Gemcitabine plus cisplatin (GC) is effective in urothelial and other cancers. We investigated GC combined with escalating doses of temsirolimus (T), intravenous mTOR inhibitor. Adults with histologically confirmed solid tumours were enrolled. The primary endpoint was safety of GC with T, including dose limiting toxicity. Exploratory endpoints included pharmacokinetics and circulating tumour DNA (ctDNA) analyses. Fourteen participants (6 bladder cancer) were enrolled. Four dose levels were evaluated, adverse events were common and led to dose reductions, delays and omissions. Plasma concentrations of gemcitabine metabolites and cisplatin were unaffected by temsirolimus. ctDNA was detected in all samples taken from a sub set of patients. Levels of ctDNA changed earlier and correlated with imaging, while biologically relevant mutations e.g. PIK3CAwere detected. Our results confirm the poor tolerability of three-drug combinations including GC and T but highlight the potential for ctDNA monitoring in Phase 1 cancer trials.