ackground: Molecular stratification of patients to early phase trials of targeted therapies is a rational approach to drug development to help maximise benefit for individuals and provide an early indication of drug efficacy. Tumour characterisation is often performed on archival biopsies which may not reflect the current and complete genetic profile of disease and there may be practical issues and delays with obtaining archival specimens. Analysis of circulating tumour DNA (ctDNA) will provide a rapid and contemporaneous profile, perhaps representing tumour heterogeneity and thus a more complete molecular profile than a single biopsy can achieve. The Tumour chARacterisation to Guide Experimental Targeted Therapy Trial (TARGET) will test the hypothesis that ctDNA molecular profiling can be used to help guide selection of experimental medicines and monitor tumour response for patients that receive a matched targeted therapy. Methods: This is a single centre prospective study at the Manchester Cancer Research Centre. Eligible patients referred for consideration of phase 1 trials will be consented for blood sampling, archival tumour analysis and optional fresh biopsies. Circulating free DNA will be extracted from plasma using standard Qiagen protocols and subjected to enrichment for a 654 gene panel followed by next generation sequencing on an Illumina platform. In Part A of the trial, 100 patients will undergo ctDNA analysis for optimisation and reporting of results within 28 days to the Molecular Tumour Board. Data will be considered alongside sequencing of tumour to assess confidence in utilising ctDNA for decision making. In part B results will be required within 14 days for real-time clinical trial selection for up to 250 patients. Serial samples for ctDNA will be collected for patients matched with targeted therapies. Outcomes will include number of patients for which ctDNA analysis guided trial selection and response rates/PFS to matched targeted drugs. Patient derived xenografts will be created to explore drug sensitivity and resistance mechanisms in cases of ctDNA molecular aberrations of uncertain clinical significance. Recruitment commenced in April 2015 and will accrue over 3.5 years.