The hedgehog (Hh) signalling pathway is aberrantly activated in solid tumours. Inhibition of Hh signalling by SMO inhibitors is effective in the treatment of basal cell carcinomas and medulloblastomas whereas combination treatments may be required in other solid tumours. When given with an SMO inhibitor in preclinical models, the efficacy of paclitaxel is enhanced and there is potential reversal of mechanisms of resistance to paclitaxel supporting clinical investigation of the combination. In this phase I trial, the safety and feasibility of the oral SMO inhibitor, taladegib, was evaluated in combination with weekly paclitaxel in patients with advanced solid tumours. This was an open-label, nonrandomised, multicentre, dose escalation trial using a standard 3 + 3 design (EudraCT: 2014-004695-37 ISRCTN15903698). Primary objectives were to determine dose-limiting toxicities and the maximum tolerated dose of the combination. Patients received up to 6 cycles of paclitaxel 80 mg/m2 (day 1, 8 and 15 of a 28-day cycle). Then, 16 patients were recruited into 3 cohorts and received taladegib at 100 mg, 200 mg and 400 mg once daily, respectively. Grade 2/3 peripheral sensory neuropathy was the dose-limiting toxicity. The maximum tolerated dose of taladegib in combination with weekly paclitaxel was 200 mg once daily. Four patients had a partial response and 4 had confirmed stable disease at 16 weeks. The combination is feasible but cumulative neuropathy may limit longer term treatment. Hh signalling may be implicated in chemotherapy-induced neuropathy.