Phase I study and preclinical efficacy evaluation of the mTOR inhibitor sirolimus plus gemcitabine in patients with advanced solid tumours
2014 (English)In: British Journal of Cancer, ISSN 0007-0920, E-ISSN 1532-1827, Vol. 111, no 5, 858-865 p.Article in journal (Refereed) Published
Background: We conducted a phase I study in patients with advanced solid tumours to identify the recommended dose, assess pharmacokinetics (PK), pharmacodynamic activity and preclinical antitumour efficacy of the combination of sirolimus and gemcitabine. Methods: Nineteen patients were treated with sirolimus 2 or 5mg daily and gemcitabine 800 or 1000 mg m(-2) on days 1 and 8. Dose escalation depended on dose-limiting toxicity (DLT) rate during the first 3-week period. Paired skin biopsies were evaluated for phosphorylated S6 (pS6) as marker of mTOR (mammalian target of rapamycin) inhibition. Pharmacokinetics and preclinical evaluation of efficacy using two different sarcoma cell lines and leiomyosarcoma xenografts were also conducted. Results: Three DLTs were observed: grade 3 transaminitis, grade 3 thrombocytopenia and grade 4 thrombocytopenia. Common treatment-related adverse events included anaemia, neutropenia, thrombocytopenia and transaminitis. Pharmacodynamic analyses demonstrated mTOR inhibition with sirolimus 5mg and PK showed no influence of sirolimus concentrations on gemcitabine clearance. In vitro and in vivo studies suggested mTOR pathway hyperactivation by gemcitabine that was reversed by sirolimus. Tumour growth in leiomyosarcoma xenografts was dramatically inhibited by the treatment. Conclusions: Recommended dose was sirolimus 5mg per 24 h plus gemcitabine 800 mg m(-2). Antitumour activity in preclinical sarcoma models and mTOR signalling inhibition were observed. A phase II study is currently ongoing.
Place, publisher, year, edition, pages
2014. Vol. 111, no 5, 858-865 p.
gemcitabine, sirolimus, rapamycin, mTOR, phase I
Cancer and Oncology
IdentifiersURN: urn:nbn:se:uu:diva-233583DOI: 10.1038/bjc.2014.370ISI: 000341527100007OAI: oai:DiVA.org:uu-233583DiVA: diva2:754951