Axitinib Monotherapy With Early Dynamic Contrast Enhanced Ultrasound Monitoring in Chemorefractory Third Line Metastatic Colorectal Cancer

Colorectal cancer is the second most common cause of cancer death in the UK with an average 5-year survival of 50%. There is a lack of classical chemotherapy response in metastatic colorectal cancer with the approved drugs currently on the market, which has prompted the investigation of angiogenesis inhibitors as a new chemotherapeutic agent. Pre-clinical use of angiogenesis inhibitors with conventional cytotoxic chemotherapy has shown to have more effect, but so far these results have not been replicated in human studies. Furthermore, the toxicity profiles for these drugs when combined with chemotherapy has so far outweighed any benefit they may hold for patients. With this in mind, is perhaps the dosing incorrect? Would changing the dosing schedule optimise the balance between efficacy versus toxicity?

AXMUS-C is a phase II randomised, placebo-controlled study testing the efficacy of the VEGF inhibitor, Axitinib, as monotherapy for patients with chemo-refractory colorectal cancer with liver metastases.

A-013736 (Axitinib) is a selective inhibitor of vascular endothelial growth factor (VEGF) receptors 1, 2 and 3, and is therefore classed as an angiogenesis inhibitor with VEGF receptors effectively being blocked and thus cannot stimulate the signalling pathway responsible for cell proliferation resulting in the growth of blood vessels to feed the tumour. Several studies in other solid tumours have shown that when taken orally the main side effect of Axitinib is fatigue, with 51% of subjects reporting varying grades of severity. Axitinib has been approved by the U.S. Food and Drug Administration (FDA) for the treatment of advanced renal cell carcinoma after failure of one prior systemic therapy. It has not been approved for colorectal cancer.

Additionally, the research will also assess the potential for early CEHPI (Contrast Enhanced Hepatic Perfusion Index) reduction to predict response to therapy with Axitinib, with the hypothesis being that patients with an early ≥20% reduction in CEHPI will have improved overall survival, compared to those who do not. Early relative reductions of over 20% has previously been shown to correlate with conventional stable disease and partial response by RECIST. \[CEHPI\] has been developed with the idea that it can identify responders to the anti-VEGF therapy much earlier than the conventionally used established RECIST method. It is a technique that measures the changes in how the blood vessels pump blood into the different liver metastases (tumours) and therefore can be used to assess and predict response to treatment, as it is known that arterialisation support the growth of malignant tumours in the liver whereas usually the portal vein supplies 70% of the blood to normal liver parenchyma. Contrast enhanced ultrasound differ from the standard ultrasound with the intravenous injection of 2mL of SonoVue before the Philips iu22 platform and a C5-1 transducer are used to record a one-minute cine loop.