Background: 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 metabolomics and MCT-1 and MCT-4 tumour expression by immunohistochemistry. Results: 35 patients (20M:15F median age 65) were treated at dose levels 5, 10, 20, and 30mg od and 15 and 10mg bd. AZD3965 was generally well tolerated with nausea and fatigue (CTCAE Gr1-2) the most commonly reported side effects. A single DLT of cardiac troponin rise was observed at 20mg od. Asymptomatic, reversible retinal ERG changes were observed in all but the lowest dose levels, with DLTs observed at doses above 20mg od. PK data indicate exposures in the preclinical efficacy range. Metabolomic changes in urinary lactate and urinary ketones correlate with on-target activity. The increase in urinary ketones is likely to be attributable to the role of MCT1 in physiological ketone transport. Conclusions: The MCT1 inhibitor AZD3965 can be administered to patients at doses which engage the drug target, with a MTD of 20mg od po. DLTs seen were primarily dose dependent, asymptomatic and reversible changes in retinal function, which were an expected on-target effect. Investigation of the activity of AZD3965 is ongoing in tumours known to express MCT1. Clinical trial information: NCT01791595