Abstract
2516Background: A key metabolic alteration in tumour cells is an increased dependency on the glycolysis, resulting in the production of lactate, which is transported out of cells by MCTs. Inhibition of MCT-1 leads to a profound inhibition of cancer cell growth in preclinical models. AZD3965 is a FIC inhibitor of MCT-1, and we report results from the phase I study of this agent. Methods: Patients with advanced solid tumours were treated with oral (po) AZD3965 at total daily doses of 5-30mg given once (od) and twice daily (bd). Exclusion criteria included a history of retinal or cardiac disease due to preclinical toxicology findings in the eye and heart (which express MCT-1). The primary objectives were to determine the safety, dose limiting toxicities (DLT) and maximum tolerated dose (MTD) of AZD3965. Intensive pharmacokinetic (PK) profiling was performed with subsequent modelling for receptor occupancy. Pharmacodynamic profiling included imaging to detect pH changes and tumour glucose uptake; plasma/urine...
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