ASA404 (DMXAA, formerly AS1404)
ASA404 (DMXAA) is a small-molecule Tumour-Vascular Disrupting Agent
(Tumour-VDA) that selectively disrupts established tumour blood
vessels. It is currently in clinical trials for lung and prostate
cancers. Antisoma has licensed the world-wide rights for
ASA404 to Novartis AG. Novartis is now responsible for all further
development work on the drug. Antisoma has an option to
co-commercialise the drug with Novartis in the United States.
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Latest presentations
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Targeting established tumour blood vessels
Solid tumours rely on a network of blood vessels in order to survive and grow. ASA404 targets established tumour blood vessels causing apoptosis (death) of tumour endothelial cells and the local release of vasoactive molecules including tumour necrosis factor (TNF) and nitric oxide. This results in rapid reduction in blood flow to the tumour, leading to tumour necrosis. The action of ASA404 is distinct from that of angiogenesis inhibitors, which inhibit the formation of new tumour blood vessels.
Potential in combination with other cancer treatments
The therapeutic potential of ASA404 lies in combination with cytotoxic agents and other cancer treatments. Preclinical tests have shown synergistic (more than additive) effects with such combinations, and they have now become the focus for human clinical trials. Antisoma has conducted phase II trials with ASA404 in combination with standard chemotherapy in lung, prostate and ovarian cancers.
Lung cancer - the lead indication for ASA404
The lead indication for ASA404 is non-small cell lung cancer. Novartis will be conducting a pivotal phase III trial in this indication, which will build on supportive data from phase II studies carried out previously by Antisoma, as described below.
A randomised phase II study in lung cancer included patients with stage IIIb/IV non-small cell lung cancer of any histology. Median survival was 14.0 months in patients receiving ASA404 plus carboplatin and paclitaxel chemotherapy, compared with 8.8 months in patients receiving chemotherapy alone. Addition of ASA404 to chemotherapy was generally well tolerated. Full details are available in the poster presentation.
A single-arm study was conducted as an extension to the phase II trial. This also included non-small cell lung cancer patients with stage IIIb or IV disease of any histology. In this study, an 1800mg/m2; dose of ASA404 was combined with carboplatin and paclitaxel (whereas all the randomised studies in lung and other cancers used a 1200mg/m2 dose). Median survival was 14.9 months. Full details can be found in the poster presentation.
Data from these phase II studies show that patients with both squamous and non-squamous types of non-small cell lung cancer experienced a survival benefit with ASA404. Full details can be found in the poster presentation at ASCO 2008.
Prostate cancer
A randomised phase II study has been conducted in hormone-refractory metastatic prostate cancer. This compares patients receiving docetaxel alone with patients receiving docetaxel plus ASA404. The PSA response rate (proportion of patients showing a sustained >50% reduction in levels of the biomarker PSA) was markedly higher in patients receiving the combination than in patients receiving chemotherapy alone (59% vs 37%). Details of the PSA findings have been presented at conferences (see ASCO 2007 poster presentation). It has now also been announced that tumour response rates in patients assessable by 'RECIST' were higher in patients who received ASA404 and that time to disease progression was marginally longer in patients who received ASA404 (see ASCO 2008 slide presentation). Addition of ASA404 to docetaxel was generally well tolerated. Median survival data are expected in the second half of 2008.
Ovarian cancer
A randomised phase II study has been conducted in patients with recurrent, platinum sensitive ovarian cancer. Patients received either carboplatin and paclitaxel chemotherapy or carboplatin and paclitaxel plus ASA404. Results available in July 2007 show there to be no advantage in median time to tumour progression in the ASA404 arm compared with the control arm. One-year survival rates were 74% for the ASA404 arm and 92% for the control arm. Independently-determined response rates were consistent with those previously reported at IGCS 2006 and showed a higher response rate in the ASA404 arm. Addition of ASA404 to chemotherapy was generally well tolerated. Ovarian cancer is no longer a priority indication for development of ASA404.
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