 561).

Ongoing phase III studies of vadimezan are employing a dose of 1800 mg/m2. The results of a phase II study of this dose in previously untreated NSCLC patients have been described, revealing acceptable safety and activity. Thirty patients who had not received chemotherapy were given carboplatin AUC 6 mg/ml and paclitaxel 175 mg/m2 plus vadimezan every 21 days for up to 6 cycles. Coadministration with vadimezan did not appear to affect the pharmacokinetics of carboplatin or paclitaxel and was generally well tolerated. Safety was similar between squamous and nonsquamous patients. There were 15 treatment-emergent serious adverse events, and 5 withdrawals were adverse event-related. The most common grade 3-4 toxicities were neutropenia and leukopenia. For activity, 37.9% of patients had a partial response, while 48.3% had stable disease, according to independent assessment. These figures were 46.7 and 43.3%, respectively, by investigator assessment. The median time to progression was 5.5 months by investigator assessment data and median survival was 14.9 months. The results were in line with those from a previous phase II study of vadimezan 1200 mg/m2 in similar patients (McKeage, M.J. et al. Lung Cancer 2009, 65(2): 192).

Antisoma has completed enrollment in the randomized, double-blind, placebo-controlled, multicenter phase III ATTRACT-1 trial of vadimezan in non-small cell lung cancer. The trial is being conducted by Novartis and has enrolled 1,200 patients in the U.S., E.U., Japan and other territories. It opened in April 2008 and has enrolled patients with all NSCLC histologies, including squamous and nonsquamous cancers. Patients have been randomized 1:1 to receive either vadimezan plus chemotherapy (carboplatin/paclitaxel) or a placebo plus chemotherapy (carboplatin/paclitaxel) as a control. Phase II trials are also under way for the treatment of hormone-refractory prostate cancer.