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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.<\/jats:p>","DOI":"10.1007\/s10637-026-01612-4","type":"journal-article","created":{"date-parts":[[2026,5,2]],"date-time":"2026-05-02T06:56:14Z","timestamp":1777704974000},"page":"264-273","update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Hedgehog Inhibitor and Paclitaxel: A Phase I Trial of the Oral Hedgehog inhibitor Taladegib in Combination with Weekly Paclitaxel in Patients with Advanced Solid Tumours"],"prefix":"10.1007","volume":"44","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-5000-1680","authenticated-orcid":false,"given":"Rosalind","family":"Glasspool","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8783-3491","authenticated-orcid":false,"given":"Sarah Patricia","family":"Blagden","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9281-5789","authenticated-orcid":false,"given":"Michelle","family":"Lockley","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Elaine","family":"McCartney","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Carol","family":"Evans","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Fiona","family":"Thomson","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jennifer","family":"Brown","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Laura","family":"Spiers","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chantevy","family":"Pou","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Liz-Anne","family":"Lewsley","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9387-7586","authenticated-orcid":false,"given":"Iain A.","family":"McNeish","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"T.R. 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Research funding (payable to institution) from Boehringer Ingelheim, Lilly and Clovis Oncology.\u00a0FT owns stock from Merck & Co, AstraZeneca and Organon.\u00a0IMcN has acted on advisory boards for GSK, Abbvie, AstraZeneca, pharma& and BioNTech outside the scope of this manuscript. TRJE is the Editor-in-Chief of the BJC and also discloses: Consulting or Advisory Role (payable to employing institution): Ascelia, AstraZeneca, Bicycle Therapeutics, BMS, Eisai, Medivir, MSD, Nucana, Roche\/Genentech, and Seagen Speaker (payable to\u00a0employing institution): AstraZeneca, BMS, Eisai, Medivir, MSD, Nucana, Roche\/Genentech, and United Medical. Institutional Funding\/Research Grants: Adaptimmune, Astellas Pharma, AstraZeneca, Athenex, Avacta, Basilea, Bayer, Beigene, BergPharma, Bicycle Therapeutics, BiolineRx, Boehringer Ingelheim, BMS, Celgene, Clovis Oncology, Codiak, CytomX Therapeutics, Eisai, GlaxoSmithKline, Halozyme, Immunocore, iOnctura, Iovance Biotherapeutics, Janssen, Johnson & Johnson, Lilly, Medivir, Merck Serono, MSD, MiNA Therapeutics, Modulate Pharma, Novartis, Nucana, Nurix, Plexxikon, Roche\/Genentech, Sanofi\/Aventis, Sapience Therapeutics, Seagen, Seattle Genetics, Sierra Pharma, Starpharma, T3P, UCB, Verastem, and Vertex; Expert Testimony (payable to employing institution): Medivir. Travel Grant (personal): BMS, Celgene, Eisai, MSD, Nucana, Pierre Fabre, and Roche","order":1,"name":"Ethics","label":"Competing interests","group":{"name":"EthicsHeading","label":"Declarations"}}]}}